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The secret to regenerating lost limbs may lie in our genes. And the keys to recognizing which genes have this potential may lie in studies of other animals.

Last year I had a nasty, infected cut on my big toe. The doctor suggested I might want to have it amputated. I told her, OK, if you think a new one will grow back, let's go ahead and amputate it, but if you don't, let's see if we can't do something about the infection.

Saving my toe, however, cost me and my insurance company, mostly my insurance company, over $300 thousand dollars. People who don't have really good health insurance, or a few hundred thousand dollars lying around, often have to have amputations.

It would be nice if humans, like salamanders, could grow amputated limbs back. Maybe by studying salamanders and similar creatures researchers will find a way to do that.

Zeroing In on the Zebrafish to Understand Regeneration

Fruit flies have genes that enable them to regenerate lost limbs. Salamanders and lizards and zebrafish have genes that enable them to regenerate lost limbs. Even mice and, surprisingly, human have analogous genes that don't perform the obvious task. How could the regeneration genes in humans somehow be activated?

To answer this question, scientists have taken a closer look at the zebrafish. Researchers love to study zebrafish, because their females lay eggs with transparent shells. They can easily watch the prenatal development of the babies without destroying the egg, observing the sequence of steps through which the zebrafish "recapitulates" its evolutionary development (as it is understood by biology).

Specific enzymes help the embryonic zebrafish organize cells into organs. Some of these enzymes continue to work even after the fish has hatched. If a zebrafish escapes a predator but swims away with an injured fin, the injury activated a gene for fibroblast growth factors that help it regrow the injured fin. It also has active genes for a protein called leptin b that can repair damage to its heart.

Genetic Enhancers That Make Repair Genes Superactive

The researchers also observed that some zebrafish regrow missing fins faster and more completely than others. To find out why this happens, they did a detailed study of the base pairs of DNA around the genes that enable regeneration. They discovered "tissue regeneration enhancer elements" that can (but don't always) turn on the regeneration genes at the site of an injury, or "turn up" the production of the proteins that start the process that restores the tissues.

The next step in the research was to genetically modify zebrafish so that enhancer elements were "welded" to the DNA coding the genes for regeneration. The result was super-regenerating zebrafish with superior abilities to restore damaged tissues. Next the researchers transferred the enhancer elements to the DNA of mice to see if the genetic modification would help mice recover from injuries to their paws and hearts.

Obviously, it doesn't do a mouse (or a human) a lot of good to acquire the ability to grow a new zebrafish fin. These enhancer elements don't dictate the exact proteins that the recipient body will make. But they do generate a diffusible signal that stimulates existing genes to do the task.

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