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Tuesday, September 9, 2008

Cells Disclose their Ailments

MIT researchers gauge the progress of malaria using a novel imaging technique.

Vibrant cells: MIT’s Michael Feld and Subra Suresh, with the aid of a technique developed in Feld’s lab, were able to image the vibrations of the membrane of a blood cell infected with the malaria parasite (top). Feld’s technique also provided images of the interior of the cells (bottom), allowing the researchers to correlate the cells’ vibrational frequencies with the progress of the disease.
Credit: Michael Feld and Subra Suresh

Bridging physics, engineering, and microbiology, researchers at MIT have measured the frequency at which red blood cells vibrate and have shown that those frequencies reflect the health of the cells. The research could lead to better medical diagnostics.

The work was performed in collaboration between MIT physicist Michael Feld and Subra Suresh, dean of MIT's school of engineering and a materials scientist. Feld heads MIT's Laser Biomedical Research Center, which has developed an imaging technique that can create three-dimensional images of living cells. Suresh's laboratory has conducted experiments to measure things like the stiffness of red blood cells infected by malaria parasites.

A red blood cell has electrical, chemical, and biological activity taking place inside it, which causes nanoscale vibrations at its surface. To measure the cells' vibrational frequencies, the researchers combined Feld's imaging technique with diffraction phase microscopy, in which a laser beam that passes through a cell rejoins a reference beam that does not, creating a distinctive interference pattern. To establish the connection between the cells' vibration and their health, the researchers used Feld's technique to create three-dimensional images of a malarial parasite inside a red blood cell. They also measured the levels of hemoglobin inside the cells during various stages of a malarial infection.

"This thing has never been done before," says Ares Rosakis, professor of aeronautics and mechanical engineering at the California Institute of Technology. "Scaling down optical techniques to [the nanoscale] level is extremely challenging." (Rosakis was not involved in the work, although one of his former graduate students was.)

Rosakis sees two uses for the new techniques. One is to improve computer models of cells, because Feld and Suresh's measurements are so much more accurate than previous measurements. The other is better diagnostics. The U.S. Centers for Disease Control (CDC) note that the main test for malaria currently does not work for acute malaria: it can recognize the disease only after the fact. Eventually, a technique like Feld and Suresh's could provide a way to detect malaria as it's happening. "Think of the future of a doctor or even an untrained technician having [the technology] built inside a commercial microscope and . . . instantaneously getting a reading on the state of the disease," Rosakis says.

Suresh notes that it was rare for mechanical engineers to work on cell biology, and rarer still to do it with physicists. But he and Feld "don't need to leave the building" to collaborate, he says.

The two began working together about two and a half years ago, after Feld invited Suresh to give a talk about the work his lab was doing on malaria cells. After Suresh's talk, the two decided to combine forces--and instruments--to measure the speed at which healthy and diseased red blood cells vibrate.

They chose malarial cells because of Suresh's experience working with them, but it meant that Feld's lab had to be refitted to meet the CDC's Level 2 biosafety standards. That project was led by one of the researchers on Suresh's team, Monica Diez-Silva, the only microbiologist in either group.

It takes 48 hours for a malarial invader to run through its life cycle, developing, reproducing, and being expelled from the cell. The researchers thus had to evaluate infected cells from each stage of that 48-hour process, at temperatures that simulated the fever and cooling that the human body experiences during a malarial infection.

Vibrating cell membranes move mere nanometers at a time, and those movements take place in microseconds--millionths of a second. To capture the data from the laser beam passing through the cells, the researchers used Feld's imaging technique, which stitches multiple images together into a composite. The technique is a species of tomography, the principle that underlies computed-tomography (CT) scans.

Rosakis says that imaging with interference patterns is particularly challenging when looking at red blood cells, which are doughnut-shaped and fluid, constantly changing shape in all directions.

Suresh and Feld's first set of experiments took almost eight months, including "weeks and weeks" to assemble the 3-D images of the parasites inside the cells. Then they decided to look at hemoglobin levels, which also took months. They spent almost six months writing up the results, which will be published in the Proceedings of the National Academy of Sciences this week.

Suresh says that the research should apply to any other type of living cells. He and Feld want to look at red blood cells with sickle anemia, and possibly cancer cells, although it will be more difficult to study cells that have a nucleus.

Suresh's and Feld's techniques can't yet be used for diagnosing illnesses, but Suresh says that their work "makes the scientific foundation that you can measure" disease at the cellular level.