When Genetic ‘Brakes’ Are Out, the Cells Will Grow

Genetic studies of rare disease bring hope for insight into common diseases

When the brakes go out, your car won’t stop, and you’re in danger of a crash.

Adan Treviño, left, and his wife, Virginia, visit with John Spudich, Ph.D., holder of the Robert A.Welch Distinguished Chair in Chemistry at the UT Medical School at Houston, and Hope Northrup, M.D., right, professor of pediatrics and speaker at the President’s Executive Luncheon. A founder of KXLN, the first Spanish language television station in the Houston area, Treviño now is president and chief executive officer of AMEX Investments Inc. Photo by Nancy Hudgins

When certain genes go out, your cells won’t stop growing, and you’re in danger of a disease.

Hope Northrup, M.D., professor of pediatrics, and her research team at The University of Texas Medical School at Houston have learned that when either of two specific genes fail, tuberous sclerosis results.

Tuberous Sclerosis Complex (TSC) is a rare genetic condition that causes the growth of benign tumors in major organs, including the brain, heart, kidneys and skin. Symptoms may include mental retardation, epilepsy and autism.

Northrup discussed results of her 19 years of tuberous sclerosis research at the President’s Executive Luncheon in April at the River Oaks Country Club.

In 1987 the first genetic linkage studies of tuberous sclerosis linked the gene that causes tuberous sclerosis, named TSC1, to chromosome 9. A consortium of researchers later located a second gene linked to tuberous sclerosis, called TSC2, on chromosome 16.

The two genes belong to a group of genes called tumor suppressor genes, Northrup said. “We figured out that the way people with tuberous sclerosis develop tumors is that both copies of their gene don’t work. So both sets of brakes, if you will, are out.”

Once the genes were identified, she said, “We could develop DNA diagnostics. We could check in a patient’s family to see for sure who had the disease and who didn’t. We started studying changes in the genes trying to correlate them with the physical findings in the patient. Could we make a correlation to give people prognostic information, to help them know what would happen to them?

“But even more important, after we found the genes, the basic scientists got real excited because we figured out that these genes function in a very basic pathway in cells,” she said. “In your body, when a cell is sitting there, normally that cell is resting. But as nutrients come to the cell, and insulin comes to the cell, conditions are right for the cell to grow and the pathway is turned on. What keeps the cells from growing when they’re not supposed to are the tuberous sclerosis genes. They’re the brakes to keep the cells from growing.”

This is the first therapy for this disease that will help patients prevent
their tumors from growing and even help the tumors disappear.”

That discovery – and much more research – led to a treatment for tuberous sclerosis patients with rapamycin, a well-known drug that performs the same function as the tuberous sclerosis genes, repressing cell growth. Preliminary reports at scientific meetings and a recent publication in the Annals of Neurology indicate that rapamycin stops both kidney and brain tumors from growing and even reduced the size of the tumors in tuberous sclerosis patients.

“This is the first therapy for this disease that will help patients prevent their tumors from growing and even help the tumors disappear – and maybe prevent surgery and other more serious complications,” Northrup said.

She left the audience with three take-home messages.

“First, when we study genetic diseases, it isn’t just an intellectual curiosity,” she said. “We want to find those genes because we want to find treatment for patients. And in tuberous sclerosis that’s now a reality. I’m so happy that after all those years we were looking for the genes, finding them and figuring out what they did, we can now give that back to the patients and families who all so willingly participated in this research.

“Second, by studying rare genetic diseases, we can sometimes learn information that’s very important for more common diseases. We studied a rare disease that affects only one in 6,000 people, about a thousand Houstonians. But what we’ve learned about tuberous sclerosis is going to help us learn more about autism, epilepsy, cancer, probably diabetes and maybe even obesity.

“My last take-home message is that research is a long-term investment,” she said. “Investing in research does pay off. It might not be next year or in three years or five years. It might be 15 or 20 years down the road. What we’ve learned in 19 years of research on tuberous sclerosis is just really amazing, but it did take many people doing research on it and having many research dollars to get where we are today.”

By Ina Fried, Public Affairs