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Alcino Silva puts cognitive research on its head

AAAS Fellow Alcino Silva holds a mouse that he describes as having come from

It's a long-held precept that mice -- and people -- who are born with cognitive deficits can't be cured. With some neurodevelopmental disorders, if your brain's ability to learn and change is diminished, then how you're born is essentially how you'll remain.

But Alcino Silva has shown that in some cases, you can change a brain.

In the Silva Lab at the University of California at Los Angeles, the AAAS fellow has led projects in which adult mice with neurofibromatosis type 1 (NF1)—a genetic disorder that can cause molecular brain changes that result in learning and memory deficits—were given drugs that improved their memories.

Silva, a professor in the departments of neurobiology, psychiatry and psychology, couched the research question this way: "If you fix one thing ... is it enough to bring your brain to a level of functionality that lets you lead a normal life?"

He hopes he is demonstrating that it is.

NF1 is an inherited disorder that occurs in 1 in 3,000 births. It can cause tumors to grow along nerves, and every patient is affected differently. It can cause scoliosis, overgrowth of bone, and tumors of the eye and brain. By varying estimates, anywhere from 50 percent to 90 percent of children with the disorder have learning disabilities.

In his research, Silva discovered that signals in the brains of mice with NF1 do not function normally on the molecular level. Through different experiments, the researchers found that cholesterol-lowering drugs known as statins restored their normal function.

Researchers at the Silva Lab are exploring treatments for learning disorders, research on aging and cognitive decline, and possible methods for reversing psychiatric problems in adults.

Despite its focus on such weighty issues, the lab is a casual, relaxed place—so casual, in fact, that it wasn't until Silva had developed three generations of mice with NF1 that anyone in his lab would agree to try out his theory.

"The whole idea was so foolish that I couldn't get anyone to do the experiment," Silva said.

Of course, he says he would never insist that anyone do any experiment, so as not to stifle innovation.

"I go out of my way to tell people that they are to ignore what I tell them."

The approach is not surprising. Silva talks about neuroscience the way other people talk about cars and fashion. He makes you forget how complicated it is.

He credits the educational system in his native Portugal—where philosophy is taught in high school—for starting him on the road to discoveries in neuroscience.

"The world around us is a very recent world," he said. "I wanted to know how all of this is possible. How do we know what we know?"

He started out as a philosophy major.

He moved to the United States, alone, at 16. He was inspired, he says, by a jazz band from a Midwestern university that had toured Portugal. He wanted to see the place they came from in order to understand their music.

As an undergraduate at Rutgers University, he studied philosophy, biology and epistemology.

Later, he studied with pioneering genetics researchers Ray White and John Roth, and Nobel Laureate Mario Capecchi at the University of Utah, and worked on gene-targeting mice in the lab of Nobel Laureate Susumu Tonegawa at the Massachusetts Institute of Technology.

When he joined UCLA in 1998, Silva developed and tested adult mice with NF1. He selected this disorder to study because it is caused by a mutation in a single gene, so Silva considered it an easier route to learning how to treat problems with plasticity than a disorder like autism, which can be caused by hundreds of genes.

His breakthrough came when the mice were given statins, and the inhibitory signals in their brains started functioning normally.

"We turned their lives around," Silva said.

Statins are typically used to lower cholesterol, and most people can take them for years without significant side effects. In the brains of mice with NF1, however, Silva observed that statins decreased the level of a protein that is too high and inhibited signals between cells. When the protein level was decreased, the signals between cells started functioning normally.

These findings on the neurobiological effects of statins are now being tested in large-scale human trials, and Silva is cautiously enthusiastic about the results of using the drugs to improve memory in NF1 patients.

"The word is still out as to whether statins are a good drug. One of these studies will prove this one way or another."

As clinical trials continue, the outcomes are important for patients.

"About 90 percent of kids with NF1 have some kind of learning disability," said Annette Bakker, chief scientific officer of the Children's Tumor Foundation, which has funded much of Silva's research.

"He has made some discoveries that help us understand a little better the underpinnings of this biology. We believe that his work will have an impact on our patients."