Rex Kerr (left) can measure neuron activity in worms as they sense chemicals in their environment. Tim Harris says worms and fruit flies are a good start for eventually answering questions about the brains of larger animals.

Harris spent the early part of his career at Bell Labs, where he developed optical methods for studying semiconductors. Later, at Helicos Biosciences and elsewhere, he became interested in biological measurements that generate huge amounts of data. He sees neuroscience as one big measurement problem. All science depends on good measurements. But the unbelievably complex brain makes measuring particularly challenging. The human brain has more than 80 billion neurons, and each neuron can have 10,000 connections to other neurons. There’s no way to measure the whole thing at once.

Taking it apart, however, isn’t the answer. The brain is a live, working system; cut out a piece and you’re left with a blob of goo. Then there’s the problem of the unyielding skull. Cutting a hole in it opens a window to the electrical signals that carry information but offers only a limited view: “If I punch a hole in a wall and look through the hole, I can see many things. I’m not sure what fraction of them are engaged in my problem and what fraction are not relevant to my problem,” Harris says.

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To study the brain, he adds, “the question is, where did the electricity go and when did it go? The essence of all neuroscience is summed up in that one thing.” Since it’s impossible to work out the entire human brain at once, Harris and the other instrument experts at Janelia help neuroscientists figure out what they can measure and how to do it. They’re getting at the brain by studying simpler animals, like nematodes and fruit flies, with tools that can measure electricity either directly, with an electrode, or indirectly, with proteins that light up when an electrical pulse goes by.

Start Simple

One way to understand a behemoth like the Empire State Building, Harris says, is to first figure out the workings of a one-room, mud-brick hut. In neuroscience, that’s the nematode Caenorhabditis elegans. The tiny, see-through worm has 302 neurons—much easier to study than a human brain. Rex Kerr, a fellow at Janelia Farm, is trying to understand how worms do what they do. And one of the tools he’s using to measure the worm’s brain was developed at Janelia by group leader Loren Looger’s team: GCaMP3, a protein that lights up in the presence of calcium and is now used in labs throughout the world.

Neurons make their electrical impulses by moving ions around. One of the main ions is calcium. GCaMP3 is a kind of protein known as a genetically encoded calcium indicator, or GECI. The cell is engineered to express GCaMP, so when a blue light is shined on it, the GCaMP lights up—giving off green light—when it detects calcium. These proteins let neuroscientists see electricity in the brain, with the help of a microscope.

“The challenge here is that we have neurons in three-dimensional space,” Kerr says. A worm’s brain is tiny and clear, but it’s still 3-D, with cells stacked on top of each other and intertwined. With instrument design experts at Janelia, Kerr developed a microscope that can image the whole brain. A laser sweeps through the brain over and over, lighting it in sheets from the side. As the laser beam touches each level, it hits the GCaMP3 proteins and they fluoresce, sending light to the waiting microscope to record which neurons are active.

Photos: Kerr: James Kegley, Harris: Paul Fetters

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