Researchers at Oregon Health & Science University have uncovered a previously unknown system within cells that functions like internal “trade winds,” facilitating the rapid transport of crucial proteins to the leading edge of the cell. This pivotal discovery alters the scientific understanding of cell movement, cancer dissemination, and wound healing.
The study, published in Nature Communications, challenges longstanding notions regarding the organization and distribution of proteins within cells.
For decades, biology textbooks have portrayed protein movement as a largely random process known as diffusion, where proteins drift until they naturally arrive at their target locations. However, the new research indicates that cells do not rely solely on chance; they actively generate directed fluid flows that push proteins toward the leading edge, where cellular extension, movement, and tissue repair occur.
From Classroom Observation to Groundbreaking Discovery
The breakthrough originated from an unexpected observation during a neurobiology course at the Marine Biological Laboratory in Massachusetts. The study’s co-corresponding authors, Catherine (Cathy) Galbraith, Ph.D., and James (Jim) Galbraith, Ph.D., were conducting a routine classroom experiment when they noticed an unusual phenomenon.
“It actually started out as an unexpected finding,” Cathy explained. “We were simply running an experiment with students.”
Employing a laser, the team temporarily rendered proteins invisible in a segment at the rear of a living cell to monitor their movement. This method is commonly used to study intracellular transport. During the experiment, a dark band appeared at the cell’s front edge, the area responsible for cellular movement.
“We initially approached it as a fun experiment and soon realized it provided a unique means to measure something previously unquantifiable,” she noted.
Further examinations revealed that this dark band signified a wave of soluble actin, a pivotal protein integral to cell movement, being actively pushed forward. Previously, it was believed that actin reached this region through random diffusion. The new findings uncovered an alternative mechanism.
“We realized the cartoon models in textbooks missed a significant aspect,” Jim remarked. “There had to be some kind of flow within the cell to propel contents forward. Cells indeed ‘go with the flow.’
Directed Flows Facilitate Protein Transport
After joining OHSU in 2013, following their work at the National Institutes of Health, Cathy and Jim collaborated with Nobel Laureate Eric Betzig, Ph.D., at the Howard Hughes Medical Institute’s Janelia Research Campus, yielding advanced imaging techniques.
Utilizing specialized imaging tools, the team discovered that cells actively generate directional fluid flows, likening them to atmospheric rivers. These flows transport actin and other proteins to the front of the cell significantly faster than diffusion.
“We found that the cell can compress at the back, effectively targeting the delivery of material,” Jim explained. “If you squeeze half a sponge, the water travels in that half. The cell operates similarly.”
These nonspecific flows can transport various types of proteins simultaneously, creating an efficient system that supports cell protrusion, adhesion, and rapid shape changes—all vital for movement, immune responses, and tissue repair.
Additionally, the researchers observed that these flows occur within a specialized region at the cell’s forefront, separated from the rest of the cell by an actin-myosin condensate barrier. This barrier serves as a physical boundary, guiding proteins to the advancing edge.
Visualizing Cellular Currents with Innovative Imaging
The team developed a modified version of a standard fluorescence technique to visualize these internal flows. Instead of deactivating fluorescence with a laser, they activated fluorescent molecules at a single point to track their movement.
They coined one of their key experiments FLOP, or Fluorescence Leaving the Original Point.
“It wasn’t a flop at all,” Cathy remarked. “In fact, it turned out to be quite a success because it functioned as intended.” This discovery could elucidate why certain cancer cells exhibit aggressive movement.
Implications for Cancer Cell Migration
The findings may clarify why some cancer cells are exceptionally invasive.
“We know that these highly invasive cells exploit a remarkable mechanism to swiftly push proteins where they are needed at the cell’s front,” Jim stated. “Although all cells share similar components, much like a Porsche and a Volkswagen, their assembled functions differ greatly.”
By grasping how cancer cells utilize this system in contrast to normal cells, researchers may devise new strategies to inhibit or halt their spread.
“Understanding these differences can inform future therapeutic approaches tailored to how cancer cells and normal cells operate,” he added.
Advanced Imaging and Collaborative Research
This research brought together experts from engineering, physics, microscopy, and cell biology. Significant contributions came from collaborators at Janelia Research Campus in Virginia, specializing in fluorescence correlation spectroscopy and 3D super-resolution imaging.
“The specific instrumentation we required is not available in most locations,” Cathy noted. “Janelia offered a unique setup that enabled us to test and confirm our observations.”
The study heavily depended on advanced imaging tools developed at Janelia, including iPALM, an interferometric technique capable of resolving structures at the nanometer scale.
“iPALM allowed us to physically visualize the compartments,” Jim explained. “There’s no other light-based technique capable of achieving that.”
A Newly Identified “Pseudo-Organelle”
The researchers describe this newly discovered system as a “pseudo-organelle,” a functional compartment that, although not membrane-bound, significantly organizes cellular behavior.
“Just as subtle shifts in the jet stream can alter weather patterns, minor changes in these cellular winds could impact disease onset or progression,” Cathy remarked.
The team anticipates that this discovery will influence multiple domains, including cancer research, drug delivery, tissue repair, and synthetic biology.
“All you had to do was look; the flows have always been there. Now we understand how cells utilize them,” Cathy concluded.
In addition to the Galbraiths, coauthors on this study include Brian English, Ph.D., from Janelia Research Campus, and Ulrike Boehm, Ph.D., formerly of Janelia and currently with Carl Zeiss AG in Germany.
This study received support from the National Institute of General Medical Sciences of the National Institutes of Health (Award number R01GM117188), the U.S. National Science Foundation (Award numbers 2345411 and 171636), the W. M. Keck Foundation, the Howard Hughes Medical Institute Janelia Visiting Scientist Program, and the Howard Hughes Medical Institute. The iPALM work was also partially funded by an award from the Advanced Imaging Center at Janelia, while the SIM imaging received partial support from a Core Research Facilities grant from OHSU School of Medicine.