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Watching the Insides of a Cell

New imaging tools provide nanoscale pictures of the happenings of individual living cells and neurons.
November 16, 2006

Researchers at MIT’s George R. Harrison Spectroscopy Lab have detected tiny twitches and vibrations in the membranes of individual cells and neurons by using a powerful and noninvasive imaging technique. Down the line, Michael Feld, director of the lab, hopes to use the technique to create three-dimensional images, illuminating even finer activities within living cells. The goal, says Feld, is to “study the structure of a living cell and the way it changes as circumstances change.”

Scientists at MIT’s George R. Harrison Spectroscopy Laboratory can now see the tiniest vibrations within living red blood cells (pictured here) and neurons, thanks to an optical imaging technique they have tweaked that’s based on interferometry. Detecting vibrations in such cells may unveil clues into diseases such as malaria and sickle-cell anemia as well as basic neuron-to-neuron communication.

Today’s molecular imaging techniques come with a host of pros and cons. Among the most widely practiced techniques is electron microscopy, which creates highly magnified images of cells by using a beam of energized electrons. The downside is that samples require various preparations, such as dehydrating or freezing cells, or coating them in a thin layer of conductive material, such as gold. As a result, electron microscopes can’t view the inner workings of living cells.

In contrast, Feld and his colleagues have been able to image live, untreated cells by using an optical technique based on interferometry: a laser beam passed through a sample is compared with a reference beam of similar wavelength that is not passed through the cell. For example, it takes longer for light to travel through a cell than through, say, water. Researchers can measure that time delay, or phase shift, and then can map the cell and its motions on the scale of nanometers.

It’s a very sensitive technique, and Feld says the tiniest vibrations, such as those caused by air being blown back and forth, could disrupt the signal. He and his colleagues have used a number of strategies to stabilize the system over the past few years. “The technique is pretty much perfected,” says Feld. “Now we are actively applying it to a number of different problems.”

One of those problems is the behavior of membranes in red blood cells. Feld’s colleague the postdoctoral associate Gabriel Popescu was able,to focus on tiny vibrations that occur in the cell membranes by using this technique. Scientists have known for decades that these vibrations indicate membrane flexibility, giving red blood cells the elasticity they need to squeeze through blood vessels and capillaries. Now Popescu has successfully illuminated these vibrations and quantified the elasticity in normal red blood cells, compared with abnormal, less elastic cells. (His findings appear in the journal Physical Review Letters.) Popescu says this application is particularly useful for studying diseases such as sickle-cell anemia, malaria, and chronic alcoholism, all of which involve membrane abnormalities in red blood cells.

“In malaria, our first measurements indicate that the membrane stiffens as the parasite ages inside the cell,” says Popescu. “In fact, the cell membrane behaves much like a guitar string. The tighter or stiffer it is, the higher the pitch produced. So, our technique can be regarded as an incredibly sensitive microphone.” In the long term, he says, this kind of optical imaging may have clinical applications: it could yield a way to help reverse such diseases.

Meanwhile, a separate research group in the Spectroscopy Lab, led by postdoctoral associate Christopher Fang-Yen, is using optical interferometry to watch the activity of individual neurons. With this technique, Fang-Yen was able to detect small twitches of a few nanometers in nerve fibers and single neurons during an action potential, or electrical impulse. “Many researchers have observed a transient swelling in nerves during the action potential,” says Fang-Yen. “We’re interested in imaging these motions to detect signaling between neurons.”

Illuminating the mechanical changes in activated neurons may provide a new way of probing the activity of neural circuits, particularly for studies of learning and memory. Current optical imaging techniques for neurons use fluorescent markers, or dyes, that stain for things like calcium ions, an indirect measure of electrical activity. However, Fang-Yen says fluorescence methods are marred by photobleaching, phototoxicity, and slow time scales. The optical technique developed by the Spectroscopy Lab creates nanometer-scale images in less than a millisecond, and it’s not subject to photobleaching or phototoxicity.

John Sedat, professor of biochemistry at the University of California, in San Francisco, sees this optical imaging technique as a new perspective in an evolving field. “There’s a kind of miniature revolution taking place in microscopy,” he says. “This is an example of physics people coming into biology and bringing in a lot of new ways of seeing things.”

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