A protein sensor is beefed up to illuminate the language of neural networks.

Playing catch seems easy, right? As a ball arcs toward you, you reach out and snag it. Within the brain of the catcher, however, that seemingly simple action requires the interplay and integration of neural networks so complex that scientists have barely begun to map them.

The problem, at least in part, is lack of tools. Electrophysiology—implanting electrodes into the brain to record electrical activity—is fast and exquisitely sensitive, but also invasive (no fun for the catcher) and inaccurate: researchers can't know exactly which cell types they are measuring. Fluorescent synthetic sensors, which make signaling cells light up under a microscope, can probe many cells simultaneously. But the dyes are toxic and invasive (also a problem for the catcher), and they don't last long.

More recently, researchers devised proteins that fluoresce in response to calcium. (Calcium flux is a hallmark of neural activity.) They're called genetically encoded calcium indicators (GECIs)—one is called GCaMP2—and they can illuminate neural networks with cellular precision.

GECIs aren't used in ballplayers or any other humans, but they can tell us a lot about the brains of mice, flies, and worms. Unfortunately, they have not performed as well as synthetic sensors or microelectrodes. Ideally, sensors will detect individual action potentials, the electrical pulses that are the language of neural signaling. But GECIs, being less bright, less sensitive to calcium, and relatively anemic upon activation, act more like weak dimmers than light switches—not to mention, unreliable monitors of neural activity.

“We had been frustrated with older versions of GCaMP,” says Vivek Jayaraman, a Drosophila neurobiologist and group leader at HHMI's Janelia Farm Research Campus. When he used the proteins, they did not even flicker in response to activity that was easily detectable with electrodes. Daniel Huber, a postdoc with Janelia group leader Karel Svoboda, likewise found early GECIs too dim and insensitive for work in mice.

A better reagent was required. Enter protein engineer Loren Looger, who joined Janelia Farm as a group leader in 2006. Setting his sights on improving GCaMP2, Looger first solved the protein's molecular structure. He then iteratively tweaked its sequence to make the protein brighter and more responsive, sharing the intermediate options with anyone willing to try them.

He found two willing partners at Janelia Farm: Jayaraman, who tested the proteins in fruit flies, and Svoboda, who did the same in mice. HHMI investigator Cornelia Bargmann at Rockefeller University rounded out the mix with the roundworm Caenorhabditis elegans.

Illustration: Alex Robbins

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