Pinky and the (lab-grown) Brain

It’s not great to be a lab rat. And it turns out, lab rats might not be that great for science either. Could the future be little lab-grown brain clumps? Guests: Rachel Nuwer, science journalist; Lisa Genzel, professor of neuroscience at Radboud University This episode has been updated. An earlier version didn’t differentiate between two stages of drug development. For show transcripts, go to vox.com/unxtranscripts For more, go to vox.com/unexplainable And please email us! [email protected] We read every email. Support Unexplainable by becoming a Vox Member today: vox.com/members Learn more about your ad choices. Visit podcastchoices.com/adchoices

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  Every year, an estimated 100 million animals are used for scientific research. It's mostly rats and mice, but there's also dogs, monkeys, rabbits, birds, fish, all kinds of animals. Scientists use animal research to study biology and develop new medicines without putting people at risk. And it's led to huge medical breakthroughs. From the first antibiotics in the early 1900s.

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  The use of animals like rats and mice is one of the most important scientific aspects of the experiment.

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  The COVID vaccine just a few years ago.

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  Preclinical testing on hamsters showing signs the vaccine works.

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  And these successes have led to a lot of hype.

• 1:40Speaker 04

  A new cancer treatment has wiped out all of the tumors in a group of mice, according to scientists.

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  Scientists have shown they can make paralyzed rats walk again. Eliminate HIV in animals.

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  But if you listen closely to the headlines, you'll hear that these breakthroughs are usually just in animals.

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  They often don't work on humans. Science is bumping up against the limitations.

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  Of what animals can offer us.

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  That's science reporter Rachel Neuer.

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  Animal models may weed out drugs that might work in people. And they also sometimes pass drugs that are actually toxic for people, but in animals, they're not.

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  It's really tricky translating what we learn from studying animals into something that can cure people.

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  Ultimately, they aren't human beings.

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  And there's a cost to the animals, too. It means that there are animals being experimented on in ways that could cause them unnecessary harm, especially if the research isn't that solid in the first place.

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  So can science do better?

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  We need better models that actually recreate the human body in a way that a mouse or a rat or just some other species can never do.

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  I'm Manning Nguyen, and this week on Unexplainable, if not animal testing, then what?

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  In the past couple decades, scientists have been trying to get around this animal research problem, and they have a few promising solutions. One of them lets them work directly with human cells. It's called an organ on a chip.

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  Actually, let me just grab my organ on a chip.

• 3:22Speaker 02

  Oh, you have one?

• 3:23Speaker 06

  Yeah, they gave me one. I was so excited. One second.

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  So each chip represents an organ?

• 3:28Speaker 06

  Yeah, exactly, exactly.

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  There's a bunch of different companies making these chips right now, and Rachel visited one of them called Emulate. It was founded by the scientists who first developed the technology about 14 years ago.

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  So it's this flexible little chip. I mean, it's about the size of a domino.

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  It's made of this clear, flexible plastic, and inside of it, there are these overlapping channels that scientists can put living cells in.

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  So, you know, it could be like liver cells, blood cells, like whatever you're trying to build here.

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  These aren't full organs. They're just cells. But they're designed to mimic organ functions pretty closely, like how lungs breathe oxygen or how kidneys filter urine. You can have an intestine, liver, or even a blood-brain barrier on a chip.

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  And you can link these chips together to create basically full organ systems and perhaps in the future even like mimic an entire human system.

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  Scientists can use these organ chips to see how a disease might progress in actual organs and test all kinds of substances.

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  Whether that's like a virus, bacteria, cigarette smoke, a pharmaceutical.

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  And these organ chips are actually pretty good at identifying what's toxic or not to humans, especially when it comes to a specific organ.

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  Their liver chip is really popular because one of the main reasons that new drugs fail in animal models is because they don't reveal liver toxicity.

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  At all?

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  Not at all, but they they just very frequently miss it.

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  This is a big problem because liver injury side effects are one of the most common reasons that drugs get pulled off the market.

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  So Emulate did a study to test how well the organ chips detected liver toxicity. They took a bunch of drugs, some known to be toxic and some known to be safe. Then they tested these in the liver chips. They found that the organ chips correctly identified the toxic drugs almost 90% of the time. And these were drugs that none of the animal tests flagged as toxic.

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  Furthermore, the chips didn't label any safe drugs as toxic.

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  And not only are these organ chips more accurate, they're also a lot cheaper to use. Moderna actually tested these organ chips on a bunch of potential drug delivery molecules. It cost less than a half a million dollars and they finished in a year and a half.

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  And they compared that to if they had used non-human primates and that would have taken $5 million in five years.

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  But while organ chips work and are cheap, they're still pretty basic. A lung on a chip could mimic the lung contracting and show air and blood flowing through it, but it can't represent the whole organ. And while scientists can link organ chips into these multi-organ systems, it's still tough to capture the full complexity of interacting systems.

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  The point of these chips isn't to perfectly recreate someone's liver, for example. You don't have to create an entire human liver to find out if this or that drug is going to be toxic, or you know, how somebody is going to respond to like, an environmental pollutant, or cigarette smoke, or whatever the researchers want to run through these chips as a test case.

• 6:29Speaker 02

  So that's organ chips. These mini-organs that can capture the main functions of an organ, but can't act like the whole thing. Then there's another technology called organoids. They're these little 3D cell cultures that scientists can grow in the lab.

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  If you look at them, it's, it's like, imagine a Petri dish, but there's like a few really pale dip and dots floating inside. I don't know if you've ever had dip and dots. I used to have those as a kid.

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  I did too.

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  Yeah, so they just look like little dip and dots.

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  Scientists make organoids by growing stem cells in environments that mimic parts of the body. And that's how they coax them to grow into the cells of any organ, like the heart, guts, or even the brain.

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  Not only are these, you know, human tissues, they're specific to a person. So, you know, they are actually a reflection of that individual person's brain cells.

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  This means that scientists can tailor treatments to the individual, and also tackle diseases that would usually be too expensive to study with typical drug development trials.

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  People with rare diseases, they oftentimes don't have any options for treatments because it's not profitable for a pharmaceutical company to invest millions and millions of dollars into developing a treatment for a disease that just a handful of people have.

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  Rachel visited a few labs to see this work up close.

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  So one researcher, a molecular biologist I met when I was visiting Johns Hopkins, she's creating, uh, brain organoids for Alzheimer's disease because, um, she was actually inspired by her grandmother who was diagnosed with the disease a few years ago.

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  Alzheimer's is usually studied in animals. And while that research has taught us a lot about how it impacts the brain, it's not led to any successful treatments in humans. So this researcher Rachel talked to is taking a different approach.

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  She starts by taking a blood sample from a patient with Alzheimer's disease, and she uses that blood to make pluripotent stem cells, which she can then differentiate into brain cells. And those brain cells come together to form these organoids.

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  These clusters of brain cells look a lot more like a sick human brain than a rat brain does.

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  And within about four months, those organoids actually start showing signs of Alzheimer's disease.

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  It's pretty incredible. And scientists can try out different drugs on these organoids to see how effective they are. But organoids also have their limits. They grow really slowly. And just like organ chips, they can't represent all the functions of an organ, mainly because they're just too small.

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  But there's also a totally different way to do this kind of research. Scientists are finding that especially for toxicity testing, computer models might be a good replacement.

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  So instead of having to apply that chemical in toxicity testing to a bunch of animals and see like, you know, how it kills animals and how many and at what doses, you can just use algorithms to predict that.

• 9:24Speaker 02

  Computer models have been around for a while, longer than the other kinds of alternatives. And they've only grown more powerful with AI. Studies looking at hundreds of known chemicals found that computer models were better at predicting toxicity than animals were. Plus, these models are faster and cheaper compared to all the other alternatives out there. But these models are only as strong as the data scientists feed them. And a lot of that comes from animal research, which we know can sometimes fall short when predicting human outcomes. So scientists have to take a lot of time making sure that the data they're using is relevant and accurate. Still, Rachel's pretty optimistic about animal alternatives.

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  They've just advanced so much compared to just 10 years ago that now it's actually becoming viable and realistic for labs to pursue this on their own.

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  Scientists are using these technologies to study everything from radiation exposure to influenza to malnutrition. And legislation is beginning to catch up, too. A couple of years ago, the Biden administration passed a bill that ended the requirement that drugs needed to be tested on animals before going to human trials.

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  Passing this bill will put a stop to the needless suffering and death of millions of animals in labs across the country.

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  But transitioning away from animal research won't be easy.

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  There's a lot of inertia here, and a lot of researchers aren't ready to make the switch just yet.

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  Researchers aren't going to switch over to alternatives to animals if they don't feel confident that the data they produce using those alternative methods is going to be accepted. The fear is that if a company or a research group goes through all the rigmarole of producing data for some new drug not using animals, they'll get to the FDA and then the FDA will just say, well, you know, wait a minute, like, you need to go back and do all this testing with animals because, like, there just aren't clear guidelines.

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  But there's a more fundamental issue here. Despite the fact that the vast majority of drugs that work in animal models fail in human trials, some researchers are still reluctant to move on because they say there's certain things that we can only learn from animals. So what would we lose without animal models? That's next.

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  We don't. Test unexplainable on animals. So we've been talking about the limitations of animal models, all the ways they may not work. But there's a lot of stuff we'd lose without them. Because animals aren't just used for testing drugs and chemicals.

• 15:16Speaker 06

  When you think about animal research, most people will think of pharmaceutical testing. So where you're saying, I have a disease, I have a symptom, and now I'm going to see if this drug works. That's just one part of animal research.

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  This is Lisa Genzel, a neuroscientist who recently co-authored a couple papers on why science needs animal research. She says that we need animals, especially when it comes to answering basic biological questions.

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  How does the healthy physiological system work? Right? What's going on there? There's also basic preclinical research where it's more about, I have a disease, but I don't understand what's wrong in the disease. I just want to understand the basic fundamental principles before I can even think about where I could target and actually cure the disease.

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  Lisa specifically uses rats to study how the brain consolidates memory. Knowing how the brain chooses what we remember and what we forget could potentially give us a better understanding of diseases that we still don't really know how to treat.

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  As a memory researcher, I like to think that most diseases like depression, potentially schizophrenia, that they potentially are just actually memory gone wrong.

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  And when it comes to the research she's been doing to understand this basic biology, animal tests are usually more useful than alternatives for a few reasons. One is that animal tests let scientists study complex interconnected systems in a way that other models can't.

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  If you want to understand how two brain areas interact, or even how the gut interacts and the microbiome, for example, interacts with the brain, then you need a full system.

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  And Lisa says that studying memory is one of the things that requires a full system. Because memory research is a field that does a good job at showing us how little we understand about the brain.

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  I mean, every time we think we understand something, for example, oh, we know about neurons, the cells in the brain that fire, those are the ones that encode everything. Oops, no, it turns out it's the protein around it. It's the other cells that are supporting those cells that also encode for memory. So at this point, we're currently just finding out that we know even less than we thought before.

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  To do her experiments, Lisa has to first train rats to navigate these big mazes. Then, using small brain implants, she tracks their brain activity as they find their treats at the end of the correct path or get lost along the way.

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  For me, of course, I want to see the behavior. I need to see the output of all that computation in the brain.

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  Finding a treat at the end of a maze isn't something that an organoid can do. But just to be clear, Lisa's not opposed to working with non-animal alternatives. She says they definitely can play a role in basic biological research.

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  In neuroscience, for example, these innovations really can help us understand certain research questions like how specific cells differentiate during development or specific small interactions within a local network. Then, the best model will be a brain organoid that's based on human tissue.

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  But to completely replace animals in her research, something like an organoid would need to be a lot more complex.

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  I would need a cell cluster that is complex enough that different brain areas interact and that they could produce a behavioral output. The problem is, at the point that that cell cluster would be at that sophistication, it would count as an animal.

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  Lisa says that, at least in her field, it's more realistic for non-animal alternatives to be used alongside animal research.

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  One thing that I do work with is computer models.

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  After Lisa collects data on the behavior of her rats, she sends it to another team to make a computer model of the rat brain. The model predicts which neurons are being activated, where, and when.

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  Then I can go back into the animal and see if this is true. So did the computer model correctly predict what happened in the brain?

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  The computer model helps Lisa focus on which brain areas to look more closely at in her rats. She can then tinker with it, see how it impacts their behavior, and then get more data that she can plug back into the computer model.

• 19:21Speaker 06

  And so like that, you can go back and forth, back and forth between the animal and the computer. And in a way, what it allows you to do, it doesn't really replace animals. It allows you to maybe use less animals as well as just have much more targeted experiments.

• 19:39Speaker 02

  As all these alternative technologies get better, they're going to enable scientists to be more creative and more precise with how they go about their research. But they're not going to replace animals in research anytime soon, at least not completely. Lisa says that it all goes back to the question scientists are trying to answer.

• 19:57Speaker 06

  Each model comes just with its advantages and disadvantages. And then every researcher will choose a model that is the best model to answer their research question.

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  That's the challenge for a lot of scientists. There's no perfect model. It's about understanding the strengths and limits of each tool and knowing when to use them.

• 20:16Speaker 06

  All models are bad, but some are useful. Because of course, a model by default will be reductionistic and can never be the perfect representation of what you're trying to model, else it would just be the thing.

• 20:29Speaker 02

  What's exciting is how quickly tools like organ chips, organoids, and computer models are evolving. Science is already moving beyond just using animals to understand human biology. Because as our questions become more sophisticated, more complex, we're going to need tools that can capture exactly what makes our biology unique.

• 20:59Speaker 02

  If you want to learn more about alternatives to animal testing, check out Rachel's article at Scientific American. It's called "The End of the Lab Rat." This episode was produced by me, Maning Wain. We had editing from Meredith Hodnot, sound design and mixing from Christian Ayala, music from Noam Hassenfeld, fact checking from Anouk Doussou, and Byrd Pinkerton stared as the pufferfish queen waggled her fins back at her. The two of them waggled and waggled and waggled. And suddenly, the pufferfish queen puffed herself up, spun around, and then Bird saw it, swimming over the reef, the pufferfish army.

• 21:40Speaker 02

  Special thanks to Paul Locke, Kristy Sullivan, and Aisha Akhtar. And as always, thank you to Brian Resnick for co-founding the show. If you have thoughts about the show, send us an email. We're at [email protected]. And we'd love to hear your thoughts, your criticisms, your suggestions. And if you can, go leave us a review or a rating wherever you listen. It really helps us find new listeners. This podcast is free, in part because of gifts from our readers and listeners. You can go to vox.com/give to give today. Unexplainable is part of the Vox Media Podcast Network. We're off next week for the holiday, so we'll be back in your feed in two weeks.

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