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Rewriting Life

Lightning Bolts within Cells

A new nanoscale tool reveals strong electric fields inside cells.

Using novel voltage-sensitive nanoparticles, researchers have found electric fields inside cells as strong as those produced in lightning bolts. Previously, it has only been possible to measure electric fields across cell membranes, not within the main bulk of cells. It’s not clear what causes these strong fields or what they might mean. But now that it’s possible to measure them, researchers hope to learn about disease states such as cancer by studying these electric fields.

The cell electric: Encapsulated in a polymer shell just 30 nanometers across, voltage-sensitive dyes (red) emit red and green light when illuminated with blue light. These encapsulated dyes make it possible to measure electric fields inside cells.

University of Michigan researchers led by chemistry professor Raoul Kopelman encapsulated voltage-sensitive dyes in polymer spheres just 30 nanometers in diameter. When illuminated with blue light, the voltage-sensitive dyes emit a mixture of red and green light; the exact frequency of light emitted is influenced by the strength of local electric fields, allowing the researchers to measure those fields. Testing these nanoparticles in the internal fluid of brain-cancer cells, Kopelman found electric fields as strong as 15 million volts per meter, perhaps five times stronger than the field found in a lightning bolt.

“They have developed a tool that allows you to look at cellular changes on a very local level,” says Piotr Grodzinski, director of the National Cancer Institute Alliance for Nanotechnology in Cancer. Traditional techniques for studying disease at the level of tissues average out differences between cells. Grodzinski says that many developments in cancer research over the past few years have been “more reactive,” working toward developing diagnostics for catching the disease in its earlier stages and for better predicting to which drugs patients will respond. Despite how far cancer treatments have come, the way that cancer progresses at the cellular level is still not very well understood. With a better understanding, researchers hope to further improve diagnostics and personalized care. “This development represents an attempt to start using nanoscale tools to understand how disease develops,” says Grodzinski.

Jerry S.H. Lee, a nanotechnology project manager also at the National Cancer Institute, says that Kopelman’s research bolsters the set of nanoscale tools that scientists are developing to probe cells’ physical properties, such as special microscopic probes for measuring cell stiffness. (See “The Feel of Cancer Cells.”) In the past decade, researchers have improved cancer diagnosis by examining protein markers and genetic signatures. Now they’re “thinking of how nanotechnology can make tools to look at additional signatures” like electric fields, says Lee.

Voltage-sensitive dyes are not new. For decades, neuroscientists have used them to measure voltages across cell membranes in studies of how nerve cells generate and respond to electrical charges. But Kopelman says that it’s not possible to control the placement of these dyes in cells. They are hydrophobic and aggregate in cell membranes, so it has not been possible to use them to study the cytosol, the bulk of the interior of the cell. Kopelman also says that these dyes might be reacting with enzymes and other molecules in cells. His encapsulated dyes aren’t hydrophobic and can operate anywhere in the cell, not just in membranes. Because it’s possible to place his encapsulated dyes in a cell with a greater degree of control, Kopelman likens them to voltmeters. “Nano voltmeters do not perturb [the cellular] environment, and you can control where you put them,” he says.

The existence of strong electric fields across cellular membranes is accepted as a basic fact of cell biology. Maintaining gradients of charged molecules and ions allows for many cellular functions, from control over cell volume to the electrical discharges of nerve and muscle cells.

The fact that cells have internal electric fields, however, is surprising. Kopelman presented his results at the annual meeting of the American Society for Cell Biology this month. “There has been no skepticism as to the measurements,” says Kopelman. “But we don’t have an interpretation.”

Daniel Chu of the University of Washington in Seattle agrees that Kopelman’s work provides proof of concept that cells have internal electric fields. “It’s bound to be important, but nobody has looked at it yet,” Chu says.

Grodzinski says that an interesting application of the voltmeters will be to examine whether there’s a difference in electrical signals between healthy and diseased cells, and whether different disease stages might have characteristic electrical signatures. To gauge the viability of the technique, researchers will need to “start tying it to biology by studying cell lines from the clinic,” says Grodzinski. “This is a first demonstration.”

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