Hey, welcome to sign Stuff, a production of iHeartRadio. I'm hoore Chim and today we're asking why can't we regrow limbs? If you lose an arm or a leg, we know that that arm or leg is not going to grow back, but we know there are animals in nature that can do that. If you cut off a starfish arm or a salamander's leg, it'll regrow a new one. There's even a fish that can regrow its heart if you cut off a piece of it. So how do they do
it and why can't we do it? We're going to talk to several regeneration and animal experts and we're gonna find out if it's possible to activate that ability in people. So get ready to go out on a limb with us as we explore the regeneration of body parts. I promise it won't cost you an arm and a leg. Enjoy Hey everyone. To answer this question, I started by looking up a list of animals that can regrow their body parts. Not all animals can do it, but a few if you cut off a part of their body
doultes regrow it back. On this list are starfish, flatworms, salamanders like the axe lotto and some fishes like the zebrafish and the Mexican tetrafish. We're going to talk to experts in each of these animals, and while we talk to them, we're going to learn three things. Number one, how these animals regrow their limbs, like what's their secret? Number two why humans can't regrow our limbs or can we? And three why do some animals evolve this ability and
others don't? It seems like a pretty handy skill to have, all right. The first expert I talked to was doctor Andrew Wolff. Doctor Wolf is a researcher at the University of Maryland, Baltimore County who studies regenerate in starfish and flatworms. The first thing I wanted to know is can these animals really regrow anything? Well, let's start with the starfish and then we'll do the flatworms.
So starfish are what are called a kinoderm, so that's a phylum of animals. So it's things like sea urchins, sea cucumbers, things called sea lilies or crinoids, where they also have sort of called feather stars that can move, and also brittle stars, so they're somewhat closely related. To vertebrates.
What do we know about tissue regeneration in sea stars and sea urchins?
So my work was understanding regeneration in their larvae. So they're very small, probably like a millimeter or so, very clear. They started to swim around the ocean for about two months or so until they metamorphous into the adult. So you can cut them in half, but those halves will regenerate.
Okay, so you're saying, if you cut at the bottom, half will grow a top and the top will grow by and you'll get too identical animals. Yes, huh. And what about the flatworm?
That's what I'm interested now. And so it not only does it regrow what's lost, it sort of reshapes everything else such that it's not out of proportion. So let's say you cut a worm in the three pieces like a top, of a middle, on a bottom. They'll all regrow what was lost, but the actual ending size of that worm is going to be smaller than the original wholeworm because if the tail regrows to be really small, the brain is going to be too big for the
new body size. So now it needs to reshape everything to be in proportion to the new size that it is.
So these animals will pretty much regenerate anything. If you cut them in half or in three pieces, each piece will regrow what's missing, and then you'll end up with almost identical copies of the original. Next, I talked to doctor Nadia f. Frobish, who is an expert in salamanders.
My name is Nadia Flebish. I work at the Natural History Museum in Berlin and at Humboldt University. I'm a professor for evolutionary biology. Actually, everything that's alive can regenerate tissue to a certain degree, which is very convenient because otherwise I think we would all grow up with a lot of open scrapes and scratches as we go through childhood.
That makes sense, Yeah.
So of course we can all do wound healing to a certain degree, but some animals are even better at it than we are among vertebrates. So the animals that have a background, it's only salamanders that are the masters of regeneration. I think a lot of people are familiar with lizards regenerating tales and sort of throwing them off as a decoy for predators. But lizards, in contrast to salamanders, only get sort of like a fake tale back. It's
more like a rotch of cartilage that's in there. And salamanders, if they lose their tail, they get a brand new tail with retever column and you know, spinal cord and musculature, so just like it was before. And they cannot only do that with their tails. They can also regenerate their limbs. They can regenerate the lenses of their eyes, a huge portion of their hearts, liver, so they're really really excellent regeneration.
Pretty much any part of the body has been tested.
Oh yes, this has been tested. Not any part, but a lot of the parts of the body. So they cannot lose their entire heart, for instance, and then regenerated. There still has to be like a critical amount left in order for regeneration to proceed.
So the muscles, toenails, everything indeed.
And sometimes it's really amazing because when the salamanders bite each other they can have quite gruesome injuries, so where like, for instance, the upper arm bone is sticking out and all the soft tissue is gone. Looking at it, you would think, oh my god, this is never going to grow back, but it does, and it's really quite amazing.
And the last expert I talked to was Ezra Sengul, a graduate researcher at Oxford University who studies Mexican cavefish.
I am Estra, and I use animal models, particularly Mexican cavefish and zebra fish.
Okay, what do we know about tissue regeneration from zebrafish and cayfish?
To start with zebra fish. Together with zebrafish, there are certain kinds of cavefish have regeneration catasity, and they have a remarkable precision. While doing that, they repair their sins, they replace it with an new functional one. They also regenerate their heart, spinal cord, retinas, and kidneys. They use them to study heart repay it in particular because unlike humans, the heart damage leads to starting in unspins, and zebra fish the heart cells replace that lost tissue.
So all these animals basically have a superpower. If you're thinking of Deadpool or Wolverine from the Marvel movies, these animals can do what they do and they're real. Chop off leg and a new one grows back. Cut some of them in half, and both halves regrow into whole new organisms. I had a lot of questions. First of all, how do you even regrow a limb? And second of all, why can't we and other animals like cats and dogs
and birds do this? To start, I asked our experts to give me a play by play of what actually happens when these animals are missing a body part. According to them, it's a step by step process, and it's pretty similar whether you're a starfish or a flatworm or a salamander. Step one is basically stop the bleeding.
So the very first thing that's happening and that has to happen in order for regeneration to proceed is the wound healing. So the wound has to close over just like you know, we would have a wound if you.
Think you're in the water. You don't want a bunch of stuff coming in and bacteria and all that stuff. So you have to heal the wound. There's different mechanisms that they do. Think like a purse string it sort of steals it, or you just have cells that spread that just close it up. Obviously, if you don't heal, then you're gonna fall apart. So there's a structural component.
But that's the first thing, okay that makes sense. You first have to close off the gaping wound. That happens when you get an arm or a leg cut off, but that also happens when we get cut Our bodies also close the wounds. So why do we stop there and those animals don't.
And it's really interesting is that the wound itself can signal to the rest of the body that regeneration needs to happen, big major thing that needs to happen for regeneration to proceed. So it's like a general response to a wound. But then from there it either says now I need to regrow or not.
It says different signals.
There's some sort of mechanism that they can detect that tissue was lost versus I just sort of made a cut. Something from the wound itself is able to recognize now I need to regrow ahead.
So this is a key part of the process. Somehow these animals as bodies are able to tell it's missing a limb or a body part. There's some kind of signaling that happens that says, hey, this isn't just a flesh wound. We're missing an arm or a leg, and that calls in the cavalry. So once this signal goes out. You said it mobilizes things. What does that mean?
So for regeneration, you need cells to make stuff right. Anything that you need that was lost needs to regrow, so you need to have cells for that. They have some sort of stem cells that mobilizes, stay, divide, then move to whatever they need to be, and they become the tissues that need to become.
In salamanders, you have a few stem cells that are still in the system, but you also have cells that are sort of losing their identity that are sort of re entering the cell cycle to become something you're everywhere in the body, and then are recruited to that side.
They actually move.
Yeah, cells move a lot all the time. Actually, really.
Okay. The next step is for the body to recruit a bunch of cells where you want the missing body part to grow. But these aren't just any cells. They have to be stem cells. If you haven't heard what these are. Stem cells are cells that can become any other kind of cell. If you think about it, the cells in your skin are very different than your eye cells,
or your muscle cells, or your brain cells. That's because these are all cells that have become specialized parts of their DNA have been switched on or off so that they grow a stertin way. That's good because you wouldn't want your skin cells to suddenly turn into an eyeball cell, or you wouldn't want your brain cells to suddenly become muscle cells. Stem cells are cells that still have all their options open, and these are the cells that get
called up to regrow a missing body part. Now, what's interesting is that some animals just have stem cells floating around their bodies, and some animals are also able to roll back their specialized cells to become stem cells. This part is going to be important later, but for now, just imagine a whole bunch of stem cells congregating at the wound site where the animal lost a body part.
And they form this sort of massive cells at the wound site. Oh okay, last, it's a term for sort of they haven't fully met their fate. Yeah, they sort of accumulate at the wound site, which.
Is sort of like a nose if you want to, like a cone on the end of the limb, which is the gross thoughe where all the cells are proliferating.
Okay, so where you cut off a limb or a piece of heart or a fin A blob of stem cells forms, and from that blob grows the new part. We're gonna talk about how that blob knows what shape to grow into, which is super fascinating, and we'll talk about why us humans can't do any of this. But first let's take a quick break. You're listening to sign stuff. Okay, all right, So now we've got this massive of cells who are there to regrow whatever's missing. How do they know what to regrow?
It's a great question, a very complicated question that we don't quite one hundred percent know the answer to. It depends on sort of what the tissue is. There's some sort of way that the animal is able to detect this is what's missing, and I think it's related to the idea of physitional information.
Okay, we talked about how when you cut off a limb or a body part, these animals with this superpower start by closing the wound and then amassing a lump of stem cells where the body part used to be. The next question is how do these cells know what to grow into? I mean, you wouldn't want a tail or a brain to grow where your arm used to be and The answer is that every cell in your body gets signals about its positional information. That is, somehow cells seem to know where they are or where they
should be in the body. And this is something that scientists don't fully understand yet, but it involves basically every cell talking to every other cell through special chemicals and molecules. And in this case, scientists have noticed an interesting pattern about how this works.
The way it works is that the tip of what has been lost is sort of specified first genetically, and then you have sort of a dissonance between that very tip and whatever the stump area is, and that dissonance or that disconnect between those two genetic identities leads to that growth and to the exact replacement of everything that's.
In the middle betweening. Wow, how does the tip not to turn into the tip?
It's a genetic marker sort of their genes expressed there that are saying you are the tip now and like giving it that identity.
Oh I see. It's like the distensios that are at the tip, they're like, okay, I don't see anyone else around us. We must be the tip exactly. That's fascinating. But then how do the cells in the middle know how to fill in the middle.
Well, we haven't actually sort of researched all the details of that entire process. It's really it's sort of an interplay between cells dividing and genetic markers giving those cells positional identity, like saying this is where you are now you are a wrist bone, or you will be part of the wrist area, or you will be part of the musculature that is in the lower arm, kind of like that. It's an incredibly complex process actually, so it's quite amazing that it works so well.
In other words, scientists don't quite know how the cells in animals that regrow body parts know what's missing or where they are or what shape they're supposed to. Mank, they just do, Like all of that is in our DNA to recognize, Oh, I'm between the tip, I'm about three quarts of the way between the tip and the shoulder. I must be you know, for our bicyle cell.
Wow, Yes, it's all in the genetic markers.
Like I said, it's a superpower. But as our experts point out, it's basically what happens when you grow in the first place, when you go from a fertilized egg to a fetus and eventually to a grown person. Somehow your cells know how to grow every part of you. Animals that regrow their body parts basically just reactivate that growing ability we all have in our DNA. Okay, the next big question is why don't all animals have this ability? How's a starfish, a flatworm, or a salamander different than
us or dogs or cats or monkeys. Why can't every animal regrow limbs? What do you think it is that flatworms and starfish have the humans don't have?
Yeah, the million dollar questions people always like, if you find something in the lab, can I just grind up the worms and inject it into my arm?
You could be a starfish man.
Yeah, I mean, hey, that wouldn't be too bad, I guess.
So.
One other thing that I haven't mentioned so far is scarring. It stops regeneration and a lot of context. So if you cut off your hand, God forbid, you have obviously a wound response, and it's going to heal and it's going to scar. When a lot of these other things regenerate. The starfish, the worms, even things like a salamander, an axle auto, they don't scar. It's a major sort of block of regeneration, and also that inflammation prevents a lot
of these other steps that could be happening. There's little to no inflammation and a lot of these animals that can regenerate. So it's a relationship between scar and inflammation and ability to regrow.
Ah, here's the first piece of the puzzle. Animals with the ability to regrow body parts don't scar and they don't get inflammation when they get cut. Making a scar is basically like patching a hole in your wall with a giant pile of bricks. Scar tissue is thick and tough and dense, and it basically gets in the way of regrowing a new body part.
But these simpler animals, they just seal it up and that seems to be enough.
They don't make a scar, basically, they do not, So that's one factor. The other fact that you said was inflammation. So when we get cut, it becomes inflamed, and how does that make things hard to regenerate?
So it prevents any of the later steps from happening. It just prevents the ability of the tissue to regrow.
It's not a happy state for cells to regenerate. No, that is not. What doctor Wolf is saying is that when we get an arm or a leg cut off, our body basically overreacts. It rushes to patch up the wound, building thick SCRs that block any regrowth, and it deploys the immune system, which makes everything so inflame that it prevents all the steps needed to regrow the body part. Cells don't revert back to stem cells, they don't divide well, so they don't form that block of generic cells that
can then become the missing part. So now the question is why do we do that? Why do our bodies react that way, especially because at some point in our evolutionary history it seems we did something different. Okay, now the question is why can't humans regrow our lips or can we? Is that possible?
Well, that's a question that always comes to all people who who work the regeneration. We always get that question, and that's not an easy question to answer because it's probably a combination of very complex factors that play the role in this.
But we know from the.
Fossil record that a lot of the ancient amphibians could regenerate too, and lungfish are the closest living relatives of os fourlimd vertebrates can also regenerate very similar to salamanders. So it is likely that regeneration as we see it in salamanders now is actually not something that is special to modern salamanders that evolved. But salamanders probably are the
only living vertebrates today that can still regenerate. Back in evolutionary history, that was probably a widespread feature that then got lost in the course of evolution.
Oh so interesting. It's not like they developed the special ability, they're the only ones who kept it exactly. Oh my goodness. What doctor Frobish is saying is that at some point basic all animals were able to regrow their body parts. Salamanders, starfish, flatworms. They don't have a superpower. It used to be a standard feature of all animals. But evolution at some point said, eh, you know what, let's not do that. It's not a skill some species evolved, it's a skill some of us lost. Okay.
The obvious next two questions are why did evolution choose not to regrow limbs in species like ours? And if it's something we had but lost, could we bring it back. We'll answer both those questions after the break. We'll be
right back, and we're back all right. We just learned a shocking piece of information, which is that scientists believe it's likely that basically all animals, these ambiotes, which are all for legged animals, used to be able to regrow missing body parts, but at some point in our evolution this ability was selected as not being the best for our survival, which is strange because you think that being able to regrow limbs would be a good thing. I mean, if you use a leg you can't really run away
from a predator that's trying to eat you. So I asked our experts, why would we lose this ability?
It seems like something so useful to have, right, that capacity to regenerate, but it also comes at the cost. So during the course of evolution, it probably was a matter of a trade off, and it's probably for that reason that regeneration was selected against during evolution at some point in amniote evolution. And it could have happened once, it probably had happened multiple times.
Oh well, what's the trade of.
Salamander's a giant cells, So they have like huge cells because they do have a lot of DNA that they accumulate. They just can afford to have all that DNA, But all that DNA has to be the transcribed, right, it has to be done for a second copy, and that caused a lot of energy and resources.
Okay, the first reason we might have lost our ability to regrow body parts is that there's a cost to having that ability. First of all, it requires extra DNA. The program to regrow LIMB takes extra instructions and extra genes that can come at a cost, especially if you want to move faster and have a faster metabolism. I wonder if what you're saying is that at some point in our lineage, the evolution pressure was to like, hey,
let's make things more efficient. We don't need all this DNA, and maybe one of the cuts was our ability to regenerate.
Yes, that's it. So it's not just that we lost DNA. It's also that we have to go through cell cycles at a certain speed in order to keep our very high metabolism that allows us to run really fast, to sustain a constant body temperature, and do really powerful energy consuming things like run and fly and do these kind of things. If you have a very high metabolism, you have to go through these processes of making new cells quicker than when you're an organism with a very slow metabolism.
We're constantly building new cells all the time, regenerate your skin, your hair is growing, You're making new blood cells all the time. Salamander's day can regenerate because they don't have to sustain such a high metabolism. We cannot regenerate, but we can run fast and keep our body temperature or fly in these kind of things.
What doctor Frobish is saying is that any extra ability meets extra DNA, and that can come at a cost if you want to be more active, because being more active means you're cycling through cells more. And each time you make new cells, you have to copy all that DNA, which takes a lot of energy. And the other cost is that it's just a lot to grow a new arm and a leg. I mean, you have to make a whole new limb from nothing.
Can you imagine having a stump for how long to regrow all of this complex tissue. It would take a lot of energy and it'd take a lot of time. If the best thing to do is just to close it and seal it and make sure the structure there. With that scar is sound. Then maybe that's for the best, maybe more advantageous energetically and also just structurally to do that.
Oh interesting, Maybe we don't need that extra arm. Maybe huh, I guess you don't. Technically, you don't need an extra arm to have more babies.
Yes, that is all true.
So that's the reason we can't regrow limbs. We, meaning four legged animals, used to be able to, but evolution at some point decided it's not worth it. Losing an arm or a leg is a huge deal if it happens to one of us, but as a species, maybe it's okay. Maybe it's better to just cut our losses, patch things up quickly with scar tissue, clean it up, and move on if it means everyone collectively being more
efficient and having a faster metabolism. Now you're probably thinking, if the ability to regrow body parts was in the DNA of our animal ancestors, could we revive it somehow so that we can all regrow limbs again. I'll get to that in a minute, but first I wanted to tell you about something kind of cool about the Mexican tetrafish that sort of proves the whole hypothesis about why we can't regrow limbs. Here's how Ezra describe these fish.
It is such a unique and perfectly slitted model organism to study it because it has two different sometimes. So the surface dewelling version has this silver colored functional eyes and dailian streams. They look very much like what we know f fish. But the cave dwelling version is tail pink. It is almost translucent. They don't have functional eyes.
Okay, the Mexican tetarfish is fascinating because it's at a point where it's about to possibly evolve into two different species. There are currently two kinds of Mexican tetarfish. The ones that live normally in the rivers above ground. Those are called the surface dwelling kind, and there are the ones
that live inside of caves. And the ones that live in the rivers on the surface can regenerate their hearts, but the ones that live in caves can't, even though the still technically the same species, So some of them can and some of them cannot. You said, it's related to where they live. What do you mean it's related to where they live.
During evolution, the cave dwelling version lost its ability to regenerate their hearts, and it is because they entered the caves, they got thropped there and they had to continue living in a complete darkness with no enough food and no external food sources. They had to minimize their metabolism, and they had to find a way to compromise from the things that they don't really need to survive, and heart regeneration happened to be one of them.
So basically we're seeing the whole theory of why we can't regrow limbs play out right in front of us. Some of the tetrafish have migrated to live deep inside caves and because there is little food, low oxygen, and not as many predators, we can see evolution in real time basically say, eh, we don't really need to regenerate hearts. It's better to throw out that skill and save energy. Wow, that's so interesting that they would lose that ability. Do they know how they lost it?
There are some genes that are responsible, but there are so many we only started exploring these.
And this is where we get to the edge of current signs, because if we can figure out how exactly we lost our ability to regrow limbs, like if we figure out which genes got turned off or lost, then maybe we can get that ability back. I asked our experts if they thought this was possible. All right, last question, doctor Wolf. If you could enable humans to regenerate limbs, parts of our organs, how would you do it?
Ooh, okay, Well, technically, I will say we do have some regeneritive capacity, so parts of your liver can regenerate. There's also a lot of research and information about the tips of your fingers, so kids could regrow the tips through your fingers.
I've had that happen to me.
Yeah.
Yeah, So we do have.
Some ability, but over time you just begin to lose that ability, so we're not quite the worst. I believe birds are famously not that regenerative. But if I had to make a human regenerate, I think there's several things that need to happen. One is, scarring needs to be minimized, Inflammation needs to be minimized. We need to mobilize those cells enough.
What you said that it's probably the same kind of signaling that happens when we're first growing to art. Originally, yes, that would be the idea.
So how is it that digits were made in an embryo, take some of that information and see if those sorts of things can be turned on again because we have them now.
There might be a sheer genetic program in all forlimp vertebrates that is still present to a certain degree.
Meaning it might still be hidden somewhere in our DNA, but somehow it's not activated. How would that work, like through gene editing, go into human DNA and like, oh wait, here's something that needs to be tweaked, and this here and there and there, and oh, now we have the ability to regenerate limbs.
So it will require a lot of different scientists coming together, which will be like the biomedical people, the molecular biologists, people working specifically with Excel models and other organisms as model organisms to really understand all the details of the processes. So I think in the end, all these lines of evidence will come together to know what the process is triggered by and how to maybe implemented in humans at some point in time.
All right, So the answer to the question why can we regrow limbs seems to be who says we can't? That ability might be hidden inside of us and all we have to do is regrow it. Thanks for joining us. Be sure to subscribe. See you next time you've been listening to Science Stuff production of iHeartRadio written and produced by Me or Hey Cham candited by Rose Seguda, executive producer Jerry Rowland, and audio engineer and mixer Jasey pepperm
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