A Biologist on the Mysteries of Regeneration

You study axolotl salamanders. Why?

Axolotls can do things humans can’t — they can regrow body parts, and they do it with precision. Although scientists have known this for a couple hundred years, no one’s cracked the molecular details of how they do it. Doing so could offer a blueprint for understanding how limbs can be regenerated. An axolotl is the best model among salamanders because it has the shortest generation time — about a year from egg to adult — and you can do real genetics on axolotls. You can knock a gene out and, in a few years, see what the real effect is. There are a lot of new tools developed to study axolotl genetics that do not exist for other salamanders.

The ultimate goal of your efforts is to enable limb regeneration in humans. What about human biology hints that this is even possible?

First, some 350 million years ago, humans and salamanders shared an ancestor that was likely able to regenerate limbs. We think this based on genetic analysis but also on fossils of ancient salamander precursors, some of which were fossilized while regenerating body parts. It’s a clue that in our ancient shared evolutionary history, the common ancestor likely had the ability to regenerate. We still share most of our genes with salamanders, which hints at a genetic program that could be reawakened in a human.

Second, our lab has uncovered a role for a body-wide cell proliferation response to amputation in the salamander, and we show it can promote regeneration. Another lab has shown something similar happens in mice, and mice don’t regenerate limbs. But if we consider the mouse closer to humans, then I would predict humans have this systemic activation response that’s intimately tied to the ability to regenerate. I would guess human amputees are taking the first molecular steps toward regeneration, but our organism is genetically blocked from taking the next steps in most cases, with the exception of digit tips, which can regrow.

Third, one of the most common effects of limb loss in humans is something called a neuroma, which is the spot where the nerves that service an amputee’s limb continue to grow, because humans have intrinsic peripheral nerve regeneration capabilities. These growing nerves no longer have a limb to go into, but it’s yet another clue that some regeneration is happening in human amputees. Peripheral innervation is critical to salamander limb regeneration. If we are ever able to provoke limb regeneration in humans, peripheral innervation will be a key ingredient in that recipe.

Why did humans lose their ability to regenerate? That’s the big question. Some of the work that’s come out of invertebrates shows trade-offs to the overall growth of the organism, but I think there’s more to the story. I think it probably has something to do with the real-world pressures faced by different species, such as the likelihood of losing a limb to predation. Other factors probably include the ability to heal wounds quickly to avoid blood loss and molecular mechanisms to prevent tumor growth. The same insults that would cause a tumor in a mammal will induce an extra limb to grow in a salamander. There is some mysterious and important biology at the interface of cancer and regeneration. 

How did you end up in science and how did you choose regenerative biology?

I’m the first scientist in my family. I come from a blue-collar family in Michigan. Most of my male relatives and my grandparents worked in factories. My father worked on the assembly line at General Motors for nearly thirty years. My mother, who is brilliant, had me very young, at 18. She was an amazing teacher, even though she hadn’t yet been trained to do that when I was a small kid. We didn’t have a lot of money, so our entertainment was the outdoors. She got me into the woods and collecting butterflies in fields. Later in life, she went to college, and she’s a second-grade teacher now. But back then, this is what we spent our free time doing. I attribute my interest in biology to her. 

My dad pursued side gigs because there was a lot of downtime when people were laid off. He would take on odd jobs, and one of them was to raise earthworms to sell to the tackle shop in Michigan, so he built a worm breeding colony in our backyard. When it would rain, we would accompany him into a big field across from the house, where the earthworms would come up — we called them night crawlers — and we would help him collect night crawlers to seed the farm and sell to the bait shop for extra money. 

I didn’t realize you could make a career out of science until college. I dual-majored in philosophy and biological sciences. I was very much into philosophy, but even then, I sensed some trepidation about the job market, and coming from a blue-collar family, I had to think about that. My philosophy professor told me that he’d give his left big toe to be a biologist in this era.

What brings you the greatest joy in this line of work?

That moment when you know something no other human has ever known before, which could turn out to be a really important secret in the natural world. I love that. That’s the adrenaline rush that comes from doing research. Very closely tied to this is mentoring, and I’ve had some great mentors myself. The sheer joy of influencing the next generation of scientists is why I do what I do. It’s a way to touch the trajectory of science as a whole but also to influence individual lives and career paths. This can take many forms. It’s the postdoc who’s been here for nine years because she came in as a PhD student. It could be an undergraduate having their first science experience in my lab. Later today, I am meeting a fourth-grader who wrote me about helping her with a school project.

How do you cope with disappointment or failure?

I have a high tolerance for failure and delayed gratification. I had a grandfather who had several amputations for his peripheral artery disease before he passed away, and this too motivates my long-term objective, even if I don’t live to see it come true. Of course, sometimes I get bummed out, but I try to remember it’s the long game that matters. If I’m really stressed, almost the only thing that can cure me is getting in the woods. The other is perspective.

I think one of the reasons why I have higher tolerance for failure is having the perspective of where I came from. When I get frustrated about something, I ask myself: “What was actually expected of me given where I started from in Monroe, Michigan, which is a town that right now is pretty bleak from many vantage points?” Getting to where I am on this campus, I really can’t get too depressed. I have two kids. My twin boys are almost 16 and doing well. They have a normal life. They are healthy. I just remember those things and I’m like, “It’s OK.”

Ekaterina Pesheva is the director of science communications and media relations in the Office of Communications and External Relations at HMS.