Stuart Schreiber and Linda Hsieh-Wilson create new molecules to test pathways and circuits, and, if they’re lucky, discover exciting new things about biology.

Both Chang’s undergraduate degree and his Ph.D. are in chemistry. But now he studies the brain. His lab at the University of California, Berkeley, looks as much like a biology lab as a chemistry lab, with microscopes and mice and cell cultures. He’s one of a handful of HHMI scientists—and a growing number of scientists around the country—who are applying their background in chemistry to biological problems.

These chemists are driven by a fascination with the complexity of biology and a desire to work in a fast-moving field. But the way they approach problems is distinct from biologists—they break organisms down to their most miniscule atomic parts to study how they work. And they build those biological systems back up using new chemicals they create from scratch.

“Chemists are able to not only study things at this molecular scale, but we can also reorganize things and build them from the ground up,” says Chang. “It is this ability of chemists to create things that allows us to look at problems differently.” Like structural engineers who design buildings and genetic engineers who create new genes from scratch, chemists are engineers of the molecular world.

Biology-interested chemists face no shortage of biological questions to answer. Chemical approaches are solving problems in neuroscience, immunology, cell signaling, and cancer biology.

“Anything you see or touch or taste, it all comes down to these elements in different combinations.”

Chris Chang

“There are chemists now that are indistinguishable from biologists at the cutting edge of biological discovery,” says Carolyn Bertozzi, another HHMI investigator whose research overlaps the two fields. “And then there are chemists who collaborate closely with biologists.”

As biologists and chemists learn to bridge the gap between their fields, with training programs and increased appreciation for what the other has to offer, they are realizing just how complementary their skills can be.

Brain Chemistry

Choosing where to apply his chemistry knowledge wasn’t hard for Chang. “There’s nothing more complex or beautiful in biology than the brain,” he says. Lucky for him, the brain is full of unique chemistry that’s ripe for investigation. When Chang was launching his research career, he discovered that the brain has at least 20 times more copper than most of the body, and no one could explain why. As a chemist, he saw an opportunity—copper is a chemical element, the simplest building block of an organism. By studying copper in the brain, Chang could fulfill his desire to explore neuroscience and put his background in chemistry to use.

Biologists, however, had no way to visualize where the copper was in the brain. They couldn’t track its movement or see where it was being integrated into larger molecules. So Chang created a new kind of copper—a copper atom attached to chemical probes that offer a way to watch copper’s path in the brain. He engineered the copper so that the probes could light up under a fluorescence microscope or potentially be visualized in an MRI of the brain.

In an April 2011 paper published in the Proceedings of the National Academy of Sciences, Chang’s team used the method to determine just how dynamic copper is in brain cells. They found that when a neuron receives a signal—in the form of calcium molecules—a wave of copper moves from one end of the neuron to the other.

“We showed that copper is not this static building block of brain cells like many believed. It’s a dynamic, mobile signaling molecule,” says Chang. “And this is the first time that someone can watch it flow through brain cells in real time.” Next, the group aims to understand what this wave of copper movement triggers.

Copper is far from the only dynamic chemical in the brain. Linda C. Hsieh-Wilson, an HHMI investigator at the California Institute of Technology, has used her combined knowledge of organic chemistry and neuroscience to discover how a set of molecules—glycosaminoglycans, or GAGs—influences neuron growth. GAGs are long strings of carbohydrates that attach to proteins and influence their behaviors.

Photos: Schreiber: Jared Leeds; Hsieh-Wilson: Darcy Hemley

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