Zon's team recently screened a library of 2,500 chemicals to find small molecules that spark the production of blood stem cells, a prerequisite for developing immune systems. The researchers discovered that prostaglandins—which, like hormones, regulate diverse chemical reactions—help to boost these stem cells. In particular, Zon's search identified a promising version of prostaglandin E2 (PGE2), made by drug manufacturer Upjohn in the 1980s.

To see how well the candidate PGE2 could help regenerate a damaged immune system, Zon's lab first irradiated zebrafish, essentially wiping out their native immune systems. When the researchers injected the irradiated fish with PGE2, the animals readily produced new blood stem cells. In related experiments on mice, they extracted blood marrow, bathed it in PGE2 for two hours, and found that the treated marrow at least doubled its rate of blood stem cell production for several months.

"This PGE2 derivative is the first known small-molecule mediator of stem cells and regeneration," says Zon. And that makes it a potential drug candidate. In a small but growing number of cases, doctors have successfully replenished a patient's weakened immune system by providing blood transplants from umbilical cord blood, which contains blood stem cells. In the future, physicians might instead administer a drug such as the PGE2 derivative. Joining forces, Zon and Moon are now studying how Wnt and PGE2, as well as their respective signaling pathways, work together to regenerate tissue in zebrafish.

Cancer patients aren't the only ones who could benefit from regenerative therapy. This year, more than 1 million Americans will have a heart attack, according to the American Heart Association. An injured human heart cannot regenerate; instead, it scars. Too much scarring limits the heart's capacity to pump blood and can trigger abnormal heart rhythms, or arrhythmias.

While an HHMI investigator at Harvard Medical School, Mark T. Keating revealed, through a decade of studies in newts, mice, and zebrafish, that certain molecular signals enable specialized cells at the site of an injury to "dedifferentiate," or revert to stem cells, and then respecialize into the types of tissue needed to replace the lost or damaged cells.

Keating and colleagues at Children's Hospital Boston later uncovered some key biochemistry that naturally inhibits heart regeneration. In a 2005 study in Genes and Development, Keating's team revealed that an enzyme known as p38 MAP kinase suppresses rat heart cells, or cardiomyocytes, so they cannot multiply. When the team chemically inhibited this enzyme, however, the cells replicated in a petri dish. "Our work laid out some of the basic molecular mechanisms needed for heart regeneration," explains Keating, now a vice president and head of ophthalmology at the Novartis Institute of Biomedical Research in Boston. "I think we accelerated the field."

Indeed, Keating's work inspired ongoing heart regeneration research. His collaborators at Children's Hospital reported last year that rats injected with two drugs, to inhibit p38 MAP kinase and grow blood vessels, regained heart function after damage. That preliminary work continues.

Meanwhile, one of Keating's former postdoctoral researchers, Kenneth D. Poss, now a cell biologist at Duke University, is continuing the heart studies in zebrafish. While tiny—only a millimeter across and a microliter in volume—the zebrafish heart offers big lessons in regeneration basics. The Poss lab has developed a technique to clip off a piece of one ventricle—about a quarter of the chamber—and document how one population of cells, known as "progenitor" cells, effectively rebuilds the lost cardiac muscle in two months. Now, the lab is attempting to characterize the progenitor cells that launch heart regrowth.

		Download the video Urodele amphibians—newts and salamanders—are able to regenerate fully functional limbs in response to amputation. HHMI BioInteractive

While scientists work toward one day regenerating the human heart, another organ already regrows naturally: the liver. Even after surgeons remove almost two-thirds of the liver, remaining cells can rebuild a complete organ in three to six months. As they reported last January in Nature, Melton and his colleagues studied developing mice to compare, up close, the growth habits of the liver and its neighbor, the pancreas. Melton's long-term research aim is to learn how to generate pancreatic beta cells, which produce insulin, to cure type 1 diabetes.

His team applied two genetic techniques to alter the number of progenitor cells in the liver and pancreas of mouse embryos. In one set of experiments, they destroyed different numbers of pancreatic progenitor cells to challenge the pancreas. In a second set, they injected pancreatic progenitor cells into a strain of mice deficient in this cell type. Across all the experiments, the number of progenitor cells predicted the organ's final size: fewer cells, smaller pancreas; more cells, larger pancreas.

The liver, however, proved more adaptable. Its final size was normal, virtually regardless of the number of liver progenitor cells the researchers left in or injected into the embryos.

	PAGE 1 2 3 4 5	Go Back | Continue