My Thymus, Myself
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Hey, I'm Latif Nasser. This is Radiolab. Today, I'm handing over the reins to our senior correspondent, Molly Webster. Hi. Hey. So what do you got for us, Molly? Okay. So I think you know that for the last couple of years, I've been doing a lot of reporting on immunity.

It's like with COVID and vaccines and everything, it just kind of feels like the waters we've all been swimming in. For sure. For today, I have a story that's not exactly about COVID and vaccines, but it is about this part of the body that feels like...

One of the most elemental and mysterious parts of the immune system, if not certainly the most philosophical. Ooh, like I have no idea what you're about to say. What is it? Well, it is a tiny organ called the thymus.

And I want us to, I don't know, shall we say dissect this? Get into this by going back to a conversation that I had with Jad about a year ago when I first learned some of this stuff. Okay. Are you ready? Go for it. Cool.

All right. So, yeah, start where you want to start. I'm here. I feel like this story is kind of like a bad joke where a protein, a cell, and a funny little molecule walk into the thymus and then a joke ensues is what I feel like this story is.

That's a joke that would land with only a certain group of people. What the f*** is even the thymus? I don't even know what the thymus is. Oh, that's so great. I'm going to say it's in the brain, but I'm not even sure. No, no, no. It's not in the brain. It's in the throat? This is great that you said that because you're actually talking about a different organ. Oh, I am. People mix it up with thyroid. Thyroid? Nah. The thyroid is higher up and does different things. Oh.

Yeah. So the woman setting the record straight is immunologist Jenny Punt. I'm a professor of immunology at the University of Pennsylvania School of Veterinary Medicine. And she's an expert on the thymus. Okay. So the thymus is an organ right above your heart. It literally lays on top of the heart. There are these two lobes that drape over the heart. In kids, it's about the size of an adult person's palm. And people say it has the texture of a moist cornbread.

People do eat thymus. Really? Oh, yeah. The thymus of a cow can be quite big and people say it's tasty. I think I've had some, but because I know about the cells in it, it's a little bit too freaky. It's freaky because the thymus, and this is how scientists have put it to me, the thymus teaches the body what is you and what is not you.

I love that sentence. Right? It's like so existential. Yeah. It is existential. It is like the metaphysical thing of all of us. Like, how do we know what belongs to us? But the thing is, according to Jenny and then our new friend who just popped in here, Sharon Strandford. Professor at Pomona College. And I'm also an immunologist. When it comes to the work of the immune system, this is the thing.

This is actually a real-world practical question. Because somehow your immune system only attacks when it notices something foreign and doesn't attack your own tissues and cells. If you're a little immune thing in the body, like you don't know anything. You're just a cell. So like how do you figure out like, oh, that's a bit of liver. That's good. Whereas that thing over there,

That weird globule, that looks foreign. Right. And how does it know when something is foreign? Unless it knows what's self. And that is what the thymus does. It teaches the immune system the difference between self and not self. Yeah. Okay, good, good, good. I'm in. Perfect. We're going to kick off with a little immune system 101. Okay. Okay.

So, the immune system has lots of different cells. Is made of so many different types of cells, right? There's B cells and T cells. The ones we've heard of, the T cells, the B cells. Then there's all the other white blood cells. There's also like natural killer cells and these other ones called dendritic cells. Yeah, this is funny. I mean, this is like, I'm sorry to interrupt. No, interrupt. It's just like every time I hear about the immune system, it's a little bit like...

about the 15 different types of Navy SEALs or something? Like there's like seven, like there's the JSOC unit and there's the special ops unit. There's just such a crowd of different specialized things. There are so many, but for our purposes, I'm just going to focus us on the T-cells.

Okay. Which are famously, you probably know this, like the warrior cells, the ones that go out and fight viruses or bacteria or pathogens. But T-cells do not start as these warrior cells. They start, like all immune cells do, in the bone marrow, where they are sort of like... Wannabe T-cells. Baby T-cells. And what happens is, at some point, they sort of leave the bone marrow, they head out into the bloodstream, and in ways people don't fully understand, they get...

called to the thymus. And it turns out the T in T cells is thymus. Really? Yeah, it's thymusite cell because the thymus is the training ground for the cell. Yes, its primary and almost pure function is to generate your T cells.

and to test them. So the first thing these baby T cells need to do before anything else is just be able to grab onto things around them, which means right when they get to the thymus, they have to make a receptor, a real T cell receptor, which is sort of like a tower or an arm that comes off the surface of the cell and lets them grab things. What does it look like?

So it was described to me as take your arms, push your forearms together from your elbows to your wrists. And you can sort of think of your arms as what's sticking out from the surface of the cell. And then you have the fists of your hands on top and the fists of your hand are really like the receptor part that lock into things. So it's just this thing protruding outward? Yeah. It can like match with another molecule or object. Flow.

floating around. Got it. Like a lock and key. That fits somebody else. That is designed to grab onto some particular thing around it, but... But you don't know who else. Now, each T-cell only gets one receptor. So the trick for the thymus and the T-cells is if anything super random from the outside...

ever gets into the body. We're talking like little viruses, bacteria. Billion different things that we haven't even anticipated. Things that we've never even seen before. The T cells have to have a receptor to potentially catch that thing. It's like they have to plan for the unexpected. And so the way that you plan for the unexpected is to create the unexpected in the genome. In the DNA, you can think...

that there's something like a recipe for making these receptors. The ingredients are nucleotides, A's, C's, G's, T's. But what the T cells can actually do is they can rearrange the recipe. Loop that out and get rid of it. Add a few nucleotides. It's like dashes of pepper, dashes of salt. Allowing each T cell to create a receptor unlike any other. Randomly generate what can be up to a billion different receptors.

and they're all different they're like snowflakes as my mother used to say so then now each one of them knows one thing one thing the thing that that my receptor will click into yeah and if we make enough of these things with enough variations

We might be covered. Yeah. If you go forward a million years, grab a virus from there, give it back to us now. There should be a receptor in there that recognizes it. We would develop an immune response to it. Whoa. So you've got all of these baby T cells trying to make these receptors prove their worth. But it's actually very hard to make these receptors. And so if it doesn't work, you're just killed.

Because you're useless. You're useless to the body. Wow. Okay. It's pretty draconian. It's a killing. It's rather than a... It's like a culling. It's a culling. It's a culling. Now, if you can make a good receptor, you are rewarded by getting to go on to the second round of training.

Because if an army of billions of T cells is ready to attack anything, by random chance, some will have receptors that will want to glom on and attack you. And so this is where knowing what is self and not self comes into play. Because what the thymus does next is it creates something that's like a shadow version of you.

Part of it, the self-shadow stuff is very cool. It's able, in this shadow kind of way, to mimic and imitate things in your body. What? I know, it sounds so trippy, but even like one of the biggest science papers on the thymus talks about an immunological self-shadow.

So what the thymus actually does. Yeah, so now we're at air. Air. Starts with this thing with a very mysterious name. Air. Like air that we breathe? Air? It's spelled A-I-R-E and it stands for autoimmune regulator. Maybe tell me what air is. Oh, it's a good question. So air is a protein.

Air is a big, long protein, and it's not simple. So air lives inside certain cells in the thymus, and it gives these cells like a superpower, which is that every cell in the body has a full copy of DNA, but each cell uses only the part that applies to it.

So the heart uses the heart stuff and the liver uses the liver stuff. But air allows the thymus cells to access almost any part of the DNA. Air is something that sort of runs around the DNA, helps to unwind things and open it up. Which means that those cells can make...

Every possible protein that your body could make. Proteins that should be only in the brain or proteins that should only be in your big toe. I don't think there are any of those. Proteins that only should be in your gut. You're literally creating a version of yourself in this little spot above your heart. Yeah. Yeah. Whoa.

Now all that U stuff is in there. Now this is where the test comes in. The thymus puts this lineup of these little pieces of U in front of the T cells. And as T cells pass by... I imagine like the T cells with their receptors kind of gently...

just sniff and touch all of self. In the meanwhile, you have the thymus just sitting there watching, waiting to see what happens. Because if any of those T cells bond too strongly to the tiny bits of you that are being presented to them... Like...

hey, that piece looks super exciting. I'd bind to it really strongly. Then once again, the body will kill that T-cell. The idea is you want to eliminate that T-cell because it sees self. Because it's just latched onto and in a sense attacked a part of self.

Who does the killing? Well, they actually get signals just to commit suicide. Oh, if you say the right word, they blow up. Literally, there are lots of dead wannabe T cells in the thymus. Yeah. And so billions of T cells go through this process of making receptors and getting tested. And 90 to 95 percent of them are killed. 90 to 95 percent? Yeah. God. Yeah.

But, you know, if you're in the 5% that didn't get killed, you're let loose. You become one of these super badass warrior cells off in the immune system protecting us. Okay, this is, I have a whole new appreciation for thymus. Yeah, now you know what the thymus actually is. One of the coolest parts of this for me is that there's this whole idea that the thymus and the T cells know you.

But really, what you got is a bunch of cells that know everything but you. We keep the things that don't bind to self. We get rid of the things that do bind to the self. So in an interesting way, there's some sense that self-knowledge, at least as it applies to the immune system, is really all about the negative space.

Oh, man. I just won't be able to stop picturing, like, a dissembled version of myself. I had never even heard of this organ, and now this is, like, in the running for the coolest one. Well, I'm very glad you dig it, because I am about to take this Thymus thing up a notch. ♪

Because that was a conversation that I had with Chad a while ago. But a few months ago, I learned a whole other part of this story, which is while the thymus has this ability to know you and save your life day in and day out, we are just now figuring out how to use this part of you that knows you to save the life of someone else.

What? Boom, boom, boom. How is that even possible? Well, you will find out after the break.

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Hey, this is Latif Nasser. We're back with our very own Molly Webster telling us all about thymine, which is the plural of thymus, the kind of unsung hero of the immune system that teaches our body how to know itself so that it doesn't kill itself. Yes, exactly.

So we've been talking about how the thymic sense of self protects you, but now we're going to see how that sense of you could actually protect someone else. Okay. It'll make sense in a minute. Okay. Okay. Bye. Bye.

So to start, a few months ago, I went to Duke University to talk to a guy named Joe Turk. So I'm chief of pediatric heart surgery here, and I'm one of the executive co-directors of our pediatric and congenital heart center. Joe does a lot of heart surgeries on babies. And for him, the thymus, this organ that lays on top of the heart, was always just sort of an annoyance.

Yes. So when you were doing anything with the heart, you were like thymus. Meh. Yeah. Move over. Yeah. It's in the way. But then about five years ago, something happened that completely changed his relationship with the thymus. It's actually a neat story. He was actually just sitting in his office one day and he got a message from one of his colleagues. Dr. Marker asked to have a meeting with me. Hi, Molly. Hi, Apple.

This is Dr. Markert. Mary Louise Markert. She goes by Louise. I have been at Duke for a very long time, since 1975, actually, until my retirement in 2021. Oh, you just retired.

Yes. But at the time that she called Joe, she was sort of science famous for this technique that she developed where you could take a bit of thymus from one person and you could put it in another. Yes. The idea is that sometimes...

kids are born with no thymus or with a thymus that doesn't work right. And so what if you get a bit of thymus from a heart surgery? The surgeon will have to cut out some of it in order to get to where he or she is operating on the heart. So you could take that little bit of thymus that's normally

probably tossed in the trash, and then take it back to the lab, do some fancy lab work stuff on it to flush out existing T-cells. Then we could put these little slices in the patient. Put it into the kid that didn't have the working thymus. And the idea is that thymus is going to, you know, kick into gear. The process of making T-cells. And hopefully a healthy immune system. Wow.

So when Louise called up Joe that day... She said, do you know why I want to talk to you? And I said, oh, sure, Louise. You know, we take out part of the thymus because it's in our way when we're trying to do aortic surgery. And you need thymus for your work. And so I'm just kind of assuming you're coming to me for some thymus. She said, no, but it's more than that, Joe. I don't just want you to be getting me thymus. She said, I've been looking for a partner to collaborate with because I've got an idea. I was...

You know, just thinking that... We can combine this work that we've done, culturing thymus, along with organ transplantation. Combine it with a heart transplant. Because the problem with a heart transplant or any organ transplant is that the body's immune system will attack the new organ because it's not part of self. So Louise is suddenly thinking, wait a second.

I think the big problem here is the thymus, this thymus sense of self, because once you put in an organ, you're no longer just self, right? So she said to Joe, what if when we're doing a heart transplant, we also get a little bit of the donor's thymus and we transplant the heart and the thymus together into a recipient? And then maybe the recipient's body wouldn't reject the heart because the thymus would be there too.

So that they would not need to be on immunosuppression the rest of their lives. And that makes a big difference. And basically, Joe said, yes, I'm in. I think we should try this. And from there, they just had to, you know, wait until the right case came along where they could test this out. And Louise and I, from that day on, just started working on this project. And, you know, that was early in, you know, that was in 2017 when...

And then just last year... This patient came along. Named Easton. Baby Easton, who has single ventricle type heart disease, so pretty severe. So Easton was waiting for a heart transplant. And then at the same time, they figured out... Easton needed an immune system. He wasn't really making that many T cells. In addition to the heart problem. In addition to the heart problems. Right. I mean, clearly the light bulb goes off. Here's a baby that...

needs a new immune system, and needs a new heart. We know how to treat each of those individually, and it would be an opportunity to actually treat them together. Try the dual thymus heart transplant, and we can actually see if we're able to bring this baby off immune-suppressant drugs.

under the guidance of the new thymus. So last summer, 2021, they got a heart and they got a bit of thymus from the same donor. They did the heart transplant right away. We just dealt with the heart. Easton recovered very well, did great. But as for the thymus, they take out baby Easton's original thymus with the heart. But for the new thymus, they actually had to wait for that because

because they need to prep the thymus first. So they take that chunk that they got from the donor. And then slice it. Chop it into these really, really paper-thin sections. Letting them sit in a lab, feed them with nutrients. Daily for 12 to 21 days. 18 for Easton. And then... In that two-week time span, they sort of...

the T-cells that are packed inside of them. And so by the end of it, you get... The scaffolding. The thymus training structure, but missing T-cells from the donor because the T-cells that are trained in the donor's body would see Easton's body as an outsider and attack it. So you basically end up with chunks of cleaned up thymus from the donor. How big are the chunks? Oh my gosh, they're so small. You know, probably...

half the size of a dime. It's almost like a piece of snot, to be honest with you. Okay. But the thing was, initially, it's like, well, where would we put them? It seems very dangerous to, like, re-crack open the chest and then try and, like, weave this little bit of thymus tissue back onto this new fragile heart.

And at the same time, you need to have a good blood supply. You need a lot of blood to like turn these little bits of tissue back on again. So the location where they do this, you know, I feel like there's a drum. Oh, drum roll, please. Yeah. Yeah. So the location where they do this is the thigh.

Really? Thigh, thymus. Yeah, that's why I joke that's why they call it the thymus, right? What? No. And so you go down to the thigh muscle, and then it's like planting tulips. Now, when you plant a tulip— I heard you are a gardener. Yeah.

And you poke a hole in the ground and you put in the bulb and then you fill in the dirt. So, yeah, this is us taking these off these filter paper. Those are the little pieces of thymus. That's me. That's you? Yeah, yeah. Dunking it down. They're planting tulips, like Louise would say. Wow.

And we actually used both of his thighs just to make sure that we gave ourselves the best opportunity possible to make sure that this thymus would engraft. And the idea is that these bits of thymus from the thigh would actually start training up new T-cells. Wow. How old was Easton by the time the transplants happened? I think he was five months old when he got his transplant. That was in August. Yes.

The thymus tissue did start working again, and the thymus is now releasing new T cells to the body. He's able to produce T cells now. The levels were where we wanted them. So the next step that we have is to start to slowly pull back on our immunosuppression.

And then they will know if the new T cells with the thymus, the donor thymus that knows this heart as its own, will allow Easton's body to fully accept it and fully accept it as self. You know, recognizes both his transplanted heart and his body as self.

So that part of it, do we know if that works yet? I mean, not exactly. They can tell right now that the immune system doesn't appear to be attacking the heart. Even though it's on immune suppressant drugs, no funny business seems to be happening. Or the rest of the body, for that matter. Or the rest of the body, for that matter. And so it's like, right now, they're counting it as a success. Yeah. But by the end of the summer is when they're going to start taking Easton off the immune suppressants. Hmm.

If those T cells recognize both his new heart and his body itself, then, you know, this could change everything. It's not just for children who need hearts, but it could be for adults who need hearts or adults who need liver or children who need kidneys or, yeah, it changed everything.

I'm... Puzzled. This is like really smart to pull in the new thymus, but I'm still kind of confused about... Okay. Okay, so thymus and heart are both coming from the donor. The thymus is...

training T cells based on the donor DNA. Yes. Now they're both in thymus and heart in the recipient's body. Now when the T cells come out of the thymus, they look at the heart, they're like, I recognize you, no problem. But then when they look at the rest of the body, that's all recipient DNA, which they theoretically won't recognize. Like won't they now attack the rest of the body?

the recipient body? No, I mean, this can all get pretty gnarly, like the closer you stare at it. And I'm not sure that anyone would say this is like exactly how it works. But I think the general idea is that, you know, part of the training is in the thymus with thymus cells, which are from the donor. But it seems like there's another part of the training which

is in the way the thymus is actually interacting with the body that it's in, which is the new body. So in a way, it's like the T cells are being trained on two selves. Oh, wow. So it's like training it to be bilingual or like biselfal. It's like a two for one. Yeah, you know, it's funny. Like it's on the first hand, it sounds like it's two becomes one.

I haven't been able to get the Spice Girls out of my head like the whole time I've been reporting this. But I've also been thinking that it's more than that. There's a sense that what we know of as self can be extended. It's not that two becomes one. It's just that two is one or it could be. Or who knows, like maybe even more. You can pull in other selves and they can pull in you individually.

Suddenly you is just a lot less singular. That was our senior correspondent, Molly Webster. I want to give a thousand special thanks to Hannah Meyer, Salome Carsey, and Joshua Torres. They're all part of Hannah's lab at Cold Spring Harbor Laboratory. They let me come see a real thymus in the flesh, a mouse one. For those of you listening who are members of the lab, keep your eyes and ears on the feed. We're going to be dropping some bonus audio content next.

From that visit to the lab, a little juicy piece of conversation that will make you think profound thoughts.

Special thanks also go to Diane Mathis and Kate Webb. And oh, oh, oh, by the way, Radiolab is looking for a remote intern. If you happen to be a creative, science-obsessed nerd who is interested in learning how to make long-form radio, apply. Please. We would love to work with you. You can find more info at wnyc.org slash careers. Until next time. Thank you for listening. Goodbye. Goodbye.

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