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TIL You can make a frog's entire leg regrow after cutting it off
Cool research by Michael Levin’s lab
Today I learned that you can make an adult frog's entire leg grow back after cutting it off. I was pretty surprised that the science of limb regeneration has come this far.
It took the frog 18 months to regrow the leg, but the treatment only lasted for 24 hours (!) immediately after cutting off the leg. The treatment consisted of putting a "wearable bioreactor" over the stump of the cut-off leg. This bioreactor either contained just a gel with silk protein or the silk protein gel and additionally 5 drugs to help with regeneration. Intriguingly, adult frogs apparently have similar regenerative capacity to humans, so, presumably, this isn't "just a frog thing"1.
Here's one of their figures:
There's a lot going on in this figure, but pay attention to C at the bottom right. ND stands for no device and is the control group. BD stands for "BioDome" (the wearable bioreactor with no added factors), and MDT stands for multidrug treatment (wearable bioreactor + 5 drugs). As you can see, the MDT group regrows something that looks like a pretty nice frog leg after 18 months. I'm slightly confused by the paper saying that frogs have a similar regenerative capacity as humans, but the ND group also regrowing a bunch of soft tissue that kinda looks like the beginning of a leg. In my experience, humans with amputated legs don't regrow these spindly leg-adjacent structures like the ND group.
But was the regrown leg actually functional? Yes (I think).
As far as I can tell, the way they tested the leg's functionality was just poking the regrown limb with a stick and observing if the frog reacted, i.e., whether there were sensory nerve endings to pick up the stimulus and motor nerves to make the leg move2. They applied different amounts of force, and in the control (ND) group, the frog didn't react even at a force of 300 g. As would be expected, uninjured (UI) animals reacted to even the tiniest poke. Remarkably, the regrown legs of animals in the MDT were mostly as sensitive as uninjured legs!
The big open question for me is whether the frogs with regrown legs could hop around and do normal frog stuff after 18 months. If you download the supplementary material, they actually included a video of the stick-poking and the frog squirming after being poked. Still, I am not sure how much that really tells you about functionality. In this video, the regrown leg also doesn't look as great as the one in the figure above for some reason.
Paul Rand: Let’s talk a little bit about regeneration and specifically getting into humans. And I think most people know if they lose a toenail, that toenail will grow back. I learned by doing reading that humans between ages of 7 and 11 can regrow the tips of fingertips. But generally, if you lose an arm, you’re not going to regrow an arm, are you?
Michael Levin: This is true. Humans do not regrow their limbs. Although, interestingly enough, there are sporadic reports in the medical literature of people regrowing certain organs. For example, kidneys, and this is very rare, but there have been reports. We do regenerate our liver. So our liver is highly regenerative. So it’s not as if regeneration is somehow impossible for mammals. It’s just that humans don’t happen to be very good at it, and this we hope to change. Now after that, you want to ask yourself, “How is that going to happen?” And I think you need two things. I think you need an informational signal.
Paul Rand: And you’ve done some of this. You actually regenerated a back leg of a frog.
Michael Levin: That’s correct. We started with tails on tadpoles, and so there’s a stage at which tadpoles do not regenerate their tails. Tadpole tails are cool because they’ve got spinal cord and muscle and blood vessels, and so we were able to use bioelectric signals to grow back a tail. And then from there we went to legs and we did figure out how to induce the formation of the hind leg in an adult frog, which had not been done before. And now we’ve moved to mammals. We’re in mice now. We’re trying it, I’m not claiming it works with, this is still all unpublished. So all I’m saying is this is what we’re attempting now.
Also, this technology might be able to provide us with an unlimited supply of frog legs (Don't tell the French).
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"Like mammals, adult X. laevis exhibits modest tissue renewal, few pluripotent stem cell pools, and an age-dependent decline of regenerative ability that is similar to that of human finger amputations"
"To evaluate the sensorimotor capability of the regenerate, animals were assessed at 18 mpa. Each animal was placed into a glass tank filled with 2 liters of frog water and acclimated for 5 min until movement ceased completely. A video camera (iPod Touch 5th generation, Apple, CA, USA) was placed over the enclosure to capture recordings of the testing procedure. Standardized Von Frey (VF) filaments (Touch Test, Stoelting, IL, USA) were used to assess the sensory threshold of the regenerates. Filaments ranging from 0.008g to 300g in force were applied to the distal portion of the regenerate, from lowest to highest force. The first filament that induced a clear response (movement from the stationary position) was recorded. Animals were tested twice over a 2-day period, and the average threshold was reported." (lol at using a 2012 iPod Touch as a camera. Probably, the grad student in charge of this found it in some drawer at home and brought it into the lab.)