The barrel-shaped green fluorescent protein, GFP, was first isolated from a glowing jellyfish.

Tsien explained that his work inventing calcium dyes at Cambridge was the fourth project within his dissertation; his first three efforts had run into dead ends. When he started work on the calcium indicator he didn't tell his advisor, who surely would have vetoed the effort. The subterfuge paid off, and his career was launched. Today, researchers around the world rely on the dyes Tsien created to study calcium, pH, sodium, and other molecules.

At the Janelia lecture, he showed an image sequence called the Blush of Conception. When a sperm fertilizes an egg, it initiates a wave of changes inside the cell, including creating an intracellular wave of calcium. Tsien made those processes visible. As the sperm hit the egg, the calcium change was depicted as a wave of color—as if the egg were blushing—washing across it from the point of contact.

Mark Ellisman, a professor of neurosciences and bioengineering at UC San Diego, notes that each time Tsien develops a new tool, in the paper that introduces it he affirms its value by showing how it can be used to understand some substantive problem in biology. “As soon as that's out, the world picks up on it and starts to use the technology on a large number of problems,” says Ellisman, who collaborates so closely with Tsien that the two sometimes hold joint lab meetings.

“He's passionate about things that are useful to society,” Ellisman adds. “He's got a very beautiful orientation to what's important.”

As a young faculty member at the University of California, Berkeley, Tsien's personal insecurity drove his next big success. Surely, he thought, the prestigious biochemists and molecular biologists at Berkeley were looking down their noses at a scientist in the physiology department working on a “mere metal ion like calcium.” So he decided to find a way to use a process called FRET to build indicators of the essential cellular messenger cyclic AMP (cAMP).

When two fluorescent dyes get close to each other, one steals energy from the other, changing the color it emits. The process—called fluorescence resonance energy transfer, or FRET—is particularly useful in watching cAMP split apart the subunits of protein kinases that depend on cAMP.

Tsien began collaborating with Susan Taylor at UC San Diego, the world's expert on cAMP-dependent protein kinase. But sending samples by FedEx between Berkeley and San Diego wasn't working, so Tsien moved south.

“Even after the move, it took a year of my people being physically in the lab adjacent to Susan's for us to make the cAMP reporter work,” Tsien says. “It required laboriously growing bacteria, purifying two proteins, chemically labeling them in a test tube with two different colors, recombining and repurifying them, and then microinjecting them into the cells of interest”—and the cells had to be large enough to handle microinjection.

Tsien fretted over these limitations. There had to be an easier way.

Image: Tsien Lab

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