Harry Dietz went back to the drawing board to rethink the cause of Marfan syndrome—and now he has a treatment in clinical trials.

Fifteen years ago, Harry C. Dietz and his research group made a big discovery: Mutations in the fibrillin-1 gene cause Marfan syndrome, a genetic disease that weakens connective tissues in the body, including the structural meshwork of blood vessels, and can lead to sudden death if undiagnosed.

The celebration, however, was short-lived. “Things began to look problematic almost immediately,” recalls Dietz, an HHMI investigator at the Johns Hopkins University School of Medicine. “Because fibrillin-1 is a structural protein—and very important during development—there was a suggestion that people with Marfan syndrome are born without a proper quotient or quality of elastic fibers.” Yet he knew that figuring out a way to compensate for the missing elastic fibers—particularly during early development—was a challenge that molecular medicine was not ready to handle.

“The possibility of finding a productive treatment strategy was analogous to repairing a house with a rotten frame,” he says. “There is no way you could imagine addressing the situation without tearing the house down and starting over.”

As researchers considered their options during what Dietz calls “those dark days,” one question in particular gnawed at Dietz: How could a disease with such complex characteristics—overgrowth of bones, thickened mitral valves, aortic aneurysm, craniofacial deformities, lung problems—be explained by structural deficiency alone? “It just didn't add up,” he recalls.

To build a new intellectual framework, scientists in Dietz's lab turned to a mouse model of Marfan syndrome they had developed by genetically engineering a mutation in the fibrillin-1 gene. They knew that people with Marfan syndrome often develop problems that resemble emphysema—with widening of the air spaces that can lead to rupture of the lungs—so they first focused on any lung abnormalities they saw in the mutant mice.

They did not expect to find lung problems in the young mice because they believed this kind of destructive emphysema occurs later in life—the cumulative result of stresses over time. “We thought that only over the course of months to years would we begin to see structural damage to the lung,” Dietz recalls. “Instead, we saw a diffuse widening of the air spaces in the absence of any evidence of tissue damage or inflammation in the lung right from the day of birth.”

Photo: Elena Dorfman

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