Newly discovered electrical activity in cells could change the way researchers think about biological chemistry

The human body is highly dependent on electrical charges. Lightning-like impulses of energy fly through the brain and nerves, and most biological processes depend on electrical ions moving across the membranes of every cell in our body.

These electrical signals are possible in part because of the imbalance of electrical charges that exist on either side of the cell membrane. Until recently, researchers believed that the membrane was an essential part of creating this imbalance. But that thought was overturned when researchers at Stanford University discovered that similarly unbalanced electrical charges can exist between microdroplets of water and air.

Now, researchers at Duke University have discovered that these types of electric fields also exist in and around another type of cellular structure called biological condensates. Like oil droplets floating in water, these structures exist because of density differences. They form compartments within the cell without the physical boundary of a membrane.

Inspired by previous research that showed that microdroplets of water interacting with air or solid surfaces create small electrical imbalances, the researchers set out to see if the same was true for small biological condensates. They also wanted to see if this imbalance caused reactive oxygen, “redox,” reactions like those in other systems.

Appears April 28 in the magazine Chem, their fundamental discovery could change the way researchers think about biological chemistry. It could also provide a clue to how the first life on Earth used the energy needed to emerge.

“Where will the energy come from in a prebiotic environment without enzymes to catalyze reactions?” asked Yifan Dai, a Duke postdoctoral researcher in the lab of Ashutosh Chilkoti, the Alan L. Kaganov Distinguished Professor of Biomedical Engineering, and Lingchong You, the James L. Merriam Distinguished Professor of Biomedical Engineering.

“This finding provides a plausible explanation for where the reaction energy could have come from, just like the potential energy imparted to a point charge placed in an electric field,” Dai said.

When electrical charges pass between one material and another, they can create molecular fragments that can pair up to form hydroxyl radicals, which have the chemical formula OH. They can then pair again to form hydrogen peroxide (H2O2) in small but detectable amounts.

“But interfaces have rarely been studied in biological regimes other than the cell membrane, which is one of the most important parts of biology,” Dai said. “So we wondered what might happen at the interface of biological condensates, that is, whether it is also an asymmetric system.”

Cells can form biological condensates to separate or trap certain proteins and molecules, inhibiting or promoting their activity. Researchers are just beginning to understand how condensates work and what they might be used for.

Because the Chilkoti lab specializes in creating synthetic versions of naturally occurring biological condensates, the researchers were able to easily create a testbed for their theory. After putting together the right formula of building blocks to create tiny condensates, with the help of postdoctoral researcher Marco Messina? Christopher J. Chang’s group at the University of California, Berkeley, they added a dye to the system that glows in the presence of reactive oxygen species.

Their hunch was right. When the environmental conditions were right, a substantial glow started from the edges of the condensates, confirming that a previously unknown phenomenon was at work. Dai then talked with Richard Zar, the Marguerite Blake Wilbur professor of chemistry at Stanford, whose group determined the electrical behavior of water droplets. Zare was excited to learn about the new behavior in biological systems and began working with the group on the underlying mechanism.

“Inspired by previous work with water droplets, my graduate student Christian Chamberlain and I thought that the same physical principles might apply and drive redox chemistry, such as the formation of hydrogen peroxide molecules,” Zare said. “These findings show why condensates are so important in cell function.”

“Most previous work on biomolecular condensates has focused on their internal organs,” Chilkoti said. “Yifan’s discovery that biomolecular condensates appear to be universally redox-active suggests that condensates not only evolved to perform specific biological functions, as is commonly understood, but that they also have an important chemical function essential to cells.”

Although the biological consequences of this reaction in our cells are unknown, Dai points to a prebiotic example of how powerful its effects could be. Our cellular powerhouses, called mitochondria, generate energy for all of our life functions through the same basic chemical process. But before mitochondria, or even the simplest cells, existed, something had to provide the energy for the first life functions to begin.

Researchers have suggested that thermal vents in the oceans or hot springs provided the energy. Others have proposed that this same redox reaction occurring in water microdroplets was produced by ocean wave spray.

But why not condensates?

“Magic can happen when substances become tiny and the interface becomes huge relative to its volume,” Dai said. “I think impact is important in many different areas.”