Regrowing frogs' limbs

Putting the spring back in the step of our amphibious friends with the hope one day of helping humans...
26 January 2022

Interview with 

Michael Levin, Tufts University

African clawed frog

An African clawed frog, Xenopus laevis


At the moment, unless you're a salamander - which can regenerate whole chunks of itself - if you lose a limb, or any complex body part for that matter, it won't grow back. But that doesn't mean it can't. The cells of our bodies have, as Michael Levin from Tufts University puts it, got the collective "know how" for doing this. It's just a question of telling them to use it rather than reverting to the default option, which is to seal up a wound with a scar. After all, our entire bodies built themselves within the space of just 40 weeks from a single fertilised egg. So, can we reactivate certain parts of that same developmental programme to put ourselves right? In frogs, at least, as he explains to Chris Smith, Michael Levin thinks he can..

Michael - In our lab, we have discovered certain signals, triggers (in particular, bioelectric ones) that kickstart very complex downstream programs such as making eyes and brains and other things. Our goal is to identify the triggers that convince the cells to go to a regeneration route as opposed to a scarring route.

Chris - In this instance, you were looking at limb regeneration in an amphibian. Talk us through what you actually did. What would happen if you didn't intervene and what actually happened when you did?

Michael - We chose the frogs Xenopis laevis, a frog species that's used for a lot of work in immunology and cancer in developmental biology and neuroscience. We used adult animals - very large frogs. They do not regenerate proper legs back if they're lost. We wanted to provide two things -  first, we wanted to provide a localised microenvironment to the wound - so, very tightly control the environment around that wound site to convince these cells that they were in a safe circumstance; that they could go on to regenerate. Then, we provided some drugs which would activate certain pathways that would shift that decision point towards regeneration. There's a thing called a bioreactor, which contains a silk based gel which carries some of the drugs that fit onto the amputation wound. It stays on for just 24 hours and the leg growth is apparent well over a year after that process.

Chris - So, if you just removed a limb from one of these animals normally, they would get very little regeneration, but you put this silk soaked cocktail onto the wound site, just for a day, and then you get something that continues to develop for a year?

Michael - Correct. Normally, at best, they would make this little flap of tissue that is quite soft -  it has no feeling to it, it has no ability to be used to support weight. It's just this little flap of tissue. When you confront these cells with a bioreactor carrying these drugs in the first 24 hours, you trigger a very lengthy and very complex patterning process that results in lots of new tissue growth, bone growth, nerve growth, blood vessels, and ultimately a pretty good limb that is functional. It's both sensitive to touch and it's motile (the animal can use it to get around).

Chris - How does the leg know how big the frog is? In other words, it's going to grow, it's going to keep growing for a year, so how does it know when to stop?

Michael - That's an outstanding question that is actually very poorly understood. It's the same question as asking how do the cells of a frog know how big the frog should be in the first place during embryogenesis. Frankly, we still don't really understand that.

Chris - And the growth does stop? You're not going to end up with a giant leg with a little frog attached at the end of this? Does it actually make a frog sized matched replacement body part?

Michael - That's correct. The body part is absolutely scaled properly to the rest of the tissue.

Chris - And have you taken this beyond frogs yet? We know that many of the factors that make these sorts of things happen in frogs, they exist in us as well, don't they? So have you now started to try this on more complicated, higher animals to see if the same can occur.

Michael - Yes. Those are exactly our next steps. We have a spinoff company called Morphoceuticals, Inc., whose mission is to try to take this technology towards a point where someday it will be useful for therapeutics and human patients, and we are just beginning to work in mammalian models.

Chris - What about if you come back to people that had their injury years ago? In this instance, you made the injury, while the wound is fresh you apply the bioreactor to it for that 24 hour period, what would happen if you went back to a frog that lost a limb a year ago? Would the window have closed by then? It's too late?

Michael - It's a good question. We don't know because we haven't done it yet, but I don't believe it would be too late. I think, at worst, you might have to reopen a cut surface there, but I think the fundamentals which make this possible are still there. In other words, you still have cells there that have all of the information needed to know what a correct frog looks like, and all of these cells are constantly undergoing maintenance and keeping that frog together despite the fact that individual cells are always aging and dying and keeping cells from turning cancerous and so on. That type of homeostasis, that ability of these cells to continue to work together towards maintaining a good organism, is always there, and I think that once we really crack some of the big scientific questions here we will be able to trigger that even long after the original injury.


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