Nature already solved limb regrowth. Can Aztekin wants to crack its code.

Millions of people worldwide live with deformed limbs, for example an arm or a leg is shorter or entirely missing. Others have had a limb amputated say after an accident or a severe infection. And as diabetes and vascular disease become more common, that number is only set to grow. Today, prosthetics remain the only real replacement option. Can Aztekin, Research Group Leader at the Friedrich Miescher Laboratory in Tübingen and leader of the NRP 79 project "Studying limb development and regeneration using simplified systems" wants to change that. His team built lab models that don’t rely on animal experiments to understand how limbs form, and how the ability to regenerate them might one day be switched back on. These models are based on frog limb explants, tissue samples kept alive and studied outside the living animal on the one hand, and on stem cell-based systems on the other.

Fresh from winning both the 2025 Rising Star Award from the International Society of Regenerative Biology, ISRB, and a prestigious European Research Council (ERC) Starting Grant, Aztekin spoke with us about frogs, salamanders and the future of limb regeneration research.

Let's start with the big picture: humans can't regrow a lost limb, but some animals can. What's actually going on inside a salamander that makes this possible?

Salamanders and frog tadpoles have this remarkable ability, and it starts almost immediately after amputation: skin cells migrate over the wound and cover it within six to twelve hours. As soon as that new skin covers the wound, they form a unique regenerative skin cell type that starts influencing the cell populations underneath – muscle, bone, connective tissue. All of these different populations begin interacting with this unique cell type and start losing their specialised identity. Together they build up a pool of cells that can turn into different tissue types. This cell pool then reconstructs the entire limb: bone, muscle, nerves, everything. Humans and other mammals can heal smaller wounds perfectly well, but it is a rather slow process and we never form that regenerative skin state nor can we form a pool of regenerative cells. The process simply stops instead of continuing into regeneration.

Your project title mentions "simplified systems". What do these alternative models actually look like, and how do they stand in for a live frog or mouse in the lab?

We work with two main categories of simplified systems. The first is based on isolated limbs which we grow and study directly in a petri dish instead of in a living animal. The second method is based on special cells that allow us to generate the specific cell types that are relevant for limb regeneration in a dish. Both approaches give us far more experimental control than we would have in a live frog or mouse, and both significantly reduce the number of animals we need.

How did you create these models?

Developing these models was a bit like fine-tuning a recipe. We used certain proteins and signals to guide cells, trying to copy what naturally happens during development, so the cells turn into the type we want. It takes a lot of trial and error to get it right, but once it works, it's easy to repeat.

You've studied both limb development and limb regeneration. How are the two connected, and why does understanding one help with the other?

Development and regeneration share real similarities, but they're not the same process. Development follows a coordinated blueprint: it builds a structure, like a limb, for the very first time. Regeneration is different because it starts from an injury: cells have to coordinate to rebuild a structure from what is essentially a chaotic starting point, without a pre-planned blueprint to follow. Understanding development gives us a blueprint to compare against, but regeneration can actually take several different, equally effective routes to reach the same functional outcome.

Millions of people live with limb loss or limb differences, and the main option available to them today is a prosthetic limb. How close are we to research like yours actually changing that?

Full regeneration of a human limb is still a long way off. But over the past decade, new methods have given us much more concrete answers about which cell types and mechanisms are actually involved, and that is real progress. Full regeneration also isn't the only outcome that matters – even partial regeneration, i.e. being able to regrow an amputated upper leg down to the knee, could make a real difference in someone's daily life. As a researcher, my own focus tends to stay on the full picture, but I'm optimistic that even partial steps could meaningfully improve quality of life for people living with amputations. It will still take many years, though.

Your project touches mainly on replace and reduce. Can you give us one concrete example of each from your day-to-day lab work?

For reduction, our stem cell-based systems let us generate hundreds of mini-structures from a single embryonic limb, and our in vitro approach lets us run controlled experiments using both the right and left limb from the same animal, so we need far fewer animals overall. And for replacement, our stem cell-based systems can eliminate the need for animals for certain experiments.

Your project officially wrapped up this June. Looking back, how satisfied are you with what the team achieved?

I'm genuinely satisfied with how the project turned out. One thing I valued in particular was the encouragement from the NRP 79 steering committee to take our findings further and adapt them to human stem cells. That has opened up a direction I'm excited to keep pursuing.

Your new ERC project, "Signal to Regeneration," asks whether mammals still carry a hidden capacity to regenerate. What made you believe that dormant potential might still be there?

It started with a basic question: which cell types are actually involved in regeneration? We found that mammals, including mice and humans, use similar transient cell types that appear briefly during development – but we fail to properly re-form them after an injury, suggesting the potential is still there, just switched off. More recently, we found that environmental oxygen levels seem to suppress this capacity: lowering oxygen levels around embryonic mouse limbs could trigger the very first step of regeneration. Comparing how species sense oxygen gave us clues into why the aquatic salamander axolotl can regenerate so readily, while mammals cannot.

Congratulations on winning both the ISRB Rising Star Award and an ERC Starting Grant in the same year! What do these two recognitions mean for you and your research?

They mean a lot, in quite different ways. The ERC Starting Grant gives me the freedom and the resources to pursue a genuinely high-risk project, the kind of question that's hard to get funded otherwise. The ISRB Rising Star Award feels like a validation of our overall approach of combining classic in vivo experiments, meaning experiments carried out directly in living animals, with these new simplified systems. It's encouraging to see that combination recognised by the field.