This is a transcript of the Gastropod episode, Guts and Glory, first released on May 21, 2019. It is provided as a courtesy and may contain errors.

GIULIA ENDERS: Sometimes when I’m done with work and I still have 10 or 20 minutes then I just go to the endoscopy and see if they have some small intestine to show me [LAUGHS] because I find it very pretty. I do think that if people could have this in an aquarium at home I think they might. Maybe if they knew what it was they wouldn’t but maybe they still would. Because it’s very beautiful.

CYNTHIA GRABER: I’ve never thought of my small intestine as beautiful, but you know, I’ve never seen it!

NICOLA TWILLEY: If anyone’s would be beautiful, Cynthia, I’m sure it’s yours. Anyway, Giulia would think so.

GRABER: Giulia Enders is not only a German doctor who loves to look at images of endoscopies, she’s also the author of a fantastic book called Gut: The Inside Story of our Body’s Most Underrated Organ.

TWILLEY: And that is exactly what this episode is all about: guts. The real kind, and the artificial kind. You’re listening to Gastropod, the podcast that looks at food through the lens of science and history. I’m Nicola Twilley.

GRABER: And I’m Cynthia Graber, and this episode we are exploring the entire digestive system, from when food goes in our mouths to—you know, when it comes out the other end. All the guts and the glory.

TWILLEY: Unlike Giulia, most of us never get a good look at this marvel of internal plumbing. But we did! Because we went to visit the world’s most sophisticated model gut—at dinnertime, of course. It’s called TIM.

GRABER: Not my partner Tim. There are too many Tims on our show.

TWILLEY: We wanted to know if TIM the model gut farted and pooed, of course, but also—what’s actually going on inside him? Can you really make a realistic model of our guts—one that even includes our gut bacteria?

GRABER: Our digestive systems are super complex, so any model must be at least somewhat simplified. In that case, what’s it good for? And what can these models teach us about our own biology as well?

TWILLEY: This episode was made possible thanks to generous support from the Alfred P Sloan Foundation for the Public Understanding of Science, Technology and Economics, as well as the Burroughs Wellcome Fund for our coverage of biomedical research.

PRE-ROLL

TWILLEY: There are lots of cool things about the human body. Eyes are pretty impressive, if you ask me.

GRABER: Our brains are certainly nothing to sneeze at. But Giulia, she’s pretty clear about what her favorite organ is.

ENDERS: For me personally it’s definitely the gut.

TWILLEY: This a woman who loves guts.

ENDERS: Hello, my name is Giulia Enders. I’m a doctor and author and I wrote the book Gut: The Inside Story of Our Body’s Most Underrated Organ. And today I’m on Gastropod.

GRABER: One reason the gut is underrated is that we know so little about the digestive system. It’s been really hard to study.

ROACH: Well if you go back to the early anatomy lab days, like the late 1700s, the 1800s, where you didn’t have refrigeration and air conditioning and you were studying the human body, they would throw away the gut because it stunk. And that’s where all the bacteria was. And if you left it in play, you know you left it in the body, the body would decompose so quickly that you couldn’t really study it. So they tended to just chuck it, like just get this out of here. You know we’re going to study—I don’t know. We’ll figure that out later! When they figure, when they invent refrigeration then we’ll figure that thing out.

TWILLEY: This is Mary Roach. She also wrote a book about digestion! Hers is called Gulp: Adventures on the Alimentary Canal.

GRABER: If you think about it, our digestive system has always been kind of like a black box. Stuff goes in, stuff comes out, but what is happening in between?

TWILLEY: In the early 1800s, a peep hole appeared in that black box—a peep hole by the name of Alexis St. Martin. And the peeping tom was a doctor called William Beaumont.

ROACH: Alexis St. Martin was a patient of William Beaumont. William Beaumont’s kind of like the father of physiology. He’s kind of this revered figure in the history of medicine.

TWILLEY: William lived on Mackinac Island, in Lake Huron—right up near the Canadian border. It’s now part of Michigan, but back then Michigan wasn’t even a state—this was America’s northwest frontier.

GRABER: Alexis worked for the American Fur Company as a trapper. He was French Canadian, he was poor, and he hauled pelts through the northern woods on foot and by canoe. And then he was accidentally shot when someone was trying to take down a duck.

ROACH: Alexis St Martin was shot. William Beaumont comes down from his home and is like “Oh, I’ll help this young man.” And brings him in, is treating him, realizes there’s a hole in this man’s side that enables William Beaumont to actually access the stomach. To look inside, to put his finger inside. He has stomach access, which normally you don’t have. Live action. Digestion going on. He can see it. He gets the idea because when the gunshot happens kind of like Alexis St. Martin’s breakfast kind of spills out. He’s like “Oh whoa, this is food that is in the process of being digested. Fascinating.”

TWILLEY: William was 37 and he was working as an assistant surgeon in a military outpost, which didn’t quite match up to his vision of himself as a man of science. And pretty quickly, he realized, huh, I could use this Alexis dude to study the mysteries of digestion.

GRABER: So did he really do everything he could do to close that gunshot hole?

ROACH: He says that he did. No one else has concrete evidence that he didn’t. But I’m just guessing maybe he kind of saw an opportunity here to create this permanent opening.

GRABER: So William sets to work experimenting through the opening to Alexis’s stomach. He took a silk string and proceeded to dangle bits of food through the perforation.

TWILLEY: Specifically a piece of seasoned a la mode beef, a piece of raw salted fat pork, a piece of stale bread, and a bunch of cabbage.

GRABER: And Alexis was supposed to kind of go about his normal day—at this point he’d moved out of the hospital and was living in William’s house.

ROACH: One thing he wanted to—Beaumont that is—understand is, can digestion happen if you take this weird juice that the stomach is creating, will it digest outside the body or does it need the body’s vital forces as he put it.

TWILLEY: William quickly moved on from the dangling silk string approach. He basically turned Alexis into a gastric juice spigot.

ROACH: He would kind of set up a drip. Alexis St. Martin would be producing stomach acid and various other secretions in the stomach and kind of filling bottles with it. And then William Beaumont would then put things into this material in bottles to see, Oh does it actually digest outside the body. And yes it does. And then in order to bolster his international reputation, he was in communication with physicians in Europe and he was shipping Alexis St. Martin’s gastric juices around the globe in these bottles.

GRABER: Sometimes of course the bottles broke and the gastric juices spilled out in the mail. Not too pleasant. But William was thanked by scientists in Europe, who used these to conduct their own experiments on, as one said, masticated meat.

TWILLEY: William took his commitment to the study of digestion to what we would consider extremes. For example, he wrote in his diary that when he poked his tongue into the hole and onto the mucous coating of Alexis’s empty stomach wall, he didn’t detect any hint of acidity.

ROACH: Yeah, there was a peculiar intimacy to the proceedings.

GRABER: This sounds totally gross and bizarre, but actually at the time, smell and taste were an important tool for both scientists and for doctors, to help them diagnose patients.

ROACH: So it wasn’t as kind of pervy as it sounds to kind of lean over and stick your tongue into the hole in somebody’s stomach, which I just yeah… I would love to see a photograph of that.

TWILLEY: So William was just doing what doctors do. Except perhaps for the healing part of the job description. But what about the owner of the perforated stomach?

ROACH: It was not pleasant for Alexis St. Martin. He described sort of a… feeling faint and it wasn’t fun to be, you know, a gastric juice cow. But he endured it. He was paid.

GRABER: Their relationship was a complicated one—Alexis was illiterate, he barely spoke any English, so he and William couldn’t exactly communicate well, but he had a hole in his stomach.

ROACH: They had a very odd relationship of mutual dependency. Alexis St. Martin drank a lot, had difficulty working in the fur trade. It’s hard to be a trapper when he you know he had you know he still had pain from the gunshot wound. And honestly lying around and digesting is a lot easier than the very, very hard work of checking trap lines and hauling pelts.

TWILLEY: Every so often, Alexis would take off. William would literally pay people to hunt him down. The experiment continued for years.

ROACH: But you know the two essentially spent their whole lives together kind of resenting each other the whole time but needing each other. It was a very strange kind of lifelong relationship, but not friendship.

GRABER: William died before Alexis did, but he wrote a massive tome called Experiments and Observations on Gastric Juice and the Physiology of Digestion. And he’s taught today in medical school, and recognized as one of the fathers of physiology.

TWILLEY: William’s big breakthrough was confirming that food could be broken down just using the liquid in the stomach—no agitation necessary. But that turns out not to have even been that big of a breakthrough.

ROACH: In fact there were Italian physiologists who had studied the stomach and how it breaks things down and is it mechanical or chemical. But apparently William Beaumont wasn’t familiar. This was before the internet. Didn’t know these dudes in Italy had done this work.

GRABER: The Italian dude’s name was Lazzaro Spallanzani, and he figured out this gastric juice breakthrough a few decades before William by doing experiments in chickens and other animals, as well as on himself.

TWILLEY: Still. William’s plan to achieve fame worked: Even today, he usually gets the credit.

GRABER: Since the early 1800s, of course medical science has become increasingly sophisticated, and that black box of a digestive system has become a little more transparent. For instance, researchers can stick tubes down people’s noses and throats to take samples in real time.

SUSANN BELLMAN: But these are all invasive techniques.

TWILLEY: This is Susann Bellman.

BELLMAN: I’m the head of the department or for gastrointestinal research or the TIM department as we call it here.

GRABER: TIM stands for TNO Intestinal Model, and TNO is the name of a Dutch organization for applied research. It’s a research institute meant to bridge government and industry.

TWILLEY: Susann has been feeding and analyzing and evolving TIM for more than a decade.

BELLMAN: None of the team calls their child’s TIM anymore.

TWILLEY: TIM aside, Susann told us that there are a few other tools scientists have developed more recently to study digestion in real time. You can attach isotopes—special chemicals—to food and then trace how the various nutrients get dispersed in the body.

GRABER: People can swallow tiny cameras to give researchers a close-up view of our guts from the inside. Scientists also use MRIs to carefully examine how food is distributed in someone’s stomach and how it empties into the small intestine. But these tools are expensive and time consuming. They’re not super easy to do, and they’re not a full picture window into what’s going on.

TWILLEY: But what about animals? Like the chickens used by our Italian friend Spallanzani?

BELLMAN: Animal studies are done very often still to understand food digestion. But animals have different anatomy and physiology and therefore processes there work different. So animals are a model that can be used, that is used very often. But it’s not always predictive for what happens in the human situation.

GRABER: To find a way to mimic humans more closely, scientists started to make super basic models of our digestive system.

BELLMAN: So these are beaker glasses which simulate a gastric phase and a small intestinal phase and a large intestinal phase. And then you can transfer material from the one to the other.

TWILLEY: In these beakers there would be a stirrer, like a food processor blade. And scientists would add the food and gastric juices to the first beaker, which was supposed to be the stomach, all in one go, and then after a few hours they’d dump that into the second beaker, which was the small intestine, and so on.

BELLMAN: But that’s not what happens in our gut system because the stomach empties gradually.

GRABER: And the beakers were solid glass. They couldn’t mimic the squeezing of our stomachs and small intestines, that’s called peristalsis, or peristaltic movement.

BELLMAN: So it’s a very dynamic process. So my colleagues at that time, they thought we wanted to have a model that reflects these dynamic processes.

MANS MINEKUS: So as I said at the time, mimicking the gastrointestinal tract with a simple model is like mimicking a river with a pond, you know. So it’s very static and nothing happens.

TWILLEY: Mans Minekus is one of Susann’s colleagues, and he was one of TIM’s two dads—he and a colleague named Rob actually started working on TIM in the mid 1990s.

GRABER: Other scientists in the field of digestion research and physiology? They didn’t think Mans and Rob could build an entire, working artificial gut.

MINEKUS: Yeah some of them told me that, “You should not do it because it’s too complicated.” Unfortunately I’m quite stubborn. So I said, “Okay well we’ll just go ahead and go through with it.” And also industry was already quite enthusiastic about how we proceed.

TWILLEY: Mans and Rob started by reading everything there was to read about the gut: The composition of bile liquid, each of the different enzymes, the speed that food moves through the various sections of the digestive system. They partnered with a French gastroenterologist who would drive to the Netherlands in his little Citroen every week to help them. Basically, they tried to mimic a real average human gut to the best of scientific knowledge

GRABER: Obviously our stomachs and intestines are flexible, and glass beakers aren’t, so that flexibility was one of the first things they designed into the new system.

MINEKUS: The flexible membranes I used were condoms. Because they were flexible and roughly the right size.

TWILLEY: The condoms worked surprisingly well, but they wore out quickly, so once TIM was past the proof of concept stage, Mans found a company to custom produce silicone stomach and intestine bags.

GRABER: The next major difference between the beaker system and the TIM system was how the food gets mixed up and moved along. In the beaker, there’s a blender, and then food gets dumped from one beaker into the other. But Mans and his colleagues created a squeezing motion to more closely mimic our guts—

MINEKUS: We do not, even with TIM, do not mimic them exactly. Because in real life for example the movements in the stomach are more like when you squeeze a toothpaste tube, while we squeeze it by just pressing.

GRABER: In perfect toothpaste squeezing, at least the old school kind, you’d kind of massage up from the bottom to the top of the tube. I have to admit that I don’t do that, I do in fact just squeeze in the middle—but that’s what Mans is describing, our stomachs squeeze like an idealized toothpaste tube.

TWILLEY: The squeezing—and also the valves that release food from the stomach to the small intestine and so on—they’re all controlled by TIM’s software and sensors. So they don’t let the food through all at once—they let it out gradually, when the broken down food particles get to exactly the right size.

GRABER: But even TIM’s system isn’t a perfect replica of what’s going on in our own bodies. TIM is far more advanced than the beakers, but it’s still a simplified version of our digestive system.

MINEKUS: The challenging part was not to think about what should we simplify, but what do we have to simplify. Because it’s incredibly complicated what happens in the gut and how there are feedback mechanisms. It’s all regulated and all… It works to optimize the digestion. And so on. It’s a very nice system in real life. And we have a computer to do it but we are still limited.

TWILLEY: OK, so let’s put TIM and our bodies side by side. What does TIM get right, and where do our bodies have the edge.

GRABER: We should start at the beginning of the entire process, with spit.

ENDERS: Well saliva is something that looks a little boring it doesn’t really have a taste. But then it’s like a medicine cabinet of its own. Like when you look at all the ingredients, there are just many interesting things. There’s not only one of the most potent painkillers—opiorphin—which is actually a higher potency than morphines.

GRABER: Which is a great evolutionary trick, because how frequently do I bite the inside of my cheek? Or burn the roof of my mouth when I taste something I’m cooking?

ENDERS: There’s not only that pain killer, there’s also things that strengthen our teeth. There’s things like mucins that we’ll be able to put bad bacteria or some microbes in a Spider-Man like net. And then there are also other things that will help us get more vitamins or other things out of our food, that will for example cage Vitamin B12 in a structure so that it’s not destroyed until we can absorb it in our gut.

TWILLEY: The weirdest thing Giulia told us about saliva that I totally did not know—leaving aside all that other cool stuff—saliva is basically filtered blood.

GRABER: Which did in fact blow both of our minds. Our salivary glands are filters that keep out all the stuff that makes blood red. Totally wild.

TWILLEY: The recipe for this magical filtered blood in our mouths is known to science. And so Susann and Mans just make their own artificial saliva for TIM, using off the shelf electrolytes and enzymes.

GRABER: But before they do that, first of course they have to get TIM’s dinner ready.

BELLMAN: This is our, what we call, chewing machine. This is actually a very simple juicer. And when we prepare food, we really boil potatoes. We bake and we fry. And then we put it through this machine so that we have a simulated chewed material.

TWILLEY: That’s the part our teeth do in real life, in case you were wondering.

GRABER: After we chew our food and it gets mixed up with our saliva, then we swallow it, and then that mixture goes down the esophagus—which hooks up to our stomach and enters it from the side. Which at first seems like it doesn’t make sense.

ENDERS: Because when you look at a biology book or some you know picture of the gastrointestinal tract it all looks a bit crooked and weird to be honest. It would seem so much easier to just, you know, straight go down to the stomach. But no, it has to go to one of the sides and then enter on the side. So you think, why? But then when you really get down to the science behind it just gets clever and smart. And by that, beautiful—at least to me.

TWILLEY: It’s really clever. Basically, your abs—that glorious six pack beneath your shirt—they tense up whenever you laugh, or even like when you walk, or bend or really do anything. And when they tense up, they compress your whole digestive system.

ENDERS: Which is why some people will actually sometimes fart by accident when they’re laughing heavily. But puking is not as well known when you’re laughing really hard. And that’s because of that smart side entry into the stomach. So the pressure will go up and it will hit the roof of the stomach, but not so much the sides.

GRABER: Another nifty evolutionary trick. I’m thrilled that I’m not puking when I laugh after my meals.

TWILLEY: Me too. So if this was a real tour, what would we be Instagramming inside the stomach? What’s the aesthetic?

ENDERS: We would think what are all these like folds doing here. It’s folded up heavily, so at first it looks weird. But then after like all kinds of other foods would come after us we would see it all get smoother and wider because the stomach walls can extend, and by that they will look really smooth all of the sudden and not have so many folds anymore. So we can fit like a liter, and for some people more, of volume in our stomach and just store all the food until we slowly digest it, grind it up and move it along.

GRABER: This is why even when you insist that you’re full, you sometimes can still fit that bit of dessert in at the end of your meal.

ROACH: The stomach is remarkably… compliant is the word that they use. “Compliant” meaning, “Yeah, you’re going to eat 17 hotdogs, we can handle that.” I spent some time talking with competitive eaters and the stomach does have a breaking point, but before you reach the breaking point you will reflexively throw up.

TWILLEY: Your stomach wants to save you from yourself. It has stretch receptors in its walls…

ROACH: Which you know like at a certain point tells the brain, “OK this organ is about to rupture. So empty it out.”

GRABER: Competitive eaters train so that they can override that instinct and not throw up.

TWILLEY: It’s also possible to get full too quickly for the stretch receptor warning system to sound the alarm. As a kid, I have a very vivid memory of hearing about a guy who ate a huge Tex Mex meal, felt a little uncomfortable and so decided to have some Alka Seltzer. And his stomach literally exploded. I always pictured beans and cheese everywhere.

ROACH: The stomach tends to rupture when you fill it up quickly and that tends to happen with gas. Like if you eat a lot of Alka Seltzer type, or you know bubbly water, if you end up with a lot of gas being introduced quickly, the body can’t kind of process that in time and you have a rupture.

GRABER: I admit I’m more than a little grossed out right now. And will be avoiding the Tex Mex Alka Seltzer combo forever.

TWILLEY: Accidental explosions aside, the main thing going on in the stomach is the thing William Beaumont figured out by dangling food on a string into Alexis St. Martin. The stomach mashes food up but more importantly, it produces an acidic liquid that breaks food down.

ENDERS: So if you have a raw egg and you put it in a pan and it gets you know white and changes its color a little bit. That’s because the heat breaks up the proteins. And the same thing would happen in the stomach. The acid would break up the proteins. It would look as if you had put it in a pan and fried it. So this reaction with acid on different proteins is something that you can definitely smell a little bit especially when you puke. You realize that smell and you recognize it.

GRABER: Yep. And you might not want eggs for a while.

TWILLEY: So that’s the five cent tour of our real stomach. Which, by the way, is not where you think it is.

ENDERS: The stomach is a little bit higher than many people think. At least in Germany, I hear many people say oh my stomach hurts and they put their hand on their belly button but the stomach is actually much higher. It’s like from one of your nipples, like the left nipple, to just a little bit above the sternum And when you’ve got pain there, then it can be the stomach. If it’s lower, it’s usually the small intestine or the large intestine.

GRABER: But meanwhile in the Netherlands, the stomach we were looking at was just above eye level, surrounded by tubes and sensors.

TWILLEY: TIM is basically a giant beige cabinet—a little taller and a little wider than a real person. And instead of shelves on the inside, it has all this plumbing. It basically looks like someone raided Home Depot and built a whole interlinked, intricate sequence of valves and little intake hoses and stoppers and pipe fittings and U-bends.

BELLMAN: So this is the stomach. It consists of a glass vessel which is filled with water and inside the water there is a flexible silicon sleeve.

GRABER: The movement of the water is controlled by a computer, and the flow puts pressure on the silicone stomach.

BELLMAN: So the water in this glass jacket is removed and added through these openings here which results in a squeezing and releasing of the flexible sleeve inside. GURGLING SOUNDS

TWILLEY: Food stays in the stomach—both TIMs and our own—until it’s digestible. How long that takes varies—liquids slip through quickly, unless it’s alcohol, which slows everything down. A small meal can take less than an hour to break down, but fatty chewy meats—they can take quite a bit longer.

GRABER: The stomach gets everything ready for the small intestine, and then gradually releases it. And as the broken-down food passes through the sphincter, bile and pancreatic enzymes are released at the top of the small intestine, and these break things down even more.

TWILLEY: Side bar: These are the same enzymes that you find in laundry detergent. They’re good at breaking down fats and proteins in the food you spill on your shirt as well as the stuff you eat.

GRABER: And then the small intestine is where all the business really starts to happen. That’s where most of the nutrients and vitamins from our food get absorbed.

ENDERS: OK. So the small intestine is my absolute favorite part when you look at it like, by eye, like just visibly, because it’s actually very pretty. The small intestine looks a little bit like satin when you look at it with the bare eye.

GRABER: Quick note: Giulia means velvet, not satin—velvet is the fabric with the fuzz on it.

TWILLEY: Of course the wall of the small intestine is not just pretty for the sake of prettiness. It looks like velvet because the small intestine is where all the goodness gets absorbed, so it needs a huge surface area to maximize that absorption.

ENDERS: Under microscopes, satin and the small intestine are actually very similar because they need all these tiny structures to make their surface bigger.

GRABER: These tiny little fingers or like little threads of velvet are called villi. And they not only make the surface area a LOT bigger, but they have special cells on them that transport nutrients and vitamins from food to our bloodstream.

TWILLEY: Like the stomach, the small intestine also moves. But it has its own particular choreography.

ENDERS: So it really has different ways of stomping, kneading and then also just holding the food and pressing it into its walls, so that it can mix up the digestive enzymes and not just do the same movement and then the food in the very inside of it would just stay at the same place.

GRABER: TIM, our friendly model gut, he doesn’t have villi, and the surface area of its small intestine isn’t as big as the one in our bodies. But he does have filters with tiny straws that act like villi, and they suck up the nutrients. It’s a great way to figure out what actually becomes available in our small intestine for our bodies to use from whatever food the scientists at TNO are testing.

TWILLEY: At this point, the food in TIM and in our real guts—it’s a homogenous yellowish gunk. The yellow color comes from bile. Or if you’ve eaten something with a food coloring, your food will all be that color. But what it’s not is brown and poo like.

ENDERS: When there’s no food in there the stomach, the esophagus, the small intestine are very clean and they hardly smell like anything. Many people don’t really realize this about the gut, that really from the eight metres just the very last metre has something to do with feces and being more smelly. The other ones can sometimes, you know, have food in them and some reactions by breaking up that food. But when there’s no food in there they’re very cleanly. They love cleanliness. That’s why every time we’ve not eaten for a little while, like one or two hours, they’ll have big muscular waves to like move everything forward so it’s as clean as possible there.

GRABER: And that, dear listeners, is what is happening when your stomach rumbles! First of all, it’s not just your stomach, it’s your stomach and your small intestine. And it’s not telling you you’re hungry, it’s just sweeping out any sticky stuff that might not have passed through, like a little kernel of corn. It’s cleaning up!

ENDERS: Sometimes it doesn’t even have to make a noise. But actually what you’re hearing is your gut cleaning itself and being very cleanly and eager about that. So next time maybe you’re embarrassed by it, also keep in mind that it’s just really trying to keep you tidy from inside.

MID-ROLL

TWILLEY: The next stop on our tour of our digestive system is the large intestine, otherwise known as the colon.

ENDERS: That’s where now the interplay of bacteria and the leftovers of food start.

TWILLEY: Microbes! Drink!

GRABER: When you hear about gut microbes, this is where nearly all that microbial action is taking place. And there are more and more gut microbes the further you go along the roughly five feet of the large intestine.

ENDERS: And they are actually sort of excited to see what’s coming and what kind of food they’re getting today. And depending on how much fiber we eat, they’re more or less happy.

TWILLEY: The small intestine has got every scrap of nutrition out of your food that it can. The gut microbes in the colon—they’re like the final hardcore clean-up crew—they break down resistant starches and fiber in fruits and vegetables, and they turn other leftover chemicals into vitamins.

GRABER: Food can sit in the large intestine for a while, just hanging out, maybe moving back and forth a bit. And as it sits, and the microbes do their work, they’re producing gas as a byproduct, and water is also being squeezed out of the whole mess that’s left.

ENDERS: And so let’s say at the middle of the large intestine, we’re dealing with something that has a bit more of a solid consistency and also be more brown.

TWILLEY: That brown color—that’s actually from dead bacteria.

ENDERS: Bacteria that has served us well in our large intestine, helped us with all sorts of things, but now is, you know, has retired and so we can get rid of it.

GRABER: In the Netherlands, TIM’s digestive system is split into two parts, and we had to walk into another room to see his colon.

WALKING

BELLMAN: Yes. So this is what we call the TIM 2 system. It has three units of colon in one cabinet.

TWILLEY: TIM has to keep his large intestine separate from his stomach and small intestine because conditions are very different. For starters, there’s no oxygen in the colon—the microbes are anaerobic.

GRABER: TIM’s colon looks pretty much like his stomach and small intestine, it’s just tubes and valves and sensors all in a glass case in a cabinet. But this one, it is inoculated with, yes, microbes.

BELLMAN: We use fecal donations. And then we… yeah, we typically donate ourselves and then we have somebody to mix it all.

TWILLEY: Yes, it’s true. If you work at TNO, you will be called upon for an annual donation of feces. These donations are all mixed together, and stored in a freezer until they’re required for digestion.

GRABER: The end result is a genuine human microbiome set up in this artificial colon, which is pretty wild. It won’t last forever, but the scientists can keep feeding the microbiome, and it’ll hang around for up to a month on the silicone sleeve.

TWILLEY: It even changes composition depending on what they feed it. Just like ours.

GRABER: If you’re wondering, as we were, what happens to the contents of TIM’s colon at this stage. Well, yes, it does basically poop and fart.

BELLMAN: We have sampling ports here connected and then we just take it out. And you can connect a syringe so that you’re not sort of directly in touch with it. It smells just like poop.

TWILLEY: So the scientists at TNO—they have to manually remove TIM’s poo, but for the gases that build up, they have an exhaust hose attached that vents everything to the outside of the building.

GRABER: A fart tube?

BELLMAN: Yeah. LAUGHS

GRABER: TIM is super impressive—you put food in, and a couple of days later, nutrients have been extracted, and there’s poop. Like in our bodies.

BELLMAN: There are other systems out of course. Groups in the UK and France are busy with it and also in Belgium. But I believe—and I’m a bit biased maybe—but TIM is still the most advanced system in this regard.

GRABER: But even so, it’s obviously simplified. Both Mans and Susann pointed out all the ways it’s not quite like us. So how closely does TIM really model our digestive system?

TWILLEY: Some of the scientists who conduct research using TIM have compared their results to what they get using humans. And they say TIM is 80 percent accurate to a real live gut. So, not perfect, but pretty good.

GRABER: But TIM takes up cabinets in huge rooms. What if we could shrink a model of our guts down to only about an inch?

DON INGBER: These are devices that are the size of a computer memory stick. They’re optically clear, they’re made out of a flexible rubber.

TWILLEY: This is Don Ingber. He’s a professor at Harvard and the founding director of the Wyss Institute for Biologically Inspired Engineering.

GRABER: Don and his team have designed what are called organs on a chip. The idea came from microchips in computers, which have these really tiny tubes, less than a millimeter wide—you can barely see them. On Don’s chips, the tubes are filled with fluid and lined with cells. The final product looks like a clear flexible plastic square with nearly invisible tiny black lines running through it.

INGBER: Well it’s in the Museum of Modern Arts permanent Design Collection. It won the international design award. So it is pretty. It sort of has a crystalline elegance to it.

TWILLEY: But like the best design, Don’s chips combine both form *and* function

INGBER: If you cut it in cross-section there are basically three parallel chambers. You could think of like the Holland Tunnel.

TWILLEY: In the middle tunnel, Don puts intestinal cells and blood vessel cells.

INGBER: And the side chambers we apply cyclic suction to. And because it’s all flexible, the sidewalls of the middle chamber with cells stretch out and relax. And we actually stretch and relax at the same rate and degree as when peristalsis goes on in your intestine.

GRABER: Here’s where things get super cool. Just that stretching and relaxing, plus the flow of nutrients through the tubes, that movement that’s the same as in our intestines, it actually makes the cells turn into a teeny tiny but super accurate model of our gut.

INGBER: If we give them the flow they spontaneously in the small intestine differentiate and form villi, which are those finger-like extensions that increase the absorptive efficiency and area. They form all the cell types in the intestine.

TWILLEY: When Don puts these basic cells in his colon on a chip, they form special colon cells—and they even put out mucus. This was really Don’s revolutionary idea: That the cells would just kind of build the model themselves, the same way they build our bodies themselves

INGBER: They know how to do it. You just have to give them the right physical microenvironment.

GRABER: The same cells Don uses in the tiny chip-sized guts, these cells had been grown on petri dishes, and they didn’t do much of anything. So Don’s colleagues in the field didn’t think they’d be much use in a chip.

INGBER: For 50 years they basically grow on a membrane or dish under static conditions as flattened cells. So what was amazing is when we put them on the chips, just with the flow and the peristalsis, they spontaneously formed villi for the first time—same culture medium that was used for 50 years.

TWILLEY: Not only did these cells form villi, but they formed functional villi. Don’s guts on chips can absorb nutrients, they can break down fiber—just like our guts.

GRABER: Don and his team can even culture entire microbiomes in these chips. They inoculate the micro tubes with patient poop, and the microbes set up shop and can survive for weeks. Just like in TIM.

TWILLEY: Also like TIM, and like our own bodies, Don’s digestive system is separated into parts: The chunks of the small intestine, the colon, etc. He hasn’t joined them up to make a complete gut yet, but he says he could, if he wanted to for an experiment.

GRABER: Right, experiments. These models are incredibly cool, both the cabinet-sized one and the thumb drive one, but why bother? What are scientists and companies using them for?

MID-ROLL

TWILLEY: When TIM was launched back in 1997, its first customers were food companies. They used TIM to look at how adding fiber to foods affected how much fat was absorbed, and how quickly. They used TIM to study how much protein our bodies could extract from certain foods.

GRABER: They set up TIM to mimic an infant’s digestive system, so that they could test which formulations would make more nutrients available to babies.

BELLMAN: We also used it for—it’s another funny example—for testing soil. So for example we had a case from the city of Rotterdam in the Netherlands where soil was contaminated with lead. And they wanted to build a playground for children. And then they were thinking if the children would just put the soil in their mouth is the lead absorbable or not. We even tested suppositories in it for the case that you unintentionally swallow it.

TWILLEY: More recently, TIM has been used mostly for testing drug formulations—so like how quickly the active ingredients in a pill are released and how much of it is available to be absorbed. Pharma companies use TIM to fine tune their drugs before clinical trials.

GRABER: But the team at TNO hasn’t given up on food. They’re testing whether the microbes in yogurt stick around and reach the large intestine, and they’re helping companies reformulate their yogurt probiotics. And they’re working with companies that want to design foods that help us feel full longer—turns out it helps if the dish is thick or highly viscous, like a thick oatmeal.

TWILLEY: As part of that experiment, they fed TIM a couple of bowls of Cheerios.

BELLMAN: So if you in the morning prepare your cereals and you put them in the milk and then you walk away, take a shower and you get back and then they they sort of soak and then you eat them soft. That makes a difference than whether you just poured the milk and the cereals and you chew them in your mouth and eat them crunchy. And then their gastric behavior is completely different.

TWILLEY: And it turned out that the softened Cheerios made TIM feel more full for longer, because they were more sludgy and viscous. And revolting. Who lets their cereal soften like this? Monsters!

GRABER: Not me. Anyway, Don and his colleagues are also working with food companies and pharmaceutical companies and even the FDA, which is using the gut on a chip instead of animals to test food and drug safety.

TWILLEY: But Don’s more focused on using his gut on a chip to study disease. That’s something TNO has done a little of, but they struggle with it. Susann said when they inoculate TIM’s colon with a diseased microbiome, it keeps reverting back to a healthy one.

GRABER: But Don can keep his guts sick if he needs to. For instance, he’s been studying irritable bowel syndrome, the microbiome of preemies, and what’s going on in the guts of kids who suffer from chronic malnutrition.

INGBER: In kids with malnutrition they get what is called blunting of the villi. These long finger-like projections flatten and they get increased barrier disruption. So things can pass across the barrier that shouldn’t do otherwise. We mimic exactly that.

TWILLEY: Obviously, having a model gut that is more accurate than an animal is great—less testing on animals, better results. But we were curious—these model guts are made by drawing on all of our knowledge about real live guts. But can they in turn teach us about the thing they’re mimicking? Can they teach us anything about ourselves?

GRABER: Don’s actually used his guts on a chip to make some surprising discoveries. He’s been able to figure out that it takes four different molecules that cause inflammation, as well as immune cells, to create the symptoms of irritable bowel syndrome. The chip wouldn’t develop IBS unless everything was in the system, playing off each other, to hurt the villi and break down the lining of the gut. That was a breakthrough in our understanding of the disease, and it could help scientists look for drug targets.

INGBER: We just learned what’s important and what’s not. That’s the power of this approach.

TWILLEY: TIM’s co-creator, Mans, made a similar point.

MINEKUS: You’re right that that you could say, “Okay, Tim is not a very good simulation,” because in vivo you have a lot of variation that you don’t have in TIM. That’s due to all the feedback mechanisms and so on, the differences between people and so on. So in the beginning we thought, “Hm, maybe that’s a limitation.” But soon we thought, “No, it’s not a limitation. It’s an advantage.”

TWILLEY: It’s precisely because TIM is simplified that researchers can use it to do experiments that help them figure out what to look for in the much more complicated and varied guts of real live people. Real people eating real food—there’s so many variables.

GRABER: For instance, if you ate a muffin, a lot of things might affect the way you digest that muffin. Whether you slept well, whether you go for a run right after you eat it, even your mood can have an impact on your digestion.

TWILLEY: Whereas TIM doesn’t bother with sleep or working out and he’s always mellow. So when he is fed a variety of muffins with, say, different crumb structures, researchers can be sure that the difference in how he digests the different muffins is due to the muffins, not TIM.

GRABER: But still, we are super complicated beings, and our guts are way more complicated than just a stretch of tubes and valves.

ENDERS: So basically what we have to recognize first is that there’s a huge collection of nerve cells in our gut. It’s the second largest after the brain. The spine is just like shortly after.

TWILLEY: In part, this huge gut brain, it exists to run the whole complex ballet we just told you about. That all happens without any input from our conscious brain.

ENDERS: Well most parts of digestion are very unconscious, right? We don’t really feel them. It starts when we swallow. There’s this little thing between our collar bones. This is the place where we stop really feeling what’s going on. Because otherwise we’d be shocked how much the stomach, for example, moves, how eagerly the small intestine gets stuff forward, and how weirdly the large intestine sometimes just holds things, like wants to hug them in a very romantic weird way.

GRABER: And what else is weird about this is that the gut brain, all those nerves, it has a direct link to the brain brain.

ENDERS: You could ask like, why should an organ like the small intestine, the large intestine, why should it be able to influence our brain, this mastery genius thing up there? But it’s very simple to answer that because the brain is so isolated. It’s in that bone cage, has a thick skin around it so it doesn’t really get what’s going on in the blood even. So it’s very safe and it’s good that it’s secured this way.

GRABER: But it means the brain is kind of out of touch.

TWILLEY: The gut, meanwhile, is actually collecting all this really important information about what’s going into our body, how much energy we have, what vitamins and nutrients we’re extracting, what hormones and immune responses are being triggered—it knows whats up.

ENDERS: And for that the gut actually I would say is probably the most important adviser to the brain.

GRABER: This is a really fascinating area of research right now. How is what we’re eating and the microbes in our guts affecting our conscious brain—our mood, our stress levels, even mental issues like depression?

ENDERS: It’s not that we’re saying oh bacteria in the gut will now change everything. You know they will make you happy or be the smartest person on earth. And that—if something like that would have been a result I would have been quite skeptical.

TWILLEY: But Giulia says that there are quite a few studies now that do show that different bacteria can affect your mood. It’s not a huge effect, but it’s not tiny either.

ENDERS: And I think interesting is also the thought that for some people it might have a far bigger role in how they’re feeling and how they’re maybe at risk for certain mental health conditions and in others it might not have such a big influence.

TWILLEY: Like everything about our gut microbiome, this is emerging science, so stay tuned.

GRABER: But the brain isn’t the only seemingly unrelated system that our guts affect—they also can affect how our immune system works, and our hormones. None of these systems are built into either TIM or Don’s gut-on-a-chip.

TWILLEY: Although Mans and Susann told us that they are building artificial intelligence that they can add onto TIM, to help simulate how all these complex bodily systems interact with our guts.

ENDERS: There are so many things like there’s immune cells, there’s bacteria, there’s so many hormones by the gastrointestinal tract. And then this huge independent nervous system. I think this is a bit intimidating because nice clean research can usually just try to look at one thing. But in this organ there’s so much intertwined.

GRABER: We have come a long long way from sticking food on a string into someone’s open stomach and watching it fall apart.

TWILLEY: But the more we look, the more there is to learn. Models like TIM and like Don’s gut on a chip—they’re amazing, but they’re still so far from the real deal. And that is because, as Giulia wishes everyone knew, guts are awesome.

TIM GURGLING SOUNDS

TWILLEY: Huge thanks this episode to the Alfred P Sloan Foundation for the Public Understanding of Science, Technology, and Economics, as well as the Burroughs Wellcome Fund for our coverage of biomedical research.

GRABER: Thanks as well to Giulia Enders and Mary Roach, we have links to their books on our website. Thanks also to Susann Bellman and Mans Minekus in the Netherlands and Don Ingber at the Wyss Institute. Again, find out more at gastropod.com

TWILLEY: Where we have some super cool video and photos of TIM in action! Thanks also to our amazing intern Emily Pontecorvo.

POST-ROLL

TWILLEY: We’ll be back—our next episode is in three weeks, because we have some breaking news we’ve got the exclusive on. Breaking news and great personal suffering. We were the subjects in a big experiment.

GRABER: Stay tuned!