Unraveling Nerves, Understanding the Brain

Professor Jeff W. Lichtman and his team painstakingly craft their colorful masterpieces—but their paintbrush is the genome, and their canvass the brain.

Lichtman and his colleague Joshua R. Sanes, both molecular and cellular biology professors at Harvard, are mapping neurons with a pioneering method, dubbed “brainbow” for its psychedelic appearance. Already, the technique—recently honored with a Nobel Prize in chemistry—is shedding light on the development of the human mind, and how disorders such as Alzheimer’s and even anxiety alter the brain.

“To get an idea of how the wiring of the brain changes, we have to figure out how things are wired,” Lichtman says. “Brainbow gives us an idea of how things are organized.”

Lichtman’s group recently mapped only the second “connectome”—a group of neurons dedicated to a single function—in history. The image showed neurons for a particular mouse muscle were inexplicably longer than necessary—strongly suggesting an alternative use for the pathway.

The brainbow’s bursts of color belie what its creators say is a revolutionary potential to solve the mysteries of the mind.

“I think it holds the promise of changing how we look at genetics and the brain and consciousness,” Sanes says. “It’s like the human genome project.”

Though the researchers have hopes for brainbow, the technique must clear some hurdles before it can illuminate the course of mental diseases and disorders.

To produce the maps, researches add specialized genes to individual neurons, causing them to glow fluorescently in different colors.

A connectome’s map is built by developing pictures of individual slices of nerves, and combining them to form a larger image of a passageway, like taking slices of a pipe and putting them back together.

“Picture a radio in the olden days that is full of wires soldered together,” Sanes says. “Imagine slicing it into slices one millimeter thick. With each slice you can see a little shred of each part...You need to put them together to figure out the whole wiring diagram.”

But the simple concept requires massive volumes of data—far beyond the capacity of current technologies. According to Sanes, mapping a human brain would demand enough storage space to host all the photos on Facebook millions of times over—now a wildly unrealistic demand.

“Everything” will have to advance before such data can be processed, Sanes says. More powerful computers will need to be used, as well as perhaps some way of mathematically modeling the data.

“You’d like us to tell you what this means for consciousness or for uncovering how diseases act in the brain, but we are far from that,” Sanes says.

In the meantime, Sanes has a more modest goal: mapping only the neural passageways from the eyes to the brain, carefully matching up the colors on each slice to create a complete picture of the neurons, and ultimately, their functions.

The researchers say they hope discovering how and why neurons change will help answer why human brains are truly different from those of other species—a question that scientists have yet been unable to elucidate.

Lichtman says the explanation may lie in humans’ longer period of mental development—a process tied to how connectomes change. If brainbow can illuminate such developments, scientists could begin to better understand the brain.

“I was interested in behavior in some way that was hard to put your finger on,” Sanes says. “What spot in the brain accounts for how we act? When somebody has a nervous breakdown, what is actually breaking down? We’re beginning to claw our way there.”

But as Sanes and Lichtman seek to add to human understanding, they say they’re also hoping to attract undergrads to their field. Both teach MCB 80: “Neurobiology of Behavior,” where they say the sheer amount of new material in recent years illustrates the growing importance of neurobiology.

“Sometimes there is this feeling that science has gone only so far, and all there is left to do is to pick up the scraps,” Lichtman says. “That couldn’t be farther from the truth with the brain. There is just this incredible reservoir of questions.”

—Staff writer Paul C. Mathis can be reached at pcmathis@fas.harvard.edu.