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Chop off a salamander's leg and a brand new one will sprout in no time. But most animals have lost the ability to replace missing limbs. Now, a research team at the Salk Institute for Biological Studies has been able to regenerate a wing in a chick embryo -- a species not known to be able to regrow limbs - suggesting that the potential for such regeneration exists innately in all vertebrates, including humans.

Their study, published in the advance online edition of Genes and Development on Nov. 17, demonstrates that vertebrate regeneration is under the control of the powerful Wnt signaling system: Activating it overcomes the mysterious barrier to regeneration in animals like chicks that can't normally replace missing limbs while inactivating it in animals known to be able to regenerate their limbs (frogs, zebrafish, and salamanders) shuts down their ability to replace missing legs and tails.

"In this simple experiment, we removed part of the chick embryo's wing, activated Wnt signaling, and got the whole limb back - a beautiful and perfect wing," said the lead author, Juan Carlos Izpisúa Belmonte, Ph.D., a professor in the Gene Expression Laboratory. "By changing the expression of a few genes, you can change the ability of a vertebrate to regenerate their limbs, rebuilding blood vessels, bone, muscles, and skin - everything that is needed."

This new discovery "opens up an entirely new area of research," Belmonte says. "Even though certain animals have lost their ability to regenerate limbs during evolution, conserved genetic machinery may still be present, and can be put to work again," he said. Previously, scientists believed that once stem cells turned into muscles, bone or any other type of cells, that was their fate for life -- and if those cells were injured, they didn't regenerate, but grew scar tissue.

Manipulating Wnt signaling in humans is, of course, not possible at this point, Belmonte says, but hopes that these findings may eventually offer insights into current research examining the ability of stem cells to build new human body tissues and parts. For example, he said Wnt signaling may push mature cells go back in time and "dedifferentiate" into stem-like cells, in order to be able to then differentiate once more, producing all of the different tissues needed to build a limb.

"This is the reverse of how we currently are thinking of using stem cells therapeutically, so understanding this process could be very illuminating," he says. "It could be that we could use the Wnt signaling pathway to dedifferentiate cells inside a body at the site of a limb injury, and have them carry out the job of building a new structure."

Members of the Wnt gene family (for "wingless," originally discovered in fruit flies) are known to play a role in cell proliferative processes, like fetal growth and cancer development, and Belmonte's lab has characterized the crucial role of Wnt signaling in limb growth. In 1995, the Salk researchers were first to demonstrate that they could induce the growth of extra limbs in embryonic chicks, and in 2001, they found that the Wnt signaling system played a critical role in triggering both normal and abnormal limb growth.

The current study was designed to see if Wnt signaling also was involved in the regeneration of limbs and included three groups of vertebrates: zebrafish and salamanders, which can regenerate limbs throughout their lives; frogs, which can only regenerate new limbs during a limited period during their fetal development; and chicks, which cannot regenerate limbs.

To manipulate animals' regeneration ability, the Salk researchers used inhibitory and excitatory factors for Wnt signaling, which they delivered directly to the remaining bulge after they cut a limb from the experimental embryos.

In adult zebrafish and salamanders, they found that blocking Wnt signaling with the inhibitory factors, prevented normal regeneration. And, conversely, when they treated mutant adult zebrafish that cannot regenerate with the excitatory agent, the ability to regenerate their fins was rescued, Belmonte says.

Using an inhibitory agent on frogs before the regeneration-enabled developmental window closed resulted in loss of that ability, but treating them with the excitatory agent after they had lost their regenerative capacity induced new limb growth.

They then performed the key experiment, successfully testing the ability of an excitatory factor to produce limb regeneration in chick embryos. "The signal restarted the process, and genes that were involved in the initial development of the limb were turned back on," Belmonte says. "It is simply amazing."

The procedure was tricky, however. Belmonte noted that if Wnt signaling is activated for too long of a period in these animals, cancer results. "This has to be done in a controlled way, with just a few cells for a specific amount of time," he says. "The fact is that this pathway is involved in cell proliferation, whether it is to generate or regenerate limbs, control stem cells, or produce cancer."

Researchers who also contributed to the work include postdoctoral researcher and first author Yasuhiko Kawakami, Ph.D., staff scientist, Concepción Rodriguez Esteban, Ph.D., senior research associate, Hiroko Kawakami, research assistant, Ilir Dubova, M.D. at the Salk Institute as well as researchers Marina Raya, and Merce Marti, Ph.D., at the Center for Regenerative Medicine in Barcelona, Spain.

The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.

Teeth regrown for the first time
Monday, 27 November 2006
by Hamish Clarke
Cosmos Online

SYDNEY: For the first time researchers have been able to induce the growth of replacement teeth in mammals. Unlike other vertebrates, mammals normally lose the ability after they replace their milk teeth in infancy.

"Our results may have implications for organ regeneration and bioengineering of teeth and the understanding of the genetic basis of the evolution of teeth," the authors said in a paper published in the U.S. journal Proceedings of the National Academy of Sciences.

The research was conducted at the University of Helsinki, Finland, as well as in Berlin and Kyoto, using mouse tissue.

Most vertebrates - famously including sharks - have continuous tooth generation, meaning that lost teeth are replaced with new teeth as needed. Somewhere in their evolution mammals, including humans, lost this capacity, with the sole dental replacement being permanent teeth for milk teeth.

"Intriguingly, a trend in mammalian evolution has been a reduction of number and renewal of teeth, concomitant with the evolution of progressively more complex...teeth," the researchers said.

Irma Sesloff, from the University of Helsinki, and fellow researchers stimulated a molecular trigger, called the Wnt pathway, in tooth buds extracted from mouse embryos.

Tooth buds from mice with the activated Wnt pathway gave rise to dozens of teeth with normal tooth enamel, developing roots and the usual dentin interior. The new teeth were observed to bud off from previously developed teeth, which is how tooth renewal proceeds in other vertebrates.

However the teeth weren't quite like normal mouse molars in every respect. Typically mouse molars have several points, or cusps, but the teeth from the experimental mice were simple and cone-shaped.

The authors concluded complex teeth may have been a trade-off with the ability to grow new ones at will. "These results may implicate Wnt signaling in tooth renewal, a capacity that was all but lost when mammals evolved progressively more complicated tooth shapes," they said.

The findings may also provide a greater understanding of cancer of the teeth. There were parallels between the teeth grown in mice with hyperactive Wnt signalling and odontomas, which are tumor-like malformations consisting of multiple small teeth - sometimes over 100.

The demonstration that tooth renewal can be restored in modern day mice given the right conditions is reminiscent of the 2003 finding that chicken still posess genes from their dinosaur days - now silenced -involved in tooth generation.

More importantly, it means that the potential for continuous tooth generation may also have been retained in humans. The ability to harness this latent power will depend on the progress of future research in the area. If tooth regeneration becomes viable, it will be good news for boxers, the elderly and other people whose teeth have gone walkabout.

frigidmagi wrote:Denist accross the world explode into protest. Candy companies rejoice.

Mayabird wrote:

frigidmagi wrote:Denist accross the world explode into protest. Candy companies rejoice.

I just realized that your quip would be perfect if you'd said, "From dentists around the world, there was a great wailing and gnashing of teeth."