(Originally published by Columbia University)
August 1, 2011
Rafael Yuste likens scientific research to mountain climbing. Assemble a skilled team, get the best equipment, map the route and proceed with slow, deliberate steps. “By walking up very securely, step by step, and not losing track of the summit, you can get there,” says the professor of biological sciences and co-director of the Kavli Institute for Brain Science.
Yuste knows what he’s talking about. An avid mountain climber, last summer he scaled Monte Perdido, an 11,000-foot peak in the Spanish Pyrenees whose final icy incline has claimed dozens of lives.
From the much lower elevation of his office in the Northwest Corner Building, Yuste is tackling another tall challenge: trying to untangle the cerebral cortex. It’s the largest part of a mammal’s brain and is responsible for fundamental functions like perception, memory, imagination and thinking, yet it continues to perplex scientists. “People have been studying the brain seriously for the past hundred years, but now neuroscience is in an exciting time because of the applications of all kinds of new techniques,” says Yuste, who is working toward a unified theory of the cerebral cortex—a computational formula for how the brain functions.
Yuste’s approach is to reverse-engineer the brain, much like engineers who take apart circuit boards to figure out if they are part of a toaster or a TV. “The main hypothesis of how the cortex works is that it’s a circuit built out of modules, like little bricks that repeat throughout the brain,” says Yuste. He takes slices of mice brains, a third of a millimeter thick and consisting of about 20 layers of neurons—also known as nerve cells, they are the central components of the nervous system—then studies them with techniques drawn from physics, chemistry, engineering and computer science.
In his role as co-director of the Kavli Institute (his co-director is Thomas Jessell), one of Yuste’s jobs is to promote interactions between the basic science groups at Morningside and the neuroscientists who are currently housed at the medical center. The institute, directed by Nobel laureate and University Professor Eric Kandel, is also part of the Mind Brain Behavior Initiative.
His team, for example, developed an optical mapping method that involves bathing these brain slices with a chemical that deactivates neurons, and then uses lasers to stimulate them and visualize connections with light. “This way, not only can we see the circuit in action, we can manipulate it with light and be able to get the circuit to become activated and inactivated in an arbitrary fashion,” says Yuste.
Neurons either fire or they don’t; excitatory neurons activate other neurons while inhibitory neurons prevent them from firing. One conundrum neuroscientists face is the relationship between the two kinds of neurons. Yuste recently published research in the journal Neuron demonstrating the multiple connections between inhibitory and excitatory neurons using his optical mapping method. The study supported a long-standing hypothesis that the brain is active in the absence of input, or to put it more technically, the circuits in the brain can generate “intrinsic activity.” It’s one piece of the puzzle Yuste hopes will contribute to the unified theory of the cortex.
Yuste’s training started when he was a high school student, analyzing blood samples in a laboratory run by his mother, a pharmacist in Madrid. His father was a lawyer who was a member of Spain’s State Council and ran a cultural foundation. Attracted to the idea of both doing research and treating patients, Yuste went to medical school in Spain but began considering basic neuroscience research when he did a rotation in the psychiatry ward.
“I realized we were treating schizophrenics without any deep understanding of what goes wrong,” he recalls. “The same argument can be made for many types of epilepsy, Alzheimer’s and bipolar disorders. It’s very difficult to come up with therapies when we don’t understand how the circuit works.” After a six-month research stint in Cambridge, England, Yuste decided to drop medicine and move to the United States to get his Ph.D. at The Rockefeller University. He was a post-doctoral fellow at Bell Labs before joining Columbia in 1996.
Like a mountaineer who can visualize the summit, Yuste is optimistic. “The rest of the body is pretty well understood, but once you go higher than the nose, we’re in uncharted territory,” he says. The unified theory he envisions would be as simple and elegant as the DNA double helix, and could likewise have a galvanizing effect on the field. “Many of us have a feeling that a big breakthrough is about to occur that would illuminate everything.”