ArcLight protein illuminates new path toward understanding the brain

Protein illuminates path to observing the brain
Photo by Annelisa Leinbach.

Yale School of Medicine neurobiology professor Vincent A. Pieribone has uncovered a new method for mapping brain activity that skeptics once deemed impossible. His finding is the realization of what he called a “career-long dream” — to capture the brain’s electrical activity without using any invasive procedures.

Pieribone and his co-authors — Yale medical school professors Michael N. Nitabach and Lawrence B. Cohen — discovered a fluorescent protein, dubbed ArcLight, that releases light of varying intensities to reflect changes in electrical activity within cells. The researchers said the ArcLight protein facilitates the direct measurement of voltage in areas of the brain that were previously inaccessible, allowing researchers to better understand how neural circuits process information. The paper detailing the discovery was published in the Aug. 8 edition of the journal Cell.

Scientists have been engineering fluorescent proteins for the past 15 years, but the ArcLight protein is the only one to successfully map activity in the cells of a living animal. ArcLight works because of a mysterious mutation that researchers are still in the process of trying to understand.

Cohen said Arclight is superior to existing methods of measuring brain activity. The protein measures neuron activity directly, whereas current optical methods such as fMRI — which measures changes in brain blood flow — have a higher signal to noise ratio.

Pieribone said the “unexpected” discovery was one of the most exciting of his career.

“Discoveries die a thousand deaths before they finally make it. We thought it wouldn’t work. ArcLight had multiple deaths and revivals,” he said. “Fortunately, we dragged out the ‘aha’ moments all the way to the end.”

When Pieribone and his team were conducting their research last year, they were the only scientists in the world working on this approach to mapping brain activity. When his colleagues examined data from ArcLight that seemed to indicate success, many of them thought it was a fluke. Until the lab hired a “naive” research assistant who was willing to repeat the experiment to confirm these results, members of the team team doubted their initial findings.

“I was like, ‘Holy cow, this shouldn’t be like this,’” Pieribone said. “Everyone was saying this couldn’t be real. I took a picture on my phone’s camera and [my colleague] still has that photo on the wall of his lab.”

The research was part of President Barack Obama’s Brain Research through Advancing Innovative Neurotechnologies, or BRAIN, Initiative, which has allocated $100 million toward the goal of revolutionizing our understanding of the human brain. The project has been met with controversy, according to neurosurgery professor Angelique Bordey.

“Some people say it’s premature,” she said. “There’s always the fear of the unknown and the fear that we won’t get our money’s worth. The research is a little bit like science-fiction. But I think we just have to be open minded.”

Indeed, Pieribone’s goals do not sound so unlike science fiction. His hope is to capture human brain activity in people with locked-in syndrome, the inability to move or communicate due to paralysis from the neck down, and give them the ability to move prosthetic limbs with ease.

Pieribone’s lab is funded in part by the U.S. army, an entity which he suspects has some “creative” ideas for the use of this new technology.

“The possibilities are endless,” he said. “But the first step is extracting the information from the human tissue. All the work on computing and robotics is pretty much done. We have algorithms and fast computers, just no way to drive them.”

Alan Anticevic, an assistant professor of psychiatry at the medical school, is excited about the prospects of mapping brain activity but careful to explain the difficulties involved in doing so.

“There are kilometers of brain connections, kilometers of wiring. You’re essentially talking about the level of complexity of something like the universe,” Anticevic said. “I think the gap between our understanding of the brain and all the complex human behaviors is still very vast. That said, I think [the BRAIN initiative] is an optimistic effort and certainly something that we ought to be doing.”

The BRAIN Initiative was announced on April 2.

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