Short Wave - The Tiny Worm At The Heart Of Regeneration Science

Episode Date: September 29, 2023

A tiny worm that regenerates entire organs. A South American snail that can regrow its eyes. A killifish that suspends animation in dry weather and reanimates in water. These are the organisms at the heart of regeneration science. But exactly how they do these things is still a mystery to scientists. Today on the show, Regina G. Barber talks to microbiologist Alejandro Sánchez Alvarado about this mystery. They get into what regeneration looks like, why humans can't do it (yet) and where the science may lead us in the decades to come. Listen to Short Wave on Spotify, Apple Podcasts and Google Podcasts.Have a science mystery? Send us your questions to [e-mail] 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

Before we begin, heads up that next week is NPR's Climate Week, where we'll spend seven days focused on innovators working to build a better world for the next generation and the one after that. On Monday's episode of Shortwave, we'll hear how a robot is cleaning up toxic seaweed. And you can also check out more stories of human ambition fighting very human problems at npr.org slash climate week for a spotlight on solutions. You're listening to Shortwave. from NPR. This year I moved to Washington, D.C. I was completely intoxicated by the idea of being in a city,

seeing massive buildings and people buzzing around, because after years of living in a sleepy town in the Pacific Northwest, all I want is life. But as Alejandro Sanchez Avarado knows, really whether it's a bustling city or the countryside, basically anywhere. There's life. I grew up in a large city in Caracas, Venezuela, but it's been my summers in a cattle ranch, which was run by my grandfather. And while we were trying to raise cattle, nature had other

ideas. There were all kinds of animals trying to eat our cattle. There were all kinds of insects trying to get us sick. There was all kinds of things going on. But what I remember most distinctly from those days is the immense diversity of life. both plants and animals that would just pop out of nowhere. But it wasn't until only later in his life that he realized how these early experiences shaped his love for biology. Today, Alejandro is a molecular developmental biologist, and he doesn't go anywhere without looking for life forms, even in some pretty unlikely places, like the stagnant water

in an abandoned fountain. Literally puns come. There was all kinds of critters living in there, trash, all kinds of crap. One noteworthy creature in the ponds gum, a strain of planaria called Shmetaia Mediterranean, a type of flatworm. They are about the size of atonial clipping. Their eyes look like their cock eyes, so they look almost like a manga cartoon. And they locomote with this cilia on their ventral surface that makes them look like they are gliding on ice on a surface of water. And it turns out these little worms are helping biologists like Alejandro solve a huge biological riddle.

regeneration. I'm not the regeneration of personality, not the regeneration of spirituality, but no, just the regeneration of missing body parts. Things that we can quantify, we can measure, and we can objectively say that this damaged tissue that is no longer functional was restored to its full functionality

by a process called regeneration, which still remains mechanistically mysterious. Alessandro spends his time studying a few animals in hopes of understanding regeneration better. A South American snail that has eyes similar to humans but can regrow them. A Mozambique killafish that suspends animation in dry weather and then reanimates around water. And this particular flatworm that Alejandro is especially interested in because... You can cut these animals in any way that you like, and each of the fragments will go on to regenerate a complete animal.

That's the equivalent of me cutting a piece of myself, and watching that piece regenerate another me. These animals, out of a piece of flesh, can reorganize every component such that they can produce a head, they can produce eyes, they can produce a digestive system, and all of it end up looking like the original animal. Without prior experience or practice, it's really amazing. So today on the show, how a tiny worm-like organism is changing science now,

and why Alejandro envisions a future of human regeneration, thanks to animals like this worm, and technology like AI. I'm Regina Barber, and you're listening to Shortwave from NPR. Okay, so Alejandro, when you're talking about regeneration, I kind of start to think about things like immortality, reverse aging, stuff that I'm skeptical of, right? But scientists have known for hundreds of years that flat worms can regenerate. Yes. So what's so special about that? one you found in this pond scope. So we were looking for something that would be amenable

to molecular dissection. So more often than not, animals in the wild, they manage their genetic information in ways that is quite different from the organisms that we usually use in the lab. What do I mean by that? You and I are deploids, so we have 23 pairs of chromosomes. where some animals out there that are triploid, tetroploid, pentaploid, hexaploid. So they copy their genome multiple times in their cells. And that adds an extra layer of complexity to dissecting the molecular or their pinnings of the process that we wanted to identify an animal that would be diploid like you and me, that would have the ability to regenerate easily and rapidly.

And we also wanted something that had a relatively small genome size. because we imagine that as technology progress, if we were to find an animal with a small genome, we should be able to sequence the genome of these animals. And so that was one of the main reasons that we decided to select these animals, besides the fact that they regenerate like there is no tomorrow. But humans are different, right? We can't regenerate eyes or limbs. So as a biologist, what happens to our human tissue and our cells as we age?

Okay, I'll up the ante. We don't know why we die. Forget disease, forget wasting. Imagine that you're perfectly healthy. You have all your faculties. You may be 100 years old. And your physician tells you, well, you know, you're old, but you know you're fine.

And the next day you're dead. We don't know why we die. And so even the most fundamental questions, right, we don't have answers to. I mean, I like to know the answer to that. And here's the problem, Regina, as I see it, is that we only get interested in human biology when we're sick.

Yeah. But what happens when you try to cure a disease whose origins, you just don't know. And why don't you know? Because you don't really know how the normal tissues before they get sick actually work. And so, you know, genes that are associated with human cancers, okay? They were discovered in diseased tissues. Like, I give an example. There's a molecule called P53.

People assume that the reason why these tumors are wrong, is because P53 and a few other genes have been mutated. That's not necessarily cause and effect. That's a correlation. You can go back in evolutionary distance to a simple organism, one that only has one cell called coanoflagellate. And if you sequence its genome and you look at what genes are in that genome, you find these cancer genes.

And so what is a single cellular organism doing with a tumor suppressor? So that suggests to us that the ancestral functions of many of these genes probably has nothing to do with disease. So I think it behooves us to understand the fundamental functions that all of the genes codified in our genomes actually do. And we really don't know. We have so many genes whose functions are completely unknown to us. Then what is your best hypothesis on why it's so challenging for humans and seeing that? by many impossible to regenerate. One hypothesis that we like to believe my providers with a little understanding of why this

phenomenon is so unevenly distributed across animals may actually reside in those parts of our genome that do not code for genes. This is what people wrongly referred to as junk DNA, the space of the genome sequence that did not code for any proteins, right? But these particular segments have functions that allow genes to be turned on or turned off. They're kind of like switches. And we really don't understand what the circuit board looks like. We know there are switches in there.

We know we can delete one of those switches. And then all of a sudden, you lose the function of a gene because it's not being turned on or it's not being turned off. And so one hypothesis that is alive in the lab right now is that this switch. are actually changing through evolution. And depending on what the selected pressure was on a particular organism to grow to adulthood and reach sexual maturity so it can actually reproduce and perpetuate itself, may have required them to lose one part of the switch that allow them to regenerate. And so what we're finding is that we have a shared switch, us humans, with killifish.

And in killifish, that switch is required for driving regeneration of the tail in the animal, including heart regeneration. We have that switch. Wow. But that switch in us only works during moon healing, but not in regeneration. And so we could, in principle, compare those switches to each other and then see what makes it possible to regenerate in the killifish, and what is it that humans may have lost or modified that prevents that activity from taking place.

I mean, but that's one switch. Now, imagine a chip, because that's what that circuit board looks like, a chip with like, you know, 300,000 transistors, right? Each transistor being a switch, that's really what our genome looks like, and we just have to go one switch at a time to try to figure this out. So I don't think it's going to happen tomorrow, but I do think that it's going to happen, at least in this century. I do think this is the century where a lot of these biological problems, problems are ultimately going to succumb to scientific inquiry. So you had just said, you think there's going to be these advances this century. Can you tell me a little bit more about that? So in the, let's say, 18 and 19th century where biology became a somewhat respectable science, data was very, very difficult to collect. So biology was awash in theories, plenty of them. But now we can collect data like there is no tomorrow.

And the reason for that is because technology has turned from linear technologies to exponential technologies. So it used to be that one PhD student in the 70s, his or her PhD thesis would be sequencing one gene. Okay? We can sequence a whole genome in a day. And so I believe that while we have some principles in biology, we understand, we need to discover a lot of new biology that will lead us to the discovery of new principles of biology. that are currently operating, but they're invisible to us. And so I think that this next 10, 15, 20 years are going to see an emergence of that kind of thinking.

And that's also going to be aided by, you know, machine learning and artificial intelligence. Right. And who knows? We'll get a quantum computer in the next 10 years. And all of these calculations will be absolutely trivial. I mean, who knows, right? Yeah. Because on top of that, Regina, we also have this new technology, Chris Perkast 9, that allows us to really modify gene.

at will. And so all of those elements combined made me think that we really are at an inflection point in the history of biology. So 10, 20 years, you think that we're going to get to a point where we can actually analyze this data. All these new discoveries are going to come up. What do you think then is the timeline or the soonest, the tiniest bit of regeneration can happen in a human? We are going to get really good at regenerating. issues, for example. I mean, that's already happening. I think it's going to take a little longer for us to be able to regenerate like complete appendages, for example. But I think if you want to regenerate neurons, for example, if you want to regenerate muscle, for example, if you want

to regenerate things like the cells that produce insulin in the pancreas, I think that those things will become a reality. I mean, they are becoming a reality in the next decade or so. Oh, wow. You know, we have a situation, for example, of a stem cell-based therapy that allows people who are blinded by chemicals on their cornea to remove that cornea and use the eye that was not burned to regrow cells to regrow our cornea. And this individuals recover their vision. What? Yes. This is already past phase three clinical trials.

But, you know, regenerating a brain or a full heart or lung, that's going to take a, a significant amount of work because we still don't understand how these organs are really fashioned, how they are regulated in their specific functions, and how they have the right numbers and the right types of cells to execute their work. But I think in due course, and I would say less than 100 years, we should really have a very clear idea of how these processes may be taking place. Thank you so much for talking to us today. I've learned so much. I'm very thankful for the opportunity. Thank you. If you've been enjoying this episode, give us a follow on your podcast app,

so you get alerted each time we publish a new episode. And if you have any story ideas, send them our way. Our email is shortwave at npr.org. This episode was produced by Rachel Carlson and edited by our managing producer Rebecca Ramirez. NILOza Check the Facts, and the audio engineer was Robert Rodriguez. Bet Donovan is our senior director, and Anya Grunman is our senior.

vice president of programming. I'm Regina Barber. Thank you for listening to Shortwave from NPR. So I just wish I were younger. That's all I have to say. I wish I were younger so I could see this. Well, if your work is successful, you know, you can keep on doing this for him. I guess that's true. I guess that's true. I guess I could be my own guinea pig, I guess. That's right.