Short Wave - Rethinking The Lab Rat

Episode Date: June 23, 2023

For generations, scientists have leaned on seven key species, including rats and mice, for research. They're called model organisms and they've been standardized over the year — removing as much individuality as possible. But as research questions become more complicated, some researchers are turning to more niche critters to study. Host Regina Barber talks to reporter Anil Oza about the shift.See pcm.adswizz.com for information about our collection and use of personal data for sponsorship and to manage your podcast sponsorship preferences.NPR Privacy Policy

You're listening to Shortwave from NPR. Hey, Sherwaivers, Regina Barber here with reporter extraordinaire Anil Oza. Hi, Gina. Hey, Anil. Okay, so I want you to close your eyes. Okay. And picture like an earliest 20-century lab for me. Okay.

Very sterile room. Lots of microscopes, sinks, tiled floors. Maybe lots of dudes and lab coats. Yep, but you're missing the most important people in that room. The rats. Rat test subjects. I am missing them. You're right. Yeah. And someone who's really interested in those test subjects is Sonia Shaw. She's a scientist journalist that I spoke to recently, and she's been looking into how using mice in research has changed over time.

And she says that by the mid-20th century, some scientists were trying to figure out how to standardize the animals that they use in research. You know, we started having new therapeutics that needed to be tested. You know, you test the same dose of insulin on, you know, a group of. of guinea pigs. Well, some guinea pigs are going to react in one way, and some guinea pigs react in a totally different way, and it's because there's individual variation. Sonia is really interested in the relationship between animals and humans, and she's been looking into it recently for this big story she wrote for The New Yorker. And lab rats are a big deal. They're sort of synonymous with research. Here in the U.S., we use close to 100 million

them a year for research. That's a shockingly high number. Like 100 million? Yeah, absolutely. That's a huge number. But the problem is, is that increasingly researchers, especially those that work on drugs, are becoming concerned that lap rats aren't actually a good proxy for human research. Do researchers have any idea about why that is? Like, why rats may not actually be a very good proxy for human research? Yeah, in Sonia's reporting, she found that scientist from around a century ago, frustrated with the variability in their different results,

tried to not just standardize the animals that they were using, but standardized within a given type of animal, too. By controlling the germs and by controlling the genes, we could somehow make this animal that was deprived of all individuality. It was basically a unit, a thing, a commodity, a widget. They could be standardized. One after the other, they would always respond the same way, just like, you know, you press on a lever and the same thing always happens. There was a scientific race to sort of sterilize everything that we're using in the rat or a mouse to control everything inside of them. Their genes, the type of food they eat, their microbiomes.

But today, some researchers are trying to reverse that by letting their lab animals live a semi-natural environment. We humans aren't all the same. And so there's been times when drugs move from mice to humans, and we sort of find these side effects that we weren't seeing in these mice that are carbon copies of each other. And so in recent years, the question has emerged. If these uniform model organisms aren't working, what makes a better model organism? Recent technological developments have meant that researchers can have a bigger imagination of what animals they study and how. Here's what biologist Alejandro Sanchez Alvarado told me. New technology, as it has grown in the past 20 years,

one of the byproducts is that it has made biology that was inaccessible, really, really accessible, and vulnerable to interrogation. This is a new phenomenon in the history of biology. I believe that the opportunities for us to understand biology much fuller, much more deeply, has been kicked open. So today on the show, the future of lab rats. And how scientists are reimagining the rest of the lab animal world. I'm Regina Barber.

And I'm Anil Oza. And you're listening to Shortwave, the science podcast from NPR. So Gina, what do you think makes a good model organism? I actually don't know. I'm guessing it has to do with like a short life. So you get like a lot of data with a lot of trials. Yeah, forever. We've chosen our animals based on them being small and able to reproduce quickly.

More recently, researchers are looking for drama queens. Drama queens? Like, what does that even mean? Alejandro told me that you should sort of start with whatever your research question is, what you want to study, what questions that you have, and then you should find an animal that does that, but to the extreme. In other words, do I really need to reinvent the wheel? If the biological attributes that you want to study are not, you know, saliently manifested

in already available species, but there's another animal out there that actually does and exaggerates what you really want to study. That is the reason to go after that individual species and try to bring it to the lab and extract its secrets as best as you can. Extract its secrets. I know. I love it. It's so dramatic. This all lets you see what you're trying to study really, really clearly. And it lets you see whatever mechanism is underpending your research question. Like fruit flies, they have a ton of genes that we can very easily compare to our own.

But they reproduce really quickly, too. Okay. So is this why so many people study rats and mice? Because they have these really exaggerated effects? Yeah, I would call rats drama, please. But this exaggerated effect is not really in relation to research questions that we have. The animals that were selected for research today, they were selected for entirely practical reasons. It's not that they occupy a very specific area in the evolution of life that would allow us to reveal, you know, unfathomal secrets.

No, they were selected because they really exaggerated the biological artery. So back in the earlier 20th century, when we were sort of choosing these animals for research, our biggest questions are about genetics and inheritance, and especially when we couldn't do fancy things like analyzing genomes or using CRISPR, small animals that you can keep in a small space and reproduce really, really quickly were really great. And that's why rats and fruit flies were great early model organisms. Okay, so if Alejandro is pretty clear about like the realities about common model organisms, for better or worse. How has this changed what he uses as a model organism?

Yeah, so it's changed what he studies, and he studies a few different animals, but they have one really, really cool property to him. Repairing themselves. And he's really practical about his reasons for studying these kind of weird animals. Take the snail. They have a camera type eye, very similar to yours and mine, with a cornea, a lens, and a retina. And as you know, if you poke your eye, which your mom probably warn you about, that's not going to repair very well. But in snails, if you amputate the eyes, they'll actually grow back as if nothing had happened. I was so, so excited to talk to him about his model organisms because he was telling me that it's really rare to find another lab that's steady snails. But I actually use the study snails,

and I love them. I think they're so cute. I love watching them eat lettuce. They're so tasty. No, I wouldn't eat them. I love them too much. But it was a nice switch up from fly brains, which is a lot of people use in neuroscience. But anyway, in terms of science, they have a really simple nervous system with these important neurons that you could easily isolate and track from that are pretty close to what we have. Okay, so if that's the case, should we be replacing all lab rats with fish and snails, or are there other animals we definitely should be considering too? Not entirely. One of the barriers to using these funky model organisms is the technology, like I mentioned before. There's this whole industry around rats and mice and selling these sort of genetic knockouts for mice where we know we take out one gene so we can study them in these mice. but there's also tools and other things that people use to study mice that we have really downpacked.

Okay. This is something that I talked to neuroscientists Kelly Duncan at Vassar College about. Right now, she studies finches. But there was a lot of other animals that she used along the way. Like, she started out with mosquitoes. She's worked with Norwegian rats, Japanese quail, chickens, and even an ostrich brain. Overachiever. Aren't we all, though?

Here's where she finally ended up. When I first applied for grad school, I initially was really, really scared of birds. Not scared, but I had like a fear of like the movie, the birds. And I thought like birds were going to be pecking out my eyes in the lab. I mean, I'm terrified of like seagulls at the beach pooping on me. So I understand her fear. But what made her land on this type of bird?

Yeah. She's looking at them as this bigger project into traumatic brain injuries and how the hormone estrogen helps the brain heal. Because these finches have a really supercharged estrogen response compared to what we have. And it makes it really, really easy for her to see it in these birds. So I get to see that extreme reaction to this estrogen response and then say, like, okay, if this is what the max reaction is, what would it look like when it's a little slower? Like in humans? Exactly.

And that's what we actually found out, that we see the same reaction, but the time and the scale is so much greater in the birds that it's just such a better model for asking the same question. And then we can go back and say, okay, we found this here. are we seeing the same factors in humans, right? And so that's kind of the question that we ask. It's, okay, if that's what they do, I wonder if this is conserved among many different kind of vertebrates. And how does estrogen fit into all of this? Like, what does a supercharged estrogen response in the brain look like?

Yeah, so estrogen does two things. First, when estrogen is released, it helps protect the brain. Second, it kicks off this feedback loop that turns off inflammation in the brain. And then so that same response that turned it on is actually being turned off by that estrogen so you don't end up with this massive neuroinflammatory response in things like adema and swelling. Wow. Okay. But isn't it harder to use birds? Oh, absolutely. On top of teaching all of her new students how to become really pro bird catchers, she and Alejandro said that there's some improvising that goes on because less people are using their model organisms.

So what's the next step in all this? Is everyone just trying to promote their own, like ideal model organism? So I'm definitely teen-tail. However, Kelly's told me, that what she wants researchers to be is more intentional about their rodent research and sort of just defaulting to it. The problem is we get so kind of pigeonholed and this idea that everything has to be, this mice, rodent model,

that we forget that, like, oh, yeah, there's this whole systems approach, and there could be these natural variations that could really help us target what animals are best for answering this question. There's something to be said for, you know, if you're studying the spinal cord, what is so unique about a lizard who can basically break off a part of their spinal cord and regenerate it?

Like, that's a lot of power. And when I asked Alejandro the same question, he expanded this point about pigeonholing ourselves into a really interesting way. He pointed out, most or many researchers are really only focusing on seven traditional model organisms. Are seven species enough to tell us everything we need to know about what's possible in biology? That's seven species versus an estimated 8 million species of animals out there. It is not a statistically significant representative number of the number of diversity, solutions, and biological activities that are already happening in the natural world. Okay, seven compared to 8 million is really drastic.

Is there any animal he would like labs to start working with now? Yeah, so when I asked him what I could expect in 20 years, if I could walk into a research building and see just like a whole zoo of animals. He told me that his ideal research ecosystem looks like this. You have no impediments to study the biology you need to study because the biology was inaccessible in some exotic organism. We may be able to discover entirely new principles in biology that will help us understand much better how we look the way we look,

why our organs are proportioned the way they are. Lots of questions that probably can be answered by studying a much broader collection of organisms that already exist on the planet. Wow, Anil, I've learned so much. Thank you so much for bringing this story to us. Thanks, Gina. This episode was produced by Liz Metzker and Margaret Serino, edited by our managing producer Rebecca Ramirez and fact-checked by Britt Hansen. The audio engineer was Carly Strange. Beth Donovan is our senior director and Anya Grunman,

our senior vice president of programming. I'm Regina Barber. And I'm Anil Oza. Thanks for listening to Shortwave from NPR. See you next time.