Summary

Scientists have long wondered why many unrelated animals can regrow limbs and other body parts. New research identifies common genetic factors that promote regeneration.

Killifish

A peculiar question has long puzzled biologists: If a salamander can regrow a missing leg, and a fish can replace a damaged fin, why can’t humans regrow so much as a hand or a whole finger?

Howard Hughes Medical Institute Investigator Alejandro Sánchez Alvarado has searched for the answer among animals with amazing abilities to regenerate, such as tiny flatworms called planarians. Now, he and colleagues have described genetic mechanisms that help explain why some animals can regenerate body parts while others cannot, the team reports September 3, 2020, in the journal Science.

Learning from other animals’ regenerative processes could one day, perhaps, help us improve our own. But first, Sánchez Alvarado says, we need to understand more about how regeneration works at the molecular level.

Many animal species, from sea stars to salamanders, have some sort of regenerative ability. Planarians, for instance, can regenerate an entire new body from just a tiny clipping, and axolotl salamanders can even regenerate portions of their brain. Humans, meanwhile, refresh our bodies over time, to the tune of replacing some 10 billion cells per day. But we’re not very good at regenerating missing body parts, says Sánchez Alvarado, a developmental biologist at the Stowers Institute for Medical Research. “Don’t try it at home,” he says.

Regenerating Killifish tail

Over two decades of studying planarians, Sánchez Alvarado has learned that in order to regenerate body parts, animals need to have tremendous genetic flexibility. “They’re capable of turning genes on and off as needed to produce new tissues after injury,” he says. His team wanted to understand not only which genes are active during regeneration, but also how they’re turned on and off, and dialed up and down in activity.

In the new study, the team looked for stretches of DNA that regulate the activity of genes important in regrowing body parts. They call these genetic elements regeneration-responsive enhancers. They kick into action after an injury and boost the activity of genes needed for regrowth.

The team compared regeneration in two different fish species: the well-studied zebrafish and the turquoise killifish, Nothobranchius furzeri, a colorful African species. The two species can both regenerate fins but have very different evolutionary histories. That allowed the researchers to examine which regeneration elements are specific to each species, and which they shared; any shared genetic factors might be important in other animals as well.

When the researchers clipped the fishes’ tailfins and compared gene activity as the tails regrew, they found that only a small number of genes and enhancers were involved in regeneration in both species.

“So these elements must have been the ancestral responses to injury and regeneration which were maintained in both of these species even after they separated from each other, around 235 million years ago,” Sánchez Alvarado says.

The team then zeroed in on a particular stretch of DNA (known as K-IEN) involved in cranking gene activity up or down. Deleting or blocking it halted regeneration in the fish, they found. Finally, the team identified a similar snippet of DNA in mice and humans. When cloned into killifish, it turned on during regeneration, though later in the process.

That suggests that this genetic element has changed throughout the course of evolution, Sánchez Alvarado says, which could explain why some animals can regenerate tissues and others can’t. Humans and mice, for instance, appear to have inherited parts of the regeneration response found in killifish, but it doesn’t work for us. This may be because that part of the genome was repurposed over time, Sánchez Alvarado says.

Once the genetic tools for regeneration are understood, it could in theory be possible to reverse-engineer some regenerative processes back into animals that have lost them, Sánchez Alvarado says. “But one cannot underestimate the fact that this repurposing took place for a reason,” he notes. Tinkering with one biological process could end up harming another.

The team’s discovery of shared regeneration mechanisms is significant, says Igor Schneider, an evolutionary developmental biologist at Federal University of Pará in Brazil. “Their findings support the enticing idea that organ regeneration in animals is coordinated by an ancestral genetic tool kit, modified along the course of evolution.” Next, he says, it will be important to assess the mechanisms in other species and in different organs and tissues.

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Citation

Wei Wang et al. “Changes in regeneration-responsive enhancers shape regenerative capacities in vertebrates.” Science. Published online September 3, 2020. doi: 10.1126/science.aaz3090

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