It may be difficult for many people to imagine being the first individual to know some fact about the universe or to explain a previously mysterious phenomenon. But for most scientists it’s that possibility that makes research so enticing. “That excitement is definitely one of the most rewarding parts about science,” says Kenneth Poss. As a developmental biologist, he has experienced that thrill firsthand several times while studying a rather unassuming one-and-a-half-inch-long striped fish.
Poss’s fascination with Danio rerio, commonly known as the zebrafish, began when he was a graduate student in the lab of former HHMI investigator Susumu Tonegawa at the Massachusetts Institute of Technology. In the lab next door to his, a few of his friends were studying early development in zebrafish. As he listened to their discussions, Poss was intrigued by accounts of how this fish could easily regenerate a severed fin. Zebrafish can readily regrow amputated fins, damaged spinal cord and retina, and, as Poss would later demonstrate, injured heart muscle.
Poss was so intrigued that he chose to study regeneration in zebrafish during his postdoc with Mark Keating, then an HHMI investigator at Children’s Hospital Boston. There he discovered that zebrafish have the ability to replace lost heart tissue after as much as 20 percent of the organ is removed. Such a dramatic degree of regrowth in this complex organ had not previously been known. “The fact that the heart is still contracting every second of the day and night and performing a critical function for the animal throughout these regenerative events is pretty amazing,” says Poss.
Understanding how this regeneration occurs in zebrafish could lead to ways to encourage regeneration in mammalian tissues that cannot naturally fix themselves. “If we understand how this works naturally in fish,” he explains, “then we can figure out some way to apply that to poorly regenerative animals like mice or humans.”
With this goal in mind, shortly after setting up his laboratory at Duke University School of Medicine, Poss established what is now one of the largest zebrafish facilities in the country. It will eventually house more than 100,000 fish in 7,600 tanks—a quantity necessary to begin to identify the different players in regeneration. Many of the fish in the facility have been engineered with genes that are either inactive or overly active. Studies with these mutant animals by Poss and others will help define the molecular networks leading to regeneration.
Poss has already made some headway in understanding cardiac regeneration, focusing on the epicardium—the layer of cells that cover the hearts of vertebrates—from zebrafish to humans. Researchers had extensively examined the epicardium’s critical role in contributing vascular cells to the growing mouse or chick heart during embryonic development, but little was known about its function later in life.
Poss found that cells in the epicardium essentially lie dormant in healthy adult zebrafish. But if the heart is wounded, by a deep cut for example, epicardium cells start to rapidly divide. The new cells appear to move to cover the surface of the wound. Some of these cells then migrate deep into the injured area to help provide new vasculature to regenerating muscle—in a way, reactivating the epicardium’s role during development. “We found that within just a day or two after injury there is this tremendous activation of genes that are normally expressed during development, and proliferation of cells surrounding the entire heart, even in response to a very local injury,” he says. “That level of activity really surprised us at the time.”
When Poss blocked the function of a key gene, the regeneration process halted, causing the zebrafish heart to act more like a mammalian heart, which scars instead of regenerating. This finding suggests the possibility that scarring after heart attacks in humans may be avoided if there were a way to awaken the regenerative response.
Poss is now developing genetic tools to learn how injury stimulates cell growth in the heart and other tissues and how new cells correctly integrate into tissue that is being repaired. “The more we learn about successful regeneration in the context of zebrafish,” Poss says, “the better we’ll be able to understand regenerative failures in mammals.”