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Protein Engineered to Boost Nerve Cell Imaging

Nerve cell image

Mouse brain nerve cells illuminated with Archon1 protein (Mass. Institute of Technology)

27 February 2018. Engineers and neuroscientists developed a synthetic protein that illuminates electrical activity in animal brain nerve cells, with a process using robotics to test millions of protein candidates in cells. A team from Massachusetts Institute of Technology and Harvard Medical School describes its discoveries in yesterday’s issue of the journal Nature Chemical Biology (paid subscription required).

Researchers led by MIT biological engineering professor Edward Boyden are seeking better ways to directly measure and document electrical activity among nerve cells in the brain. Most current methods use electrodes implanted in the brain, which requires invasive procedures, such as surgery, and is at best incomplete in capturing all the activity taking place. “If you put an electrode in the brain,” says Boyden in an MIT statement, “it’s like trying to understand a phone conversation by hearing only one person talk. Now we can record the neural activity of many cells in a neural circuit and hear them as they talk to each other.”

Boyden’s Synthetic Neurobiology lab studies processes for mapping the brain’s wiring and molecules affecting its dynamics. In their paper, the researchers describe development of a protein that expresses variations in voltage during nerve cell transmissions in the brain. Fluorescent molecules are available today for tracking biological processes, but nerve cells present special challenges for imaging: molecules must respond very quickly, be sensitive to fine changes in voltage, and not fade when exposed to light.

Their task is complicated further by the sheer number of protein candidates, numbering in the millions, expressed by genes in nature. The team automated the assessment of these genes and their mutations to emulate natural evolution, but at vastly greater speeds. They started with a previously known synthetic fluorescent protein called QuasAr2 that reports on cell voltage. The researchers then generated some 1.5 million variations of QuasAr2 as if it naturally mutated.

The team evaluated each of these mutations in lab cultures using robotic automated microscopes to find protein molecules with the greatest uptake in cells as well as high brightness, a process yielding 5 candidate proteins. With these candidates, the researchers then generated another 8 million variations, and again with the help of robotic microscopes, identified 7 top performing molecules. From these finalists, the winning synthetic protein emerged that the team calls Archon1.

The researchers tested Archon1 in the lab with zebrafish larvae and C. elegans worms, lower animal forms but also transparent, making it possible to visualize and measure nerve cell electrical activity in real time. In addition, the team tested Archon1 with slices of brain tissue taken from mice, where they show Archon1 can visualize electrical activity between the synapses or junctions of nerve cells.

With C. elegans species, the researchers went further and tested responses of nerve cells to different light colors. Their tests indicate Archon1 can measure voltage variations from variations of red-orange light waves, with voltage changing as the percentage of red content in the light wave also changes. Other tests shone blue light on C. elegans nerve cells, with comparable results. These findings have implications for optogenetics, an emerging field employing light waves to influence light-sensitive proteins and genes.

As reported in Science and Enterprise, Boyden is co-founder of the company Cognito Therapeutics developing medical devices to treat neurodegenerative disorders, such as Alzheimer’s disease. In a paper published in December 2016, Boyden and fellow MIT neuroscientist Li-Huei Tsai used optogenetic techniques to reduce amyloid-beta plaque deposits associated with Alzheimer’s disease in lab mice. Tsai is also a co-founder of Cognito Therapeutics.

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