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Biomedicine

Cells, Live and in 3-D

A new kind of microscope creates detailed, three-dimensional movies of living cells as they respond to changes in the environment.

MIT researchers have designed a microscope for generating three-dimensional movies of live cells. The microscope, which works like a cellular CT scanner, will let scientists watch how cells behave in real time at a greater level of detail. This new device overcomes a trade-off between resolution and live action that has hindered researchers’ ability to examine cells and could lead to new methods for screening drugs.

A glimpse inside: This image of a live, one millimeter-long worm taken with a new 3-D microscope clearly shows internal structures including the digestive system. The worm’s mouth is at the top and the thick red band is the worm’s pharynx.

Cells can’t be examined under a traditional microscope because they don’t absorb very much visible light. So the MIT microscope relies on another optical property of cells: how they refract light. As light passes through a cell, its direction and wavelength shift. Different parts of the cell refract light in different ways, so the MIT microscope can show the parts in all their detail.

Michael Feld, a professor of physics at MIT who led the development of the new microscope, says other methods for creating three-dimensional images of cells only allow researchers to look at “controlled artifacts.” To be viewed using a conventional microscope cells have to be treated with fixing agents and stains, and are dead; what’s visible in these images is “not really what a cell looks like,” he says. “Our technique allows you to study cells in their native state with no preparation at all.” It can, for example, capture chromosomes spooling during cell division or a cervical cancer cell shriveling up when treated with acetic acid.

The microscope creates three-dimensional images by combining many pictures of a cell taken from several different angles. It currently takes only a tenth of a second to generate each three-dimensional image, fast enough to watch cells respond in real time. This processing technique, called tomography, is also used for medical imaging in CT scans, which combine X-ray images taken from many different angles to create three-dimensional images of the body.

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But the MIT microscope operates at a much smaller scale than medical imaging devices. The researchers have created images of single cells, including cervical cancer cells, and of very small worms, called C. elegans. Each worm is only a millimeter long and is made up of only about a thousand cells. Feld says the microscope cannot currently image anything much bigger than this because thicker tissues containing a large number of cells scatter light, creating a “foggy” image. Future versions of the microscope might overcome this limitation by emitting and detecting light from a single location; the current microscope shines light on one side of the sample and collects it on the other.

Using Feld’s microscope, “you can capture cells in their natural environment and see how they respond to changes,” says Maryann Fitzmaurice, associate professor of pathology at Case Western Reserve University. “Otherwise you just get a snapshot in time of a cell.” Fitzmaurice says that because the technique is so new, it’s not clear what researchers will learn about cells by looking at refraction images. “It’s a very basic technique, with a lot of potential uses,” she says. One potential application may be in drug screening tests in live cells. Researchers could dose cells with a potential therapeutic compound and use the microscope to watch their response.

Feld and collaborators at Harvard Medical School have already used their microscope to illuminate the workings of a medical test. During pelvic exams, doctors sometimes perform a visual test for cervical cancer by applying acetic acid to the cervix, which causes pre-cancerous tissues to turn white. Fitzmaurice says doctors have known that this works, but not why. Using the MIT microscope, researchers were able to “clearly see the changes in different parts of the cell, which is very valuable in understanding this test” says Fitzmaurice.

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