Brain Balls

0:28Wait, you're listening. microscopes, computers, experiments. And off in one corner... Hello. Hi, how's it going? Wearing glasses and a white lab coat is this scientist named Dr. Madeline Lancaster. Call me Madeline. Madeline has just finished her PhD and moved to Austria, just joined the lab to start her postdoc research. So still sort of making friends. Still trying to make a good impression. Getting to know people, you know. And one of the first things her boss asked her to do was something called a screen. Just basically looking for specific genes in mouse neural stem cells. So that's like baby brain cells of mice?

1:05Yeah. Now, she hadn't done exactly this kind of gene screen before. And that's probably why I didn't really, you know, I was kind of naive about it all. Hmm. But she got to work. Preparing the baby mouse cells. The cells all become loose and apart from each other. That part she'd actually done before, so, you know, easy enough. Yeah, but... Then, something she hadn't done before, she needed to get those cells to stick flat to the glass bottom of her dish so that she could do that screen. And to do that, she needed to use special organic proteins as a glue. And I hadn't, they hadn't come in yet.

1:46I'd ordered them, but they hadn't come in yet. And instead of just, you know, waiting for them to arrive... I don't know. I was so anxious to do the experiment. She decided to improvise. And so I just kind of like rummaged through the freezer. Found a random tube of glue-like proteins. I don't know how old they were. And anyway, and I used those. Squirted it on the dishes, pipetted in the cells, popped them in the incubator, and went home for the night. Next morning. Came in. Took a look in her Petri dishes, hoping to see a nice, clean, clear layer of cells. Like flat on the dish. But instead, everything in there was...

2:22Really cloudy. Hmm. Shouldn't be cloudy. Cloudy means those cells are floating freely around in there, which means that those tubes of protein glue she used... You know, we're no good, and the cells hadn't stuck. And if the cells aren't stuck in the protein, that means they're probably dead. Yeah, all the cells are dead. I'll just throw it away. Hmm. And I don't know why I did this, but... Right before she tossed it, she thought... You know, but I'll check it. I'll just take a peek. Why not? So she slides these cloudy dishes under the microscope, peers into the eyepiece and in the circle of light, she sees these weird blobs.

3:00The cells weren't dead. They were alive and healthy and clumped into three or four blobs. Huh. Yeah, can you as vividly as you can describe them? I mean, they're like a sort of beige color, like an off-white tiny. About the size of a grain of sand. Or these floating balls of cells. And she's like, huh. Weird. So she zeroes in on one of these blobs, turns the dial on the microscope to zoom in until she's looking basically inside the blob. And that's when she sees... A tube. A tube. Yeah. So she's like looking down into like one end of the tube. So it looks... Almost like a donut shape. Had you ever seen anything like that before?

3:43No. No. Huh. Yeah. I mean, as far as she knew, if the cells weren't in that protein stuff, stuck, you know, flat to the bottom, they should sort of die and fall apart and make a big random mess. But these ones seem to be coming together to make this shape. So she gets up from the microscope and starts... Sort of going around the lab a little bit subtly at first, kind of just like, hey, has anybody ever, like, seen cells do funny things, you know, clump up together? And everybody was just sort of like, oh, well, if they're supposed to be laying flat, if they're not laying flat, you screwed it up.

4:26Like, they just weren't that interested. No. So I just kind of like put it in formaldehyde, put it away in the fridge for a little while and was like, OK. Let's try this gene screen again. But this time. No floaty clumps. Going to get those cells to stick flat on the bottle. And eventually she decides to try something new. This thing that I had read about called Matrigel. Basically, cellular crazy glue. Like, she's not taking any chances. I'm just going to put a whole bunch in my dish. So she squirts a lot of it on there. Okay. She puts her cells on top. And again. Pops them in the incubator, crosses her fingers, and goes home for the night.

5:04She comes back in the morning. Yeah, same thing. You go to the incubator. You take it out of the incubator. You look at it. And I was like, okay, this is weird. Once again. There's a bunch of stuff floating in there. Huh. I was like, okay, well, the Matri-gel didn't work like it was supposed to. Again, it seemed like the cells had started clumping together. And that's when I then took them, put them on the tissue culture microscope, looked down the eyepiece, and again... There they were. Funny-shaped balls. These ones were also beige-ish. Off-white kind of color. But they were bigger. And they sort of have, like, bulges coming off of them.

5:42And this time, when she looked inside, she saw full-on... Architecture. There was a tube, but also... A little circle, sort of oblong-shaped thing. And a fat layer of tightly packed cells... All lined up around a space in the middle. They were making structures, they were making things. Kind of like what cells do as an embryo is developing, which to Madeline didn't make any sense. Everybody had always taught me that cells need things coming from other tissues in the body, you know, of the embryo that are necessary for building that embryo. And here was a situation where nothing was telling them what to do because they'd been completely taken out of the embryo.

6:27And they were like forming structures with no instructions. She's like, oh my God, like this is like, there are things developing here. But toward what? What? Well, to Madeline, it kind of looked like... They were building a brain. So these are neural stem cells, which inside a developing mouse... Starts out as a sheet of cells, and then they fold up and close and form a tube. And then the neural tube elongates, and that becomes the spinal cord. One end of it balloons out, and that becomes the brain. And that's what it looked like the cells in Madeline's dish were doing. it seemed like these cells on their own were starting to try to make themselves into a mouse brain.

7:19At the time, yeah, at the time, I was just kind of confused. So she showed some other people around the lab what she'd seen. I showed some of these structures. Tubes, the circles, the lines, but... Several people in the lab were just kind of, I think they were just totally bored. They were like, I don't know, sometimes things just grow weird. You probably just did the gel wrong. And the director of the lab, her boss, was like, I thought you were going to do a screen. You know, make a flat dish of cells to screen for genes. What are you doing? And I was like, don't worry, I'm working on it. And so over the next few months, Madeline focused on getting a nice flat layer of mouse neural stem cells on the bottom of her Petri dishes so she could do those screens.

8:03And so that was like mostly what I was talking about with people in the lab. Yeah. But at the same time. Off by herself in her little corner when no one was paying attention. I was always still playing around with Matrigel, growing these weird balls of cells. Tweaking the recipe. Trying to make sure I could get it to happen reproducibly. And then one day, she gets her hands on some human stem cells. Cells that come from skin or blood that you can reprogram to an embryonic state. Where do you get those from? I think these were actually made from discarded human foreskin. Wow. So specific. Okay.

8:43What a detail. All right. Thank you for that. Because it's just a bit of tissue that's thrown away. Yeah. Right. Of course. Of course. Literally thrown away. All right. Okay. So, wow. Yeah. So anyway, so then... So she got these human stem cells. She put them in the matrigel, swirled them around in this nutrient-rich fluid so they could kind of eat. and she would watch as these formerly foreskin cells started forming into clumpy parts of a human brain. Oh my God. And then she kept tweaking when and how much of the matrigel she would add and she would just watch these blob shapes over time get bigger.

9:21I mean, they can get as big as like a pencil eraser. Side note, at the time, she was pregnant. Yeah, my oldest, I was pregnant with her. So she said she had this extra maternal instinct and she was like just really nurturing these little brain balls. Yeah. And then one day, a couple months after, she's been tweaking her ball recipe. And I looked under the microscope. Inside. Yeah. On this beige lump, she could see a perfect ring of black pigment. And that was just, I looked at that. I was like, that's a developing eye. Shut up. And it was growing on a developing human brain. You're like, no, what?

10:05Yeah. No, you, what? And then, then. That was then when she went to her weekly lab meeting. I presented this data. I showed this picture of this beginning of an eye. And I remember hearing audible gasps. And then she showed them pictures of the cells forming tubes and lobes and. Ventricles, like an actual brain. Everybody in the lab started to get it. They were like, hey, wait a second. It's like you have a version of an early human brain in this dish and you can actually watch the earliest stages of this process of development. That we know almost nothing about. Is that true, though? Do we not know anything about early human brain development?

10:49I just think you get all these little. Like when you're pregnant, you get a scan here, a scan there. Maybe we know something from animal models. But this was literally the first time anyone in human history had ever watched the early brain develop right from the beginning like this. Yeah. Which is especially important when something in the brain has gone wrong. Now we can actually watch this process instead of just looking at the end when the person is already severely suffering. We can try to understand how it got there. So Madeline and her boss, Juergen Knoblik, who's on board with the whole project now, in 2013, they team up with a bunch of other researchers and publish a paper in the journal Nature.

11:31In that paper, they describe how this disorder microcephaly develops in a fetal brain. And they were like, oh, and to see all of this, we use these tiny 3D brain balls, which we have decided to call cerebral organoids. That's when, like, everything changed. If you were studying human brain development, it was like someone just invented the microscope. Yes. You can see things that were invisible before. So this is Carl Zimmer, science journalist, New York Times columnist, book writer. Ah, you got Zimmer. Yeah. As soon as I heard about this stuff, of course, he's my first phone call. And he was all over it.

12:09Sort of like humanoid, organoid. Very sci-fi. And the first thing that he pointed out is that there are so many neurological disorders where... where the key moments are during development. It's like the key plot points are happening when we can't watch the movie. Right. Totally off limits. But 2013, Madeline and Juergen published their paper, and boom. We could watch human progenitor brain cells give rise to parts of the brain. What would you do with that? Like, what would you see? So one example is a, there's a scientist at Stanford, Sergio Opasca, and he studied a very rare disease called Timothy syndrome, which is caused by a mutation that produces autistic behavior.

12:53As well as a bunch of other things like seizures. And he basically created an organoid with that mutation so that he could see how a brain with Timothy syndrome develops, like from the beginning. Yeah. Now you can actually see what Timothy syndrome is about. So what did he see? So there are certain kinds of cells called interneurons, and they make very important connections between different parts of the brain. And with kids with Timothy syndrome, they just don't. They just fail to get where they need to go. And now that he knew what was going wrong... He started testing out some drugs to see if he could fix that.

13:33Yeah. And he and his colleagues actually ended up finding a small drug that actually did help these neurons to find their way in an organoid. So he cured it in an organoid. Right. Huh. And they are on track to actually start clinical trials with that drug next year. Wow. And you could imagine that's one disorder. That's right. A lot of other conditions. epilepsy, schizophrenia, autism. Any of these brain conditions that have an issue starting in development or where we might even suspect they might start that early but aren't sure yet, now you can see it. A lot of people in the field said, whoa, I got to try this.

14:20This whole field of neural organoids has just totally exploded. I think there's thousands of labs actually using these tools now. The study of the brain is fundamentally different now. So that's what we are doing on Radiolab today. We are just, Lulu, we're going to jump into the ball pit of brain balls. Okay. In which there are tons of new opportunities, but also confounding questions. Are there thoughts in there? Is there thinking in there? How brainy are these balls? We are going to get there after the break.

15:18All right, here we are. I'm in the 72nd Street subway station, and I am walking to go see a fridge full of brains. Hey, I'm Latif Nasser. I'm Lulu Miller. This is Radiolab. More specifically, a fridge full of brain organoids. Just before the break, we learned from Madeline that now thousands of labs around the world are growing these brain organoids. And it turns out that one of them happens to be just up the street from our studio in New York City. Only when you're recording are you truly conscious of, like, how much you breathe. So we sent our producer, Mona McGaulker. Laboratory, caution, hazardous materials.

15:56To check them out. Where are we entering? So we're entering, so we have special rooms called cell culture rooms where we grow, oops, we grow the organoids. This is Dr. Howard Fine. I'm a medical and neuro-oncologist. And this is his lab at the Weill Cornell Medical Center where he studies brain cancer. The type of brain tumor known as a glioblastoma. A very bad kind. Probably now the most lethal of all human cancers. The average survival is about 15 or 16 months. And Dr. Fine says around 15 years ago or so, he hit a wall in his research. We've probably made the least amount of progress with. So he'd been studying glioblastoma, mostly, of course, in mice.

16:37Right. And he admits he actually calls this at the time it was the dirty little secret of oncology that for all this research, they were basically getting nowhere. Whoa. But then, you know, he came across Madeline's work on organoids. And it was Lancaster's paper. I read in Nature, and it's like, literally, not many times in my 37 career, did I truly have a light bulb moment? And I read that paper and said, this is what we're looking for. And that's when he pivoted away from mice and started making brain organoids. Can we see them? We can take a look. Okay, so he's opening the incubator, and he's pulling out.

17:16These are the stem cells. And they looked just like Madeline described. They're kind of like a beige color. They look like a kidney bean or like a nerd candy. Little beige balls floating in liquid, and it is. And under the microscope... I see like a dark shape, and then I see these little bubbles off the side, almost like little popcorn-y shapes. You can see structure. Dr. Reinhard, these are from specific patients, like your patients? Yes. But the difference between these organoids and Madeline's organoids was that these ones had cancer. So the idea is we're going to make a mini brain from an individual patient.

17:54And then... Oh, these are the glioma cells. Wow. They take cells from that patient's brain tumor. Almost just looks like sugar that hasn't dissolved in tea. And then we retroengineer the patient's own glioma stem cells into the mini brain. Basically, they can put a version of your brain tumor on your... A version of your brain. on a version of your brain, and they can basically make a bunch of those. We can test hundreds or thousands of drugs. And then try a bunch of medicines on them. To look for the drugs or combination of drugs that might be most effective. So you're saying that, like, you can try every chemotherapy that's out there and decide, like, which one?

18:32Everything, only limited by resources, as you could imagine. Oh, my God. That is beautiful. I mean, that just thinking about a way of like a kind of bespoke medical future exploration. Right. Way better than just using mice. Oh, my gosh. Partly because it also could help us leapfrog one of the biggest reasons on average 90 percent of clinical trials for neurological drugs fail. And for brain cancer, by the way, that number is even higher, 95 percent. They're failing because they're not predicting whether the drug actually works on the disease. And this is something that Madeline told me, too. You might have a drug that works really well for treating mouse spinal cord injury.

19:21Like it's like, OK, great. This is not going to kill you. Because you've got the animal work to show you that it's safe. But it also doesn't make them better after the spinal cord injury. But now, sure, they can do a mouse trial for safety. But they can also test that drug to see if it works on a spinal cord organoid, which is, you know, just a tiny version of an actual human spinal cord. Wait, what? I thought we were talking brain organoids. Are there spinal cord organoids? Spinal cord organoids? Yeah. Okay, so as Madeline was developing her brain organoids, independently, around the same time, other scientists all over the world are growing...

20:03Intestinal organoids. Lung organoids. Liver organoids. Muscle organoids. Skin organoids. Pancreas organoids. Stomach organoids. Heart organoids. Kidney organoids. Breast tissue organoids that actually produce milk. Ah. They can have a breast tissue organoid that can make milk? Yes. Weird. Has anyone tasted that milk? I certainly haven't. I've only read about it. I don't know. I don't know. That's a good question. Anyway. That's science writer Carl Zimmer again. And he says now you can make an organoid of basically any part of the body. And then you can connect them. What? You can, like, you can...

20:43Does that work? You can do that? Oh, yeah. They call them assembloids. Assembloids. Yeah. No. Oh, like you can Mr. Potato Head assemble? Correct. But then do they attach to each other? They attach to each other, yeah. And do they communicate with each other? They communicate with each other, yeah. Okay, and then do what? With your charm bracelet human body? So here's an example. So Sergio Pasca, neuroscientist at Stanford University, and his colleagues thought, can we use an assembloid to study pain? The pathway of pain. so they started with the finger a finger organoid no no no sorry just a nerve in the finger okay the sensory organoid connect that like with some other cells in the dish another organoid the spinal cord yeah it's a little teeny piece of spinal cord now we're going to connect that to a brain organoid that is specifically the thalamus which is the central hub in the brain that directs signals in all sorts of different ways and finally we're going to connect that one to one more brain organoid.

21:47A cortex organoid. Whoa. This is so weird. I mean, it's like Legos. It's like Legos. With the human body. Correct. So then they took capsaicin. That's the molecule in... In like spicy food, is that right? In spicy food, in chili peppers. Yeah. It can be very painful to the skin. Okay. And they said, okay, let's hit it with capsaicin and see what happens. Uh-huh. Boom. Immediately, that sensory organoid goes... Right. And starts sending really strong signals. And those signals, Carl says, zoom right up through this assembloid. To the spinal cord, the thalamus, to the cortex. Just like it would in your own body.

22:25And they can see some kind of registering? Correct. And when they watch the way the signal travels, which is something that's normally hidden inside a body. They've discovered all sorts of things about what happens when we feel pain that they didn't know about before. Like, for example, signals from different parts of the assembloid began firing together in these synchronized waves of signals. Okay. And the more you know about how those signals work or move, the better chance you have at stopping them. You could, for example, say, okay, can I put a molecule into this assembloid that will stop the pain?

22:59Oh, wow. But, um, so if they're using these things to study pain, is it feeling pain? No, probably not. These organoids are just little bits of human tissue. In order to feel pain the way we feel pain, there are other parts of the brain that come into play. The assembloid is just this super basic circuit that you send a signal through. So, like, this pain, it seems to be superficially registering it. And, like, what is the it, I think? The capsaicin in that case. No, no, no. I'm the first it. Oh, the first it. It's like it is this little ball, but is the it a thing? Like, what is it? Well, they crackle with electricity.

23:45They form connections called synapses. They replicate parts of the human brain with astonishing accuracy. But Carl says... They're not brains. They're not brains. That's right. If there's like a slider and on one end is brains and then on the other end is just like some neurons in a dish, where is this on the slider and how do you... I would say that it's closer still for the time being to the neuron end of the slider, simply based on numbers. Our brain has something like 80 billion neurons. And the biggest human brain organoids contain about 2 million cells. That's 0.0025%. Well under 1%, yeah.

24:35And, you know, these things don't have blood vessels. So that is a very important key limiting factor to how big and complex it can get. And they're not in a body. So they can't interact with the world in like a meaningful way. Okay. Well. But when I was talking to Carl about this. So. He said that a lot of that might no longer be true. Some scientists have, you know, taken organoids from human cells and have put them into the brains of rats. What? So basically what they did is they basically took a rat and they like carved out a chunk of its brain. But they left some of it? They left most of it.

25:18And it's almost like, think about it, it's almost like they gave a rat a little human tumor or something. Yes, but the tumor is like just human brain. It's human brain. It's human brain. And these human organides are pretty happy in there. It's sort of wired in. They connect up with the rat neurons. They get supplied by the rat blood system. So they have made, in a real sense, like a new kind of being. Yeah, yeah, yeah. That did not exist before this. Correct. Okay. Feels like there should have been a bigger press release. But okay, do the rats act any differently? Are they suddenly like into podcasts and coffee?

26:01When you do studies on these rats, behavioral tests, memory tests, all sorts of things, they're just rats. There seems to be nothing human-y about them. Okay. But one thing they did notice, when you tickle its whiskers. Yeah. You can actually measure signals from the human brain organoid neurons. The human part of the brain lights up. What? Yeah. So it's registering the feeling. They are receiving signals from the rats senses. I mean, strictly speaking, they are receiving signals from the rats senses. Are they feeling it? Feeling it gets hard because it's kind of the pain question again. But yeah, but now they're in a body.

26:52I mean, they're in a being. Yes, but they're not the like driving force of that being. They're like a house guest in the attic. Okay, Latif, would you make a brain organoid of your brain cell and put it in a rat?

27:11If I'm being honest, probably not. Probably not. Okay, so I don't know, but I just think you're more on my side that this is a little scary than you in your little with your reporter's wand are letting on to because, yes, there's exciting research. But it just feels like every time you try to comfort me with what we know about these things, you then end up not comforting me. And then the scientists take it one step further anyway. OK, well, it's it's as if you have seen the future and what the next chapter holds, because that exact thing is going to happen. It's going to get weirder and creepier and stranger.

27:51And that's all after the break. Stick with us.