Scientists have discovered that torrents of microscopic waves propel white blood cells toward invading microbes. The discovery - recorded on videotape -- holds the potential for better understanding and treatment of cancer and heart disease.
Visible only under a very high-resolution light microscope, the dynamic waves are made of a signaling protein that directs cell movement. This protein and a second key player were already known to trigger cells to move, but their interaction to generate the self-sustaining waves has now been revealed.
"Seeing the wavelike dynamics of this protein, Hem-1, for the first time was easily the most instantly thrilling and illuminating finding in my scientific career," says Orion Weiner, PhD, of the University of California, San Francisco, who led the scientific team. "It immediately suggested how this protein might be organizing cell movement - an idea that our subsequent experiments validated.
"We never expected to see this sort of complex behavior within cells, but in retrospect it is an absolutely ingenious way to organize cell movement. We're getting our first glimpses that take us beyond knowing that this protein is important for cell motility to learning how it might organize the complex choreography of cell movement."
The videotape of the unsuspected action shows wave upon wave advancing like a series of exploding fireworks. The novel behavior can be viewed at cvri.ucsf.edu/~weiner.
The research findings are reported in the August 13, 2007 online edition of the journal "Public Library of Science (PLoS) Biology." Lead author is Weiner, who is assistant professor of biochemistry at UCSF.
Because the same kind of components scrutinized in the new research also drive cancer cell metastasis, the finding may lead to strategies to block cancer growth. Similarly, faulty regulation of white blood cell movement plays a role in heart attack - another promising target for applying the new insights of the regulation of cell movement, the authors say.
White blood cells, or neutrophils, are the body's first line of defense against potentially harmful microbes, and are one of the swiftest cells in the body. The wave action that speeds them along is generated by the same kind of three-part circuit that fires electrical signals along a neuron or prods the heart to beat, the researchers observe.
Videotaping allowed the scientists to watch as wave upon wave of the Hem-1 protein push neutrophils toward a chemical signal made by invading microbes. The researchers fluorescently tagged Hem-1 to view its dynamic propulsive power under the microscope.
Self-generating waves of Hem-1 control the pattern of assembly of building blocks of a second protein, actin. This protein physically contacts the cell membrane and prods it forward. But actin is not only an output of Hem-1 action; it also appears to eliminate the Hem-1 that has assembled it, the new research shows. The scientists think that this cycle of Hem-1 propulsion and annihilation is likely to produce the series of waves seen under the microscope.
The cell-propelling circuit contains a third component that makes it self-sustaining. The researchers found evidence that before each Hem-1 protein is eliminated, it recruits an additional Hem-1 right "next door." As each Hem-1 succumbs, a new one appears - but only on one side. Weiner thinks the structure of actin physically blocks Hem-1 from recruiting its daughter Hem-1 on one side, so Hem-1 is sequentially added only in one direction. This determines the direction of cell movement.
Weiner likens it to a Lego tower on its side. "If you kept adding blocks to one end and removing them from the other, you would have a moving tower that was the same size but kept adding new material. This is very similar to what is going on in a Hem-1 wave," he says.
The Hem-1 recruitment assures the cycle will continue. The cycle, or circuit, of activation, recruitment and inhibition, as it is called, can continue without "orders" from another part of the cell, the scientists report.
"One of the things that I find fascinating about these waves is how relatively simple patterns of protein interaction can generate very complex behaviors," says Weiner. "Evolution has found the same solution to generating waves again and again even with completely different molecules, and at different scales of space and time -- encouraging for those of us who want to uncover general organizing principles in biology."
Weiner is an investigator in both the UCSF Cardiovascular Research Institute and the California Institute for Quantitative Biosciences, or QB3, headquartered at UCSF.
Weiner initiated the research as a postdoctoral fellow in the lab of Marc Kirschner, PhD, professor and chair of systems biology at Harvard Medical School. Kirschner is a co-author on the paper.
The cycle the scientists studied is very similar in concept to the circuit that generates neuronal conduction, the beating of the heart, and many other waves in biology, according to Weiner.
"All of these use a self-activating signal that plants the seeds for its own destruction, even while it is progressing. This results in a wave that moves undiminished because of the self-activation, and in one direction, because of the inhibition it leaves in its wake," he says.
The scientists observed the Hem-1 activation of actin assembly and actin's inhibition of Hem-1 accumulation. The "recruitment" component was not directly observed, but is consistent with their observations and experiments.
In the research, the team used the fluorescently tagged Hem-1 to determine whether the protein participated in the wave action, or was the wave itself.
Using optical tricks to label specific pools of Hem-1, they found that molecules of Hem-1 don't move, but pass information between molecules to generate a wave.
The research is now focusing on how external signals influence this wave generator to guide the cells. They also want to learn if the wave action they have discovered in neutrophils also controls movement and shapes changes in other cells and organisms.
Co-authors on the PLoS paper and collaborators in the research are William Marganski, PhD, a scientist at Ikonisys, in Connecticut; Lani F. Wu, PhD, and Steven Altschuler, PhD, both assistant professors of pharmacology at University of Texas Southwestern.
The research was supported by the National Institutes of Health, the Leukemia and Lymphoma Society, the Endowed Scholars Program, and the Welch Foundation.
UCSF is a leading university that advances health worldwide by conducting advanced biomedical research, educating graduate students in the life sciences and health professions, and providing complex patient care.
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