My stars and gar-ters

Genes responsible for regenerating fins in garfish are found to also be present in humans

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EAST LANSING, Mich.—The only time you’ll see humans regenerating limbs is in sci-fi, but in the animal world, it happens all the time. Starfish and octopi can regenerate lost limbs—and sometimes sacrifice them on purpose to make a quick escape—while salamanders can regenerate their tail, limbs, eyes or even their jaw. Also among their ranks is the gar, a toothy freshwater fish that can regrow its fins. While its regenerative powers aren’t the strongest (salamanders hold that place of honor), it’s of greater interest to researchers given the similarity between gar and human genomes.
A team of scientists from Michigan State University (MSU) have published research in the Proceedings of the National Academy of Sciences exploring these similarities and looking to answer questions about how gar can regenerate.
Garfish is what is known as a “bridge species,” with a genome similar to zebrafish (which closely resemble humans genetically) and humans. Ingo Braasch, an assistant professor of integrative biology at MSU and head of this most recent work, led the team that discovered those genomic similarities.
What they found was that humans share many of the genes that drive regeneration in these fish—with one key difference.
“The genes responsible for this action in fish also are largely present in humans,” Braasch said. “What’s missing, though, are the genetic mechanisms that activate these genes in humans. It is likely that the genetic switches that activate the genes have been lost or altered during the evolution of mammals, including humans.”
Braasch notes that zebrafish, a common choice for research, offer several advantages in the lab, such as rapid development, large amounts of offspring and transparent embryos for easy imaging. They cannot regenerate paired appendages the way gar can, however.
“Gar is being developed as a new model for vertebrate biology, evolution, development, genomics and regeneration in my lab. Gars are so-called ‘ancient fishes’ because both their body plan as well as their genetics are more similar than that of zebrafish to the extinct fish ancestors of humans,” he tells DDNews. “In terms of the gar’s genetics, its genome resembles better the situation in human than zebrafish, and thus can help as ‘bridge species’ to translate genetic information from zebrafish to human and back. But we are not (yet) able to use gar with CRISPR-Cas9, etc. in similar ways as zebrafish is used.
“In terms of regeneration, what this new study showed is that gars and other ‘ancient fishes’ can fully regenerate their paired fins after surgical removal, something many ‘modern’ fish cannot (we don’t know why). Hence, the ‘ancient fishes’ like gar will be better models than zebrafish for this type of body part regeneration research.”
Braasch notes that the garfish regeneration is not perfect, however, noting that “The regenerated fins often show structural malformations compared to fins that normally grew through development. We do not fully understand why this is the case, but in any event, having an okay fin regenerate is still better than no regenerated fin at all (as the zebrafish would have). The fish can properly swim with the regenerated fin, and we do not see much of a swim performance problem, at least not in our laboratory aquaria.”
The next step, he says, is to get into the genetics of gar regeneration, such as how the genes are turned on, if they’re only turned on for regeneration, and the order of the process.
“For the most part, it appears that these genes are not regeneration-specific, meaning they have multiple functions and roles, regeneration being just one of them,” Braasch points out. “It is the usual characteristic of a gene to have multiple roles or co-called subfunctions. This is also the reason why they are present in the human genome, it’s just that the regeneration-specific subfunction no longer exists, but the genes do their other work. The mentioned genetic switches are often what controls the gene activities in context-specific situations, and we hypothesize that the fish and the salamander have such regeneration-specific switches that control the regeneration subfunction.”
Braasch cautions that it will be a long time before this translates into humans, if it ever does.
“We are still very far from any direct transfer to human, but at least, once we have better characterized the genetic switches in fish, we can at least look whether they do exist in human, maybe in a very different form,” he concludes. “I suspect that it will be very hard to impossible to find traces of such switches in the human genome still. But I don’t want to exclude the possibility to one day being able to activate the right genes in the right place and order and amounts in human to start regeneration; the genes themselves should mostly be present in human.”

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