What It Takes to Regenerate

Some animals have can regrow entire limbs, while others don’t. Short DNA sequences called enhancers seem to play a big part.

Lost limb, no problem?

Many animals have an impressive ability to regenerate lost tissue. Some salamanders and fish can regrow entire tails and limbs. Even more extreme, flatworms known as planarians can literally be cut into hundreds of pieces (279 according to very old research), and regenerate each piece into a complete individual.

Mammals, including ourselves, have pulled the short straw in this department. Even if we lose something as small as a fingertip, we’re not able to regrow it.

Why this difference in regenerative capacity among animals?

We don’t really know.

As you can imagine, it’s an active area of research and the field of regenerative medicine is pursuing this research avenue, exploring technologies such as stem cells and tissue engineering, to help us recover from injuries and amputations. Even the ancient Greeks wondered whether it would be possible to have people regrow lost limbs.

Still, the molecular mechanisms and genetics underlying regeneration remain stubbornly murky. One of the difficulties is that it’s tricky to separate the species-specific genetic involvement from the conserved mechanisms which are shared by many species.

Fish and enhancers

A new study, however, lifts the veil of ignorance a little bit.

The researchers compared the regenerative response in African killifish and zebrafish. Both of these species are capable of regenerating several body parts such as fins, their tail, retina, etc.

Both species diverged around 230 million years ago, and live in very different habitats (zebrafish in flowing freshwater in Southern Asia versus killifish in ponds that dry out seasonally in Southeast Africa). This means that they have had plenty of time and selective pressure to evolve species-specific regenerative responses, but these two fish species are also sufficiently related to possibly share some genetics/molecular mechanisms controlling regeneration.

And that’s exactly what the researchers found. There were several substantial differences in the genetic responses to tail damage. Interestingly, though, there were also some shared elements, hinting at en evolutionarily conserved ‘regeneration program’. More specifically, the scientists were able to identify a regeneration-responsive enhancer, which is a DNA sequence that ‘enhances’ the activity of a specific gene, in this case, the gene inhibin beta A (or INHBA).

We also have that gene. Even better, we also have an enhancer for that gene.

Alas, evolution threw a wrench in the wheels. Or mutations in the DNA.

When the researchers introduced the human enhancer into killifish and disabled the killifish one, the fish were unable to regrow their tail. This, according to the authors, suggests that:

In extant species, regeneration-competent animals maintain the ancestral enhancer activities to activate both injury and regeneration responses, whereas in regeneration-incompetent animals, repurposing of ancestral enhancers may have led to the retention of injury response activities but to the loss of the regeneration response.

In other words, in species with a substantial regenerative capacity, injury response and regeneration are genetically ‘coupled’. In species that lack this ability, the injury response and regeneration have been decoupled, and the enhancer has been repurposed for other tasks, drastically reducing the regeneration potential.

Here’s a video in which the first author of the study (Wei Wang) explains the research:

If we ever want to become able to regenerate our limbs, we might have to figure out how to enhance our enhancers.

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