Linda Restifo: Finding ways to treat mental retardation and autism

Linda Restifo has good reason to believe that drugs can treat the brain cells whose abnormalities cause autism and mental retardation. And she wants to see them on the market and helping children in her lifetime.

“Life is short,” she says. “And I’m impatient. It astonishes me that people traditionally have assumed that mental retardation is untreatable,” she says. “I’d like people to think of these disorders the way they think of high blood pressure—something that can be improved by medical intervention.

“There is a basic science view that if we simply try to discover all the steps leading to a disease, we’ll figure out what the best treatments are. I’m taking a more direct bench-to-bedside approach because there have been too many blind alleys and dead ends in brain disease research. Instead of looking at the details of the mechanism by which mutations cause brain defects, we’re using the genetic mutations to discover treatments,” explains Restifo, a UA professor of neuroscience, neurology, and cell biology, and a member of the BIO5 Institute.

In a first-of-its-kind experiment funded by the National Institutes of Health (NIH), Restifo and her team, including Research Associate Robert Kraft, PhD, have uncovered four dozen compounds, most of which are already approved by the FDA, which means they have a known safety record. The compounds are potentially useful for at least two types of mental retardation: tuberous sclerosis and Rubinstein-Taybi Syndrome.

Fruit flies are the stepping stones in her drug discovery research odyssey. Hundreds of genes in humans can cause mental retardations, 90 percent of them can be found in fruit flies, and 70 percent appear to be doing similar things in fruit flies. As research tools, fruit flies are simple and small enough to be practical for experiments but their brains are complex enough to be relevant to human disorders of brain development.

Fruit flies have been engineered to have genetic abnormalities that are comparable to those that cause autism and mental retardation in humans. Restifo takes advantage of the work already done and also breeds for new mutations. Then she and her lab members determine which features of brain development have been altered by the mutations.

Staff and students in the Restifo lab grow cells from mutant fruit flies in culture dishes. Drug compounds are screened by adding them to the abnormal cells. “You can find out which drugs make those cells look normal again,” says Restifo.

Her team has discovered drug compounds that make mutant brain cells with curly branches grow straight. They are curly because of the lack of fascin—a protein important to brain development. If the drugs overcome the lack of fascin and allow the brain cells to develop normally those drugs could someday become treatments for people.

The team also found that some of the drugs did the opposite. They made curly neurons even more curly, which happens when fascin is blocked. Excessive amounts of this protein are linked to the invasive behavior of certain tumors, including the most common type of brain tumor, glioma. Blocking fascin might block the spread of gliomas within the brain and also block the spread of common tumors from their initial locations, in the colon or breast for example, to distant sites, a process called metastasis.

“It’s so important to pay attention to unexpected implications that weren’t part of the original research plan,” says Restifo. “I had no idea 10 years ago that I would be doing cancer-related research.”

With additional funding, Restifo plans to move her tests to rodents, and eventually to human trials to determine safety and efficacy in people.

Restifo has undergraduate, medical and doctoral degrees in genetics from the University of Pennsylvania. She was a post-doctoral fellow at Brandeis University and a neurology resident at Harvard University. She came to the University of Arizona in 1990.

Psychiatric illnesses originally caught Restifo’s interest but she realized how slippery the slope was when it came to defining these disorders. That realization led her into brain research and eventually into even more focused work in mental retardation and autism.

Her interest in the brain actually began in high school. “A seventh grade science teacher introduced me to DNA and the wonders of genetics. In ninth grade, I became interested in the brain side of genetics. At that time, I didn’t know the word neurogenetics existed,” says Restifo.

Accomplishments

The Restifo research lab published the first modern, comprehensive analysis of human mental retardation genes. Restifo is the brains behind a first-of-its-kind cellular bioassay for mental retardation drug screening, and her group developed a software application, NeuronMetrics™, that greatly improves the speed and accuracy of 2D neuron image analysis. NeuronMetrics™ is distributed free to academic users through the University of Arizona’s participation in the Kaufmann Foundation’s iBridge program. The UA is one of seven universities that participate in the iBridge program, which distributes new technologies developed at academic centers. To date, more than 100 scientists have downloaded NeuronMetrics™ .

Collaborations

Restifo and her team collaborate with UA computer scientist and BIO5 member Kobus Barnard. He convinced her that a new software approach is needed to study the defects in neurons. Barnard’s approach is to have the software look at neuron images without preconceived notions so that the structure can be described in an unbiased way. Another collaboration with BIO5 member Yitzak Zohar—a mechanical engineering expert in microfluidics—could lead to RoboCulture™, an automated method for preparing brain cell cultures. Restifo also collaborates with child psychiatrist and autism expert Jaswinder Ghuman, who is helping evaluate the behavior of mutant fruit flies.