Little Biology: Why can’t I regrow my arm?

Natasha Dhamrait

RB Smith

Why can some animals regrow limbs while others can’t? Will understanding regeneration in other vertebrates help us regrow arms one day?

Our intern team has taken over the channel to talk about one of their favorite biology topics, limb regeneration! In the episode, Dayna and Kyle break down the mechanisms of regeneration and discuss why some animals can regrow organs and limbs, and why the evolutionary paths of other animals may have led to alternative responses to limb loss.

Thanks for listening! This episode of Little Biology was written and presented by Dayna De La Cruz and Kyle Smith. If you enjoyed it, please give them a hand!

Cover photo: Keating Shahmehri

• Episode Transcript

  Kyle Smith 0:07

  Approximately 185,000 amputations occur in the United States every year, and over 1 million limb amputations globally. That's one every 30 seconds.

  Dayna De La Cruz 0:17

  In the United States alone, around 2.1 million people were living with limb loss in 2005. And that number is expected to double to 3.6 million by 2050.

  Kyle Smith 0:27

  And with ongoing conflicts such as the war in Ukraine, the need for amputee treatments and prosthetics is on the rise. To the point where many Ukrainian amputees are having to find treatment in the US.

  Dayna De La Cruz 0:38

  Recovery from limb loss can be long and difficult and expensive. But beyond that, the amputee will have to learn how to live without their limb and change their sense of body image, which could psychologically impact them. According to the amputee coalition, the average lifetime health care costs for people with limb loss is about $150,000 more than for people without limb loss. That's a big difference.

  Kyle Smith 1:01

  What if there was an alternative to living with limb loss?

  Dayna De La Cruz 1:04

  Limb regeneration happens all the time. In other life forms.

  Kyle Smith 1:08

  Some animals can regenerate entire limbs. Could it one day be possible for us to do this too? What we know so far about regeneration, and what does this mean for the future of treating limb loss? I'm Kyle Smith.

  Kyle Smith 1:20

  And I'm Dayna De La Cruz.

  Kyle Smith 1:22

  And this is Little Biology.

  Kyle Smith 1:35

  Let's take a step back and look at what animals can regenerate.

  Dayna De La Cruz 1:39

  Well, one example is Planaria. These flatworms can regenerate their entire bodies from tiny fragments. The process relies on special cells called neoblasts, which divide to become all of the cell types planaria need to rebuild and run their bodies. But we're not very similar to flatworms.

  Kyle Smith 1:57

  I don't know about you, but I'm pretty happy about that. So what about species that we share more recent common ancestry with?

  Dayna De La Cruz 2:04

  Most vertebrates can't regenerate. But there are some exceptions, including the Urodele Amphibians, the newts and the salamanders. They can lose their eyes, tails and even entire limbs and still regrow them.

  Kyle Smith 2:17

  So how do they do it?

  Dayna De La Cruz 2:18

  Well, when one of these organisms loses a limb, the cells around it which all have specific roles, start to de-differentiate, meaning that they revert into stem cells. And stem cells are pluripotent, meaning they can transform into many types of cells depending on the signals they get from nearby tissues. Stem cells multiply and form a healing zone called a blastema. In the blastema, the cells re-differentiate again into bone, muscle, nerve and other cells, basically everything the animal needs for a fully functioning limb.

  Kyle Smith 2:49

  But wait, limbs are pretty complex. How do all of these different cells know where to go and what to become?

  Dayna De La Cruz 2:56

  Great question, but one we don't yet have the answer to, although plenaria provide a clue. Planaria use bioelectric fields as a kind of map that tells cells where to go and what to become as they regenerate. We can alter these fields in planaria to get new body plans like worms with two heads. And this change to the bio electric field is even heritable. Meaning if we cut this two headed worm in half, the two fragments will also regrow with two heads.

  Kyle Smith 3:32

  Planaria are like wormy superheroes, but from an evolutionary point of view, they're really distantly related to us. And even salamanders, that's still hundreds of millions of years of evolutionary distance from us. So what was it that happened in the evolution of us humans that made us lose this ability?

  Dayna De La Cruz 3:50

  Evolutionary trade-offs probably explain why humans like most species aren't great regenerators. For regeneration to even be possible, an organism would have to be able to survive without the limb long enough to get value out of spending the energy to grow it back.

  Kyle Smith 4:06

  I see. So in other words, is it worth it? If I lose an arm, would it make sense to regrow it, if it's going to take lots of time and energy for me to do so?

  Dayna De La Cruz 4:15

  Bingo!

  Kyle Smith 4:16

  But why wouldn't it be worth it to regrow my arm? I'd very much like to have it back if I lost it.

  Dayna De La Cruz 4:22

  Well, this is the thing about evolutionary trade-offs. In our past, there was some advantage to sacrificing one trait in favor of another that lineage would probably come to dominate a population. A great example here is cancer. The parts of our bodies with the greatest ability to regenerate are also most predisposed to cancer. When newts and salamanders regenerate, stem cells are the stars of the show. These unspecialized cells proliferate rapidly to replace the lost tissue. In people, the cells that are most prone to divide and diversify pose the greatest cancer risk

  Kyle Smith 4:56

  So in a way we are like planaria and amphibians, or at least parts of us are anyway.

  Dayna De La Cruz 5:01

  And just like stem cells in this species, cancerous cells grow and multiply in a process that mimics behavior of our embryonic stem cells. Like a wound that never heals, cancerous cells just keep growing and spreading.

  Kyle Smith 5:14

  Okay, that makes sense. The hyperproliferation of cancer cells is similar to what a limb needs to regrow. But controlling when and where this happens is probably as hard as getting cells growing and differentiating in the first place. So the trade off here is either making enough different cell types, or doing too much at the wrong place, at the wrong time.

  Dayna De La Cruz 5:33

  Yes, even if our cells are turned on for regeneration, turning them off to stop cancerous growth is a tough task. There's a trade-off in regulating growth. Things gotta be in the right place and at the right time, not just loads of growth and differentiation all the time.

  Kyle Smith 5:49

  Okay, so there's this trade-off. And what in the evolutionary history of some lineages like Urodeles pushed the outcome the other way?

  Dayna De La Cruz 5:56

  One thing is probably speed. Salamanders regrow limbs in three to four months, but a human arm would take years to grow. That's a crazy long time to have a healing wound, which would make us vulnerable to all sorts of infections. If it takes that long to regrow, then maybe it's better not to. Better just to form scar tissue over the wound and protect the rest of the body from infection.

  Kyle Smith 6:18

  Wow, I never thought of it like that. I bet it takes a lot of energy to regenerate too.

  Dayna De La Cruz 6:23

  It sure does. The cost of loss of appendages itself include decreased local motor performance, loss of nutrient reserves, reduced reproductive output and growth and altered social interaction. Regenerating an entire limb takes a huge amount of energy, protein and nutrients, too much for most animals to spare. Some species, however, have come up with cool and creative ways to get around these costs such as limb rearranging. For example, jellyfish can adjust the position of other arms to fill in the gap and learn to swim with this new setup. This response is much more common than regrowing arms, even when they do have that ability. We humans similarly avoid these costs by forming scar tissue instead.

  Kyle Smith 7:07

  Fine, regeneration might be rare because it's costly. But what if organisms could have just found a lot of resources? Couldn't they have just mitigated the costs and grown back limbs that way?

  Dayna De La Cruz 7:17

  The basic idea is that organisms would be more likely to regenerate, if they had access to plentiful resources. This is not something that happens very often to animals in the wild. But what if we could experimentally increase resource availability?

  Kyle Smith 7:30

  Actually, a study found that diet supplementation could induce limb regeneration. Moon jellyfish regenerated limbs more frequently when they were supplemented with an amino acid and insulin. In insects the same strategy induced tibia regeneration in adults fruit flies, and in mice, amino acid and sugar supplements induced digit regeneration.

  Kyle Smith 7:58

  In general, it seems that for us vertebrates, with our complex organization and high energy demands, sustaining large numbers of stem cells, or risking de-differentiating cells isn't worth the benefits of regenerating.

  Dayna De La Cruz 8:11

  But by simply tweaking conditions, you could induce things to regenerate that normally don't.

  Kyle Smith 8:16

  Well, maybe we humans can't regrow whole limbs, but we do have some capacity for regeneration. Our skin, for instance, can regenerate in just two weeks.

  Dayna De La Cruz 8:25

  That's true. And we can even regenerate parts of our vital organs. Well, our livers at least. We can regrow our livers to full normal size, even if we lose up to 90% of it.

  Kyle Smith 8:38

  So obviously regeneration exists on a continuum. If that's the case, then maybe there's hope of one day being able to regrow our limbs.

  Dayna De La Cruz 8:46

  Technically, yes, if we can reprogram adult somatic cells into embryonic-like stem cells, and then get these cells to form new tissues in the right places.

  Kyle Smith 8:55

  And stop when the limits regrown.

  Dayna De La Cruz 8:58

  Otherwise cancer.

  Kyle Smith 8:59

  So basically regenerating is just de-differentiate regular cells or somehow harvest the right stem cells, tell them where to go, tell them how to grow, and then tell them when to stop growing. If we could do that, then we might be able to artificially regrow limbs.

  Dayna De La Cruz 9:17

  But even just one of those hurdles is super high. We're quite a long way from that kind of medicine.

  Kyle Smith 9:22

  All the more reason to continue with basic research on planaria, salamanders, and other organisms that have a capacity that we don't have, but would very much like to.

  Dayna De La Cruz 9:32

  I guess you could say that studying them might lend us a hand.

  Kyle Smith 9:36

  Ah, did Art make you say that?

  Dayna De La Cruz 9:39

  No, but he did share a piece of his mind with this episode.

  Kyle Smith 9:43

  Okay, I'm done.

  Dayna De La Cruz 9:45

  This is Dayna De La Cruz.

  Kyle Smith 9:47

  And I'm Kyle Smith.

  Dayna De La Cruz 9:48

  And this was Little Biology.