The mutant fish whose fin is becoming a limb

Millions of years after we crawled out of the oceans, biologists have helped a fish restart the process...
24 February 2021

Interview with 

Brent Hawkins, Harvard Medical School


Mutant zebrafish fin with intermediate radials.


When our ancestors first crawled out of the oceans, among other things, they needed to evolve limbs to get around. And now, millions of years later, scientists from Harvard have helped some fish repeat the process - by finding a mutation that makes their fins seemingly start to transition into arms. Does something smell fishy? Phil Sansom went to study author Brent Hawkins to investigate…

Brent - What I found with my colleagues is the unexpected ability of a fish to transform its fin into a more limb-like configuration. And we found this in mutant zebrafish; zebrafish are kind of like the lab mouse of the fish world.

Phil - So when you say unexpected ability - this isn't one fish that can do it as a superpower?

Brent - No, no. It's actually a whole line of mutant fish that reliably reproduce this change in their fins across generations.

Phil - You said zebrafish: what is a zebrafish?

Brent - Zebrafish are small... what we call teleost fishes, that's sort of the family they're part of. They're originally from India. And back in the eighties and nineties, when geneticists were trying to find a nice genetic model that they could do these very large genetics screens in, the zebrafish was the recommended species to try, because people knew in the aquarium you could mate them very easily and get lots of eggs. You basically just need to put a male fish and a female fish together in a little tank overnight, and in the morning when the lights turn, that cues them to spawn. So it's very, very convenient.

Phil - How were you then mutating them?

Brent - The way we do mutations in the fish is we take a male fish and inject it with a chemical called ENU that's going to cause random mutations in its sperm; made it with a female; and then we look at their offspring, and those offspring will have inherited the mutated genes from the father.

Phil - You're sort of throwing genetic spaghetti at a wall then, to see what sticks and looks interesting?

Brent - Exactly. That's perfect.

Phil - So what was special about this one then?

Brent - A normal zebrafish has these very nice stripes along the body, but our mutant has a more scrambled pattern. And so that's why we picked it out initially. But in our screening process, we look at many different parts of the fish, and one of the last things we look at is doing our processing to look at the skeleton. And it was at that step that we saw that the pectoral fin had these new bones that shouldn't be there.

Phil - Was it a moment of just sudden realisation?

Brent - Oh yeah, it was a total dumbfounded Eureka moment when we saw it! It's something that shouldn't be there, ever. A normal pectoral fin has a very reduced skeleton compared to our limbs: just these series of four short bones arrayed side by side. What happens in the mutant is that instead of just having these four side by side bones, they make two more bones further away from the body, on top of those four side by side bones.

Phil - Are they sort of jointed on to the old bones?

Brent - Yes they're well-integrated! They have joints and they have musculature that allow them to articulate with the other bones.

Phil - That's a huge change!

Brent - Oh yeah. It was very surprising that with one single mutation, we got this coordinated shift in not just the skeletal system, but also the muscular system and the formation of the joints as well. And through our mapping, we did determine it is one single gene causing all of these changes.

Phil - What gene?

Brent - The mutation is residing in a gene called waslb. The waslb gene is involved in modifying microfilaments in the cell, that are involved in all sorts of processes like cell migration and displaying receptors. The gene is also involved in the transcription of other genes.

Phil - One of those pathways must be sort of a finger bone type pathway, right?

Brent - That's what we're hoping. And that's what we're looking at now more carefully. So for instance the hox genes, which have important roles in patterning many different parts of the skeleton; we found that these hox genes are actually in part controlled by the waslb gene. We know hox is important for the limb, so this is an exciting new, additional level of regulation that we didn't know about before.

Phil - Do you know then, Brent, whether you've recreated a step that some of these fish's ancestors way back would have taken to help get out of the water?

Brent - It's possible. In our research, we're only looking at the living fish; we haven't recreated evolution by any means. But what we do show is this hidden ability in a fin to become more limblike.

Phil - I just can't believe you're getting all this from a single mutation. Imagine what you could get with another two or three!

Brent - Oh yes, the prospects are wonderful! And that's actually something we're doing now: we have other genes that cause similar changes in the skeleton, and now we want to put those together in the same fish. And we're really excited about that - that one day we might have fish crawling out of the tank.


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