Cut most species of flatworm in half, and you end up with two flatworms. The front half will grow a new tail and, more impressively, the back half will grow a new head—complete with a fully functioning brain. But a few species of these worms mysteriously lack this ability, at least when it comes to regrowing a head. Now, three teams of researchers have not only zeroed in on the biological reason for this limitation, they've also managed to restore the worms' full regenerative abilities by manipulating a single genetic pathway.
The worms in question are known as planarians. Usually about a centimeter long, they live under rocks in freshwater ecosystems such as streams and ponds. Why some planarians can so easily regenerate a head but others can't is a question that has long puzzled scientists. "This is really just a classic problem in the field," says Phillip Newmark, a biologist at the University of Illinois, Urbana-Champaign. Hoping to study possible molecular mechanisms behind the difference, he dispatched his postdoc James Sikes into the field to search for specimens of Procotyla fluviatilis, the only North American species of planarian that can't regenerate its head. "He thought it would be easy!" remembers Sikes, who now runs his own lab at the University of San Francisco in California. After months of scouring the country for the tiny freshwater creatures, he finally tracked down a colony in southern Illinois. From there, he moved the worms to the lab and began chopping them to bits.
The first step was to pinpoint where exactly P. fluviatilis's head regeneration process went awry. Sikes and Newmark confirmed that the worms' wounds healed properly after being cut in two and that the cells in their tail fragments were still able to divide. "What seemed to be not working was the decision that says, 'make a head' versus 'make a new tail,' " Newmark says. That fundamental choice is governed by a molecular process known as Wnt signaling. By directing the activity of a protein called β-catenin, Wnt signaling tells developing cells what they should be when they grow up. If an amputated worm dials up Wnt signaling and produces a lot of β-catenin, it will regrow a tail. If it dials back Wnt signaling and β-catenin levels, however, it ends up growing a new head. Newmark and Sikes's P. fluviatilis tail fragments couldn't seem to activate this genetic switch either way.
This discovery "led to a really simple experiment," Newmark says. If he and Sikes knocked down the amount of β-catenin in a P. fluviatilis tail fragment, maybe they could trick it into regrowing a head. And to their amazement, that's exactly what happened. By disrupting the one gene responsible for β-catenin production, they were able to restore P. fluviatilis's ability to regenerate a lost head. "I didn't believe it when I saw it," Sikes admits. "Basically you're reversing a million years of evolution."
As it turned out, Sikes and Newmark weren't the only scientists interested in figuring out the secrets of flatworm regeneration. At the same time that they were conducting their experiments on P. fluviatilis in Illinois, a team of scientists in Europe was manipulating Wnt signaling and rescuing head regeneration in an entirely different species of planarian called Dendrocoelum lacteum. And on the other side of the world, Japanese scientists were reaching similar conclusions about β-catenin's role in preventing head regeneration in Phagocata kawakatsui, a distant cousin of the European and North American planarians. The results of all three experiments are published today in Nature.
"There's a European species, there's an American species, and there's a Japanese species. This is as broadly geographic a sample as you can possibly define, and all three laboratories independently reached the same conclusion," says Alejandro Sánchez Alvarado, a planarian biologist at the Stowers Institute for Medical Research in Kansas City, Missouri, who was not involved in any of the studies. The teams' complementary results show that a defect in Wnt signaling "seems to be a very easy way to lose head regeneration," agrees Elly Tanaka, a biologist at the Center for Regenerative Therapies Dresden in Germany who studies limb regeneration in vertebrates like salamanders.
The next step, scientists from all the teams agree, is to figure out why these three species lost the ability to grow new heads. "Because of 'survival of the fittest,' one might assume that actually everything out there should be regenerating," says Jochen Rink, a biologist at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden who led the European team. Newmark concurs, "Why would you lose this ability, which seems like it would be so useful?"
Reproductive differences between planarians that can regenerate their heads and those that can't may offer some clues, Sikes suggests. When head-regenerating planarians are cut in half, their sex organs melt away and are reabsorbed into their bodies. Freed of the pressure to continually produce eggs and sperm, the flatworms likely have more energy to direct toward regeneration. Besides, they'll have plenty of chances to reproduce once all their parts grow back.
Planarians that can't regenerate their heads, however, typically reproduce only once in their lives. "You don't want to miss that shot," even if you've just been cut in half, Sikes says. It's possible, he speculates, that the molecular signal that directs planarians like P. fluviatilis to keep their sexual organs around after their heads are amputated may also interfere with regeneration. "It's kind of a tradeoff between, do I want to regenerate or do I want to hang around and reproduce?" Sikes says.
However these differences evolved, the Nature papers all support the idea that regeneration isn't something that a few species independently evolved. Rather, it may be something that the rest of us have lost. The capacity crops up in nearly every phyla of life of Earth, suggesting to scientists that our common ancestor may have had regenerative abilities. Even humans can do it under the right circumstances; for example, Sikes says, children under the age of 2 can regenerate missing fingertips. So now that scientists can restore flatworms' vanished regenerative abilities, might they be able to do the same for other kinds of animals, such as humans? "It's a fanciful idea, but it's now one that's somewhat supported by the evidence in these three papers," Sánchez says.
Sikes is more cautious. "Will humans regenerate as well as the planarians? Never." Still, he says, the new studies show that "even though an animal can't regenerate, the underlying ability is latent. It's in there, potentially. … It's just a matter of figuring out how to unlock it."