Through engineering, a new look at the brain

When engineers don't understand something, they take it apart to analyze what's inside. One neuroscientist is using this approach, reverse engineering, to study the brain.

When engineers don’t understand something, they take it apart. In a process called reverse engineering, they try to figure out the insides in order to comprehend the whole.

This is exactly what Madrid-born physician-turned neuroscientist Rafael Yuste is doing with the brain, in an attempt to figure out some of the mysteries of human behavior and disease. Yuste is a biological sciences professor and co-director of the Kavli Institute for Brain Science at Columbia University. Using living brain slices from mice, he focuses on solving the puzzles of the largest part of a mammal’s brain: the cerebral cortex.

I recently talked with Yuste about his work. He said brain scientists haven’t made a lot of progress in understanding how the human brain works in the last century, but he is optimistic about a breakthrough. Excerpts of our conversation are below.

Why did you begin studying the brain?

As a grammar school student in Spain, I read a book called Microbe Hunters about the history of bacteriology, and I was captivated by the idea of being a scientist and helping solve problems that help mankind. I went to medical school, and I quickly realized that the most fascinating questions for medicine and biology were understanding the brain.

A brain slice of the cerebral cortex of a mouse, showing about 4,000 neurons. This picture shows a segment that is about 10 millimeters wide by 2 millimeters tall.

What do we still not understand about how the brain functions?

I think we’re still missing the whole picture. We’re still at the same stage we were 100 years ago, although we've collected much more data. Any established science has a general theoretical framework with which to understand the data. This is unfortunately still missing from neuroscience. We don't have a general theory that explains what the circuits in the brain actually do. We have a lot of little theories but not a general one. The cortex is the largest part of the brain and is the site of all cognitive functions. That's what makes us human.

What do we need to know to understand?

You could always argue, “When do you understand something?” The criteria for understanding something could be different for different people. But I think, for example, we understand an organ in the human body if we are able to fix its problems. Or you understand how a car works if you know enough about its mechanics to fix it when it breaks. If you apply that test to the brain, I’d say we cannot fix the problems. Schizophrenia, obsessive-compulsive diseases, Parkinson’s, Alzheimer's--we’re at the very early stages.

You’ve compared the cortex to a circuit built out of modules. Can you explain that?

We don’t have a general theory; we’re walking in the darkness. So we make use of other fields around us that can provide us with some ideas of what to do. It’s natural to think of [the brain] as a circuit because it’s built out of components that send electrical signals to communicate. Electrical engineering is a very successful discipline, so we look there for inspiration. You can imagine in the cortex there could be a circuit, and if that’s the case, then we need to reverse engineer it.

This is exactly what engineers do from unknown devices—they take it apart, draw the circuit diagram and make an educated guess as to what the device does. People like me are trying to do the same thing with the neocortex.

You’re studying mice. Are their brains as mysterious as ours?

I don't think we understand the brain of any animal. The assumption is that the cerebral cortex works the same, whether it is a mouse, giraffe or human. Our ultimate goal is to figure out how the human brain works so we can cure these diseases; and out of curiosity. In studying mice, we have an experimental model. We can keep slices of the mouse’s brain alive for about 12 hours in a special chamber. We have the circuit on a dish and can study the slides with optical and electrical techniques.

What other disciplines help you figure out the brain?

I think the biggest problem with neuroscience—the reason why we still haven’t figured the brain out—is the complexity of the circuits in the brain. There’s billions of neurons connected in very mysterious ways. It’s not easy to try to take it apart. What has happened in neuroscience is that new methods have been invented to tackle these formidable challenges. These methods are coming largely from the physical sciences—physics, chemistry and engineering. Engineering people in my lab have backgrounds that are interdisciplinary.

The hope is that these new methods would break this impasse and enable the gathering of data about these complicated circuits that would lead to the resolution of this basic problem.

What progress would you expect in your lifetime?

I’m optimistic. I think we’re almost there, as a field, and that there’s going to be a moment in neuroscience--that I hope will happen very soon--that will be a breakthrough, in which someone, somewhere will articulate a general theory that will be a little analogous to the moment in genetics when the DNA double helix model was proposed. It was very simple theory for how genetics works, and that was the foundation of molecular biology. I hope we’ll have something like this for the brain.

This is what I’m dreaming of—the moment when we’ll have this breakthrough of having a basic model of how these cerebral cortex circuits work. Once we have that, I’d expect a lot of the data we have floating around will fit into place.

How are your days spent?

I run a lab of 10 scientists. We work long hours and weekends, and I supervise and direct the group. I normally get to work very early, spend a couple hours answering emails and doing paperwork and then spend the rest of the morning in one-on-one meetings with people in the lab. In the afternoon I normally block time off to work on writing papers or writing grants. People like me travel a lot to meet colleagues and give talks.

I don’t do experiments anymore, but I supervise people who are doing experiments every day. Some days I feel like I’m their technician because I order their supplies and am brought in to solve their problems.

Even for an issue as critical as solving the human brain, do you still have to fight for funding?

I’ve been fortunate so far. I’ve been able to realize my dream and do the kind of science I want to do. When I started as a neuroscientist, my mentor in England told me to do good experiments and don’t worry about the rest. Somehow I think if you do good work and good science, the funding appears miraculously. We have to work to get it, but it does come.

I’m pretty convinced this is true, at least in science. I had to leave a fairly cozy life as a doctor in Spain. I came to the U.S. to start anew, with a couple suitcases, and I never regretted it. I would encourage young people to do the same. Don’t be too worried about your finances, and don’t be tied down too much to your roots. You only live once.

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