A series of experiments revealed that one of the keys to regeneration in… (James Sikes )
If you’ve spent any time in the dirt, you might have seen firsthand that earthworms and snails squirm through life just fine after losing their heads – they simply grow a new one.
What is their secret for regenerating? One of the keys is to block a specific gene that makes head growth a one-time thing. Scientists discovered this in a series of experiments published Wednesday by the journal Nature.
The trick worked so well that scientists surprised themselves by growing worms with heads on both ends. And by ramping up the gene instead of silencing it, they grew worms with two tails and no heads.
The flatworms that scientists typically study, Dugesia, can grow an entire new individual from any body fragment. Other flatworms can do this, but only from certain body regions.
Three different research groups examined regeneration-deficient flatworms. They sequenced RNA -- a molecule similar to DNA -- from their tail fragments and compared the genes to those from body regions that could regenerate heads. Then the scientists combed through the data in search of genes that behaved differently in regeneration-deficient versus regeneration-proficient tissues.
Searching for the differences that mattered was like finding “a needle in a haystack,” said James Sikes, a cell developmental biologist at the University of San Francisco who led one of the studies. “We got thousands of genes that were different.”
The researchers observed the most striking differences in genes involved in the Wnt molecular signaling pathway, which is involved in embryonic development. In the worms, they found that the genes were more active in tissues with a limited ability to regrow heads. This led the study authors to hypothesize that they could switch on a worm’s head-regrowing ability by reducing Wnt signaling. That, in turn, could be done by blocking a gene that encodes a protein called beta-catenin.
Sure enough, silencing beta-catenin in decapitated worms caused a head to emerge from tail fragments. It also caused a head to grow from back-facing wounds—where a tail would normally grow—resulting in two-headed animals.
In contrast, turning up beta-catenin caused worms with forward-facing wounds to grow tails instead of heads, giving rise to two-tailed individuals.
The new heads housed normal brains and photoreceptors, or “eyes.” Like normal flatworms, animals with regrown heads also showed sensitivity to light and regained the ability to feed.
Sikes said he was amazed that by tinkering with a single gene, he and his colleagues were able to restore an ability a flatworm species had lost millions of years ago.
When he first observed a head developing from a tail fragment in the lab, he was shocked.
“I called the entire lab,” he said. “I asked them, ‘Does it look like the head?’ This worm hasn’t regenerated a head in 3 million years, and here it’s doing it.”
Why some flatworm species lost their ability to regenerate body parts remains uncertain. Since flatworms resorb their reproductive organs when they suffer amputation, Sikes suspects that evolution weeded out regeneration in some species to maximize reproduction.
The mechanisms behind regeneration in flatworms have puzzled biologists for more than a century, said Peter Reddien, a geneticist at MIT’s Whitehead Institute for Biomedical Research, who was not involved in the studies. However, developments in gene sequencing and gene silencing techniques over the last 15 years have allowed scientists to understand how the phenomenon works at a molecular level.
The Wnt pathway could “hold the key” for unlocking latent regenerative potential in other primitive animals, Sikes said.
“If we tweak the right genes, there are huge implications for other organisms that can’t regenerate,” he said. For these animals, perhaps “the program is there but it’s a matter of finding the switch that could turn it back on.”
Though the Wnt pathway also plays a major role in the cellular processes of vertebrates, including humans, Sikes believes that recovering regenerative abilities in these more complex organisms will involve manipulation of multiple pathways. Human regeneration “is not happening tomorrow,” he said.
Still, the findings “do give hope to regenerative medicine,” he said. “It kind of gives me goosebumps.”
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