Sci. Aging Knowl. Environ., 4 May 2005
Good as New
Researchers uncover genetic instructions for remaking worm body
Weary office workers who long for a "regenerating vacation" envision a spa weekend, not a summary beheading. But that rough treatment works wonders for flatworms, spurring each fragment to grow into a new animal. For the first time, researchers have analyzed large numbers of flatworm genes to pinpoint ones that confer this ability. The work could provide hints about how our tissues manage renovations.
Salamanders can replace lost limbs. Lizards can sprout new tails after ditching the originals. And as geneticist Thomas Hunt Morgan showed in the late 1800s, the flatworms called planarians can regenerate a full body from a fragment 1/279th of the animal's original size. The crawlers also nurture flocks of stem cells called neoblasts that continually replace decrepit cells (see "Regenerating Regeneration"). Researchers dream of refurbishing age-worn human tissue by harnessing other organisms' self-renewal prowess. But a big obstacle is that the animals whose genetics and molecular biology scientists best understand--fruit flies and nematodes--are flops at regeneration. "If you cut a C. elegans in half, it's finished," says developmental biologist Alejandro Sánchez Alvarado of the University of Utah School of Medicine in Salt Lake City. To sidestep this barrier, Sánchez Alvarado and colleagues devised a technique to identify planaria genes that orchestrate rebuilding.
They used snippets of RNA (RNAi) to shut off 1065 planarian genes one at a time. After blocking a particular gene, the researchers sliced off the worm's head and tail and cataloged abnormalities as the sections regrew. To confirm that gene silencing was disrupting regeneration and not other activities, the team compared sliced worms to uncut ones dosed with the same RNA. The procedure uncovered 240 genes that control aspects of regeneration. For example, blunting any of eight genes spurred the animals to swell and sprout blisters. Other meddling made the creatures slither sideways--an abnormal behavior indicating that something had gone awry during reinstallation of their missing body parts--or halted regeneration altogether. The researchers then classified the genes by which regeneration step they helped perform, such as healing the initial wound or shaping the burgeoning tissue. That analysis suggests that different genes supervise regeneration and the day-to-day replacement of worn-out cells, says Sánchez Alvarado. Most of the genes the researchers identified have counterparts in other animals, he adds, including some that cause human diseases such as the rare eye disorder bradyopsia. Deciphering their roles might help clarify how our tissues renew themselves--or fail to do so as we age. Moreover, the worms probably sport about 15,000 to 20,000 genes, so many more await testing, he says.
The innovative work provides a new way "for ferreting out the functions of these genes" involved in regeneration, says developmental biologist David Stocum of Indiana University-Purdue University Indianapolis. Although other researchers have used RNAi to upset regeneration in planaria, nobody had looked at so many genes in one study, says developmental biologist Phillip Newmark of the University of Illinois, Urbana-Champaign. The asexual worms are "essentially immortal," he says, and learning why they can pump out fresh cells indefinitely might reveal how our own tissues control cell replacement. That could be a discovery worth losing your head over.
May 4, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150