In coral reefs, a treasure trove of tools

Few things are as mysterious and captivating as the ever-changing mosaic of colors emanating from the sea life in and around coral reefs. This shifting kaleidoscope of colors comes in part from tiny fluorescent proteins produced by coral and other marine species—part of a creative adaptation that helps them hide from predators, attract friends, and survive in the ocean’s battlegrounds. Now scientists are harnessing this evolutionary feat to develop novel, noninvasive ways to detect and monitor neurological and other diseases and, possibly, to tailor treatments.

Vincent A. Pieribone, Ph.D., professor of cellular and molecular physiology and of neurobiology, and other scientists are using these proteins to expose the electrical activity of neurons and other cells, thereby making invisible cellular processes visible in ways that are not possible with conventional imaging techniques.

For more than a decade, Pieribone and his team have been on a quest to find and clone new fluorescent proteins from such far-flung places as Australia’s Great Barrier Reef and the Solomon Islands. In the lab, they insert these proteins into animals to track and monitor brain activity and then decode how and when neural cells fire. When inserted into neural tissue, these fluorescent proteins produce a glow that is visible through the skull and skin, converting the surface of the brain into something akin to a television screen and revealing pictures of the processes within.

Every time the tissue produces an electrical signal, the intensity of light changes. These fluorescent proteins don’t just highlight the cells: Under certain conditions they can be stimulated to change the output of light intensity so that scientists can see biologic processes unfolding in real time. Using computers, researchers can record and observe this complex display of light over time to interpret the behavior of the neural tissue. Clinicians may one day be able to use these proteins to monitor and predict epileptic seizures.

“It’s allowing us to get a glimpse into the complex workings of the brain,” said Pieribone. “With these proteins, we can generate really powerful probes that we can then put into any cell and they will report the voltage of the cell as a change in fluorescence—it’s a real breakthrough to optically look at cells firing at high speeds.”

The use of fluorescence in imaging has inherent benefits, too. It avoids the use of invasive electrodes, radiation exposure, or contrast agents. “We currently stick wire electrodes into the brain to touch the cells, and when they give off electrical bursts we can try to figure out what the brain is doing and saying, but it’s invasive and causes permanent damage to the very organ you are trying to study,” Pieribone explained.

His work was initially inspired by the discovery in the early 1960s of a green fluorescent protein (GFP) in a species of jellyfish known as Aequorea victoria, which is indigenous to the Pacific Northwest. This discovery resulted in a Nobel Prize in chemistry in 2008 and has revolutionized biomedical research, he said.

Despite the discovery’s promise, Yale is one of the few academic centers in the world to engage in this type of field research. Pieribone has made a dozen trips to search some of the most diverse aquatic ecosystems for new fluorescent proteins. In all, Pieribone has identified over 100 species of fluorescent coral and other ocean life, most recently from eels and fish. “We have found fluorescent properties in a huge range of animals—far more than was thought possible,” said Pieribone. This discovery means greater opportunity and potential applications for medicine.

The irony, he says, is that the very coral reefs that produce these proteins—molecules humans could never invent on their own—are disappearing. The reefs are sensitive to warmer ocean temperatures and pollution, which cause them great stress and leave them vulnerable to disease. “We have these libraries of cool proteins vanishing from the earth as quickly as we can get them, clone them, and study them,” he said.

What does the future of fluorescent protein technology hold?

While scientists are now using light to interact with nervous tissue both to observe and to control what the brain is doing, researchers believe that these proteins might lead to better treatments down the line, perhaps even linking mind to machine. For someone with a spinal cord injury, for example, where the brain no longer communicates with the body, the hope is that a computer could convert brain activity— such thoughts as, “I want to pick up that glass”—into action.