Progress in Understanding the Genetics of Organ Regeneration

Despite some promising results, such as the one linked here, it remains an open question as to whether the mechanisms necessary for regeneration of limbs and organs, a feat that species such as salamanders and zebrafish are capable of, also remain buried in mammals, such as mice and humans. Have we lost that ability entirely over the course of evolutionary history, did our branch of the tree of life never have it, or does it remain, dormant, and possible to reactivate? Since mice, humans, salamanders, and zebrafish all grow from embryos, and since the process of organ regrowth at least superficially resembles embryonic development, there is hope that the third option is in fact the case, and that this is a path to enabling profound regeneration in our species.

"We want to know how regeneration happens, with the ultimate goal of helping humans realize their full regenerative potential." Over the last decade, researchers have identified dozens of regeneration genes in organisms like zebrafish, flies, and mice. For example, one molecule called neuregulin 1 can make heart muscle cells proliferate and others called fibroblast growth factors can promote the regeneration of a severed fin. Yet what has not been explored are the regulatory elements that turn these genes on in injured tissue, keep them on during regeneration, and then turn them off when regeneration is done. In this study, researchers wanted to determine whether or not these important stretches of DNA exist, and if so, pinpoint their location. It was already well known that small chunks of sequence, called enhancer elements, control when genes are turned on in a developing embryo. But it wasn't clear whether these elements are also used to drive regeneration.

First, the researchers looked for genes that were strongly induced during fin and heart regeneration in the zebrafish. They found that a gene called leptin b was turned on in fish with amputated fins or injured hearts. They scoured the 150,000 base pairs of sequence surrounding leptin b and identified an enhancer element roughly 7,000 base pairs away from the gene. They then whittled the enhancer down to the shortest required DNA sequence. In the process, they discovered that the element could be separated into two distinct parts: one that activates genes in an injured heart, and, next to it, another that activates genes in an injured fin. They fused these sequences to two regeneration genes, fibroblast growth factor and neuregulin 1, to create transgenic zebrafish whose fins and hearts had superior regenerative responses after injury. Finally, the researchers tested whether these "tissue regeneration enhancer elements" or TREEs could have a similar effect in mammalian systems like mice. They attached one TREE to a gene called lacZ that produces a blue color wherever it is turned on. Remarkably, they found that borrowing these elements from the genome of zebrafish could activate gene expression in the injured paws and hearts of transgenic mice.

Eventually, the researchers think that genetic elements like these could be combined with genome-editing technologies to improve the ability of mammals, even humans, to repair and regrow damaged or missing body parts. "There may be strong elements that boost expression of the gene much higher than others, or elements that activate genes in a specific cell type that is injured. Having that level of specificity may one day enable us to change a poorly regenerative tissue to a better one with near-surgical precision."



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