Basic biology courses teach that cells contain organelles – such as the nucleus, mitochondria and Golgi apparatus – set apart by lipid membranes to get things done. Recent cell biology research has revealed another organizational principle going on in cells across all orders of biology.
“Proteins and nucleic acids spontaneously organize themselves into blobs called condensates,” said Eric Dufresne, professor of physics in the College of Arts and Sciences and of materials science and engineering at Cornell Duffield College of Engineering, who is working to understand how condensates work.
Droplet-like condensates form and dissolve as cells need them, bringing selected proteins, RNA and other molecules together to coordinate biochemical reactions, said Takumi Matsuzawa, postdoctoral researcher in physics. “Their timely formation and dissolution are essential for normal cellular function, and disruptions to this process have been linked to neurodegenerative diseases,” including Alzheimer’s and Parkinson’s.
Matsuzawa and other researchers in Dufresne's Laboratory of Soft and Living Materials have developed an experimental metric useful for comparing chemical effects across different types of condensates. With their framework, they’ve uncovered some general rules governing condensates’ responses to chemicals. It’s a tool researchers can use to better understand cellular physiology and identify chemicals that can target disease-related condensates.
“Biomolecular condensates are amazing functional structures. To understand them, biologists, chemists and physicists need to work together,” said Dufresne, whose lab studies the way living things organize materials into structures, in part to inspire new engineering concepts. “Most people think of a cell as a bag of chemical reactions, but there are so many reactions that involve so many different molecules, that if cells were not organized, it would be chaos and we wouldn’t be able to do the reactions we need to stay alive.”
Matsuzawa is first author of “Susceptibility and Regulation of Biomolecular Condensates by Solutes,” published July 30 in the Proceedings of the National Academy of Sciences (PNAS), with Dufresne as corresponding author.
The study centers on phase separation, a process where two liquids “unmix” like salad dressing separating into oil and water. Although it’s known that biomolecular condensates form in cells through a similar process, the chemical complexity of cells makes the process impossible to pin down with a traditional approach, said Matsuzawa.
When there are only a few different species to consider, you can make sense of phase separation by mapping out a “phase diagram,” Matsuzawa said, similar to a diagram explaining how water becomes vapor, liquid or ice as a function of pressure and temperature.
But there are thousands of different species of proteins dissolved in a cell’s cytoplasm, and hundreds of biomolecular condensates have been reported, each with a different composition and a different response to each chemical. The true number of condensate types is likely even larger, Matsuzawa said.
“If we tried to map out the phase diagram of nearly 80 species, we’d need more bits than the number of atoms in the universe just to save the data,” Matsuzawa said. “We realized we needed a different approach.”
“Instead of mapping the whole world, we’re trying to map the neighborhood,” Dufresne said.
The physicists chose three known types of condensates that stick together for very different reasons. One is driven by “crowding,” in which molecules are pushed together by other molecules in their surroundings. Another, “stickers-and-spacers,” depends on sticky bits in a chain of proteins to bind together. A third relies on ligand-and-pocket interactions in which a molecule fits into a pocket of another macromolecule, a structural force more common with drugs, Matsuzawa said.
They tested each type of condensate with a wide range of molecules naturally found within a cell, looking for patterns.
“The most important thing we figured out was understanding the magnitude of these effects,” Dufresne said. “Some of the things we add respond very weakly. Some respond very strongly. We were able to identify a number of different physical mechanisms that underlie the response. We developed an experimental tool and a theoretical framework to interpret the data over a wide range of conditions, and I think it’s quite generalizable.”
Dufresne and the rest of the team are optimistic that their approach will help researchers identify drugs to target condensate-related diseases.
Cornell co-authors are: doctoral students Kaarthik Varma and Katherine Larina; former postdoctoral researchers in the Dufresne Lab Teagan Bate and Charlotta Lorenz; along with researchers from Harvard University, ETH Zürich, the Paul Scherrer Institute (PSI) Center for Life Sciences and the University of Basel.
The study was partially supported by the Swiss National Science Foundation and the Schmidt Science Fellows, in partnership with Rhodes Trust.
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