National Geographic : 2014 Feb
Seeing the Brain 51 Karl Deisseroth and his colleagues. To see the brain, they begin by making it disappear. On my visit to Deisseroth’s lab, undergradu- ate Jenelle Wallace led me to a bench where half a dozen beakers rested in a plastic-foam base. She pulled one out and pointed to a grape-size mouse brain resting at the bottom. I didn’t look at the brain so much as through it. It was nearly as transparent as a glass marble. Needless to say, a normal human or mouse brain is decidedly opaque, its cells swathed in fat and other compounds that block light. That’s why Cajal had to dye neurons in order to see them and why Lichtman’s group and the Allen Insti- tute scientists slice the brain into thin sections to gain access to its inner depths. The advantage of a transparent brain is that it allows us to peer into its workings while the organ is still intact. Along with postdoctoral researcher Kwanghun Chung, Deisseroth came up with a recipe to replace the light-scattering compounds in the brain with transparent molecules. After making a mouse brain transparent in this way, they can then douse the brain with glowing chemical labels that latch on to only certain proteins or trace a specific pathway connecting neurons in distant regions of the brain. The scientists can then wash out one set of chemicals and add another that re- veals the location and structure of a different type of neuron—in effect untangling the Gordian knot of neural circuits one by one. “You don’t have to take it apart to show the wiring,” says Deisseroth. It’s not easy to dazzle neuroscientists, but Deisseroth’s method, dubbed CLARITY, has left his colleagues awestruck. “It’s pretty badass,” says Christof Koch, the chief scientific officer at the Allen Institute. Wedeen has called the research “spectacular...unlike anything else in the field.” Because of our shared evolutionary heritage, a clarified mouse brain can reveal a great deal about human brain function. But Deisseroth’s ultimate goal is to perform the same transforma- tion with a human brain—a far more difficult task, not least because a human brain is 3,000 times as large as that of a mouse. A CLARITY picture showing the location of just one type of protein in just one human brain would create a monstrous heap of data—about two petabytes, or the equivalent of several hun- dred thousand high-def movies. Deisseroth anticipates that CLARITY may someday help the sort of people he treats in his psychiatric practice, by revealing hidden features of disor- ders like autism and depression. But for now he’s keeping those hopes in check. “We have so far to go before we can affect treatments that I tell people, Don’t even think about that yet,” he says. “It’s just a voyage of dis- covery for now.” As revealing as a transparent brain may prove to be, it will still be dead. Scientists need differ- ent tools to explore the terrain of living brains. The scanners Wedeen uses to trace white mat- ter patterns can, with different programming, record the brain in action. Functional magnetic resonance imaging (fMRI) pinpoints regions of the brain recruited during a mental task. Over the past couple of decades fMRI has helped re- veal networks involved in all manner of thought processes, from recognizing faces to enjoying a cup of coffee to remembering a traumatic event. It’s easy to be dazzled by fMRI images, which festoon the brain with rainbow blobs. But it’s im- portant to bear in mind that those images are actually quite coarse. The most powerful scanners can record activity only down to the scale of a cubic millimeter—a sesame seed’s worth of tissue. Within that space, hundreds of thousands of neu- rons are firing in synchronized patterns, trading signals. How those signals give rise to the larger patterns revealed by fMRI remains mysterious. “There are ridiculously simple questions about the cortex that we can’t answer at all,” says Clay Reid, a former colleague of Jeff Lichtman’s at Har- vard who moved to the Allen Institute in 2012. Reid has come to Seattle hoping to answer some of those questions with a grand series of experiments he and his colleagues call Mind- Scope. Their goal is to understand how a large to see the brain, scientists at stanford university begin by making it as transparent as a glass marble. for more on the mind, tune in to the third season of brain games, premiering in january on the national geographic channel. check local listings.