Can we control brain cells with light? New clues from frozen proteins

Scientists have discovered a rare group of proteins that appear to give microbes in cold environments a strange advantage. These proteins, called cryorhodopsins, respond to light in surprising ways.

Now, researchers think the proteins could be turned into powerful tools for neuroscience and biotechnology.

The icy peaks of the Himalayas, the deep chill of Finnish groundwater, and the ancient glaciers of Greenland all have something in common – they host microscopic life that has adapted to extreme cold.

In doing so, these organisms may have evolved tools that could change how we study and influence the human brain.

Unlikely proteins found in the cold

It started with a bit of online browsing. While combing through protein databases, a scientist noticed something strange: microbial rhodopsins – proteins usually found in warm, aquatic environments – were popping up in places like frozen lakes and glaciers.

Even more oddly, the cold-weather rhodopsins were nearly identical, despite being found in microbes living thousands of kilometers apart. That kind of similarity usually means they serve a crucial function. The team gave them a name to match their habitat: cryorhodopsins.

“In my work, I search for unusual rhodopsins and try to understand what they do,” said structural biologist Kirill Kovalev of EMBL Hamburg. “Such molecules could have undiscovered functions that we could benefit from.”

Searching for light-sensitive proteins

Rhodopsins are light-sensitive proteins. Some of them have already been engineered to act like switches inside cells.

When exposed to light, they trigger changes in electrical activity. This technique, called optogenetics, is widely used in neuroscience.

But researchers are still hunting for new types of rhodopsins that could expand the method’s possibilities – especially rhodopsins with different colors, since different wavelengths of light can penetrate biological tissues in different ways.

Cold proteins change the game

The cryorhodopsins stood out. Some weren’t the usual orange or pink – they were blue. “I can actually tell what’s going on with cryorhodopsin simply by looking at its color,” said Kovalev.

Using advanced structural biology tools, the team discovered that the same rare structural quirk that first caught their attention also explains why these cryorhodopsins are blue.

The blue rhodopsins are especially valuable because they can be activated with red light, which travels deeper into tissues and can be used non-invasively.

“Now that we understand what makes them blue, we can design synthetic blue rhodopsins tailored to different applications,” Kovalev said.

Light switches for the brain

To test whether cryorhodopsins could be useful in optogenetics, the team expressed them in cultured brain cells. The results were exciting. When exposed to UV light, the proteins triggered electrical currents.

Then, depending on the follow-up light exposure – green or red – the cells either became more excitable or less.

“New optogenetic tools to efficiently switch the cell’s electric activity both ‘on’ and ‘off’ would be incredibly useful in research, biotechnology and medicine,” said Tobias Moser of the University Medical Center Göttingen.

“For example, in my group, we develop new optical cochlear implants for patients that can optogenetically restore hearing in patients. Developing the utility of such a multi-purpose rhodopsin for future applications is an important task for the next studies.”

According to Kovalev, the cryorhodopsins aren’t ready to be used as tools yet, but they’re an excellent prototype. “They have all the key features that, based on our findings, could be engineered to become more effective for optogenetics.”

Sensing more than just light

The surprises didn’t stop there. Researchers at Goethe University Frankfurt tested cryorhodopsins and found something unusual. These proteins are the slowest of all known rhodopsins when responding to light – and they’re sensitive to UV.

That slowness might be a feature, not a bug. It could let microbes “see” UV light, which would be a first. UV radiation is especially intense in high-altitude or polar environments. Being able to sense radiation might help microbes protect themselves.

However, the question remained: can microbes actually sense UV light? The search for an answer led the team to a genetic mystery.

Discovery of tiny, unknown proteins

The cryorhodopsin gene always came packaged with another gene encoding a small, unknown protein. The team suspected it might be a messenger – a partner protein that helps transmit the UV light signal inside the cell.

Using the AI tool AlphaFold, the researchers predicted that five copies of the tiny protein form a ring that hugs the cryorhodopsin from the inside.

When the rhodopsin detects UV light, the small protein might break off and carry the signal further into the cell.

“It was fascinating to uncover a new mechanism via which the light-sensitive signal from cryorhodopsins could be passed on to other parts of the cell. It is always a thrill to learn what the functions are for uncharacterized proteins,” noted the researchers.

“In fact, we find these proteins also in organisms that do not contain cryorhodopsin, perhaps hinting at a much wider range of jobs for these proteins.”

Proteins didn’t evolve due to cold

While the full picture isn’t clear yet, the researchers have a strong hunch. Kovalev said the team suspects that cryorhodopsins evolved their unique features not because of the cold, but rather to let microbes sense UV light, which can be harmful to them.

“In cold environments, such as the top of a mountain, bacteria face intense UV radiation. Cryorhodopsins might help them sense it, so they could protect themselves. This hypothesis aligns well with our findings,” noted Kovalev.

“Discovering extraordinary molecules like these wouldn’t be possible without scientific expeditions to often remote locations, to study the adaptations of the organisms living there. We can learn so much from that!”

Cryorhodopsins aren’t ready to be used in the lab or the clinic just yet, but they are a solid starting point. Ultimately, they might offer a way to sense UV light inside of living cells.

The proteins could also serve as new light-controlled tools for brain research, precision medicine, or even advanced prosthetics.

The full study was published in the journal Science Advances.

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