[RADIOLAB INTRO]

LATIF NASSER: Okay, Lulu?

LULU MILLER: Yeah.

LATIF: We're gonna start today back in 2010 in a lab in Vienna.

LULU: Oh! Jumping right in.

LATIF: Yeah. Just picture sort of a lab with microscopes, computers, experiments. And off in one corner ...

MADELINE LANCASTER: Hello.

LATIF: Hi! How's it going? Okay ...

LATIF: ... wearing glasses and a white lab coat is this scientist named Dr. Madeline Lancaster.

MADELINE LANCASTER: Call me Madeline.

LATIF: Madeline has just finished her PhD and moved to Austria, just joined the lab to start her postdoc research.

MADELINE LANCASTER: I was still sort of making friends.

LATIF: Still trying to make a good impression.

MADELINE LANCASTER: Getting to know people, you know?

LATIF: 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.

LULU: So that's like baby brain cells of mice?

LATIF: Yeah. Now she hadn't done exactly this kind of gene screen before.

MADELINE LANCASTER: And that's probably why I didn't really—you know, I was kind of naïve about it all.

LULU: Hmm!

LATIF: But ...

MADELINE LANCASTER: So anyway ...

LATIF: She got to work.

MADELINE LANCASTER: You put this enzyme on. It just cuts those proteins ...

LATIF: Preparing the baby mouse cells.

MADELINE LANCASTER: The cells all become loose and apart from each other.

LATIF: Ah!

LATIF: That part she'd actually done before so, you know, easy enough.

MADELINE LANCASTER: Yeah. But ...

LATIF: 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.

MADELINE LANCASTER: And I hadn't—they hadn't come in yet. I'd ordered them but they hadn't come in yet.

LATIF: And instead of just, you know, waiting for them to arrive ...

MADELINE LANCASTER: I don't know. I was so anxious to do the experiment.

LATIF: ... she decided to improvise.

MADELINE LANCASTER: And so I just kind of like rummaged through the freezer.

LATIF: Found a random tube of glue-like proteins.

MADELINE LANCASTER: I don't know how old they were.

LATIF: [laughs]

MADELINE LANCASTER: And anyway, and I used those.

LATIF: Squirted it on the dishes, pipetted in the cells, popped them in the incubator and went home for the night. Next morning ...

MADELINE LANCASTER: Came in.

LATIF: Took a look in her Petri dishes, hoping to see a nice clean, clear layer of cells.

MADELINE LANCASTER: Like, flat on the dish.

LATIF: But instead, everything in there was ...

MADELINE LANCASTER: Really cloudy.

LATIF: Hmm.

MADELINE LANCASTER: It shouldn't be cloudy.

LATIF: Cloudy means those cells are floating freely around in there, which means that those tubes of protein glue she used ...

MADELINE LANCASTER: You know, were no good. And the cells hadn't stuck.

LATIF: And if the cells aren't stuck in the protein, that means they're probably dead.

MADELINE LANCASTER: Yeah. All the cells are dead. I'll just throw it away.

LULU: Hmm.

MADELINE LANCASTER: And I don't know why I did this, but ...

LATIF: Right before she tossed it, she thought ...

MADELINE LANCASTER: You know, but I'll check it.

LATIF: ... "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 ...

MADELINE LANCASTER: These weird blobs.

LATIF: The cells weren't dead. They were ...

MADELINE LANCASTER: Alive and healthy and ...

LATIF: Clumped into three or four blobs.

LULU: Hmm!

LATIF: What did they—yeah, can you as vividly as you can describe them?

MADELINE LANCASTER: I mean, they're like a sort of beige color, like an off-white. Tiny.

LATIF: About the size of a grain of sand.

MADELINE LANCASTER: These floating balls of cells.

LATIF: And she's like, "Huh!"

MADELINE LANCASTER: Weird!

LATIF: 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 ...

MADELINE LANCASTER: A tube.

LULU: A tube?

LATIF: Yeah. So she's, like, looking down into, like, one end of the tube. So it looks ...

MADELINE LANCASTER: Almost like a doughnut shape.

LATIF: Had you ever seen anything like that before?

MADELINE LANCASTER: No.

LATIF: No.

LULU: Huh!

LATIF: 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 seemed to be coming together to make this shape. So she gets up from the microscope and starts ...

MADELINE LANCASTER: Sort of running 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 ..."

LATIF: Huh!

MADELINE LANCASTER: "... like, clump up together?"

LATIF: [laughs]

LATIF: And everybody was just sort of like, "Oh. Well if—if they're—they're supposed to be laying flat. If they're not laying flat, you screwed it up." Like, they just weren't that interested.

MADELINE LANCASTER: No.

LATIF: So ...

MADELINE LANCASTER: I just kind of like put it in formaldehyde, put it away in the fridge for a little while. And was like, "Okay …"

LATIF: "Let's try this gene screen again."

MADELINE LANCASTER: But this time ...

LATIF: No floaty clumps. Gonna get those cells to stick flat on the bottom. And eventually she decides try something new.

MADELINE LANCASTER: This thing I had read about called Matrigel.

LATIF: Basically cellular crazy glue. Like, she's not taking any chances.

MADELINE LANCASTER: I'm just gonna put a whole bunch in my dish.

LATIF: So she squirts a lot of it on there.

LULU: [laughs] Okay.

LATIF: She puts her cells on top.

MADELINE LANCASTER: And again ...

LATIF: Pops them in the incubator, crosses her fingers, and goes home for the night. She comes back in the morning ...

MADELINE LANCASTER: 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."

LATIF: Once again ...

MADELINE LANCASTER: There's a bunch of stuff floating in there.

LULU: Huh!

MADELINE LANCASTER: I was like, okay, well the Matrigel didn't work like it was supposed to.

LATIF: Again, it seemed like the cells had started clumping together.

MADELINE LANCASTER: And that's when I then took them, put them on the tissue culture microscope, looked down the eyepiece. And again ...

LATIF: There they were.

MADELINE LANCASTER: Funny-shaped balls.

LATIF: These ones were also beige-ish.

MADELINE LANCASTER: Off-white kind of color.

LATIF: But they were bigger.

MADELINE LANCASTER: And they sort of have, like, bulges coming off of them.

LATIF: And this time when she looked inside, she saw full-on ...

MADELINE LANCASTER: Architecture.

LULU: [laughs]

LATIF: There was a tube, but also ...

MADELINE LANCASTER: A little circle sort of oblong-shaped thing.

LATIF: And a fat layer of tightly packed cells ...

MADELINE LANCASTER: All lined up around a space in the middle. They were making structures, they were making things.

LATIF: Kind of like what cells do as an embryo is developing, which to Madeline didn't make any sense.

MADELINE LANCASTER: 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.

LATIF: Hmm!

MADELINE LANCASTER: And they were, like, forming structures with no instructions.

LATIF: She's like, "Oh my God! Like, this is—there are things developing here."

LULU: But toward what?

LATIF: Well to Madeline, it kind of looked like ...

MADELINE LANCASTER: They were building a brain.

LULU: [laughs] Wait!

LATIF: So these are—these are neural stem cells. So these are stem cells, which inside of a developing mouse ...

MADELINE LANCASTER: 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 a spinal cord. One end of it balloons out, and that becomes the brain.

LATIF: 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.

MADELINE LANCASTER: At the time—yeah, at the time, I was—I was just kind of confused.

LATIF: So she showed some other people around the lab what she'd seen.

MADELINE LANCASTER: I showed some of these structures.

LATIF: The tubes, the circles, the lines. But ...

MADELINE LANCASTER: Several people in the lab were just kind of—I think they were just totally bored.

LATIF: 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 ...

MADELINE LANCASTER: "I thought you were gonna do a screen?"

LATIF: You know, make a flat dish of cells to screen for genes?

MADELINE LANCASTER: "What are you doing?" And I was like, "Don't worry. I'm working on it."

LATIF: Hmm.

LATIF: 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.

MADELINE LANCASTER: And so that was, like, mostly what I was talking about with people in the lab.

LATIF: Yeah.

MADELINE LANCASTER: But at the same time ...

LATIF: Off by herself in her little corner when no one was paying attention ...

MADELINE LANCASTER: I was always still playing around with Matrigel, growing these weird balls of cells.

LATIF: Tweaking the recipe.

MADELINE LANCASTER: Trying to make sure I could get it to happen reproducibly.

LATIF: And then one day she gets her hands on some human stem cells.

MADELINE LANCASTER: Cells that come from skin or blood that you can reprogram to an embryonic state.

LATIF: Where do you get those from?

MADELINE LANCASTER: I think these were actually made from discarded human foreskin.

LATIF: Wow! So specific! Okay, what a detail! All right.

MADELINE LANCASTER: [laughs]

LATIF: Thank you for that.

MADELINE LANCASTER: Because it's just a bit of tissue that's thrown away.

LATIF: Yeah. Right, of course. Of course, literally thrown away. All right. Okay, so—wow!

MADELINE LANCASTER: Yeah. So anyway, so then ...

LATIF: 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 clump-y parts of a human brain.

LULU: [laughs] Oh my God!

LATIF: 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.

MADELINE LANCASTER: I mean, they can get as big as, like, a pencil eraser.

LATIF: Side note: at the time she was pregnant.

MADELINE LANCASTER: Yeah, my oldest. I was pregnant with her.

LATIF: So she said she had this extra maternal instinct, that she was, like, just really nurturing these little brain balls.

LULU: Yeah.

LATIF: And then one day, couple months after she's been tweaking her ball recipe ...

MADELINE LANCASTER: And I looked under the microscope.

LATIF: Inside ...

LULU: Yeah?

LATIF: ... on this beige lump, she could see a perfect ring of black pigment.

MADELINE LANCASTER: And that was just—I looked at that. I was like, "That's a developing eye."

LULU: Shut up!

LATIF: And it was growing on a developing human brain.

LULU: You're ly—no, what?

LATIF: Yeah.

LULU: No, you—what?

MADELINE LANCASTER: And then—then ...

LATIF: That was then when she went to her weekly lab meeting.

MADELINE LANCASTER: I presented this data. I showed this picture of this beginning of an eye. And I remember hearing audible gasps.

LATIF: And then she showed them pictures of the cells forming tubes and lobes and ...

MADELINE LANCASTER: Ventricles, like an actual brain.

LATIF: 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."

MADELINE LANCASTER: That we know almost nothing about.

LULU: Is that true, though? Do we not know anything about early human brain development? I just think you get all these little ...

LATIF: Like, when you're pregnant you get a scan here, a scan there.

LULU: Yeah.

LATIF: 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.

LULU: Yeah.

LATIF: Which is especially important when something in the brain has gone wrong.

MADELINE LANCASTER: 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.

LATIF: So Madeline and her boss, Jürgen Knoblich—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. In 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 used these tiny 3D brain balls which we have decided to call "cerebral organoids."

MADELINE LANCASTER: That's when, like, everything changed.

LATIF: If you were studying human brain development, it was like someone had just invented the microscope.

CARL ZIMMER: Yes, you can see things that were invisible before. I don't know ...

LATIF: So this is Carl Zimmer, science journalist, New York Times columnist, book writer.

LULU: Oh, you got Zimmer!

LATIF: Yeah. As soon as I heard about this stuff, of course he's my first phone call. And he was all over it.

CARL ZIMMER: Sort of like humanoid, organoid. Very sci-fi.

LATIF: And the first thing that he pointed out is that there are so many neurological disorders where ...

CARL ZIMMER: The key moments are during development.

LATIF: It's like the key plot points are happening when we can't watch the movie.

CARL ZIMMER: Right. Totally off limits. But 2013 ...

LATIF: Madeline and Jürgen publish their paper, and ...

CARL ZIMMER: Boom! We could watch human progenitor brain cells give rise to parts of the brain.

LATIF: But what would you do with that? Like, what would you see?

CARL ZIMMER: So one example is a—there's a scientist at Stanford named Sergiu Pasca, and he studied a very rare disease called Timothy syndrome.

LATIF: It's caused by a genetic mutation that causes severe neurodevelopmental problems. 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.

CARL ZIMMER: Yeah. Now you can actually see what Timothy syndrome is about.

LATIF: So—and what did he see?

CARL ZIMMER: 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.

LATIF: And now that he knew what was going wrong ...

CARL ZIMMER: He started testing out some drugs to see if he could fix that.

LATIF: Yeah.

CARL ZIMMER: And he and his colleagues actually ended up finding a small drug that actually did help these neurons to find their way.

LATIF: Ah!

CARL ZIMMER: In an organoid.

LATIF: Oh, so he cured it in an organoid.

CARL ZIMMER: Right.

LATIF: Huh!

CARL ZIMMER: And they are on track to actually start clinical trials with that drug next year.

LULU: Wow! And you could imagine that's one disorder.

LATIF: That's right.

CARL ZIMMER: A lot of other conditions ...

LATIF: Epilepsy.

CARL ZIMMER: Schizophrenia.

LATIF: Fetal alcohol syndrome. 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.

CARL ZIMMER: A lot of people in the field said, "Whoa, I gotta try this!"

MADELINE LANCASTER: This whole field of neural organoids has just totally exploded. There's—I think there's thousands of labs actually using these tools now.

CARL ZIMMER: The study of the brain is—is fundamentally different now.

LATIF: That's what we are doing on Radiolab today. We are just—Lulu, we're gonna jump into the ball pit of brain balls.

LULU: [laughs] Okay.

LATIF: In which there are tons of new opportunities, but also confounding questions.

LULU: Are there thoughts in there? Is there thinking in there? How brainy are these balls?

LATIF: We are gonna get there after the break.

MONA MADGAVKAR: All right. Here we are. I'm in the 72nd Street subway station, and I am walking to go see a fridge full of brain.

LATIF: Hey, I'm Latif Nasser.

LULU: I'm Lulu Miller. This is Radiolab.

MONA: More specifically, a fridge full of brain organoids.

LATIF: 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.

MONA: Only when you're recording are you truly conscious of, like, how much you breathe.

LATIF: So we sent our producer Mona Madgavkar ...

MONA: Ooh, "Laboratory. Caution: hazardous materials."

LATIF: ... to check them out.

MONA: Where are we entering?

HOWARD FINE: So we are entering—so we have special rooms called "cell culture rooms" where we grow—oops! We grow the organoids.

LATIF: This is Dr. Howard Fine.

HOWARD FINE: I'm a medical and neuro-oncologist.

LATIF: And this is his lab at the Weill Cornell Medical Center where he studies brain cancer.

HOWARD FINE: The type of brain tumor known as a glioblastoma.

LATIF: A very bad kind.

HOWARD FINE: Probably now the most lethal of all human cancers. The average survival is about 15 or 16 months.

LATIF: And Dr. Fine says around 15 years ago or so, he hit a wall in his research.

HOWARD FINE: ... disease, we'd probably made the least amount of progress with ...

LATIF: So he'd been studying glioblastoma, mostly of course in mice, right?

LULU: Mm-hmm.

LATIF: 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.

LULU: Whoa!

LATIF: But then ...

HOWARD FINE: You know ...

LATIF: ... he came across Madeline's work on organoids.

HOWARD FINE: ... it was Lancaster's paper. I read it in Nature, and it's like—literally, it's not many times, you know, 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."

LATIF: And that's when he pivoted away from mice and started making brain organoids.

MONA: Can we see them?

HOWARD FINE: Oh, we can take a look.

MONA: Okay, so he's opening the incubator and he's pulling out ...

RESEARCHER: So these are the stem cells ...

LATIF: And they looked just like Madeline described.

MONA: They're kind of like a beige color. They look like a kidney bean or like a Nerd candy.

LATIF: Little beige balls floating in liquid in a dish.

RESEARCHER: They're surrounded by a micro-shell.

LATIF: And under the microscope ...

MONA: I see, like, a dark shape and then I see these little bubbles off the side, almost like little popcorn-y shapes.

LATIF: ... you could see structure.

MONA: And these—Dr. Fine, these are from specific patients? Like, your patients?

HOWARD FINE: Yes.

LATIF: The difference between these organoids and Madeline's organoids was that these ones had cancer.

HOWARD FINE: And so the idea is we're going to make a mini-brain from an individual patient.

LATIF: And then ...

MONA: Oh, these are the glioma cells. Wow!

LATIF: ... they take cells from that patient's brain tumor ...

MONA: Almost just looks like sugar that hasn't dissolved in tea.

HOWARD FINE: Yeah. Yeah, yeah. And then we retro-engineer the patient's own glioma stem cells into the mini-brain.

LATIF: Basically, they can put a version of your brain tumor on your ...

LULU: A version of your brain.

LATIF: On a version of your brain. And they can basically make a bunch of those.

HOWARD FINE: We can test hundreds or thousands of drugs.

LATIF: And then try a bunch of medicines on them.

HOWARD FINE: To look for the drugs or combination of drugs that might be most effective.

MONA: So you're saying that, like, you can try every chemotherapy that's out there and decide, like, which one.

HOWARD FINE: Every—only limited by resources. As you can imagine, these are ...

LULU: Oh my God! That is—that is beautiful. I mean, that, just thinking about a way of, like, a kind of bespoke medical future exploration. Ahh!

LATIF: Right? Way better than just using mice.

LULU: Oh my gosh!

LATIF: 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's even higher—95 percent.

MADELINE LANCASTER: They're failing because they're not predicting whether the drug actually works on the disease.

LATIF: And this is something that Madeline told me, too.

MADELINE LANCASTER: You might have a drug that works really well for treating mouse spinal cord injury.

LATIF: Like, it's like, okay great! This is not gonna kill you ...

MADELINE LANCASTER: 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.

LATIF: 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.

LULU: Wait, what? I thought we were talking brain organoids. Are there spinal cord organoids? Spinal cord organoids?

LATIF: Yeah. Okay, so as Madeline was developing her brain organoids, independently around the same time, other scientists all over the world are growing ...

CARL ZIMMER: Intestinal organoids.

LATIF: Lung organoids.

CARL ZIMMER: Liver organoids.

LATIF: Muscle organoids. Skin organoids.

CARL ZIMMER: Pancreas organoids. A stomach organoid.

LATIF: Heart organoids. Kidney organoids.

CARL ZIMMER: Breast tissue organoids that actually produce milk.

LATIF: Huh! They can have a breast tissue organoid that can make milk?

CARL ZIMMER: Yes.

LATIF: Weird! Has anyone tasted that milk?

CARL ZIMMER: [laughs] I certainly haven't. I've only read about it. I don't know. That's a good question.

LATIF: [laughs]

CARL ZIMMER: Anyway ...

LATIF: That's science writer Carl Zimmer again. And he says now you can make an organoid of basically any part of the body.

CARL ZIMMER: And then you can connect them.

LATIF: What? You can, like—you can—does that work? You can do that?

CARL ZIMMER: Oh, yeah. They call them "assembloids."

LATIF: Assembloids!

CARL ZIMMER: Yeah.

LULU: No! Like, you can Mr. Potato Head assemble ...

LATIF: Correct.

LULU: But then do they attach to each other?

LATIF: They attach to each other, yeah.

LULU: And do they communicate with each other?

LATIF: They communicate with each other, yeah.

LULU: Okay. And then what—do what with your charm bracelet human body?

CARL ZIMMER: So here's an example. So Sergiu Pasca ...

LATIF: Neuroscientist at Stanford University.

CARL ZIMMER: ... and his colleagues ...

LATIF: Thought, can we use an assembloid to study pain?

CARL ZIMMER: The pathway of pain. So they started with ...

LATIF: The finger.

LULU: A finger organoid?

LATIF: No, sorry. Just a nerve in the finger.

LULU: [laughs] Oh, okay.

CARL ZIMMER: A sensory organoid. Connect that ...

LATIF: Like, with some other cells in a dish.

CARL ZIMMER: ... to another organoid, the spinal cord.

LATIF: Just a little, teeny piece of spinal cord.

CARL ZIMMER: Now we're gonna connect that ...

LATIF: To a brain organoid that is specifically ...

CARL ZIMMER: A thalamus, which is the central hub in the brain that directs signals in all sorts of different ways.

LATIF: And finally ...

CARL ZIMMER: We're gonna connect that one ...

LATIF: To one more brain organoid.

CARL ZIMMER: A cortex organoid.

LULU: Whoa, this is so weird! I mean, it's like Legos.

LATIF: It's like Legos.

LULU: With the human body.

LATIF: Correct.

CARL ZIMMER: So then they took capsaicin. That's the molecule in ...

LATIF: In, like, spicy food? Is that right?

CARL ZIMMER: In spicy food, in chili peppers. Yeah. It can be very painful to the skin.

LATIF: Okay.

CARL ZIMMER: And they said, "Okay, let's hit it with capsaicin and see what happens."

LATIF: Uh-huh?

CARL ZIMMER: Boom! Immediately, that sensory organoid goes—bzzt!

LATIF: Right.

CARL ZIMMER: And starts sending really strong signals.

LATIF: And those signals, Carl says, zoom right up through this assembloid ...

CARL ZIMMER: To the spinal cord, the thalamus to the cortex.

LATIF: Just like it would in your own body.

LULU: And they can see some kind of registering?

LATIF: Correct. And when they watched the way the signal travels, which is something that's normally hidden inside a body ...

CARL ZIMMER: They've discovered all sorts of things about what happens when we feel pain that they didn't know about before.

LATIF: Like, for example, signals from different parts of the assembloid began firing together in these synchronized waves of signals.

LULU: Okay?

LATIF: And the more you know about how those signals work or move, the better chance you have at stopping them.

CARL ZIMMER: You could, for example, say, "Okay. Can I put a molecule into this assembloid that will stop the pain?"

LATIF: Oh, wow!

CARL ZIMMER: In signals.

LULU: But so if they're using these things to study pain, is it feeling pain?

LATIF: No. Probably not.

CARL ZIMMER: 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.

LATIF: The assemboid is just this super basic circuit that you send a signal through. So, like, this pain, it seems to be so superficially registering it. But ...

LULU: And, like, what is "it," I think?

LATIF: The capsaicin in that case.

LULU: No, no, no. I'm—the first thing.

LATIF: The first thing.

LULU: It. It's like, it is this little ball, but is it a thing? Like, what is it?

CARL ZIMMER: Well, they crackle with electricity. They form connections called synapses. They replicate parts of the human brain with astonishing accuracy.

LATIF: But, Carl says ...

CARL ZIMMER: They're not brains.

LATIF: They're not brains.

CARL ZIMMER: That's right.

LATIF: Okay, so 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—yeah.

CARL ZIMMER: I would say that it's closer still for the time being to the neuron end of the slider.

LATIF: Mm-hmm?

CARL ZIMMER: Simply based on numbers.

LATIF: Our brain has something like 80 billion neurons.

CARL ZIMMER: And the biggest human brain organoids contain about two million cells.

LATIF: That's 0.0025 percent.

CARL ZIMMER: Well under one percent. Yeah.

LATIF: And, 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.

LULU: Yeah.

LATIF: And they're not in a body, so they can't interact with the world in, like, a meaningful way.

LULU: Okay.

CARL ZIMMER: Well ...

LATIF: But when I was talking to Carl about this ...

CARL ZIMMER: So ...

LATIF: ... he said that a lot of that might no longer be true.

CARL ZIMMER: Some scientists have, you know, taken organoids from human cells.

LATIF: Yeah.

CARL ZIMMER: And have put them into the brains of rats.

LATIF: [laughs]

LULU: What?

LATIF: So basically what they did is they basically took a rat and they, like, carved out a chunk of its brain.

LULU: But they left some of it?

LATIF: They left most of it.

LULU: Okay.

LATIF: And it's almost like—like, think about it like it's almost like they gave a rat a little human tumor or something.

LULU: Yeah.

LATIF: I mean, it doesn't ...

LULU: But the tumor is, like, just brain.

LATIF: Human brain.

LULU: Human brain. It's human brain. Oh my God!

LATIF: It's human brain.

CARL ZIMMER: And these human organoids are pretty happy in there.

LATIF: It's sort of wired in.

CARL ZIMMER: They connect up with the rat neurons. They get supplied by the rat blood system.

LULU: So they have made in a real sense, like a new kind of being.

LATIF: Yeah. Yeah, yeah. That did not exist before this. Correct.

LULU: [laughs] Okay. Feels like there should've been a bigger press release, but okay, do the—do the rats act any differently? Are they suddenly, like, into podcasts and coffee?

LATIF: [laughs]

CARL ZIMMER: When you do all sorts of studies on these rats—behavioral tests, memory tests, all sorts of things—they're just rats.

LATIF: There seems to be nothing human-y about them.

LULU: Okay.

LATIF: But one thing they did notice, when you tickle its whiskers ...

LULU: Yeah?

CARL ZIMMER: You can actually measure signals from the human brain organoid neurons.

LATIF: ... the human part of the brain lights up.

LULU: What?

LATIF: Yeah.

LULU: So it's registering the feeling?

CARL ZIMMER: They are receiving signals from the rat's senses.

LATIF: I mean, strictly speaking, they are receiving signals from the rat's senses. Are they feeling it? Feeling—it gets hard, because it's kind of the pain question again.

LULU: Yeah, but now they're in a body. I mean, they're in a being.

LATIF: Yes, but they are not the, like, driving force of that being. They're like a—they're like a houseguest in the attic.

LULU: Okay, Latif. Would you put—make a brain ball, brain organoid of your brain cell and put it in a rat?

LATIF: [laughs] If I'm being honest ...

LULU: Would you?

LATIF: ... probably not. Probably not.

LULU: Okay. Okay. So I don't know, but I just think you're more on my side that this is a little scary, than you with your reporter's wand are letting into, 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.

LATIF: Okay. Well, it's as if you have seen the future and what the next chapter holds.

LULU: Okay.

LATIF: Because that exact thing is gonna happen. It's gonna get weirder and creepier and stranger. And that's all after the break.

LULU: [sighs] Stick with us.

LATIF: Latif.

LULU: Lulu. Radiolab.

LATIF: We are back, talking about brain balls, you know, bitty brains, bobo brains, the brain-ish in a dish.

LULU: [laughs] Yes, ha ha with all your clever wordplay, but you were about to send us into the next existential tailspin about how people are using these things?

LATIF: It is possible.

BRETT KAGAN: So the final thing I was told to do is push 'record.'

LATIF: Record, yes. That's an important button. Now tell me who you are.

BRETT KAGAN: I'm Brett.

LATIF: This is Brett Kagan. He's a neuroscientist.

BRETT KAGAN: I'm the chief scientific officer here at Cortical Labs.

LULU: Cortical Labs.

BRETT KAGAN: We're a small tech start-up here in Melbourne, Australia.

LATIF: Did you start it? Did someone else start it?

BRETT KAGAN: No, well it was founded by—there was a few of us, and I was contacted by Dr. Hon Weng Chong and Andy Kitchen. And they were looking for a neuroscientist.

LATIF: Brett had been an academic obsessed with this particular question.

BRETT KAGAN: How do you get intelligence out of brain cells that are in a dish?

LATIF: And this company was like, "Why don't you leave academia and help us find out?"

BRETT KAGAN: And the question they had was can brain cells in a dish do anything at all that we might want them to do?

LULU: Hmm! Like, do what?

BRETT KAGAN: What better to pick than Pong?

LULU: [laughs] Pong? That, like, '70s computer game?

LATIF: Yeah. The game with the paddles and the little ball.

LULU: Why that?

BRETT KAGAN: Everybody knows Pong. It was one of the first computer games. It was the first thing that machine learning, which people now like to call AI, really was trained on as a big breakout success.

LATIF: And he figured the brain runs on electricity.

BRETT KAGAN: And it's also a shared language with silicon computing.

LATIF: So why wouldn't we be able to get neurons to do something a computer could do?

BRETT KAGAN: Exactly.

LATIF: Like play a simple video game.

BRETT KAGAN: We used some hardware that allowed us to record the activity of the cells, processed that and then deliver small electrical pulses back into the cultures.

LATIF: And they did it.

[NEWS CLIP: Scientists just put pieces of human and mice brain on a plate and wired it to a computer to play Pong!]

[ARCHIVE CLIP: They want to track the ball and control a paddle.]

[ARCHIVE CLIP: Seriously, this is one of the craziest things I've ever covered. So here's what's going on.]

LULU: What? No!

LATIF: Yeah. And this wasn't even an organoid. This was just a flat sheet of neurons in a dish.

LULU: I mean, how could it possibly be doing that? Like, I mean, can really dumb things do that? Could, like, a—could, like, a tree do that?

LATIF: Trees don't have neurons, so I don't think a tree could do that.

LULU: Okay, so—but what does this mean? Like, are they learning?

LATIF: Well, Brett says yes.

BRETT KAGAN: I called it "learning." And I think learning was an incredibly fair definition, because what would an improvement over time in a way that would suit a goal be called other than learning?

LATIF: But other people, including Madeline Lancaster ...

MADELINE LANCASTER: I actually remain to be convinced anybody has really shown that.

LATIF: ... say no.

MADELINE LANCASTER: Because it's really hard to interpret the signals coming from the neurons.

LATIF: She says when you teach brain cells to play Pong, they're, you know, connected to a computer.

MADELINE LANCASTER: And so what people do is they use algorithms to sort of decode that message and then send a signal back to neurons. And so you kind of have, like, two black boxes that you've just hooked up.

LATIF: It's sort of a collaboration between the brain cells and the computer.

MADELINE LANCASTER: And you don't really know what either of them are doing.

LATIF: Anyway, whatever is happening here, what Brett and his team took away from this is if neurons can do something a computer does, why don't we use neurons as computers?

LULU: What?

LATIF: Yeah. Literally a couple months ago they released their first computer called the CL-1. And it is—they don't call it this, but it's practically a biocomputer. It has neurons in it.

LULU: Eww! Brain—sticky, real human brain matter in it?

LATIF: Yeah. It's got, like, little brain organoids in it. It has 800,000 neurons interfaced with a silicon chip. You can use it to do computer stuff with.

LULU: Uh, okay. I mean, can get behind the brain balls being used for neurological disorder research. Great. You know what? Bespoke cancer treatments? Cool. But why are we hooking up human brain cells to computers to, like, make money? That, to me, feels like not worth the risk. [laughs] Like ...

LATIF: Well, think about the problems we are having right now with all of these data centers chugging all this energy.

LULU: Yes. Absolutely wrecking the planet.

LATIF: Right? So our brains are so impressively efficient. Energy wise? We have like a dim light bulb, like, screwed into our heads, right? That's the amount of energy that we need to do all the complex things that we do.

LULU: Yeah.

LATIF: If AI or if some supercomputer was doing the equivalent, it would need millions of times more power. Like the difference between a single light bulb and a large town.

LULU: [laughs] So flattering!

LATIF: The other thing is that, like, think about these AIs. You need to train on the whole internet, right? A human brain is much quicker to learn. If you could harness that energy efficiency, if you could harness that kind of, like, knowledge efficiency in a computer, you could move mountains.

LULU: Okay. But I guess my authentic question at this point is like, okay, you've shown us all this stuff. At this point it seems pretty clear that they can definitely register input, right?

LATIF: Uh-huh.

LULU: Like, they've—there's the tickle, the pain, the signal they're getting from Pong.

LATIF: Mm-hmm.

LULU: Okay? And then the Pong example at least shows us they are then able, based on that input, to produce some kind of output.

LATIF: Yeah. Okay, so let's say it is. Yeah.

LULU: Okay. So my question is: if they can do those things, wouldn't they have to have some thrumming level of consciousness?

LATIF: Uh, no, actually. No, they really don't. Like—like, a bunch of the things you just talked about, AI can do those. Is AI conscious? Even going further than that, like, a Roomba can do, like, navigate a room.

LULU: A Roomba?

LATIF: Is a Roomba conscious? That's a signal in and out, right?

LULU: Well, yeah. Right. A Roomba's going, "Oh, there's an edge. Let me go there."

LATIF: That's a signal in and out.

INSOO HYUN: When we talk about human consciousness, we mean self consciousness. Like, you are aware of yourself.

LATIF: Hmm.

INSOO HYUN: You have a past, you have a future that you're concerned about. There's like that continuity of experience.

LATIF: This is Dr. Insoo Hyun.

INSOO HYUN: I'm the director of the Center for Life Sciences at the Museum of Science in Boston.

LATIF: He's a bioethicist, and he's worked on a bunch of teams with scientists who are studying brain organoids.

INSOO HYUN: We try to identify what are the emerging scientific and ethical issues.

LATIF: You're, like, kind of like their conscience? Is that sort of the thing?

INSOO HYUN: [laughs] You know what? Sometimes I feel like a priest in secular clothes.

LATIF: And he says at this point, he is not worried about brain organoids having anything like human consciousness.

INSOO HYUN: The brain organoids in a dish don't have that continuity, they don't have all the regions, they don't have the interaction with the outside world.

LATIF: But when he thinks about the future that Brett and others are trying to create, where maybe people start connecting more and more complicated and even more and more structured clumps of human brain cells to computers ...

INSOO HYUN: Maybe you get—it might not even be a human consciousness, but some kind of consciousness could emerge. It's hooked up to the world.

LULU: Yeah. Okay, so what—what about this, Latif? I would—if I may, I would like to just issue a commandment that all the smart people who are, like, excited by brain organoids, they all take one year to stop making organoids, and use their smarts and their technologies and their labs to, like, try to understand the consciousness of the organoids that have already been made. You know, like, ideally they could all be in a dark room and just have candles and quietly, meditatively watch for any flickers to understand what's going on. And then—and then we have a grand assembly where everyone reports back and we all collectively decide what to do.

LATIF: But I know that, like, some of these scientists have this fire inside them to be like, "How many cures am I not gonna find in that year? Like, how many people am I not gonna help in that year?" Like, the glioblastoma, like, those people don't have a year.

LULU: And those people are telling me to just shut up because this is a piece of discarded foreskin.

LATIF: That's right.

MADELINE LANCASTER: If we have a tool that we don't use ...

LATIF: Madeline Lancaster again.

MADELINE LANCASTER: ... and there are millions of actually conscious human beings out there that don't have treatments, but we decide no, we're gonna put the value of organoids higher than those people, that would be unethical.

LATIF: It's funny. Like, at the beginning, like, you asked me, like, "Would you make a brain ball of yourself?" And I said no. And then at some point, like, my thinking switched where I'm like, oh no, unless it would save someone's life.

LULU: Well, that's noble. And now I feel even worse saying I don't know that I would. I just—I mean, yeah, okay, if it's my own kid? Sure, and I don't care if I'm, like, a little enslaved human consciousness if it saves my kid. But as you have shown us, the scientists are gonna do more, they're gonna try new things, they're gonna build bigger brains. And, like, there is a line and we will cross it, and we won't know that we've crossed it, you know?

LATIF: Right. And the thing about these organoids is that they're already crossing all kinds of lines.

INSOO HYUN: You disrupt categories that we thought were so neat and tidy and distinguishable: life-non life, human-non human, human-computer. We thought those were pretty clean categories, but this research is kind of upsetting the very foundations of what we think separates these categories apart.

LATIF: It does feel like it's like, oh, we've created a new category of thing. Like, a new category of thing that is maybe alive.

CARL ZIMMER: It is alive.

LATIF: We have created a new category of thing that is alive. That is—that is—that is weird!

CARL ZIMMER: Oh, yeah.

MADELINE LANCASTER: It's hard. It's hard to actually put it into a category that already exists, I think. Because—because they're not actual brains. That we can say absolutely certainly. But they're also not just a few neurons in a dish either.

CARL ZIMMER: We almost don't really even have the words for it.

MADELINE LANCASTER: I think it's kind of a new—a new thing.

LULU: Latif Nasser.

LATIF: This episode was produced by Annie McEwen, Mona Madgavkar and Pat Walters. It was edited by Alex Neason and Pat Walters, with fact-checking by Natalie Middleton and Rebecca Rand. Special thank you shout outs to Lynn Levy, Jason Yamada-Hanff, David Fajgenbaum, Andrew Verstein, Anne Hamilton, Christopher Mason, Madeline Mason-Mariarty, plus Howard Fine and his whole team at Weill Cornell for hosting us.

LATIF: And if you're looking for more musings on the nature of life and what it means to be alive, Carl Zimmer has a terrific book out all about this stuff. It's called Life's Edge: The Search for What It Means to Be Alive. Get it at your local bookstore. That's it for us, from our brain balls to yours. See you next week.

[LISTENER: Okay, start now. No, you don't need to press anymore. We're recording now. Hi, I'm Ellie Combs, and I'm from Louisville, Kentucky. And here are the staff credits. And she's Natalie's niece. Yeah. [laughs] Radiolab is hosted by Lulu Miller and Latif Nasser. Soren Wheeler is our executive editor. Sarah Sandbach is our executive director. Our managing editor is Pat Walters. Dylan Keefe is our director of sound design. Our staff includes: Jeremy Bloom, W. Harry Fortuna, David Gebel, Maria Paz Gutiérrez, Sindhu Gnanasambandan, Matt Kielty, Mona Madgavkar, Annie McEwen, Alex Neason, Sarah Qari, Anisa Vietze, Arianne Wack, Molly Webster and Jessica Yung. With help from Rebecca Rand. Our fact-checkers are Diane Kelly, Emily Krieger and Natalie Middleton.]

[LISTENER: Leadership support for Radiolab's science programming is provided by the Simons Foundation and the John Templeton Foundation. Foundational support for Radiolab was provided by the Alfred P. Sloan Foundation.]

 

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