Thoughts are tangible things—waves of electric potential carried along the axons and dendrites of our neurons by metal ions rushing across brain cell membranes. These ions trigger the release of other molecules, called neurotransmitters, that cross the gaps between neurons and stimulate nerve impulses in them, starting and stopping these processes afresh with each thought or movement.
The brain accumulates very high concentrations of metal ions—10 to 20 times higher than in other tissues—and Christopher Chang, at the University of California, Berkeley, is fascinated by them. "Why do we need so much in this particular part of the body? It must be biologically relevant," he says. "The brain needs to control all these unique functions: learning, memory, motor skills, sensory functions. I think there is a link between these special abilities and the need for high brain levels of metal nutrients," he says.
Chang's training is in inorganic chemistry. After earning an undergraduate degree from the California Institute of Technology, he studied for one year at the Université Louis Pasteur in Strasbourg, France, on a Fulbright scholarship. After earning a Ph.D. at the Massachusetts Institute of Technology with Dan Nocera in renewable energy chemistry, he began applying his knowledge of inorganic chemistry to biological problems as a postdoctoral fellow in the Massachusetts Institute of Technology lab of Steve Lippard, where he developed sensors for tracking the metal zinc in cellular systems.
To investigate the roles of metals in the brain, Chang uses his chemical expertise to build new molecules called smart probes—"molecules that can report on other molecules," as he puts it. The smart probes bind to their targets and then light up. An optical fluorescence microscope enables a researcher to pinpoint their location inside a single cell.
Chang's group recently developed the first such smart probe for copper and revealed that the metal plays an unexpected role in the brain. Sodium, calcium, and potassium all move in and out of nerve cells, but Chang's probe reveals that copper does too. "It moves in puffs or waves as the neurons fire," says Chang. "If you stimulate a neuron, you see bursts of copper as cells communicate with each other. Copper was not known to do this before we were able to directly see this with molecular imaging."
Why it does is still a mystery. The copper waves appear to correlate with the movement of calcium, but the underlying molecular details aren't clear. Nor, says Chang, do we know much about how copper waves are linked to other events in the brain. Scientists know that overabundant and misplaced copper and iron stores are a characteristic of Alzheimer's disease and other neurodegenerative illnesses. So the same metals that play vital roles in healthy neurons become a burden later in life. "What goes wrong and how does it correlate with aging?" asks Chang.
Before he can tackle that question, Chang says it's essential to figure out copper's beneficial roles when everything is working properly. He's been using his smart probes to track copper movement in cultured cells and is now starting to work with the brains of model organisms like zebrafish. Teasing out the normal state is a complicated problem, Chang says, partly because these metals can't be synthesized by the body; they come only from the environment and diet, which vary widely. Metal management also is likely to have a genetic component, as the metal-handling abilities of people can vary widely. "The field of metals in medicine remains a wide-open frontier," he says.
Beyond his copper research—work that Chang's colleagues say may rewrite the role of metals in biology—Chang is interested in the chemistry and biology of hydrogen peroxide, and he has developed the first smart molecular probe to track it. Hydrogen peroxide is a simple, highly reactive molecule better known as a disinfectant. It's also present in the body, however, where it's been considered potentially damaging to cells through free radical chemistry. But with the discovery of a cell-signaling role for another free radical, nitric oxide, researchers have been taking another look at hydrogen peroxide.
"Nitric oxide taught us you can't think that free radical chemistry is only bad for you—it can serve a biological function as well," says Chang. "Our hypothesis is that hydrogen peroxide can serve as a signaling agent" in much the same way as nitric oxide. Specifically, he intends to explore its function in brain cell signaling, growth, and differentiation. Says Chang, "I've been interested in hydrogen peroxide's role in stem cell development," a line of research he plans to pursue.
The biological role of hydrogen peroxide, like that of copper, is a complicated problem. But for Chang, that's part of the allure. "I've always been interested in complexity," he says. "I went to school to be an engineer, and I ended up a chemist." Part of that, he says, is because "I've always been fascinated by the brain, nature's most complex and beautiful system, and how it works."