Research News

For more than a decade, neuroscience researchers—including Hod Dana, PhD—have been trying to improve red fluorescent sensors, a key tool for examining brain activity. Since the brain is notoriously difficult to study, organizations like the National Institutes of Health Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative provide financial support for researchers to accelerate innovation and development.

Dr. Dana is part of a team of researchers across five institutions who recently received an award from the BRAIN Initiative. They will begin a large-scale project over the next five years to develop better red sensors and advance the research done using these sensors. His Cleveland Clinic lab will work with teams from the University of Washington, Princeton University, the University of Maryland and Northwestern University.

Revolutionizing red

Dr. Dana has examined red fluorescent calcium and neuromodulator sensors in his research for many years. The sensors are important for helping scientists observe brain activity in preclinical research by “lighting up” when they sense the presence of certain signals. Most of the research work done today relies on green sensors, which are more advanced and provide higher-quality signals (due to a “glow” that comes from a specially engineered protein also found in jellyfish). However, red sensors can penetrate better through biological tissue, which is a key advantage for biomedical research.

To illustrate why red sensors are preferable for neuroscience research, think about what happens if you press a bright flashlight against the back of your finger. Turn your palm up, and the tissues inside your finger appear to “glow”; you may even be able to see veins and arteries. Similarly, red sensors are engineered to amplify brightness when something happens in a cell, such as when neurons in the brain fire in response to a stimulus.

In his doctoral and postdoctoral work, Dr. Dana concentrated on the more technological side of neuroscience: the building and applications of imaging systems. In 2016, he published an article in eLife that established two types of red sensors. Considered “best in class” at the time, the article is still regarded as the baseline construct for continuing to improve the red sensors.

“Several researchers have made some improvements to the red sensors since 2016, but most labs are limited with their testing capacity,” says Dr. Dana. “What is needed to develop substantially better red sensors are capacity and volume—and this grant from the BRAIN Initiative will provide our broad team of researchers with the ability to test more possibilities, more efficiently.”

Combining specialties to chase success

Each lab will contribute to the project in a way that reflects the strengths of its researchers and institution. The lab at the University of Washington, for example, has developed machine learning algorithms that evaluate large datasets. Trained using data that Dr. Dana generated in 2015, the algorithms will expand the scale at which the full research team can test sensor candidates.

The Dana Lab will work to validate the data generated at the University of Washington, and serve as test users. In addition to Dr. Dana’s years of experience, his team members are trained in the specialized imaging techniques needed for this research. His lab also has sophisticated equipment that is not found in many other labs, including two-photon microscopy. These techniques and tools help researchers learn more about brain function, disease progression and neurodegeneration.

A more colorful, knowledgeable future

Dr. Dana hopes that these and other new tools will allow researchers to look deeper in the brain; current optical methods are powerful, but still limited to the superficial parts of the brain. He also hopes that improving the red sensors will pave the way for translating the same approach to improve sensors with other colors. This would allow scientists to study different cell types and understand how they work in side-by-side configurations.

“I believe that these are accessible goals, but what I like about science is that it’s hard to tell,” he says. “The sensors we developed in the past are also used for applications I couldn’t foresee, including cardiology and drug development. I’m excited to see what we can accomplish over the next five years with the contributions of the Cores at Cleveland Clinic and our partner labs across the country, as well as the support of the NIH.”