Brain Balls

When neuroscientist Madeline Lancaster was a brand new postdoc, she accidentally used an expired protein gel in a lab experiment and noticed something weird. The stem cells she was trying to grow in a dish were self-assembling. The result? Madeline was the first person ever to grow what she called a “cerebral organoid,” a tiny, 3D version of a human brain the size of a peppercorn. In about a decade, these mini human brain balls were everywhere. They were revealing bombshell secrets about how our brains develop in the womb, helping treat advanced cancer patients, being implanted into animals, even playing the video game Pong. But what are they? Are these brain balls capable of sensing, feeling, learning, being? Are they tiny, trapped humans? And if they were, how would we know? Special thanks to Lynn Levy, Jason Yamada-Hanff, David Fajgenbaum, Andrew Verstein, Anne Hamilton, Christopher Mason, Madeline Mason-Mariarty, the team at the Boston Museum of Science, and Howard Fine, Stefano Cirigliano, and the team at Weill-Cornell. EPISODE CREDITS: Reported by - Latif Nasserwith help from - Mona MadgavkarProduced by - Annie McEwen, Mona Madgavkar, and Pat Walterswith mixing help from - Jeremy BloomFact-checking by - Natalie Middleton and Rebecca Randand Edited by - Alex Neason and Pat Walters EPISODE CITATIONS: Videos - “Growing Mini Brains to Discover What Makes Us Human,” Madeline Lancaster’s TEDxCERN Talk, Nov 2015 (https://zpr.io/6WP7xfA27auR) Brain cells playing Pong (https://zpr.io/pqgSqguJeAPK) Reuters report on CL1 computer launch in March 2025 (https://zpr.io/cdMf8Yjvayyd) Articles - Madeline Lancaster: The accidental organoid – mini-brains as models for human brain development (https://zpr.io/nnwFwUwnm2p6), MRC Laboratory of Molecular Biology What We Can Learn From Brain Organoids (https://zpr.io/frUfsg4pxKsb), by Carl Zimmer. NYT, November 6, 2025 Ethical Issues Related to Brain Organoid Research (https://zpr.io/qyiATHEhdnSa), by Insoo Hyun et al, Brain Research, 2020 Brain organoids get cancer, too, opening a new frontier in personalized medicine (https://zpr.io/nqMCQ) STAT Profile of Howard Fine and his lab’s glioblastoma research at Weill Cornell Medical Center: By re-creating neural pathway in dish, Stanford Medicine research may speed pain treatment (https://zpr.io/UnegZeQZfqn2) Stanford Medicine profile of Sergiu Pasca’s research on pain in organoids A brief history of organoids (https://zpr.io/waSbUCSrL9va) by Corrò et al, American Journal of Physiology - Cell Physiology, Books - Carl Zimmer Life’s Edge: The Search for What it Means to be Alive (https://carlzimmer.com/books/lifes-edge/) Sign up for our newsletter!! It includes short essays, recommendations, and details about other ways to interact with the show. Signup (https://radiolab.org/newsletter)! Radiolab is supported by listeners like you. Support Radiolab by becoming a member of The Lab (https://members.radiolab.org/) today. Follow our show on Instagram, Twitter and Facebook @radiolab, and share your thoughts with us by emailing [email protected]. 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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  You're listening to Radiolab.

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  Radiolab.

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  From...

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  WNYC.

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  See?

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  Yep.

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  Okay, Lulu.

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  Yeah.

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  We're gonna start today.

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  Mm-hmm.

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  Back in 2010, in a lab in Vienna.

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  Oh, jumping right in?

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  Yeah. You just picture sort of a lab with microscopes, computers, experiments. And off in one corner...

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  Hello.

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  Hi, how's it going? Wearing glasses and a white lab coat is this scientist named Dr. Madeline Lancaster.

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  Call me Madeline.

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

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  So still sort of making friends.

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  Still trying to make a good impression.

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  Getting to know people, you know.

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  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.

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  So that's like baby brain cells of mice?

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

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  And that's probably why I didn't really, you know, I was kind of naive about it all. Hmm.

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  But...

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  So anyways, so then...

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  She got to work.

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  You put this enzyme on, it just cuts those...

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  Preparing the baby mouse cells.

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  The cells all become loose and apart from each other.

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

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  Yeah, but...

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  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.

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  And I hadn't, they hadn't come in yet. I'd ordered them, but they hadn't come in yet.

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

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

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  She decided to improvise.

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

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  Found a random tube of glue-like proteins.

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  I don't know how old they were. And anyway, and I used those.

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

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  Next morning.

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  Came in.

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

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  Like, flat on the dish.

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  But instead, everything in there was...

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  Really cloudy.

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  Hmm.

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  Shouldn't be cloudy.

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

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  You know, were no good, and the cells hadn't stuck.

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

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  Yeah, all the cells are dead. I'll just throw it away.

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  Hmm.

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

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  Right before she tossed it, she thought...

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  You know, but I'll check it.

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  Hmm, 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...

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  These weird blobs.

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

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  Alive and healthy and...

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  Plumped into three or four blobs.

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  Hmm.

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  Did they... Yeah, can you, as vividly as you can, describe them?

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  I mean, they're like a sort of beige color, like an off-white, tiny...

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  About the size of a grain of sand.

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  Or these floating balls of cells.

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  And she's like, huh.

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  Weird.

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  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...

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  A tube.

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  A tube? Yeah, so she's like, looking down into, like, one end of the tube. So it looks...

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  Almost like a doughnut shape.

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  What... Had you ever seen anything like that before?

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  No.

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  No?

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  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.

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  So she gets up from the microscope and starts-

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  Sort of going around the lab, a little bit subtly at first, kind of just like, "Hey, has anybody ever seen cells do funny things, you know, clump up together?"

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  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." Like, they just weren't that interested.

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  No.

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  So-

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  I just kind of like, put it in formaldehyde, put it away in the fridge for a little while, and was like, "Okay."

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  "Let's try this gene screen again."

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  But this time-

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

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  This thing that I had read about called Matri-Gel.

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

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

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  So she squirts a lot of it on there.

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  Okay.

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  She puts her cells on top-

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  And again.

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

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  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."

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  Once again-

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  There's a bunch of stuff floating in there.

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  Huh.

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  I was like, "Okay, well, the Matri-Gel didn't work like it was supposed to."

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

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  And that's when I then took them, put them on the tissue culture microscope, looked down the eyepiece, and again-

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  There they were.

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  Funny shaped balls.

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  These ones were also beige-ish.

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  Off-white kind of color.

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  But they were bigger.

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  And they sort of have like bulges coming off of them.

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

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  Architecture.

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  There was a tube, but also-

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  A little circle, sort of oblong shaped thing.

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  And a fat layer of tightly packed cells.

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

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

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  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.

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  Hmm.

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  And they were like forming-

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  Structures with no instructions.

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  She's like, oh my God, like this is like, there are things developing here.

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  But toward what?

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  Well, to Madeline, it kinda looked like.

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  They were building a brain.

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  So these are, these are neural stem cells, which inside a developing mouse.

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  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.

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  And that's what it looked like the cells in Madeline's dish were doing. It, it seemed like these cells on their own were starting to try to make themselves into a mouse brain.

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  At the time, yeah, at the time I was, I was just kind of confused.

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

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  I showed some of these structures.

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  Tubes, the circles, the lines, but.

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  Several people in the lab were just kind of, I think they were just totally bored.

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  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.

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  I thought you were gonna do a screen.

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

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  What are you doing? And I was like, don't worry, I'm working on it.

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  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.

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

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  Yeah.

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  But at the same time.

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

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  I was always still playing around with matrix gel, growing these weird balls of cells.

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  Tweaking the recipe.

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  Trying to make sure I could get it to happen reproducibly.

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

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

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  Where do you get those from?

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  I think these were actually made from discarded human foreskin.

• 8:39Speaker 03

  Wow, so specific. Okay, what a detail. All right, thank you for that.

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  Because it's just bit of tissue that's thrown away.

• 8:49Speaker 03

  Yeah, right, of course, of course, literally thrown away. All right, okay, so, wow.

• 8:54Speaker 01

  Yeah, so anyway, so then what?

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  So she got these human stem cells. She put them in the matra gel, 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.

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  Oh my god.

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  And then she kept tweaking when and how much of the matra gel she would add. And she would just watch these blob shapes over time get bigger.

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

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  Side note, at the time, she was pregnant.

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  Yeah, my oldest, I was pregnant with her.

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

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  Yeah.

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

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  And I looked under the microscope.

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  Inside.

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  Yeah.

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  On this beige lump, she could see a perfect ring of black pigment.

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  And that was just, I looked at that, I was like, that's a developing eye. Shut up.

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  And it was growing on a developing human brain.

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  You're, no, what?

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  Yeah.

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  No, you, what? And then, then.

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

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

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

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  Ventricles, like an actual brain.

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  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.

• 10:40Speaker 01

  That we know almost nothing about.

• 10:44Speaker 04

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

• 10:52Speaker 03

  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.

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  Yeah.

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

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  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.

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  So Madeline and her boss, Jürgen Knoblick, 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 use these tiny 3D brain balls, which we have decided to call cerebral organoids.

• 11:46Speaker 01

  That's when, like, everything changed.

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

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  Yes. You can see things that were invisible before.

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

• 12:03Speaker 04

  Oh, you got Zimmer.

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

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  Sort of like humanoid, organoid, very sci-fi.

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

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  The key moments are during development.

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

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  Right, totally off limits. But 2013-

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  Madeline and Jürgen published their paper and-

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  Boom, we could watch human progenitor brain cells give rise to parts of the brain.

• 12:37Speaker 03

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

• 12:39Speaker 05

  So one example is a- there's a scientist at Stanford, Sergio Apaska, and he studied a very rare disease called Timothy's syndrome.

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  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's syndrome develops, like, from the beginning.

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  Yeah, now you can actually see what Timothy's syndrome is about.

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  So what did he see?

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  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's syndrome, they just don't. They just fail to get where they need to go.

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  And now that he knew what was going wrong.

• 13:25Speaker 05

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

• 13:31Speaker 03

  Yeah.

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

• 13:41Speaker 03

  Ah.

• 13:41Speaker 05

  In an organoid.

• 13:44Speaker 03

  So he cured it in an organoid?

• 13:46Speaker 05

  Right.

• 13:47Speaker 03

  Huh.

• 13:47Speaker 05

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

• 13:55Speaker 04

  Wow. And you could imagine that's one disorder.

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  That's right.

• 14:01Speaker 05

  A lot of other conditions.

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  Epilepsy, schizophrenia. 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.

• 14:15Speaker 05

  A lot of people in the field said, whoa, I gotta try this.

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

• 14:27Speaker 05

  The study of the brain is, it's fundamentally different now.

• 14:33Speaker 03

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

• 14:43Speaker 04

  Okay.

• 14:43Speaker 03

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

• 14:51Speaker 04

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

• 14:56Speaker 03

  We are gonna get there after the break.

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• 16:39Speaker 07

  After some actual fake polls came to light, pollsters are in the hot seat. But they say, "Don't be too quick to dismiss the entire industry."

• 16:48Speaker 08

  People want to raise taxes on the rich. I can tell you that definitively because we know it from polling. And if we lose trust in polls, we have no way to understand what Americans want to be done.

• 17:01Speaker 07

  On this week's On the Media from WNYC. Find On the Media wherever you get your podcasts.

• 17:18Speaker 09

  All right. Here we are. I'm in the 72nd Street subway station and I am walking to go see a fridgeful of brains.

• 17:27Speaker 03

  Hey, I'm Lotte Nasser.

• 17:30Speaker 09

  I'm Lulu Miller. This is Radiolab. More specifically, a fridgeful of brain organoids.

• 17:34Speaker 03

  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.

• 17:47Speaker 09

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

• 17:50Speaker 03

  So we sent our producer, Mona McGaughr.

• 17:52Speaker 09

  Ooh, laboratory caution, hazardous materials.

• 17:55Speaker 03

  To check them out.

• 17:56Speaker 09

  Where are we entering?

• 17:58Speaker 10

  So we're entering, so we have special rooms called cell culture rooms where we grow, oops, we grow the organoids.

• 18:05Speaker 03

  This is Dr. Howard Fine.

• 18:07Speaker 10

  I'm a medical neuro-oncologist.

• 18:09Speaker 03

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

• 18:13Speaker 10

  The type of brain tumor known as a glioblastoma.

• 18:15Speaker 03

  A very bad kind.

• 18:16Speaker 10

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

• 18:23Speaker 03

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

• 18:29Speaker 10

  Disease we've probably made the least amount of progress with when I was a...

• 18:32Speaker 03

  So he'd been studying glioblastoma, mostly of course in mice, right? And he admits, he actually calls this at the time, it was the dirty little secret of oncology, that for all his research, they were basically getting nowhere.

• 18:46Speaker 09

  Whoa.

• 18:47Speaker 03

  But then, he came across Madeline's work on organoids.

• 18:51Speaker 10

  And it was Larian Castor's paper. I read in Nature and it's like, like literally, not many times, you know, this is my 37th career, did I truly have a lightbulb moment? And I, I read that paper and said, this is what we're looking for.

• 19:04Speaker 03

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

• 19:09Speaker 09

  Can we see them? We're gonna take a look. Okay, so. He's opening the incubator and he's pulling out.

• 19:15Speaker 03

  So these are the stem cells. And they looked just like Madeline described.

• 19:19Speaker 09

  They're kind of like a beige color. They look like a kidney bean or like a nerd candy.

• 19:23Speaker 03

  Little beige balls floating in liquid in a dish. It was surrounded by a matrix. And under the microscope.

• 19:28Speaker 09

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

• 19:34Speaker 03

  You can see structure.

• 19:35Speaker 09

  And Dr. Fine, these are from specific patients, like your patients?

• 19:39Speaker 10

  Yes.

• 19:39Speaker 03

  But the difference between these organoids and Madeline's organoids was that these ones had cancer.

• 19:47Speaker 10

  So the idea is we're going to make a mini-brain from an individual patient.

• 19:53Speaker 03

  And then.

• 19:53Speaker 09

  Oh, these are the glioma cells. Wow.

• 19:56Speaker 03

  They take cells from that patient's brain tumor.

• 19:59Speaker 09

  Almost just looks like sugar that hasn't dissolved into you.

• 20:02Speaker 10

  And then we retroengineer the patient's own glioma stem cells into the mini-brain.

• 20:07Speaker 03

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

• 20:12Speaker 04

  A version of your brain.

• 20:13Speaker 03

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

• 20:17Speaker 10

  We can test hundreds or thousands of drugs.

• 20:20Speaker 03

  And then try a bunch of medicines on them.

• 20:22Speaker 10

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

• 20:26Speaker 09

  So you're saying that like you can try every chemotherapy that's out there and decide like which one?

• 20:31Speaker 10

  Everything, only limited by resources. As you could imagine, these are expensive.

• 20:34Speaker 04

  Oh my God. That is beautiful. I mean, that, just thinking about a way of like a kind of bespoke medical future exploration. Ah.

• 20:48Speaker 03

  Right? Way better than just using mice.

• 20:51Speaker 04

  Oh my gosh.

• 20:52Speaker 03

  Partly because it also could help us leapfrog one of the biggest reasons, on average, 90% of clinical trials for neurological drugs fail. And for brain cancer, by the way, that number's even higher, 95%.

• 21:08Speaker 01

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

• 21:13Speaker 03

  And this is something that Madeline told me too.

• 21:15Speaker 01

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

• 21:20Speaker 03

  Like, it's like, okay, great, this is not going to kill you.

• 21:23Speaker 01

  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.

• 21:29Speaker 03

  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.

• 21:43Speaker 04

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

• 21:51Speaker 03

  Yeah, okay. So as Madeline was developing her brain organoids, independently, around the same time, other scientists all over the world are growing.

• 22:02Speaker 05

  Intestinal organoids.

• 22:04Speaker 03

  Lung organoids.

• 22:04Speaker 05

  Liver organoids.

• 22:05Speaker 03

  Muscle organoids, skin organoids.

• 22:07Speaker 05

  Henkies organoids, stomach organoid.

• 22:09Speaker 03

  Heart organoids, kidney organoids?

• 22:11Speaker 05

  Breast tissue organoids that actually produce milk.

• 22:16Speaker 03

  Ah, they can have a breast tissue organoid that can make milk?

• 22:21Speaker 05

  Yes.

• 22:21Speaker 03

  Weird. Has anyone tasted that milk?

• 22:24Speaker 05

  I certainly haven't. I've only read about it. I don't know. I don't know. That's a good question. Anyway.

• 22:30Speaker 03

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

• 22:37Speaker 05

  And then you can connect them.

• 22:40Speaker 03

  What? You can like, you can... Does that work? You can do that?

• 22:44Speaker 05

  Oh, yeah. They call them assembloids.

• 22:46Speaker 03

  Assembloids?

• 22:48Speaker 05

  Yeah.

• 22:48Speaker 04

  No, like you can Mr. Potato Head assemble?

• 22:51Speaker 03

  Correct.

• 22:52Speaker 04

  But then do they attach to each other?

• 22:54Speaker 03

  They attach to each other, yeah.

• 22:55Speaker 04

  And do they communicate with each other?

• 22:57Speaker 03

  They communicate with each other, yeah.

• 22:59Speaker 04

  Okay, and then what? Do what? With your charm bracelet, human body?

• 23:05Speaker 05

  So here's an example. So Sergey Apaska.

• 23:08Speaker 03

  Neuroscientist at Stanford University.

• 23:10Speaker 05

  And his colleagues.

• 23:11Speaker 03

  Thought, can we use an assembloid to study pain?

• 23:14Speaker 05

  The pathway of pain. So they started with.

• 23:20Speaker 03

  The finger.

• 23:21Speaker 04

  A finger organoid?

• 23:22Speaker 03

  No, no, no, sorry. Just a nerve in the finger.

• 23:24Speaker 04

  Oh, okay.

• 23:25Speaker 05

  A sensory organoid, connect that.

• 23:28Speaker 03

  Like with some other cells in the dish.

• 23:30Speaker 05

  Another organoid, the spinal cord.

• 23:31Speaker 03

  Just a little teeny piece of spinal cord.

• 23:33Speaker 05

  Then we're gonna connect that.

• 23:34Speaker 03

  To a brain organoid that is specifically.

• 23:37Speaker 05

  The thalamus, which is the central hub in the brain that directs signals in all sorts of different ways.

• 23:42Speaker 03

  And finally.

• 23:43Speaker 05

  We're gonna connect that one.

• 23:44Speaker 03

  To one more brain organoid.

• 23:46Speaker 05

  A cortex organoid.

• 23:47Speaker 04

  Whoa, this is. So weird. I mean, it's like Legos.

• 23:52Speaker 03

  It's like Legos.

• 23:53Speaker 04

  With the human body.

• 23:54Speaker 03

  Correct.

• 23:55Speaker 05

  So then they took capsaicin, that's the molecule in.

• 23:59Speaker 03

  In like spicy food, is that right?

• 24:00Speaker 05

  In spicy food, in chili peppers, yeah. Very, it can be very painful to the skin.

• 24:05Speaker 03

  Okay.

• 24:05Speaker 05

  And they said, okay, let's, let's hit it with capsaicin and see what happens.

• 24:08Speaker 03

  Uh huh.

• 24:09Speaker 05

  Boom. Immediately, that sensory organoid goes.

• 24:12Speaker 03

  Right.

• 24:13Speaker 05

  And starts sending really strong signals.

• 24:15Speaker 03

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

• 24:18Speaker 05

  To the spinal cord, the thalamus, to the cortex.

• 24:22Speaker 03

  Just like it would in your own body.

• 24:24Speaker 04

  And they can see some kind of registering?

• 24:26Speaker 03

  Correct. And when you watch the way the signal travels, which is something that's normally hidden inside a body.

• 24:32Speaker 05

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

• 24:38Speaker 03

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

• 24:45Speaker 04

  Okay.

• 24:46Speaker 03

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

• 24:51Speaker 05

  You could, for example, say, okay, can I put a molecule into this assembloid that will stop the pain?

• 24:58Speaker 03

  Oh, wow.

• 25:00Speaker 04

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

• 25:08Speaker 03

  No, probably not.

• 25:09Speaker 05

  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.

• 25:20Speaker 03

  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, but.

• 25:28Speaker 04

  And like, what is the it, I think?

• 25:30Speaker 03

  The capsaicin, in that case.

• 25:31Speaker 04

  No, no, no, I'm the, I'm the first it.

• 25:34Speaker 03

  The first it.

• 25:35Speaker 04

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

• 25:41Speaker 05

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

• 25:54Speaker 03

  But Carl says.

• 25:55Speaker 05

  They're not brains.

• 25:56Speaker 03

  They're not brains.

• 25:57Speaker 05

  That's right.

• 25:58Speaker 03

  Okay, so if there's like a slider, and on one end is brains, and then on the other hand is just like some neurons in a dish, where is this on the slider and, and how do you, yeah?

• 26:09Speaker 05

  I would say that it's. Closer still, for the time being, to the neuron end of the slider, simply based on numbers.

• 26:18Speaker 03

  Our brain has something like 80 billion neurons.

• 26:22Speaker 05

  And the biggest human brain organoids contain about 2 million cells.

• 26:30Speaker 03

  So that's 0.0025%.

• 26:33Speaker 05

  Well, under 1%, yeah.

• 26:34Speaker 03

  And, you know, these things don't have blood vessels, so that is a

• 26:38Speaker 04

  That's pretty big, right?

• 26:39Speaker 03

  Very important key limiting factor to how big and complex it can get.

• 26:42Speaker 04

  Yeah.

• 26:43Speaker 03

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

• 26:48Speaker 04

  Okay.

• 26:49Speaker 05

  Well.

• 26:50Speaker 03

  But when I was talking to Carl about this.

• 26:53Speaker 05

  So.

• 26:55Speaker 03

  He said that a lot of that might no longer be true.

• 26:59Speaker 05

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

• 27:04Speaker 03

  Yeah.

• 27:05Speaker 05

  And have put them into the brains of rats.

• 27:10Speaker 04

  What?

• 27:11Speaker 03

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

• 27:15Speaker 04

  But they left some of it?

• 27:16Speaker 03

  They left most of it.

• 27:17Speaker 04

  Okay.

• 27:17Speaker 03

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

• 27:22Speaker 04

  Yes.

• 27:23Speaker 03

  I mean, it doesn't.

• 27:23Speaker 04

  But the tumor is like, just brain, human brain. It's human brain. Oh, my God.

• 27:28Speaker 03

  It's human brain.

• 27:28Speaker 05

  And these human organoids are pretty happy in there.

• 27:33Speaker 03

  It's sort of wired in.

• 27:34Speaker 05

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

• 27:40Speaker 04

  So they have made, in a real sense, like a new kind of being?

• 27:45Speaker 03

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

• 27:50Speaker 04

  Okay. This feels like there should have been a bigger press release, but okay, do the, do the, do the rats act any differently? Are they suddenly like into podcasts and coffee?

• 28:01Speaker 05

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

• 28:09Speaker 03

  There seems to be nothing human-y about them.

• 28:12Speaker 04

  Okay.

• 28:12Speaker 03

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

• 28:17Speaker 04

  Yeah?

• 28:18Speaker 05

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

• 28:24Speaker 03

  The human part of the brain lights up.

• 28:26Speaker 04

  What?

• 28:27Speaker 03

  Yeah.

• 28:28Speaker 04

  So it's registering the feeling?

• 28:31Speaker 05

  They are receiving signals from the rat's senses.

• 28:37Speaker 03

  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.

• 28:49Speaker 04

  But yeah, but now they're in a body. I mean, they're in a being.

• 28:52Speaker 03

  Yes, but they're not the like, driving force of that being. They're like a, they're like a house guest in the attic.

• 28:59Speaker 04

  Okay, Latif, would you put, make a brain ball, brain organoid of your brain cell and put it in a rat?

• 29:11Speaker 03

  If I'm being honest, probably not.

• 29:13Speaker 04

  Would you?

• 29:13Speaker 03

  Probably not.

• 29:14Speaker 04

  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, 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.

• 29:38Speaker 03

  Okay, 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. And that's all after the break.

• 29:53Speaker 04

  Stick with us.

• 29:59Speaker 11

  This week on The New Yorker Radio Hour, will House Democrats try once again for impeachment?

• 30:04Speaker 00

  Let's not make a fetish out of impeachment. Let's not make a taboo out of impeachment. We understand it's not a panacea, but it is an essential tool in the constitutional toolbox that's always there.

• 30:15Speaker 11

  Congressman Jamie Raskin joins us next time on The New Yorker Radio Hour from WNYC. Listen wherever you get your podcasts.

• 30:31Speaker 03

  Latif.

• 30:32Speaker 04

  Lulu, Radiolab.

• 30:33Speaker 03

  We are back talking about brain balls. You know, bitty brains, boba brains, the brain ish in a dish.

• 30:40Speaker 04

  Yes, ha ha, with all your clever wordplay. But you are about to send us into the next existential tailspin about how people are using these things.

• 30:49Speaker 03

  It is possible.

• 30:50Speaker 12

  So the final thing I was told to do is push record?

• 30:53Speaker 03

  Record, yes, that's an important button. Now, tell me who you are.

• 30:56Speaker 12

  So I'm Brett.

• 30:57Speaker 03

  This is Brett Kagan. He's a neuroscientist.

• 31:00Speaker 12

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

• 31:03Speaker 04

  Cortical Labs.

• 31:05Speaker 12

  We're a small tech startup here in Melbourne, Australia.

• 31:08Speaker 03

  Did you start it? Did someone else start it?

• 31:09Speaker 12

  No, well, it was founded by, there was a few of us. And I was contacted by Dr. Hanwen Chong and Andy Kitchen. And they were looking for a neuroscientist.

• 31:18Speaker 03

  Brett had been an academic obsessed with this particular question.

• 31:21Speaker 12

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

• 31:25Speaker 03

  And this company was like, why don't you leave academia and help us find out?

• 31:29Speaker 12

  The question they had was, can brain cells in a dish do anything at all that we might want them to do?

• 31:34Speaker 04

  Hmm, like, do what?

• 31:37Speaker 12

  What better to pick than Pong?

• 31:40Speaker 04

  Pong? The like 70s computer game?

• 31:43Speaker 03

  Yeah, the game with the paddles and the little ball.

• 31:45Speaker 04

  Why that?

• 31:46Speaker 12

  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.

• 31:55Speaker 03

  And he figured the brain runs on electricity.

• 31:58Speaker 12

  And it's also a shared language at silicon computing.

• 32:00Speaker 03

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

• 32:04Speaker 12

  Exactly.

• 32:05Speaker 03

  Like play a simple video game?

• 32:06Speaker 12

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

• 32:16Speaker 03

  And they did it. Scientists just put pieces of human and mice brain on a plate and wired it to a computer to play Pong.

• 32:23Speaker 13

  They learned to track the ball and control a paddle.

• 32:26Speaker 04

  Seriously, this is one of the craziest things I've ever covered. So here's what's going on. What? No.

• 32:32Speaker 03

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

• 32:38Speaker 04

  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?

• 32:47Speaker 03

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

• 32:50Speaker 04

  Okay, so, so, but well, what, what does this mean? Like, are they learning?

• 32:54Speaker 03

  Well, Brett says yes.

• 32:55Speaker 12

  I called it learning, and I think learning was incredibly fair definition. Because what would an improvement over time in a way that would suit a goal be called other than learning?

• 33:06Speaker 03

  But other people, including Madeleine Lancaster-

• 33:08Speaker 01

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

• 33:12Speaker 03

  Say no.

• 33:13Speaker 01

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

• 33:17Speaker 03

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

• 33:22Speaker 01

  So what, 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.

• 33:33Speaker 03

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

• 33:36Speaker 01

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

• 33:39Speaker 03

  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?

• 33:51Speaker 04

  What?

• 33:52Speaker 03

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

• 34:04Speaker 04

  Ew, brain sticky, real human brain matter in it?

• 34:10Speaker 03

  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.

• 34:20Speaker 04

  Ah, okay. I mean, I can get behind the, 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-

• 34:42Speaker 04

  Make money? That to me feels like not worth the risk.

• 34:49Speaker 03

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

• 34:58Speaker 04

  Yes, absolutely wrecking the planet.

• 35:00Speaker 03

  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. 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.

• 35:25Speaker 04

  So flattering.

• 35:26Speaker 03

  The other thing is that, like, think about these AIs. You need to train it 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.

• 35:46Speaker 04

  Okay. But I guess my authentic question at this point is like, okay, you have shown us all this stuff. At this point, it seems pretty clear that they can definitely register input, right? Like they've, there's the tickle, the pain, the signal they're getting from Pong. Okay. And then this Pong example at least shows us they are then able, based on that input, to produce some kind of output.

• 36:08Speaker 03

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

• 36:10Speaker 04

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

• 36:20Speaker 03

  Uh, no, actually. No, they really don't. Like, like, like, just 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. Is a Roomba conscious? That's, that's a signal in and out, right?

• 36:37Speaker 04

  Right. A Roomba's going, oh, there's an edge. Let me go this way.

• 36:40Speaker 03

  That's a signal in and out.

• 36:41Speaker 14

  When we talk about human consciousness, we mean self-consciousness. Like you are aware of yourself. You have a past, you have a future that you're concerned about, just like that continuity of.

• 36:52Speaker 03

  This is Dr. Insoo Hyun.

• 36:54Speaker 14

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

• 36:58Speaker 03

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

• 37:04Speaker 14

  We tried to identify what are the emerging scientific and ethical issues.

• 37:08Speaker 03

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

• 37:11Speaker 14

  You know what? Sometimes I feel like a priest in secular clothes.

• 37:14Speaker 03

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

• 37:20Speaker 14

  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.

• 37:27Speaker 03

  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.

• 37:42Speaker 14

  Maybe you get, it might not even be human consciousness, but some kind of consciousness could emerge.

• 37:50Speaker 14

  It's hooked up to the world.

• 38:02Speaker 04

  Yeah.

• 38:06Speaker 04

  Okay, so 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.

• 38:43Speaker 04

  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.

• 38:50Speaker 03

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

• 39:02Speaker 04

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

• 39:08Speaker 03

  That's right.

• 39:08Speaker 01

  If, if we have a tool that we don't use.

• 39:11Speaker 03

  Madeleine Lancaster again.

• 39:12Speaker 01

  And there are millions of actually conscious human beings out there that don't have treatments. But we decide, no, we're going to put the value of organoids higher than those people. That would be unethical.

• 39:27Speaker 03

  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.

• 39:43Speaker 04

  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. 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 going to do more. They're going to try new things. They're going to 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?

• 40:07Speaker 03

  Right. And, well, and the thing about these organoids is that they're already crossing all kinds of lines.

• 40:12Speaker 14

  You disrupt categories that we thought were so neat and tidy and distinguishable.

• 40:20Speaker 14

  Life, non-life. Human, non-human. Human, computer. We thought those are pretty clean categories, but this research is kind of upsetting the very foundations of what we think separates these categories apart.

• 40:41Speaker 03

  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.

• 40:49Speaker 05

  It is alive.

• 40:51Speaker 03

  We have created a new category of thing that is alive. That is, that is, that is, that is weird.

• 40:59Speaker 05

  Oh, yeah.

• 41:00Speaker 01

  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.

• 41:17Speaker 05

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

• 41:21Speaker 01

  I think it's kind of a new, a new thing.

• 41:50Speaker 04

  Latif Nasr.

• 41:53Speaker 03

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

• 42:37Speaker 06

  Okay, start now. I was practicing. No, you don't need to. You don't need to practice anymore. Shh. We're recording now.

• 42:43Speaker 02

  Hi, I'm Ellie Collins and I'm from Louisville, Kentucky. And here are the staff credits.

• 42:47Speaker 06

  And she's Molly's niece.

• 42:50Speaker 02

  Yeah. Radiolab is hosted by Lulu Miller and Latif Nasser. Sorin Wheeler is our executive editor. Sarah Sandback 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 Gable, Maria Paz Gutierrez, Sindhu Nana Sambanthan, Matt Kielty, Mona Madgavkar, Annie McEwen, Alex Neeson, Sarah Kari, Enisa Vitez, Ariane Wack, Molly Webster, and Jessica Young. With help from Rebecca Rand, our fact-checkers are Diane Kelly, Emily Krieger, and Natalie Middleton.

• 43:37Speaker 02

  I love your giggle.

• 43:41Speaker 02

  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.