A Hand, a Fin, a Gene
Have you ever watched a fish swim and thought that all of the long, tiny bones in its pectoral fin looked a bit — just a little bit — like fingers? Or seen a salamander that’s regrown its tail after a close call with a predator, and wondered why we can’t regenerate our limbs? As scientists learn more about the genes that shape animal musculoskeletal systems, they’re uncovering clues about how our own limbs developed — and may someday regenerate.
For instance, while it’s long been known that there are similarities between our arm bones and other bones in a fish’s fin, scientists once thought that the skinny, finger-like bones of the pectoral fin had been lost in our common ancestor.
Now, new research from the University of Chicago suggests that an evolutionary link does exist between fish fins and mammalian hands. In the study, researchers eliminated select Hox genes, which give segments in the body identity, from the genomes of zebrafish and mice. They found that the mutations led to a mouse limb with no fingers, and a zebrafish fin with significantly reduced fin bones.
Kim Cooper, a professor of biological sciences at the University of California-San Diego, says the study’s findings indicate that the genes to make long, pectoral-fin bones in fish may have been repurposed to make hands.
“If you think about building a building, instead of going and buying all new construction materials to make a hand, you’ve gone to the salvage yard and taken some of the information that was there in the fish to make a hand by similar processes,” Cooper says.
Meanwhile, researchers at the University of California-Irvine are wrapped up in another question about limbs — namely, if other animals can regenerate their limbs, why can’t we? Dr. David Gardiner, a professor of developmental and cell biology at University of California-Irvine, is looking for answers in the axolotl, a rare Mexican salamander that’s often studied in labs for its ability to regenerate.
“When we look around and see all these animals and plants and life forms on Earth, they have evolved for hundreds of millions … of years,” Gardiner says. “And so these experiments have been going on. So you look at an axolotl and it shows you that the mechanisms are there to regenerate, and they’ve discovered how to do it. So the answer is to tease out a part experimentally, and figure out what the steps are. And then once you know the steps, then we should be able to do that in humans.”
In a video for Science Friday, researchers at the University of California-Irvine illustrate how axolotls can even grow extra limbs, like a third arm. When a wound is grafted with skin from another area of the axolotl’s arm with a different positional value, the newly neighboring cells of the wound and graft can “fill in” what would normally lie between them, like an arm.
What we don’t know yet is why human cells can’t spur the same type of regeneration. Gardiner says that our cells may already have the information they need to regenerate, and for some reason aren’t acting on it.
“The Hox genes, for example, are very stable,” Gardiner says. “And they are very positionally expressed in humans. So we’re seeing that maybe the information is there. I personally would point out that it’s very difficult to distinguish between stimulation and dis-inhibition. So we keep thinking, well why can’t humans regenerate? But the other possibility is that we do regenerate, but it’s being repressed. … Because there’s so much regeneration everywhere in the animal world.”
Cooper adds that from an evolutionary perspective, this possibility is worth exploring further. “If you look at the evolution of regeneration, we do know that it was a loss in species that can’t regenerate and not something that’s special about an axolotl, for example.”
Kim Cooper is an assistant professor of biological sciences at University of California-San Diego in San Diego, California.
David Gardiner is a professor of developmental and cell biology at University of California-Irvine. He’s based in Maui, Hawaii.
IRA FLATOW: This is Science Friday. I’m Ira Flatow. Have you ever looked at your hand or you five fingers and thought that it must be an evolutionary descendant of all those long tiny bones at the end of a fish’s pectoral fins? Up til now, many scientists have said, no, the bones even formed through different processes during development. Can’t be the same thing. But new research from the University of Chicago says, actually, there may be an evolutionary link, after all.
Here to explain it Dr. Kim Cooper, Assistant Professor of Biological Sciences, University of California San Diego. She looks at the evolution and development of bones in other animals and wrote a commentary about the research. In Chicago, Kimberly Cooper, welcome to Science Friday.
DR. KIM COOPER: Hello, Ira.
IRA FLATOW: Hey, there. Well, let’s go back a little bit and talk about what we used to think. Why wouldn’t fins and hands be related? You know, you look at them and they look like, hey, they should be related.
DR. KIM COOPER: So, superficially, they look related because both have long bones that are oriented away from the body, but actually, the skeleton of our limbs develops entirely differently. It forms in the embryo on a cartilage scaffold that is then replaced by bone, whereas in the fish fin, those long, skinny bones are actually directly formed by ossification in the skin itself.
IRA FLATOW: Hm. So this new research found that there really is a connection.
DR. KIM COOPER: So there is. Right. So we’ve known for a long time that the arm, the upper and lower arm bones were similar to other bones that are in the fish’s fin, but we long thought that those long, skinny bones were lost in the common ancestor leading to the lineage to humans and that the hand was this novel structure. And so what they found is that instead of– so if you think about building a building, instead of going and buying all new construction materials to make a hand, you’ve gone to the salvage yard and taken some of the information that was there in the fish to make it a hand by similar processes.
IRA FLATOW: Hm. So is that kind of exciting, kind of shocking?
DR. KIM COOPER: It is. It was really surprising because the two structures have a very, very different outcome in the way the bones form.
IRA FLATOW: Mm-hm. What does this say about the big picture of how mammals evolved in our relationship to modern fish?
DR. KIM COOPER: It tells us that the early developmental mechanisms that give rise to the structures of our skeleton, of our hand, if you look at a fish, the cells and the genes that make those long, skinny bones in the fish were repurposed to make our own hands. So it makes me look at fish a lot differently.
IRA FLATOW: Hm. And the discovery that there might be a common gene for both of them
DR. KIM COOPER: Yes. Yes.
IRA FLATOW: Tell us about them.
DR. KIM COOPER: Right. So the Hox genes are known to give segments throughout the body identity and some of these Hox genes are expressed in our hands. And in mice, if you mutate these Hox genes, then the mice don’t have hands. And nobody had actually done the Hox mutation in fish before because there are more of the genes that you would have to mutate, but with the CRISPR-Cas9 technology that lets you edit a genome very rapidly, the Shubin Lab was able to eliminate the three Hox genes that they were interested in and they found, surprisingly, that just like in a mouse that is missing its hand, the fish fin has a very, very severely reduced skeleton. So the same genes that are responsible for forming our hand are also responsible for forming this part of the fish fin skeleton that we thought had absolutely no relationship to our hands.
IRA FLATOW: So there’s the connection. Right?
DR. KIM COOPER: That is the connection.
IRA FLATOW: In the genes.
DR. KIM COOPER: Right. Exactly.
IRA FLATOW: Did something happen along the way? I mean, just thinking out loud there. If we change the gene in our bodies, could we make it into a fish fin or vice versa?
DR. KIM COOPER: So the way that they did the experiment, actually, it was very interesting because the fish have these Hox genes that we have, but they don’t actually have the regulatory sequence that expresses that gene in fingers. And so what they did is they took that regulatory sequence and they put it into the fish and that’s what they used to permanently mark cells that gave rise to those long, skinny bones. And so what is interesting is where did those regulatory sequences come from? How did the cells manage to develop a new program to turn those cells into fingers instead of turning them in to fins?
IRA FLATOW: Huh. So what does this say about the bigger picture of how mammals evolved in our relationship to modern fish?
DR. KIM COOPER: It tells us where our hand came from. But the lineage to mammals has been elaborated even further by evolution. So if you look at– this is one of the things that my lab is really interested in– if you look at many, many species of mammals, you’ll see that like bats have wings and horses have a single toe and dolphins have flippers. And we study this little bipedal rodent that has a very dramatically changed hindlimb that lets it jump around.
And so the work by the Shubin Lab tells us where the hand came from and then other mechanisms elaborated that structure to give us the great diversity and form that you see today.
IRA FLATOW: Wow. So where do you go from here?
DR. KIM COOPER: I’m [INAUDIBLE] around.
IRA FLATOW: What’s the next research question you want to answer?
DR. KIM COOPER: Well, the next research question that my lab wants to answer or the follow up of the Shubin paper?
IRA FLATOW: Take your pick.
DR. KIM COOPER: Right. OK. The next research question that my lab wants to answer is to try to understand how the integrated musculoskeletal system of the limb is shaped by the genome. What are the changes in the DNA sequences that deploy genes in different ways to give you different shapes of a limb? And so specifically, we’re interested in scaling of the digits. So in the Shubin work, they’re showing where the digits came from. And we’re interested in seeing how those digits get reshaped by rewriting the information, how evolution has rewritten the information in the genome to do that.
IRA FLATOW: Wow. Sounds fascinating. You’ll have it figured out by Monday, I’m sure.
DR. KIM COOPER: Yeah, you know, I’m going to just work all weekend.
IRA FLATOW: Thank you, Dr. Cooper. Nice to have you.
DR. KIM COOPER: The good thing is that evolution gives us job security.
IRA FLATOW: Stay with us because we’re going to bring on– I want to bring on another guest. I want to turn to another interesting question in the studies of limbs, which is why don’t our fingers or our hands our legs grow back when we lose them? Other animals grow back their limbs. Why can’t we?
Dr. David Gardner is Professor of Developmental and Cell Biology at the University of California Irvine. And he is a specialist in the axolotl, a salamander that’s nearly extinct in the wild, but much studied in labs because when they cut off one of their limbs, it grows back. And there’s a great video on our website showing this process in action. It’s amazing in explaining how it works and you can visit that video at sciencefriday.com/limbs. Welcome to Science Friday, Dr. Gardner.
DR. DAVID GARDNER: Great to be here, Ira.
IRA FLATOW: So how does an axolotl get its sort of magical properties? You can actually cut off a leg and it just grows right back.
DR. DAVID GARDNER: Yeah. Well, lots of animals can regenerate. We regenerate really well. If you cut off an arm, it doesn’t grow back, but all the bits and pieces of the arm pretty much regenerate really well. That’s what keeps us going. So I think the question would be more like, why since everybody else can do it, why don’t we? And there must be some selection against us regenerating the way an axolotl does.
IRA FLATOW: And how would you answer that question?
DR. DAVID GARDNER: Well, if I know the answer to that, we’d be generating arms and legs right now. But I think it goes back to the evolution question. So I really enjoyed the comments that Kim had to make because I think it’s important to realize that when we look around and see all these animals and plants and life forms on Earth, I mean they have evolved for hundreds of millions and billions of years.
And so these experiments have been going on. And so you look at an axolotl and it shows you that the mechanisms are there to regenerate it and they have discovered how to do it. So the answer is piece that apart experimentally and figure out what the steps are. And then once you know the steps, then we should be able to do that in humans. Walk through step by step that gives you the outcome of regeneration.
IRA FLATOW: But you did that and that’s what’s so fascinating about this video. You did that with the axolotl. You actually had it grow a third limb by cutting out just a section of one of the arms and then tell us– well, I’ll let you tell us how you did that.
DR. DAVID GARDNER: Well, it goes it goes back to the basic idea is that in response to injury. So injury starts it all. Then there’s going to be a sequence of events. And this is going to happen and then the next thing will trigger that and then that will trigger. So it’s step wise. It’s step by step. And the question is, what are those steps and what are the choices? And somewhere along that process of making those choices, axolotls make a choice that we don’t so we stop.
IRA FLATOW: Well, I want you to get into the exact method because it’s fascinating.
DR. DAVID GARDNER: Oh, the method itself.
IRA FLATOW: Yeah.
DR. KIM COOPER: I teach this in one of my classes and it’s really complicated.
DR. DAVID GARDNER: OK. So what it does is it’s what we call a gain of function approach. So you make a wound and the wound heals. That’s all it’s going to do because it can’t progress to the next step. So you make a wound and we know you need signals from nerves and we now understand what those signals are. And you do that by making the wound and then deviating the nerve. And it starts down this pathway to regenerate, but it’s missing one last piece, which is what the information is to tell it what to make and in this case, it’s to make the hand.
So you need the information that says, here’s the information for the thumb and here’s the information for the little finger. And then the system, once you give it that information, it can fill in and it makes all the missing pieces in between. And then you end up with an animal with an extra arm.
IRA FLATOW: So you sort of leave a space where the arm should be and the two parts on both sides of that space talk to each other and figure out how to grow the arm that needs to be there?
DR. DAVID GARDNER: Right.
IRA FLATOW: Wow.
DR. DAVID GARDNER: That’s pretty much– you just said it. And because you said a lot in there which is there’s information, the cells have the information, and the cells have the ability to talk to each other. And we understand that now. That’s the core of modern biology is how cells talk to each other and how they use that information. And they use that to control where they go. So they migrate, they proliferate, and then, eventually, they make things. They differentiate. And that’s all the controlled by cells talking to each other.
DR. KIM COOPER: But what we don’t yet know is why human cells can’t do the same thing. Right? So do we know if the positional information is missing from humans or if the human cells just don’t even know that their neighbor is not the right thing to be able to fill in that gap?
DR. DAVID GARDNER: Yeah. Right. And that’s the challenge. I think the evidence is that the information is there. I mean there are a lot now of sequencing, gene sequencing experiments. And so the Hox genes, for example. Those are very stable properties and they are very positionally expressed in humans so we’re seeing that maybe the information is there.
I personally, would point out that you can’t– it’s very difficult to distinguish between stimulation and disinhibition. So we keep thinking, well, why can’t humans regenerate? But the other possibility is that we do regenerate, but it’s being repressed. So we’re looking for repressors because there’s so much regeneration everywhere in the animal world.
IRA FLATOW: I get you. Well, we have to regenerate my IP here. This is Science Friday from PRI, Public Radio International, talking with David Gardner and Kimberly Cooper.
So this is the $64 question is how to make humans do what these other animals can do, Kimberly. Right?
DR. KIM COOPER: It is. It definitely is. And if you look at evolution of regeneration, we do know that it was a loss in species that can’t regenerate and not something that’s special about an axolotl, for example.
IRA FLATOW: But the fact that we can regrow, put limbs back, when people lose them in an accident and we can put them back together, does that give us any knowledge about how it might work?
DR. KIM COOPER: You mean in wound healing and repair?
IRA FLATOW: Yeah.
DR. KIM COOPER: I’ll let David answer that question.
DR. DAVID GARDNER: Yeah. Well, one of the important things– and this is relevant today– the important thing about regeneration is restoring the function. And so, one way to do that is to replace the structure. But what is happening right now with regenerative engineering, people are trying to get moving in that direction by changing the result of wound healing to give you a more functional outcome. And one of these days, I’m confident that we will regenerate and that we have this endogenous ability. That could be a long ways away. We’re seeing this all ready.
DR. KIM COOPER: We do to some extent. So if you back up in development, up to about six years of age, you can cut off the end of a finger– I don’t encourage anyone to do this. I actually have a new baby and I made a joke to a nurse about this who didn’t appreciate it. But if an infant or a young child loses the end of their finger, including bone, it will actually grow back and replace the finger print.
DR. DAVID GARDNER: That happens in adults, too. It just doesn’t happen quite as well.
DR. KIM COOPER: It doesn’t happen as
DR. DAVID GARDNER: It’s really quickly in young kids. But in adults, we do see– and people have studied that extensively in the mouse model how digit tips regenerate. And the answer seems it’s what one would expect. That these are sigmoid pathways that are used over and over again in development, they’re reused in regeneration. So these are growth factors, morphogens, that play really important roles in development, but then they get reactivated and that’s what a salamander seems to be able to do. It seems to be able to go back and reactive those early embryonic patterns and do it again.
DR. KIM COOPER: And also doesn’t do one thing that we do which is form massive scarring. So in an adult human, if you induce a really bad injury, you get this really dense extracellular matrix that forms a gnarly scar and it’s hard to rebuild from that.
IRA FLATOW: We’ll have to leave it at that. David Gardner, Professor of Developmental and Cell Biology, UC Irvine. Kimberly Cooper, Assistant Professor of Biological Sciences, University of California in San Diego. And really, check out this axolotl limb regeneration video online at sciencefriday.com/limbs.