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Zon says the answer lies in the trigger for demethylation. "The big prize is to figure out what the 'demethylase' is. If you could identify it, reprogramming research would take a major step forward."
HHMI investigator Yi Zhang at the University of North Carolina at Chapel Hill is hot on the trail of this trigger. Last December, he and his collaborators announced they had discovered in cultured human cells a family of proteins that demethylates not the actual DNA of genes, but sites on the spool-like histones in chromatin that package the DNA. This family of proteins is known as JHDM1.
"We're not sure if members of this protein family can remove methyl groups from DNA itself," Zhang says—adding he wouldn't be surprised, however, if this turned out to be the case. If so, it would enable researchers to ask questions that could open the door to "artificially reprogramming" an adult cell without the need for a donated human egg.
"It could be that if you put this demethylase enzyme into the donor cell, it would be all you'd need to carry out reprogramming," he says. "But I doubt that it will be that simple."
Harvard's Melton doesn't suggest waiting until one of these efforts to reprogram adult cells without the need for human eggs or embryos pays off. "The hard fact is that, at this moment, the only way to create an embryonic stem cell from a somatic cell is by nuclear transfer into oocytes," he says. "Taking advantage of this current capability is critical if we hope to realize the extraordinary clinical potential of therapies based on stem cell technology."
Germ cells, which give rise to sperm and eggs, must navigate from the tail end of an embryo, where they form, to a distant reproductive organ where they will do their work. To discover cues the cells use to guide their journey, Ruth Lehmann, an HHMI investigator at New York University School of Medicine, searches for mutant Drosophila embryos whose germ cells get lost along the way.
"Our long-term goal is to determine how germ cells are specified, how they are guided during their migration in the embryo, and how a stem cell population is selected that gives rise to egg and sperm throughout the fly's adult life," says Lehmann.
By inserting a genetic element into the genome of developing fruit flies, Lehmann and her colleagues can stain the germ cells blue and then search for wayward blue cells in thousands of developing fly embryos. Using this approach, Lehmann and her colleagues have identified gene mutations that interfere with discrete steps of germ cell migration.
In 2003, Lehmann's lab identified trapped in endoderm-1 (tre1), a mutant fly whose germ cells get stuck at the back end of the embryo and cannot cross the epithelial cell layers that form its midgut. They have since shown that the germ cells in mutants they call wunen and wunen2 cross the midgut, but then wander around the middle of the embryo in a seemingly random fashion, rarely reaching their proper destination in the developing gonads.
In separate studies, Lehmann's group and Ken Howard's group at University College in London, England, showed that the wunen genes encode enzymes that remove phosphates from phospholipids, which float in the spaces between cells and help guide germ cells as they wander through the embryo. Recently, Lehmann's team found that in germ cells Wunen appears to be part of the apparatus that detects those phospholipids and uses the lipids for migration and survival.
"The same phospholipids that could be involved in germ-cell migration have been shown to give the timing signal for lymphocytes migrating out of the lymph node," Lehmann notes. If that is true, Lehmann's group may have stumbled onto a navigation mechanism used by many types of cells as they migrate through different tissues.
—Rabiya S. Tuma