Radiolab - The Interstitium

Episode Date: November 17, 2023

In this episode we introduce you to a part of our bodies that was invisible to Western scientists until about five years ago; it’s called "the interstitium," a vast network of fluid channels inside the tissues around our organs that scientists have just begun to see, name, and understand. Along the way we look at how new technologies rub up against long-standing beliefs, and how millions of scientists and doctors failed to see what was right in front (and inside!) of their noses. We also find out how mapping the anatomy of this hidden infrastructure may help solve one of the fundamental mysteries of cancer, and perhaps provide a bridge between ancient and modern medicine.Special thanks to Aaron Wickenden, Jessica Clark, Mara (pronounced Mah-Dah) Zepeda, Darryl Holliday, Dr. Amy Chang, Kate Sassoon, Guy Huntley, John Jacobson, Scotty G, and the Village Zendo EPISODE CREDITS -  Reported by - Lulu Miller and Jenn BrandelProduced by - Matt Kieltywith help from - Ekedi Fausther-Keeyswith mixing help from - Arianne WackFact-checking by - Natalie Middletonand Edited by  - Alex Neason EPISODE CITATIONS - Articles: Check out reporter Jenn Brandel’s companion essay to this episode in Orion magazine, titled, Invisible Landscapes (https://zpr.io/NKuxvYY84RvH), which argues that the discovery of the interstitium could challenge established practices of compartmentalizing in science and society.Our newsletter comes out every Wednesday. It includes short essays, recommendations, and details about other ways to interact with the show. Sign up (https://radiolab.org/newsletter)!Radiolab is supported by listeners like you. Support Radiolab by becoming a member of The Lab (https://members.radiolab.org/) today.Follow our show on Instagram, Twitter and Facebook @radiolab, and share your thoughts with us by emailing [e-mail]. Leadership support for Radiolab’s science programming is provided by the Gordon and Betty Moore Foundation, Science Sandbox, a Simons Foundation Initiative, and the John Templeton Foundation. Foundational support for Radiolab was provided by the Alfred P. Sloan Foundation.

Listen to support it. WNYC Studios Not too many poets can say their work stands the test of time and space. A new film called Going to Mars explores the career and legacy of Nikki Giovanni. Here a conversation with the star poet on Note From America with Kai Wright. Listen, wherever you get your podcasts. Wait, you're listening. OK.

All right. OK. All right. Dordless listening to Radio Lab lab. Radio Lab. From WNYC. C-C-C. You're C-C.

This is Radio Lab, I'm Lula Miller. I'm Luttifnoss'm Laptop Nasser. Oh, hello. Along with reporter Jen Brandell. Hi. Laptop, Jen, have you guys met? We don't think so. We don't think so.

No. So Jen is a radio reporter who I've known for a long time. But these days, I'm a little hard to explain. I have been a journalist and I'm a CEO of a tech company right now I work between a few worlds between entrepreneurship democracy media blah blah blah. Yeah. Well, it's right. I'm an annoying person. I talked to it at a cocktail party because I can't really say it Sinkly. I'm not like I'm an astronaut. I'm a firefighter. Right and that'll that'll maybe come back Okay, so I don't know shall shall we just, shall we begin? Are you ready for a journey?

Yeah. Okay, so we're gonna just to kick it off. Caffeinated, bagled, ready to go. We are gonna start its NYU hospital. We're trailing some doctors and we're in this part of the hospital I had never thought about that exists but it very much exists. So this is Lulu, this is Jen, we have permission to be here. We walk into this room that looks a little bit like an industrial kitchen.

We just can't mention any identifiers. There are big metal counters and sinks and And anyway, these doctors, they're pulling out supper wares and kind of one by one, they are lifting the lids and pulling out well, human organs. So that's small intestine coming here. Organes I've heard about, but never seen before. And this is the pancreas. They pulled out a whole stomach, just like a big orangey red chunk of meat. And they pulled out.

Here's the dome of the uterus. Wow! A uterus is your ovary. Wow! And they pulled out. And here's a large fatty red tissue, and that's the breast tissue. A whole breast? They pulled out.

Wow. Okay. A liver? Great. No, this is skin. Just organ after organ. Are these organs for training? No, no, no liver? Great. No, this is skin. Just organ after organ. Are these organs for training? Or? No, no, no.

These are fresh. It looks like we're seeing this is your stomach. Blood and some of them were dripping blood. Yeah, there's blood. The red stuff is blood. Some were dripping bile. These were organs that had come out of people that day. Oh, so are you on pancakes today?

And so what that room is is it's a pathology lab where they are looking at anything that has been taken out of or off of a patient in the hospital. Coming down from the operating room all day, hundreds of specimens a day. Because maybe that person's getting a transplant or maybe they had. And what is that? That's cancer. A tumor removed. Wow, that's a big, that's like a tennis ball of it.

Yeah, now here's a... It's like a tennis ball. Yeah. Now here's like dizzying because it's these pieces of people, but they hold these full, you know someone like two floors above you is going through a huge day. Right. But the reason why we were there that day was to see a body part. Should we just go now? Yeah. Oh, okay. A sort of we're giving some sense for this procedure. I don't give a sort of organ. It just tested the syringe. A couple drops came out. Here comes the big needle. Inside the human body. That scientist had completely missed. Is that it? Are we looking at it right now? Even though it had just been sitting there. Oh my gosh, I'm wow. All this time inside of all of us.

An organ? Yeah. Well, a body part. A big deal body part. A big deal body part. A big deal body part that we'd missed. Until like five years ago. What?

Yeah, and yeah, and so today, how could that be? Well, that's the story we're gonna tell, how can we bring B? Well, that's the story we're going to tell you. How we missed it. No, people have been looking at the human body for like since the beginning. Yep, exactly. Which is why it's so bizarre that we missed it. I don't even know if I believe you. I'm like in disbelief here. As we're many. Yeah, so we're going to tell you the story of what this mysterious body part is,

what its name is, what it might be doing, why we miss it, how knowing about it might change our lives, our health, and maybe even society a little bit. Really? But I'm going to pipe down because Jen's going to tell you the rest. All right. Oh, great.

Now I just said a Google meeting pop up. Let me just kill all these things. Stop it. Okay. From your 17 other jobs. Yeah. Exactly. Okay. Stop it. Okay, from year 17, other jobs that you work. Yeah, exactly. Okay.

All right. Okay. So the story starts with this guy, Neil These. Hello. Hey, Neil, how are you doing? Dr. Neil These. I'm good. Okay, let me.

So Neil was actually one of the doctors. So this is Lulu. This is Jen. Hi. Hi. Who is showing us around the lab? Okay. He's a kind of short, mussely fellow. He's got tattoos on his arms. And he's kind of an unlikely doctor,

because he studied computer science. And he thought he was going to be a rabbi for part of his life. So I was sort of all over the map. The classic rabbi programmer. No, exactly. Exactly. What about, why did you want to become a doctor in the first place?

Sorry, I know this could be a long story, but quickly like in summation. I was freshman in college. I was gay and couldn't cope with it and I thought and I'm a child of Holocaust survivors too. So my formula was I'm gonna get old. I'll never get married I'm never gonna have kids and I'll be doing Hitler's job for him because of that and I'm going to grow old and die alone. So when he graduated with degrees in computer science and Jewish studies, he was like, what am I doing? What is my role in the world?

And then one day my mother called me up and said, Oh bad news. The doctor that she had worked for and who had Delivered him and his brother and his hometown and Connecticut had died of a heart attack on the golf course that morning and The funeral was gonna be the next day so she called me after the funeral and I said how was Dr. Robinson's funeral? And she said it was just amazing all of Hartford came out for his funeral. And I thought, oh, if you're a doctor, people come to your funeral. So that's why I went to medical school. We did. We ate so like, most people go into medicine

because they care about other people, or they say that, but you went because you wanted more people to care about you. Yeah, basically. I was terrified of being alone and I thought, I won't be alone. I'll have meaningful relationships and I'll do good things in the world and and my life won't be meaningless. So he goes off to med school, discovered pathology in the middle of it and was like, oh, I like this. Which is funny because in pathology, opening up the small intestine, you're mostly dealing with, I'm lifting up the lining of the stomach.

The parts of patients, not the actual people themselves. But I just really loved looking at beautiful puzzles. Because a lot of what pathology is. So I've got this big stack of slides here. It's taking an organ and making a tiny, cut off very, very thin slice. Little sample of it, putting it on a slide,

adding some stands to it to give it color. And then we'll look at it under the microscope. Where he'll see a pattern of colors. Oh! Shapes. Oh my god. Relationships between the shapes. Okay.

Wow. So each cell, as a particular shape, the magenta stain here is the blood vessel lining cells. Sort of like a stained glass. This is an artery, and this is a vein. The teal or greenish coffee's white spaces here and this is fat. And so see how that looks blue?

Yeah. Sit down on my microscope and I look at the slides. I know that's a bad side and I make diagnoses. So he ends up becoming a liver pathologist and like a world-renowned one at that. But he's also super accessible and like friendly and even though he's not working directly with patients, he has a lot of meaningful relationships with people, and they go to him for things.

Like if they're seeing something they've never seen before, which is what happened in 2015. When I was at Beth Israel Medical Center in New York. So he had this kush job at Beth Israel. It was very luxurious. I had my own room with a multi-headed microscope removed from all the action. So he could focus on his microscope all day long. And a colleague walks in one day. David Karlock. Neil told us you are a scope jockey.

He would say that. You know what that means? Is that a term of art? No, no, it's very, very derogatory. It's like a dig of someone who likes looking at microscope? No, no, no, no, an endoscope. Oh, endoscope? Oh, okay. They like to put it up the places and look around. Yeah, or down the places and look around. Down and up through all the ends.

Yes, very good. That's what I do. He's a gastroenterologist. Thank you. And so he comes into Niels' office and he's like, Hey, man. No, it's probably more like, excuse me, Dr. Thies. We've got this new scope.

Until now, gastroenterologists were often in the dark. A very fancy and a scope. Basically a miniature microscope. Enabling you to see what you've been missing so far. So you can see cells and a living person. With real-time microscopic information, critical to their decision-making process. So you can see cells in a living person with real-time microscopic information, critical to their decision-making process.

And it was showing us something that we didn't understand. In particular, it was showing them something in the bile duct. The bile duct. So the bile duct is this tiny, tiny organ. It looks like a tube. We looked at it with neon. I don't know, three inches long, two organ? It looks like a, just a tube. We looked at it with Neil. I don't know. Three inches long, two and a half, three inches long.

It's like a piece of spaghetti, like a little piece of spaghetti. It's called more ziti. A dried ziti, little mini ziti. Where is the bile duct? Yeah, sort of if you go about three or four inches above your belly button, straight in. And what does the bile duct do again?

So the bile duct takes bile that your body produces and it sends it to your small intestine to help with things like digestion and to fight off toxins. Okay. So a super important organ. It's purely a passive tube, but it does a lot of important things. So when patients come in and have something like abdominal pain or the white to their

eyes or yellow or maybe their skin is itchy, one of the causes of problems like that is a narrowing in the bile duct, which could be benign or it could be cancerous. So the patient gets sent to David Zowar. And then we give the patient an injection of something called this is fluoresceine. This is actually what the microscope sees, this fluorescent liquid. It will distribute itself through the blood system and fluid spaces within seconds.

It basically lights up wherever there is fluid in your body, and then after the shot, David grabs his fancy scope. So it kind of just looks like a big black hose. It's about as thick as your finger. With a flashlight at the end, and then, blah, blah, blah, blah, blah, he threads the scope. Down the Asophagus, past the stomach. Into the small intestine.

Down into the bile duct. So David and his colleague Petro Spanias, they're looking through this new fancy microscope, and they're seeing something they had never seen before. The walls of the bile duct were glowing. If you could imagine a sort of honeycomb appearance, where they'd always seen just like a dark wall, there were now these glowing holes

where the fluorescein was showing with these little dark fibers around them. And this nice regular honeycomb shape. And this is in patients who have bile ducts that are diseased or in the normal bile duct. In a normal biode. In a normal, healthy biodect he was seeing, again and again, this honeycomb of lit up holes in the wall. Well, why haven't we seen this before?

And so David took some pictures of the honeycomb. We went to Neil and they showed me the pictures and said, look, what is this thing? What does this car respond to that you've been looking at for the last 30 years? And I was like, I don't know what the hell I'm looking at. I just don't know what I'm looking at. I mean, Neil says like, you know,

I've looked at the walls of a biodect under the microscope in uncountable number of times. And there's no spaces there. It's pretty much solid. Like a dense wall. So he's looking at all these lit up holes thinking. This doesn't make any sense. Really intense cognitive dissonance, which is a lovely place

to be scientifically. For some people. Yeah. Well, you know, there's some really important piece here that will make sense of it. Just what is it and how do you find it out? So Neil took these images of the honeycomb. I couldn't find them in any textbook. And he would show them the colleagues on his lunch break.

And people were making fun of me. They were like, Neil, he's just wild about mile. People just didn't really care. Yeah, yeah. So I don't know how long it took. But eventually Neil was like, wait a second. When David uses his new scope. What you've been missing so far.

He's looking at live tissue. But all the tissue I see is dead. So a specimen comes down from the operating room. So whenever an organ lands on the lab desk of a pathologist, you do all this stuff to it and you wash it, dip it in alcohol, put it into wax because you're mummifying it. You're dehydrating it. You're turning it into wax because you're mummifying it. You're dehydrating it. You're turning it into a mummy of itself. Then you shave off a super thin slice of it. And put it under the microscope.

They'll show us this light of the bile duct. And now see all these cracks? Yeah. You see all these faint little cracks in the wall. I always thought they were cracks. Now in medical school, Neil and everybody else was taught that those cracks were caused by the heating and drying process of just making the slide. So, for 30 years, he had ignored these cracks, thinking they were just an artifact of the

process. But, after seeing David's pictures of the live tissue and then studying different samples that had been frozen rather than dried out, he realized those cracks. They're the remnants of the living spaces. They were what was left behind when the holes of this honeycomb dried out and would sort of collapse on itself. It's sort of like, have you seen those tiny little sponges

that are dehydrated and then you put them in water and they go like, boom! The ones that are shaped like a dinosaur, or something like that. The ones that are like a pellet, and then it's like, oh, that's like a dinosaur. Yeah, so you can think about the way that slides have been being made for like 100 years,

like the pellet. That's what they've been looking at. Oh. But with David's scope, they were seeing the pellet expanded into the sponge form full of holes, which is how the walls around real living biodect actually look.

And so we realized biodex are not like anything we thought they were. Huh. Which, you know, who cares about the bile duct, right? Who actually cares that the bile duct is encased in a spongy honeycomb wall. Big deal. But this is where it gets interesting. So, within days... Neil is back to doing clinical work. And he'd started to look at tissues that he sees every day, but now with a new eye. So, one day he gets into breasts. From a woman who had breast cancer and had to have a breast taken off. And the breast always comes with a portion of the skin. So, Neil did his thing.

From aldehyde, alcohol, wax. Took some of the healthy skin, put it under the microscope and saw. It had the same cracks. So that was exciting. And it wasn't just the skin. He was seeing those cracks in the collagen around the stomach, around the colon. There are cracks.

Tiny little cracks in a dense wall. It's not just the bile duct. OK, now that's more interesting. So I called the guys and I showed them and it was like, oh, this is really cool. My nail, of course, being Neil. Said, how about we use the fancy endoscope? On him.

To see if the places where you're usually seeing cracks might also not dried out have this network of fluid filled holes. Do it on me. Wow. We have scopes that can go lots of interesting places. David said that in order to do the stomach and the colon, you'd have to knock Neil out. me. Well, we have scopes that can go lots of interesting places. David said that in order to do the stomach and the colon, you'd have to knock Neil out, but.

Well, why don't we look at the skin? So we injected my vein with the dye, Florecine, and David just took the scope, just holding it, ran it across Neil's skin, scanned his skin and sure enough. Is that it? Are we looking at it right now? That's it. Yeah. Wow. There it was. The white spaces are Flcing. Like the bright orbs. We actually went up to David's OR at New York Presbyterian Hospital so we could do this on Jen. Oh that's awesome. Really? They sculpt you? Yeah it was like

it was the coolest thing. And they saw the honeycomb fluid thing? Exactly. They could see it in me, like right away. Wow. Anyway, David and Neil had now seen these honeycomb holes in the walls around the bile duct and around the skin cells. And because they knew that all these other places had the same cracks, it seemed like this honeycomb was probably surrounding all of our organs, which raised a pretty simple question.

You know, it's just, what is it? What is the structure they've never noticed before? So, okay, so they phone a friend. Becky Wells. Professor of medicine at the University of Pennsylvania. So Becky does a lot of research into how organs like hold their structure in their shape. So the body's made up of cells,

but there has to be something in between cells and around cells to keep it all together. For example, if you think about an organ like the bile duct, you can't just have a little layer of cells floating around in the middle of the abdominal cavity, it would, you know, things would leak out, it would be very unstable, it would be very fragile. So the bile duct actually has layers of collagen

to keep the bile duct together. And you'll find this throughout the body, not just around the bile duct, but in the spaces around and between most of our organs. There's this sort of thick woven mat of collagen fibers. Exactly. A very dense layer of collagen that served as a barrier. But now, here Neil had these pictures of these holes in the barrier, and he was so excited

he actually threw his slides into a backpack and hopped on a train down to Philly to Becky's lab. He came down, yes, exactly. And Becky has some really cool instruments in her lab, including a microscope that could take a set of flat slides and turn them into 3D image of that specimen. And we sat at this microscope in this completely dark room. They turned it on.

And what we could see was it was almost like waves of hair, which was the collagen. But now in 3D, they could see it was actually like a network of tubes. And we just start, you know, yelling and high-fiving each other. Yeah, yeah. And why? Well, because as far as Neil could tell. That meant that every collagen layer in the entire body, the dermis, the wrappings of all your muscles and your bones,

the collagen that wraps around every artery and every vein, the collagen that gives structure to every visceral organ, your lungs, your heart, your liver, your kidneys, your pancreas, your GI tract, fibers coverings inside your skull around the brain, the fibers coverings around the nerves coming into the brain and going out of the brain. All of these places throughout the body, that they'd always thought were just solid structural stuff

were actually shot through with little tubes and tunnels. And inside of those tunnels, there was this... Fluid. Eventually, they got a hold of some of the fluid. It's clear, but a little yellowy? Sort of like egg whites. So we have a colleague of Niels analyze it to see what's actually in it and they discover this fluid has water, glucose, insulin, hormones, proteins, and high yet flu,

rhonic acid. Eighth, eighth or high aluronic acid. Never heard of that. Well, if you're a woman, you probably have because the skin care ingredient that everyone is searching for. You've been marketed on Instagram that you should buy it because it'll plump up your skin. And reduces wrinkles for younger looking skin. So when people get injections to plump up their cheeks or whatever, a lot of times it's hyaluronic acid, because that sort of functions like a pillow

under the skin, for example. But we realized that hyaluronic acid would be a fantastic marker to map out where the fluid is going, if it's going anywhere. So here's hyaluronic acid. So they used a stain that could show them where the hyaluronic acid was, which could show them where the fluid was moving.

There are all these little brown lines that have this sort of flow. That's the hyaluronic acid cassette like little tiny tributaries from tissue to tissue from organ to organ reaching bigger streams that come together in big rivers. It's this vast fluid highway through the body that travels between organs from one organ to the other connecting everything to everything organ to the other. Connecting everything to everything else. Throughout the body. And they eventually figured out 25% of the fluid going through our body is this stuff.

What? Yeah! 25% of the liquid in our body is flowing through this and they had no idea what it was or that it existed Wait, and what percent is blood? So we don't know the exact number, but it's less than that Less than that. It's like four so it's four times the amount of blood four times the amount of blood Yeah, four times and also sorry as you mentioned it like that Like because the circulatory system has a heart, which is like something stuff through,

like what's the mechanism of stuff getting. Or, yeah, and like what's the directionality and what's that? And like why would you just all settle in your feet or something, that kind of thing? Yeah. What I think we're about to show, we're working on this,

is that the spaces around the heart have fluid in them. We know that. So when the heart contracts to push blood out the left ventricle, the spaces surrounding the heart get relaxed and fluid flows into them. And then when the heart relaxes, the spaces around the heart get a little tighter and the fluid flows out. That is the thinking and they think a same thing might be going on with the lungs because the lungs also expand and contract, expand and contract. So anyway, just a very quick recap. This tissue that everyone thought was dense like a wall and totally passive is almost like a live. It has fluids. It has a...

It's bumpin. Crazy. The walls are juicy, is what you're saying. It's a juicy wall that's bumpin' everywhere that they didn't even know. And it seems to be a system, like a unified body-wide system, similar to the nervous system or the circulatory system that they had totally missed. I started thinking that my understanding of a nato

you was extremely incomplete. And so, we got to publish. We got to publish. Now the question is, what do we call it? And they call it the interstitium. The interstitium. Who comes to mind when you hear that word? Well, I mean, if I'm being honest,

that's if I was making up a fake organ, like maybe that's the thing I would call. Okay, fair enough. But for me, like, I don't know, I think it's actually really evocative. Maybe because I'm someone who like lives my life professionally between many different worlds and ways of thinking, like I like how it evokes spaces that are unseen and in between. But there's still this overarching question. What the f*** is it doing?

Oh, there's that noise. Sorry, in my background it was my, I had a calendar update come up again. And we will try to figure out what the understition is doing after the short break. Hi Rebecca Murray here from Mount Vernon, Washington. I'm a member of Radio Labs exclusive membership program, the lab. My membership provides radio lab with a steady source of funding so the team can continue to tell stories about our crazy world and I get access to exclusive live events and bonus content

Join me in supporting the show. We love sign up at radio lab dot org slash join RadioLab.org slash join. Hi there, I'm Rianne Giddens, and I want to take you somewhere special. I got this shiver through my entire body. My hair stood on end. That's right. We're back with a new season of Aria Code, the podcast that celebrates the magic of opera, from Arias that have mesmerized us for centuries

to the masterpieces of today. This is the power of art, art either depicting life or inspiring life. No tucks or ticket required. Listen to Ariacode wherever you get podcasts. Rrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrr Okay, it might not be nobody. Okay, okay. We'll tell tell tell tell. Okay. Explain stuff. So my real job, this is the fun stuff is liver pathology and a group of scientists believes it's discovered a fluid filled tissues that makes up a previously unknown organ. Our interstitial work broke and shortly after Neal was in China, I'm doing collaborative stuff about liver disease and some of the scientists and doctors there were like, Hey, can you present on this interstitial

stuff? And I said, sure. So he gets to this stage, he gives his presentation, and after he's done. A very high level physician in China. Trained in Western medicine and traditional Chinese medicine. He was given the first question, and his first question was, what has been the response to this work of yours? And I said, well, blah, blah, blah.

Scientists have expressed skepticism that the interstitium is its own organ. Like, the science world was arguing about what to call this thing. It's an organ, it's an tissue, it's an assistant. But whatever it is, Med School anatomy books may soon include a new chapter. People are talking about this new exciting thing. And he said, well, we've been talking about it for 4,000 years.他會不會有一個新的問題他會說這個新的事情然後他說 我們已經說了4000年了

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因為因為 I don't know, I don't know. But what about the culture? What is the concept of a cold? Now, we couldn't find that doctor at the conference, but we did find another doctor in China who also had a strong reaction to the interstitial. This is the concept of a cold. Okay. Wow. His name is Qushing Chen. So our professor, Professor Shen,

is not as smart as, and he didn't have the reaction to be like, duh. So we talked to Qshing through the help of a translator. Wow. I don't even understand what has happened in Chinese. Like, I'm mind blown. So Qshing is a professor at Veterinary School in China. And he does a lot of research on the kidneys of camels, animal tissue,

clums of yaks, yes. And apparently female turtles that can store sperm in their tissue wore up to one year long. And they can still be fertilized. Whoa, that's wild. Yeah, yeah. But anyway, in 2018, he's on an airplane flying somewhere for work and he comes across the interstition paper. And he suddenly had this kind of memory of being a little boy.

He grew up in a rural village in China. One day, he had something that gave him food poison and it was so bad that he was having breathing problems. So his parents took him to go see a doctor who gave him acupuncture. And he had been given a few needles on his hands, on his legs, and then he kind of instantly felt this relief.那他在那裡就用無理刺激然後他被他給了一段時間他把他的手拿出來 然後他就在那裡

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他在那裡發生了一段他在那裡發生了一段他在那裡發生了一段他在那裡發生了一段他在那裡發生了一段 through which life energy, known as Qi, flows. That's according to this book called Huang Dijing, Huang Dijing, that's the beginning. He's in Xingcheng Li, Lung. From 2005 years ago. So he picks this pathway, this meridian, that is known to help with the gut. And he can't actually do the experiment on people because it wouldn't be ethical.

So he has to do it on animals. Wait, wait, wait, wait. Is animal acupuncture a thing? Oh, I didn't know that until reading this paper. I had no idea. My 14 year old dog, we just circled to the doctor and they're like, you could take her to acupuncture. No way.

Really? She's got arthritis and her hind legs. And the idea is like, it's like the same networks and pathways, is it? Pretty much. Huh, who knew? Pretty much. Who knew? OK. But so.

Asuna, Zhenjiu Zhihu. Qushan got some rabbits. 24 rabbits? Then gave the rabbits. Collitis. Collitis. Yes. And then Fabiungi Hu no, we're in Jiu-Diu.

It's this disease that affects the lining of the colon. So these rabbits, they're bleeding. They're having like little ulcers. They're losing weight rapidly. they're not doing well. But then, he takes these little tiny needles and puts them into like the joint around the rabbit's leg, like it's knee, and the acupuncture works. Like the inflammation gets better.

The bleeding reduces, they start getting weight again, like they're better. And some of them are just all good. Brand is new. Totally cute, just returned to normal. Yeah. Wow. So then, he uses the interstition paper, almost like a map.

And then he can find anything in the interstition that's happening that could explain this. L'Ajouciouin is a jik'a si-chang'a si-pa-jiao shi-meng-inzi. And he finds... TELLA SITE. TELLA SITE. TELLA SITE. TELLA SITE.

These cells. Oh, telocytes. Yes. Yes. Yes. Called telocytes, which are a newly discovered cell. That is just one of the residents that lives in interstitial. People aren't quite sure what it does.

It seems to have some role in immune response regulation, some role in like cell-to-cell communication or signaling. But what he saw was that in the rabbits who got acupuncture, their telecytes were like super activated. They were like throwing off chemical signals, talking to each other. They were just more active. So the telescopes are always there in the interstitium, but at least in these rabbits,

when they got acupuncture, they're on hyperdrive. Fum, fum, fum. Yeah, yeah. Okay. So I was excited by it. Like there are people in China who are really excited by it. Does he feel like China who are really excited by it does he feel like he has glimpsed

the meridians that were proposed by Chinese medicine because this feels big like this feels very big Yeah La Shushanqi wangziah but his answer was basically all I can say is that we found what we found因為基礎裡面進我裡面這些東西都有我可以說是我們知道的

因為在基礎裡面 進我裡面 這些東西都有 所以我打算 所以你並沒有覺得自己 我會說 如果你認為 這是一個很大的問題 我不能說自己講

我不能說自己講 他會說我自己講 OK pointake And he's like, I cannot sweet that myself. So, so yeah. Okay, point taken. So more to learn, he's excited by what he saw and he offers it to the world to learn more. Yeah, because it's true. He hasn't found where they're going or coming from or if they what they do.

Or exactly what they do. Yeah. But. When it comes to the body and modern approaches to health and healing, Neil says Western medicine has always had a difficult time body and modern approaches to health and healing. Neil says Western medicine has always had a difficult time talking about or understanding things like acupuncture.

Because there was no Western style anatomy to explain those clinical impressions, those personal experiences. And Neil said even though we don't know how the interstitium might be a part of acupuncture, at the very least, it provides a cultural bridge to allow people to have these discussions. Which is kind of exactly what happened with Q. Shay, who said that to him, when Neil and the team found the interstitium, they found the body, but they didn't find the soul.

They didn't find the meaning, the reason why it's doing what it's doing, what animates it, what is its purpose. But they gave him a place to look, and a place to bring these different ideas, these ancient, time-tested, Eastern ideas, together alongside modern Western medicine. And my hope is bit by bit, this community will be talking to people

in the Chinese medicine community and the Tibetan medicine community and Ayurvedic medicine because we're all talking about the same body. Okay, okay, I get that. I get that, but can I just say, like, I don't know, like it feels like we're just learning., I don't know, it feels like we're just learning. And I don't know, it feels like a jump

to rope in this whole other ancient tradition of medicine. Like maybe, it looks like it has resemblance, but it seems like it's way too early to go there, no? Would you like something that's less of a maybe? Yeah, okay, I'm excited about this, go,? Yeah. Yeah, okay. Okay, I'm excited about this. Go, Lulee. Yeah. Okay.

So, how is everything? We should be ready to go. Great. At the very last minute, Jen couldn't make this interview, but I talked to this guy. Yeah, my name is Peter Friedle. I'm a medical doctor by training. His name is Peter Friedle. For a long time, he was a dermatologist.

But then discovered that maybe science is what I am best at. Basically, he had seen so much skin cancer, melanoma. He'd seen so many people dying. And so he became a scientist. He kind of left practicing medicine behind and he became cancer scientist. Cancer scientists. Yeah. And so he, at the end of the day, I switched from applying knowledge to generating knowledge. And he was curious about like basically one of the most fundamental mysteries of cancer, which is how does it metastasize? Like how does it show up in the skin? And then at some point shows up in lung or liver or the brain. Like how does it spread? Yes, exactly. All throughout the body.

Yeah, so it was known. That obviously once cancer gets into the blood or the lymphatic vessels. It spreads all over the body and then you have to resort to chemo and things can get really, really bad. But what was not known was how exactly cancer goes from your skin tissue to a blood vessel or a lymph vessel. That's hard? It's like harder than you would think?

Yeah, because even though that might be a tiny little journey. A couple of microns, maybe millimeters. From the point of view of a cancer cell, like that journey is huge. And a very tough one. Because to a cancer cell, your body's tissue is like a thick, dense jungle. So basically, there was a hunch for a long time of how it worked.

It was thought that tumor cells... ...come tearing through tissue with... ...he calls them basukas. ...Basukas or... ...bushnives. ...like machetes. ...and scissors, all sorts of scissors. ...to get through this tissue.

...in order to move. ...so that they can pushwag their way to a to a vessel and then to the rest of your body. So this was the premise. And why was that the premise? Well, we saw that cancer cells in the petri dish, they cut everything into pieces. He says, like, you can throw cancer cells and tissue cells into a petri dish, and come back after the weekend. And the cancer will have ripped up that tissue. And so all big pharma were on it. Peter says that's where millions of dollars

of clinical trials of cancer research was focused in terms of like, okay, that's how it moves through. So what do you need to do? You need to disarm the cancer cell. But. Turned out, even if you give medicine to people that takes away the bazookas, the bush knives.

The tumours are still in vain perfectly. Which was totally puzzling, because they knew these cancer cells have these weapons at their disposal, but it was like they didn't actually need them to spread. And discovering that was like... Hundreds of million dollars were burned. Devastating to the cancer research field, I mean it was decades of drug development of clinical trials of hope poured into this type of treatment. And people took us that back and wondered, okay, what did we get wrong?

So early 2000s Peter makes this jump into science and he figures rather than studying what cancer does in a petri dish, what he really wants to do is figure out a way to watch in real time how a cancer cell moves in the body. So what he does is he gets all these mice and then we take a mouse, cut a little hole into it, into the skin on its side, and build a frame out of plastic into this hole. And then into that, they put this little piece of glass, a glass of an aquarium, so you can look through this glass

into the living tissue. Wow. Yeah. And then they take that mouse and give it a skin tumor, melanoma, and a sleeping pill. The mouse folds to sleep for three or four hours. They put the mouse on its back underneath like a big huge microscope. A microscope so powerful it is the size of a room.

And then they looked into the microscope through the glass portal into the mouse and it was spectacularly colorful right from the beginning. So imagine all the skin tissue of the mouse. And it was spectacularly colorful right from the beginning. So imagine all the skin tissue of the mouse was blue like a blue jungle of skin tissue. And then the cancer cells, they were like these green little dots and the green dots were moving. But what surprised Peter was that the cancer cells weren't moving like some wild horde blowing up tissue wherever they could. They were moving like a fluid almost.

Instead they were lining up. One after the other or neighbors even together holding hands. And streaming through an extensive root-like thingas. The mouse is skin. Basically the cancer cells were finding little channels in the tissue where they could just zoom through it and get to a vessel. In a way, it seemed to be like a highway type system that the cells were exploiting. And what were you thinking in that moment? Oh, this is interesting. Can we

observe it a little longer? So you're just like, you're just like fascinated. Yeah, absolutely. It's like a child in a reef with all the fish and all the structures. It's like fascination pure. Because remember, he's seeing this a few years before Niels and Becky and David's paper comes out. So he still like doesn't this idea of a unified system, that isn't out in the world. But he is seeing the interstitial, like the channels of the interstitial. So what did without that

information, what did he think, he thought that the cancer cells were making this channel? No, no, he can tell that the channels are in there in the skin. So after the kind of trans-fixed awe wore off. We thought, holy shit, if every tissue has these channels, how are we ever going to be able to stop the spread of cancer? There are too many channels. This is, it's like, it's, it's endless. Like there's just no way. It's clear. We're not going to stop them. It's clear we're not gonna stop them. And so for years Peter just sat staring at these cancer cells moving through these highways

Feeling hopeless Until one day He was like what if we forget about the highways trying to block them or stop them and instead just go after the cancer cell. And kill it. So what he does is he goes back to these mice and he just blasts the cancer cells with radiation. And what he discovers is that the only cells that survive the blast. What we call the merrothome runners are the cells that are running through the interstitial. So Peter starts pulling these cancer cells out of the blast. What we call the marathon runners. Are the cells that are running through the interstitial. So Peter starts pulling these cancer cells out of the mice. To find what makes the marathon runner special,

different from the rest. And what he finds is that these marathon runners, they are a smart opportunistic creatures. Rather than deploying these bazookas to rip through tissue, they have these little claws that they use to get into the interstitium and move through it, and they can also use the claws to like fuel up in a way that makes them grow bigger and stronger and harder to kill. That's already bad news, but it also is good news because if you now know what makes them special,

you can take it away. Because if you now know what makes them special, you can take it away. Fast forward, Peter develops these antibodies that basically declaw the cancer cells, and he gives these antibodies to the mice. And you give radiation therapy at the same time. The marathon runners melt away, and they die. And we can cure the mice even in tumors that otherwise are not curable. And we can cure the mice even in tumors that otherwise are not curable. So we could, and we also followed those mice up for half a year to check whether cells had made it out into the lungs or the liver or somewhere else and nine out of ten mice were clean. Whoa.

So that means we, not only, we didn't need to block the roads, We bombarded the cars in a good way. And he said the difference between that and chemo, where you just flood the body with everything, is like a huge world of difference, obviously, because you're not targeting the sick person's own immune system. I'm like finding myself getting getting emotional about this. Why? Because my mom passed away from cancer, from lymphatic leukemia and lymphoma, which are

system wide, you know, that means they've gone through the whole, they're everywhere, you know. And she got chemo and she had, she had too many white blood cells and the chemo, they were too aggressive with it and they knocked out so many white blood cells, you know, like you said, they just blast everything, that then they couldn't, the white blood cell count couldn't get high enough to fight it anymore. Like they overshot it. Oh my God. And just, is that what,

because I know she lived with it for a long time. She did, it was a chronic lymphatic leukemia, which is better than the acute where people can pass very quickly, it's really aggressive, but it was really the chemo that ultimately killed her. I think just hearing about Peter's work and I don't know, it gives me like a little hope. And I should say that Peter said this strategy of using antibodies and radiation. Whether then it is making it, it's all the way into the clinics.

As we know, one out of a thousand initially proposed strategies will make it to the patient. So we will have to see. We'll have to go through years of development of trials and humans. But at least proof of concept we made, we delivered. And that's what feels big, because what Peter was finding in mice. Issues. So this is a slide of breast.

Neil and Becky are now seeing in humans. And here are cancer cells walking along through the interstitium, like they've got a nice little path to follow through the woods. Here they are. And just marching from the interstitium to get to the lymph nodes. Yeah, so Neil and Becky, I kind of think of them as like

these cartographers where they're essentially trying to make these maps of every single organ. Of like where the interstitium is? Where would it be in the womb? Or where it isn't? There's very little actually. It's interesting. This is one of the areas where you don't see

a lot of interstitial. And it's like they are publishing as fast as they can. We've got six papers that are heading their way towards publication. And they're not claiming to know what the interstitial does or is doing throughout the body. They're just like, here are the maps. Now, all these different fields do with it what you will.

So, obviously, people are interested in the acupuncture picked this up. But there's a lot of people who are focused on primarily Alzheimer's research. They've been interested in the interstitial in the skull. Neil and I both participated in a conference at the National Institutes of Health in the spring on the interstitial as it relates to the kidney. There's people looking at kidney function. Health in the spring on the interstitium as it relates to the kidney. There's people looking at kidney function. There's people who hope the interstitium might help.

On understanding metabolic diseases like diabetes, understanding bacteria in the body, how infections might spread in places even like your mouth. I gave a talk about this at the Pendental School and you know, there's a lot of bacteria in the mouth, right? But we don't know. I mean, it's sort of wide open right now. Huh. It's just sort of amazing to think, like this little microscope goes into the body

and then opens up this whole new realm that we're just beginning to learn about. Like, this is my favorite kind of technology story where it unlocks a whole new part of our world and literally a whole new part of ourselves that we just could not have seen otherwise. Well, about that turns out you didn't actually need the microscope. Wait, it's not naked eye visible, is it? No.

It is? Really? So now what I'm going to show you, we have cut, as I said, we cut open the small intestine and the wall of the stomach. Now, this is kind of like the wildest part of the story for me. So when we were in the lab with Neil, at one point, who takes a cross section of the small intestine in his hand. And you see this.

And he started pulling at this thin, that looks kind of thready. Like layer of almost like translucent threads encasing the intestine. That is the interstitial. That's the interstitial. What? Yeah. But like that wasstition. What? Yeah.

But like that was it. Like that is it. So, okay, to get that this close. See, like here when I pull it, you see little threads sort of getting tense inside there. Yeah. Yeah. That's the interstition.

Wow. Wow. I thought this was like a technology. No, no, no, no. So, like you got a fancy scope. Any new technology that allows you to see things you didn't see before or see them in a different way is going to reveal things you hadn't noticed.

Some of them may not have been available to your eye. In this case, they were available to our eye. But we had never put it together. And what Neil said was like, no one had put it together because we've been told to discount it. You know, we all read the same textbooks and look at the same drawings by the same people to explain what is seen in the human body. And all these people had decided that this thready stuff that we were seeing in the body, like it just didn't matter. It didn't do anything important.

Yeah, we were looking, we saw it, but it had no meaning. Or even like Neil, who had been seeing cracks in tissue in slides, he'd been told since med school. This is nothing we even have to pay attention to. That the cracks in the tissue, that they don't matter. Like don't worry about the cracks. And I taught people these were just cracks for 30 years. But so it's like when when Jen brought this story to us, I originally understood it as like a fancy new technology reveals this

body part we've missed forever. But it sounds like you're like, no, like, is this actually a story just about beliefs getting in the way? Yeah. Beliefs and training and dogma, it comes back to the Shinryu Suzuki Roshi, who was the founder of San Francisco's Ed Center, said that in the mind of the beginner, there are many possibilities in the mind of the expert. There are a few. I got choked up. Why does that choke you up?

Because it's so profound. What had I been taught that got in the way? What am I missing now? The story was brought to us and reported by Jennifer Brandell. And before we go, we should say that Jen has one more kind of brain-busting chapter about the interstitial. She just published an essay about it for Orion Magazine. Orion Magazine is called Invisible Landscapes. Go read it. But Jen, can you just give it like a cliff-snope?

Sure. Yeah. So I mean, truth be told, I'm most interested in the interstitial metaphorical value. Like, if we've missed seeing this thing that connects so many organs in our bodies, like might we be missing analogous things in society? Does that make sense?

Not quite. Say one more beat. Say one more beat. What does that mean? An interstitial means to see. Yeah, like, just briefly. I mentioned at the top, I'm a person who operates between different organs in society,

or as we call them organizations, between journalism, tech, government, democracy. And in learning about the interstitial, it was kind of like the skeleton key for me that made me realize that there's this whole invisible thing That has been discounted the people the the roles that do this connective work and like like a kind of work Oh, yeah, it's like a kind of work. It's been ignored. It's like it doesn't have a job description. It's discounted and Like I think it's key to the health of the whole body like the the whole economy. And so, in the essay, I give some examples of what I mean.

Yeah, and I guess I just kind of want to hype you now. Like, you talk about work you did, connecting the city of Chicago during COVID to hospitals, churches, hotels to help people in need. It's very concrete stuff. It's really neat. Yeah, yeah, it's really. Oh, well, thanks, Lily.

I mean, basically, it's just making the interstitial, like, people visible in society. And talking about how the more we value it, the more we notice, invest in it, it could have hopefully positive ramifications for the health of the economy. And stuff like that. And stuff like that.

Go check it. Again, it is called invisible landscapes. And you can read it at orayinmagazine.org. And if you are interested in geeking out in more scientific ideas, Neil Thes, Dr. Neil Thes, just published a book that is called Notes on Complexity, a scientific theory of connection, consciousness and being.

It is really profound and great. Go check that one out as well, Notes on complexity by Dr. Neal Thies. This episode was produced by Matthew Kilti with Production Help from a Kedi Foster Keys, mixing help from Arianne Wack, fact checking by Natalie Middleton, who was edited by Alex Nieson. Big special thanks to Jessica Clark, Aaron Wichenden, Mata Zapata, Daryl Holiday, Dr. Amy Chang, Kate Sassoon, Guy Huntley, John Jacobson, The Village Zendo, Scotty G, and Rest in Peace to Mavis, the 14-year-old dog. Oh, and before we go, I guess we should just sign off with what happened after Jen was injected with Flores and Dye to get scoped. The doctors told her that if she went to a dance club,

she would glow under the black light. But she said she just went home, drank some tea. OK, and I'm just getting back to the European B. I'm staying up in Brooklyn. And I have been told that the dye that was injected is going to make my pea green. We're going to see. I have not urinated since, well, for a while, since the dye was injected.

So, all right. See here it goes. Take a look. Whoa. Oh wow. It's like highlighter yellow green. It's really, um, yeah, it's like neon greeny yellow. It's wild. Okay, I wanna take a photo.

This is what we get to do for work. What a privilege. Radio Lab was created by Chad Abumrad and is edited by Soren Wheeler, Lulu Miller and Lottef Nasser are our co-hosts. Dylan Keath is our director of sound design. Our staff includes Simon Adler, Jeremy Bloom, Becca Bressler, and Keti Foster Keys, W. Harry Fortuna, David Gabel,

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Science Sandbox, Assignments Foundation Initiative, and the John Templeton Foundation. Fundational Support for Radio Lab was provided by the Alfred P. Sloan Foundation. you