SEEING THROUGH THE BRAIN NEUROSCIENCE: Method makes
tissue transparent, could reveal brain wiring map
A
FTER MORE THAN a century of study, neu-
roscientists have yet to unlock the secrets of how people learn and form thoughts. Some researchers think a connectome, or brain wiring diagram showing how the billions of neurons there interface, will help solve the mystery. But to assemble this diagram, researchers have had to image the brain one ultrathin slice at a time. They painstakingly add series of images together to eventually render a three-dimensional picture of brain circuitry. A chemical method that makes brain tissue transparent could revolutionize this process by enabling researchers to see inside the brain without carving it up. A research team led by Karl Deisseroth of Stanford University developed the patented Clarity method, for converting brain tissue into a clear hydrogel (Nature, DOI: 10.1038/nature12107). Deisseroth’s research team infuses brain tissue with acrylamide monomers, formaldehyde, and a heatactivated initiator compound for a few days. They next warm the refrigerated tissue to initiate polymerization, forming a hydrogel mesh that anchors structures such as neurons in place. An electric field and negatively charged detergent are then used to extract the lipids that make the tissue visually impenetrable. That final step, dubbed “electrophoretic tissue clearing” by the team, was the most challenging to develop, says Kwanghun Chung, a Stanford postdoctoral researcher and lead author of the report. “We melted and burned hundreds of mouse brains before we figured
out the optimum conditions, such as voltage level.” Eventually, the Stanford team immunostained blocks of both a mouse brain and a brain from a deceased autistic patient with fluorescent antibodies of different colors to generate 3-D rainbow maps of brain features. “We can’t really understand how the brain works without knowing the connectivity of its neurons,” Chung says. “It’s like having a supercomputer and not having a blueprint of the circuit board.” But just as important as Clarity’s ability to make tissue transparent is its ability to make tissue somewhat permeable, comments Qingming Luo, a biomedical engineer and vice president of China’s Huazhong University of Science & Technology. The extracted lipids leave behind pores in the hydrogel mesh so the tissue can absorb fluorescent antibody stains targeted at different proteins and cells. “This makes it possible to colabel molecular and structural features in the same brain,” Luo says. “Clarity will undoubtedly advance neuroscience,” says Atsushi Miyawaki, a bioimaging expert at RIKEN, a research institute near Tokyo. Miyawaki developed a related tissue-clearing method, called Scale, in 2011. Clarity appears to impart greater transparency to tissue, however, while maintaining its structural integrity. Deisseroth’s team hopes to license Clarity in the future. But detailed instructions for using it are included in the Nature paper, Chung says, “so any lab can set up its own system.”—LAUREN WOLF VIDEO ONLINE
NAT U R E
NEWS OF THE WEEK
A quote by famed neuroscientist Santiago Ramón y Cajal becomes visible after a mouse brain (left) is made transparent (right) by the Clarity technique.
To explore 3-D brain renderings enabled by Clarity, go to http://cenm.ag/clarity.
PHARMACEUTICALS Bristol-Myers Squibb is latest drugmaker to name a new R&D head Bristol-Myers Squibb has named a new chief scientific officer. The appointment is the third replacement of a big pharma company research head since the beginning of the year—and probably the most amicable one. Francis Cuss will become BMS’s chief scientific officer on July 1, after the departure of Elliott Sigal, 61, who has been with the firm since 1997. Cuss, 58, joined the company in 2003 and has served in several scientific leadership roles. The change of guard at BMS follows the departure of R&D heads at AstraZen-
eca and Merck & Co. in January and April, respectively. Although CEOs rarely speak ill in public about departing executives, it was clear that AstraZeneca CEO Pascal Soriot was dissatisfied with Martin Mackay, his R&D chief. Mackay left the job immediately and was not replaced. Merck CEO Kenneth C. Frazier was also reportedly not happy with his R&D head, Peter S. Kim. Still, when the firm announced Kim’s departure in early March, it said he would stay on for another month to work with his replacement, former Merck and Amgen executive Roger M.
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Perlmutter, to ensure a smooth transition. Sigal will remain in his post for a respectable three months. And in a conference call with stock analysts to discuss the change, BMS executives, including Sigal, took pains to portray the succession as a planned management shift. CEO Lamberto Andreotti said Sigal approached him several months earlier about retiring. According to Andreotti, the two agreed that the December 2012 approval of the blood thinner Eliquis was a good transition point. “We’re capping a very strong run,” Sigal said.—MICHAEL MCCOY
