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Biomolecular condensates often appear like soap bubbles but are actually more like Silly Putty, featuring mostly elastic and viscous behaviors on different time scales. WashU researchers have devised a method to image the internal organization within condensates to arrive at a structural explanation for condensate viscoelasticity. (Image: Shutterstock)
Biomolecular condensates often appear like soap bubbles but are actually more like Silly Putty, featuring mostly elastic and viscous behaviors on different time scales. WashU researchers have devised a method to image the internal organization within condensates to arrive at a structural explanation for condensate viscoelasticity. (Image: Shutterstock)
New imaging techniques developed at Washington University in St. Louis have allowed researchers to peer into mysterious cellular structures with unprecedented clarity, revealing that the tiny blobs inside our cells behave less like liquid droplets and more like a malleable, shifting network similar to silly putty.
These microscopic structures, known as biomolecular condensates, play crucial roles in organizing cellular activities, but their internal workings have remained largely hidden from view until now. The findings, published March 14 in Nature Physics, could reshape our understanding of cellular organization and potentially inform new approaches to treating diseases like cancer and neurodegeneration.
“These blobs were once described as being ‘liquid-like’ because some of them were observed to kiss, fuse, drip and flow like raindrops on windshields,” explained Rohit Pappu, Gene K. Beare Distinguished Professor of biomedical engineering at the McKelvey School of Engineering.
But appearances can be deceiving. Through computational models and now direct observation, scientists have discovered that condensates are more complex than initially thought. Rather than behaving like simple liquid droplets, they function as dynamic networks that constantly rearrange themselves—a property that gives them their silly putty-like character.
The challenge for researchers has always been size. Traditional microscopes simply can’t provide clear images of structures so small. It’s like trying to photograph individual raindrops in a storm from miles away—the resolution just isn’t there.
To overcome this limitation, Pappu collaborated with Matthew Lew, associate professor of electrical and systems engineering, to develop a novel approach using special light-sensitive dyes called fluorogens. Unlike conventional imaging methods that try to capture everything at once, their technique employs a “one-at-a-time” strategy.
“Enabled by the interactions written into protein sequences, certain individual proteins are the hubs of the viscoelastic (silly putty) network structure within the condensate,” Lew said. “Our fluorogen sensors won’t light up until they’ve found these hubs. Tracking the movements of individual fluorogens enabled us to find and track the hubs as they formed, moved and disassembled.”
This single-molecule approach represents a significant departure from existing techniques that rely on averaging the behavior of all molecules within condensates. By focusing on individual signals, the researchers achieved resolution beyond the diffraction limit—the physical boundary that normally restricts optical microscopes.
Pappu uses an intriguing analogy to explain their methodology: “The microscopy [is] akin to sending a single ant to map and navigate a dark house. The ant will spend more time around sections where sugar has been left out for it and the map it makes will glow most bright around that sugar.”
Using multiple ants—or fluorogens—simultaneously would create confusing, overlapping signals. But by tracking just one at a time, researchers can build a precise map of the condensate’s internal structure.
“The fluorogens swim inside a condensate and help us map the internal organization for the first time,” Pappu noted. “This was made possible by Matt Lew’s innovations and the collaborations enabled by our unique center.”
Understanding these cellular structures is far more than an academic exercise. Biomolecular condensates are increasingly recognized as critical players in cellular health. When they malfunction, the consequences can be severe, potentially contributing to diseases ranging from cancer to Alzheimer’s.
The research team describes condensates as being organized around “stickers”—specific proteins that determine where and when molecules gather. “If you think of condensates as a group of people, the stickers are the friends who make the decisions about where and when to gather and whom to invite,” the researchers explained.
These “friends” create the internal network that gives condensates their distinctive properties. Rather than being homogeneous blobs, condensates contain organized regions with specific functions—like neighborhoods within a city.
The study represents a collaboration between researchers at Washington University’s Center for Biomolecular Condensates. By bringing together experts from different fields, the center has created an environment where technological innovation and biological inquiry can feed off each other, leading to breakthroughs that might not otherwise occur.
The findings open new avenues for research into cellular organization and disease mechanisms. As scientists gain a better understanding of how condensates function in healthy cells, they may also discover how these structures go awry in disease states—potentially leading to novel therapeutic approaches.
The study was funded by the Air Force Office of Scientific Research, the St. Jude Research Collaborative on the Biology and Biophysics of RNP granules, and the National Institutes of Health, highlighting the broad interest in this emerging field across both public health and defense sectors.
As researchers continue to refine these imaging techniques, we may soon gain even deeper insights into the mysterious world of cellular organization—a world that, despite its microscopic scale, has enormous implications for human health and disease.
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