Eric Schreiter and Luke Lavis thought they had figured it out. In 2021, the Janelia group leaders reported that they had developed a way to combine Schreiter's engineered protein biosensors and Lavis's bright, fluorescent Janelia Fluor dyes.

These sensors, which could track different physiological signals and brightly illuminate them in far-red light, would in theory enable scientists to perform imaging in live animals and track multiple physiological signals at the same time—two aspects of biological imaging that were difficult to do with existing sensors. Far-red light can penetrate deeper into tissues than other wavelengths, and it gives scientists an additional color to use outside the typical hues, like green and red, used in biological imaging.

"Everything was great, and it was fantastic, and we were happy—until we tried to use the sensors in animals, and it pretty much totally failed," Schreiter recalls. "It was a bit of a bummer."

Luckily, Helen Farrants had just arrived at Janelia for her postdoc in Schreiter's lab, and she accepted the challenge of re-developing the protein biosensors to carry out their original intention.

Volumetric imaging in the near-infrared of neuronal activity in zebrafish larvae with WHaloCaMP. Credit: Farrants et al.

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