 How do you fix a broken heart? According to a new study, trees can help. That is, tissue regeneration enhancer elements. The study found that these short DNA control modules from zebrafish can precisely regulate gene expression in mammals to promote healing after a heart attack. Heart attack or myocardial infarction and heart failure are common and devastating cardiac conditions, but the hearts of adult mammals can't regenerate well after injury, making treatment difficult. One option is to attempt to use gene therapy with viral vectors to enhance heart cell proliferation, thus improving cardiac regeneration. However, current gene therapies are limited in their ability to control their cargos, leading to strong continuous delivery in one or more organs. And unchecked cell proliferation can lead to problems like tumor formation, making methods for precise control essential. Zebrafish trees are promising mediators of such precise control. Trees are short sequences of genetic instructions that trigger the expression of downstream regeneration-related genes in injury sites. These instructions help provide zebrafish with remarkable regeneration potential. And importantly, the instructions include how to turn off the genes as healing is completed. However, it hasn't been tested whether zebrafish trees can be used to improve regeneration in mammals in some way, until now. In the new study, researchers tested the injury targeting and tissue restoring ability of gene therapy vectors containing zebrafish trees in mice and pigs. In both species, zebrafish trees carried by adeno-associated viruses that were delivered into the bloodstream were able to turn on genes specifically in injured heart tissues and not in uninjured heart muscle. This occurred regardless of whether the vectors were introduced before or after myocardial infarction. The researchers were also able to manipulate the expression of specific endogenous genes in mice by combining the trees with a CRISPR epigenome editing system, suggesting the potential for injury-associated control of genes within their normal genome locations. Moreover, intravenously injected tree vectors that delivered a constitutively activated form of the transcriptional regulator YOP to heart attack injured tissue in mice, increased indicators of actual cardiac regeneration, and improved the function of the injured hearts. This confirmed that the tree's molecular effects translated into real therapeutic effects. The components of the gene therapy vectors still need to be optimized for both efficacy and safety. Nevertheless, this proof-of-principle study suggests that gene therapy using targeting tools like zebrafish trees is a promising way to boost cardiac regeneration after heart injury in a spatiotemporally controlled manner, potentially even in human patients. And it's not just a matter of the heart. This approach could help regenerate other tissues, too.