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HHMI investigators Douglas Melton, Harvard University, Leonard Zon, Harvard University, and Randall Moon, University of Washington.
"We basically shut down every other project in the lab, and we've been pursuing Wnt ever since," says Moon, who heads the university's Institute for Stem Cell and Regenerative Medicine. "We were eager to know how Wnt signaling normally works—and what happens when it doesn't."
Today, Moon's long-term goal is to use Wnt signaling to coax stem cells into heart, brain, and other organs to replace, or regenerate, diseased cells. Rather than trying to grow whole limbs or sci-fi animals, Moon and a growing group of scientists focus on repairing existing tissue and organs.
"In the past, developmental biologists concentrated on the question of how you make an animal," says Douglas A. Melton, an HHMI investigator at Harvard University, who began in developmental biology before shifting his energies to stem cell medicine. "Now, researchers are returning to a question asked decades earlier: How do you maintain that animal?" He compares this shift in focus to working at a car repair shop, as opposed to a car factory. "We're beginning to appreciate the importance of maintenance, replenishment, and repair."
An eclectic range of organisms—including crustaceans, snakes, and salamanders—have evolved the ability to regrow lost tissues or limbs, whether from injury or natural biological cycles. Even humans share this talent to some degree: every day, the human body replaces an estimated 10 billion cells, including those in the liver, skin, and blood. But why do some species regenerate body parts handily, while others do not? Why can humans regrow a liver but not a pancreas? Can we borrow from nature's regeneration toolkit to treat human disease?
To address these questions, Moon and his colleagues have been documenting Wnt's mechanisms. Their studies show that zebrafish, tadpoles, mice, and potentially many other organisms respond to injury by turning on Wnt, a major signaling molecule. Wnt activates a cellular pathway, Wnt/ß-catenin, which launches the biochemistry of regeneration. Conversely, Moon's lab has found that another Wnt protein, Wnt5b, inhibits regeneration by launching a pathway that puts the brakes on regrowth signals.
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The zebrafish heart is similar to the human heart in many respects. But unlike the human heart, the fish heart closes wounds rapidly and then regenerates to nearly full function.
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HHMI BioInteractive
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In a study published online last December in Development, Moon's team demonstrated Wnt proteins in action: first they amputated zebrafish fins, and then they turned on or blocked regeneration of those fins by altering the activity of different Wnt proteins. In a related study, the researchers showed that Xenopus (African clawed frog) tadpoles also require Wnt activity to fully regenerate amputated limbs.
"We suspect that Wnt signaling is one of the earliest responses to injury in any form and is essentially a universal component of regeneration in animals," concludes Moon. "If we can fully determine the normal function of Wnt proteins, we might develop therapies for humans." By revving up certain Wnt proteins, for instance, researchers might one day replace brain cells lost to neurodegenerative disorders. Alternatively, by shutting off other Wnt proteins, they might treat certain cancers.
The first regeneration-inspired therapy could be tested in humans as early as 2008. The lab of HHMI investigator Leonard I. Zon, a hematologist/oncologist at Harvard University, hopes to clinically test a therapeutic compound that eventually could allow doctors to regenerate a patient's immune system after damage by chemotherapy.
Photos: Melton: Joshua Dalsimer,
Zon: Kathleen Dooher, Moon: Brian Smale
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