The famous architect Louis Henri Sullivan once said that "form ever follows function." As with buildings, so too with the brain, says new Janelia Farm group leader Dmitri "Mitya" Chklovskii. By mapping the brain's form, in particular, the wiring of its neuronal circuits, he seeks to understand its function—how trillions of electrical impulses make us move, talk, think, and feel.
"If we know the structure of something in biology, its function is much easier to infer," says Chklovskii, citing the discovery of the DNA double helix as the classic example. "Once Watson and Crick discovered there were two complementary strands, it was fairly obvious how that structure replicated and transferred information. My goal is to do the same thing for the brain."
Because the human brain, with its billions of neurons, presents such a daunting challenge, Chklovskii is building tools and theories literally from the ground up—the ground being home to the tiny roundworm Caenorhabditis elegans. With only 302 neurons, the C. elegans brain provides an excellent proving ground for mapping neuronal circuits, as realized by another new Janelia Farm researcher, senior fellow Sydney Brenner.
But even for C. elegans, mapping connections of each neuron is a daunting task, started by Brenner's group in the 1970s. Chklovskii's team used Brenner's lab notebooks and photographs to finalize the C. elegans wiring diagram manually.
"To take this to a bigger animal, the fruit fly or mouse, for instance, we need to automate the process," says Chklovskii. Neural reconstruction involves slicing an organism's brain into a thousand or more flimsy films, which are then photographed with an electron microscope.
"And then you have to put all the photographs back together in three-dimensional form," Chklovskii says. "That's very hard—slicing up a fly will produce something like 20,000 slices. It's too many to stack up together manually, so we're teaching computers to detect certain patterns, such as the axons and dendrites shooting out of neuron cell bodies," he says.
Chklovskii was also drawn by the interdisciplinary nature of Janelia Farm. "Because there will be a limit on how large each group can be, groups will have to team together to tackle big projects," he says. "And that's a good thing, something that's hard to find at universities."
While the technology to map the entire human brain has not been invented, Chklovskii has begun the job by drawing on experience in a field heavy on theory—solid-state physics. "I'm taking the theoretical skills I developed in physics and applying them to biology, a field that has, with the exception of Darwin, been traditionally short on theory."
The Chklovskii group: mitya AT janelia.hhmi.org
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