A major reason why malaria is so deadly – killing somewhere around a million people each year – is that red blood cells infected with the parasite become too stiff to squeeze through narrow capillaries, and so get stuck inside major organs. Yet microbiologists have not been able to take precise measurements of changes in the stiffness and other mechanical properties of cells – information that could shed light on the how malaria, as well as other diseases, progress, and how to treat them.
Now Subra Suresh, an engineer and materials scientist at MIT, is adapting nanotechnology tools such as optical tweezers to make those measurements – and in doing so has found that scientists have seriously underestimated the changes that malaria causes inside cells.
Furthermore, Suresh’s work is just the beginning of research into this promising field. His successes have helped spark the formation of a new consortium, announced last week, that will tackle major health problems – malaria, cancer, heart disease – using micromechanics.
The group, called the Global Enterprise for Micro-Mechanics and Molecular Medicine (GEM4), will bring together researchers from as far away as Singapore, France, Thailand, and Illinois. “It is very time consuming and expensive to build an infrastructure” for micromechanics research, says Suresh. The new consortium will be able to get new projects running faster by sharing existing equipment, lab space, personnel, and sources of funding. “Collectively we can take on much bigger problems than we can individually,” Suresh says.
Central to this collective undertaking is an alliance between the fields of engineering, with its quantitative measurements of mechanical properties, such as deformability and adhesion, and biology, which, says Suresh, has traditionally been more descriptive than quantitative. Suresh hopes his tools – which can measure forces as small as the push of a swimming sperm – will provide a more detailed knowledge of cells and their molecules that, in turn, can reveal ways to fight disease.
One of Suresh’s first measurements corrected previous estimates about the effects of the malaria parasite on red blood cells. Biologists have long known that malaria-infected cells are stiffer than healthy ones, and, as a result, cannot squeeze through capillaries. Suresh measured the stiffness of diseased and normal cells by attaching tiny glass beads to opposite sides of the cells and stretching them apart.
One bead is attached firmly to a movable plate. As the plate moves, the other bead is held in place by a focused laser, known as an optical tweezer. The light of the laser grips the bead with a precisely constant tension as the cell is stretched. Suresh compared how healthy cells and malaria cells changed shape under these forces. A healthy cell stretched out easily; while an infected one did not change shape.
Using this method, Suresh was able to show that previous estimates of cell stiffness were as much as four times too low. While these findings have not yet been applied, they should help researchers select among potential drugs and dosages for treating malaria, Suresh says.
In addition to studying malaria, Suresh has used these so-called microplate stretchers to measure how pancreatic cells change when supplied with a lipid that’s suspected of playing a role in metastasis (the spread of cancer cells inside the body).
Those experiments suggested that the lipid makes the cancerous cells flexible enough to squeeze through small pores that would otherwise block their spread. Such evidence could direct efforts at preventing metastasis.
Suresh’s work on malaria continues as well: since some strains of the disease cannot be cultured in labs, he’s designing inexpensive portable measuring devices to take into the field.
Suresh also plans to build microfluidic channels that mimic the body’s capillaries, possibly creating a testbed for the effects of treatments on blood samples taken from various patients, allowing for personalized medical treatment.
With the aid of computer models that Suresh has helped develop, micromechanical measurements may even reveal how the structure of diseased cells changes on a molecular scale. A group of researchers at the Institut Pasteur in Paris, one of the GEM4 members, is selectively knocking out genes in the malaria parasite that encode different proteins. Suresh can measure the stiffness of cells infected with the knockout strain, and computer models can then help identify how the missing protein fits into complex networks that control the stiffness of the membranes of red blood cells.
Such models are commonly used by engineers for analyzing synthesized materials – but the microbiologists at Pasteur didn’t think of applying them to cell biology until one of their members happened to strike up a conversation with Suresh in a Parisian cafeteria.
Suresh hopes these cross-fertilizations become regular occurrences through the consortium. “As people from one discipline move into a seemingly distant discipline with a fresh perspective,” he says, “they collectively move the field to a higher level.”
Genviève Milon of the Institut Pasteur, who has worked with Suresh, agrees. The collaboration “has created a unique niche at the interface between the two very different but related fields: life sciences and material science,” she says.
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