Going Rogue

In the 1990s, as the massive Human Genome Project claimed newspaper headlines and the public imagination, a single mutant gene captured the attention of Diane Merry, PhD.

Twenty-nine years later, it still does.

Merry, a professor in Jefferson’s Department of Biochemistry and Molecular Biology, has won dozens of major grants and co-authored 30 papers focused on how one rogue gene causes the rare neurodegenerative disease spinal-bulbar muscular atrophy (SBMA). Back in 1991, she had just finished her PhD when the discovery of SBMA’s bad gene was announced in the journal Nature. “I was fascinated by it and felt I had the tools to contribute to understanding it,” she says. As a post-doc in the University of Pennsylvania lab of one of the gene’s discoverers, Merry published early papers on the mysterious gene and its effects. Today at Jefferson, she leads one of the few labs in the U.S. dedicated solely to SBMA research.

“It’s my goal, my dream, to find a treatment that lets people with SBMA live a normal life,” she says.

There’s currently no treatment or cure for the inherited disorder, which affects about one in 40,000 men. Symptoms usually crop up at midlife, as SBMA—also called Kennedy’s disease—destroys motor neurons in the spinal cord and brain stem that control muscles for speech, chewing, and swallowing as well as for arm and leg movements. SBMA can also reduce male fertility and, new evidence suggests, increase risk for metabolic problems like insulin resistance, obesity, fatty liver, and unhealthy cholesterol levels. Women who carry the gene may have mild symptoms, like muscle cramps.

The National Institutes of Health has awarded three large, multi-year grants to Merry so she and her lab can develop a new transgenic mouse model of SBMA and look even more closely at how the disease unfolds at a molecular level. “The grants are game-changing,” she says.

Merry moved her lab into a big, newly refurbished space in Jefferson Alumni Hall in 2019 and added new researchers and staff to her team. “Normally we have five to 10 members, but we’ll go up to 13 now,” she says. “There’s a large tissue culture room where everyone can do their work. And we have a new, high-resolution microscope for live cell imaging—we can watch what’s happening inside the cell nucleus in real time. The lab, the people, the equipment, it’s all been a real game-changer. I’m excited and optimistic.”

The Merry Lab already has a long-standing reputation for discoveries that advance research on SBMA and also for a whole family of inherited diseases called polyglutamine disorders, says Harry Orr, PhD, director of the Institute for Translational Neuroscience at the University of Minnesota in Minneapolis. These related diseases include Huntington's disease and spinocerebellar ataxias, which Orr studies. “Diane’s group has made state-of-the art observations about novel and innovative concepts that move the whole field forward,” Orr says. “Her work is significant for SBMA and for a larger group of researchers. What she’s doing now is very ambitious.”

Moonlighting Androgen Receptors

SBMA’s “bad” gene carries faulty instructions for making androgen receptors—proteins that bind with testosterone. Normally, androgen receptors and testosterone hook up, waltz into a cell’s nucleus, and regulate genes for the development of male reproductive organs and for the growth of muscle and bone mass, among other duties.

But the mutant gene, which has a long strand of extra DNA subunits, creates mutant androgen receptors. They still link up with testosterone and get into the nucleus. Then, there’s trouble. The mutants fold into the wrong shape, which may affect the way they interact with DNA and with other proteins. They also pile up in the nucleus, like curbside trash during a sanitation strike. Merry is studying these abnormalities, using transgenic mice as well as cell cultures, to find a practical solution to SBMA.

“We’re trying to understand the mechanism of the disease so we can identify therapeutic targets—potential ways to intervene that don’t interfere with the normal functioning of the hormone testosterone and its androgen receptor in men,” she explains. “We want testosterone and its androgen receptor to keep on doing their day job, but we want to stop them from moonlighting and causing problems for men with SBMA.”

That’s in sharp contrast to another current research path. Testosterone fuels SBMA. Some other researchers are looking at the testosterone-blocking drug leuprorelin to reduce SBMA’s symptoms or slow its progression. Previous research using the testosterone-blocking drug dutasteride yielded small benefits, possibly because SBMA had already caused too much damage, Merry says. She and other experts suspect blocking testosterone in younger men before SBMA causes problems would stop SBMA from developing. “Nobody would argue that if you removed testosterone before any onset of the disease, you’d prevent SBMA,” Merry says. “But who would want to live that way?”

Edward Meyertholen, a retired biologist who acts as the liaison between the Kennedy Disease Association’s scientific advisory board and its board of directors, agrees. “The disease doesn’t shorten your life span. The symptoms can be severe—plenty of men end up in wheelchairs or using a cane, and swallowing problems can be dangerous. But most can still lead a full life. Taking a testosterone-stopping drug from early adulthood because you carry the gene for SBMA isn’t appealing. It would be life-changing to have a treatment that helps while leaving the healthy effects of testosterone alone.”

At the KDA, Meyertholen works with Merry, who serves on the organization’s scientific advisory board. Several years ago, Meyertholen worked as a volunteer in the Merry Lab during a sabbatical from his college teaching post. “I had the time of my life. I learned so much,” he says. “Diane’s a fantastic person. She’s dedicated to training her lab staff, furthering research, and explaining it to people with SBMA and their families. For men with Kennedy’s disease and their families, just knowing people like her are working so hard to find treatments is very reassuring.”