by Chwee Teck LIM and Kevin TAN
he March 2006 issue of Technology Review, a magazine published by the Massachusetts Institute of Technology (MIT), has identified nanobiomechanics as among the 10 emerging technologies that would soon make a significant impact on human lives. The nanobiomechanics work featured had its roots at the National University of Singapore (NUS), the only work in Asia to be cited alongside universities such as Harvard, MIT, and Stanford.
In nanobiomechanics, scientists are able to gain new understanding of diseases by observing the effects of tiny forces acting on both healthy and diseased cells and biomolecules. Human diseases can affect the mechanical properties of cells and biomolecules, changing their physiological functions in the process.
Two friends from different disciplines at NUS have combined their diverse backgrounds to tackle a problem that would be quite impossible to undertake with a single field. Chwee Teck Lim and Kevin Tan jointly observe how red blood cells change as malaria parasites mature within the hosts, the findings which have implications for understanding diseases. Lim, an associate professor at the Division of Bioengineering and Department of Mechanical Engineering, taps on his expertise in bioengineering and mechanics to manipulate the cells, while Tan, an assistant professor at the Department of Microbiology, uses his intimate knowledge about diseases to investigate the biological aspects. They employ tools like the atomic force microscope, laser tweezers, micropipette aspiration assay, and microfluidics system to study changes in human cells in infectious diseases such as malaria.
Malaria kills about 2 million people worldwide every year. It is caused by a mosquito-borne parasite that makes red blood cells stiffer and sticky. This can lead to the clogging of the capillaries that carry blood to vital organs, resulting in death in severe cases.
To study how these parasites stiffen red blood cells that are normally flexible and elastic, the NUS team work with laser tweezers -- "tweezers" that use intense concentrated laser light to exert a minute force on tiny items attached to cells -- to stretch human red blood cells in order to extract information on the physical properties at the cellular level. Applying this relatively new technology, they designed a set-up that can produce "large deformation" stretching to provide realistic information on the elastic properties of the cells.
Collaborating with a group headed by Subra Suresh at MIT, the NUS team has charted the detailed elasticity changes thered blood cell undergoes as the parasite matures within its host. The members were the first to use the laser tweezers technique to stretch malaria-infected red blood cells. In principle, the laser tweezers method has several potential advantages. It allows the researchers to impose simple and well-controlled stress states, such as the direct tensile stretching in small or large deformation of the red cells. Thus, it is complementary to the widely used micropipette aspiration method.
Also, the stress state imposed on the cell can be systematically varied by attaching multiple beads to cell membranes and using multiple laser traps to apply mechanical loading to each of these beads. From this technique, the mechanical response of the cell membrane and cytoskeleton can then be probed under different biochemical and biological conditions.
Using the new approach, the researchers found that the surface membrane of infected cells are 10 times stiffer when compared to normal cells, up to four times stiffer than was previously estimated by other groups. The rigidity and stickiness of the red blood cells contributes to the malaria disease process.
The ability to measure the properties of cells with such accuracy holds promise in appreciating the cellular intricacies that happen in the progression of various diseases. As an acknowledgment of this potential, Suresh was appointed to help set up the Global Enterprise for Micro-Mechanics and Molecular Medicine, an international consortium that will use precision nano-level measurement tools to address major health disorders such as malaria, sickle-cell anaemia, cancer of the liver and pancreas, and cardiovascular disease.
Following the success of this work, the US-Singapore team has enlisted Geneviéve Milon and Peter David from Institut Pasteur in France to jointly investigate how specific proteins confer rigidity to malaria-infected red blood cells. The three-party research recently identified a new malaria protein that causes infected cells to increase in rigidity. Using optical tweezers, the group showed that normal infected cells were rigid while cells lacking this new protein were more deformable. Molecules that make infected cells rigid may be attractive drug targets.
This nanobiomechanics work has resulted in international recognition. The team clinched both the Ribbon Award (an outstanding paper award) and the Graduate Student Award (Gold) by the Materials Research Society (MRS) in the US during the Fall Meeting in 2004 and 2005, respectively.
Lim and Tan have demonstrated how nanobiomechanics can be used to investigate the pathogenesis of a human disease -- malaria in this instance. They hope that through this study, one can gain further important insights into the pathophysiology of malaria as well as assist in developing effective diagnostics for disease detection and diagnosis. The work can also help clinicians to quantitatively evaluate the effectiveness of certain drugs and agents developed in combating the disease.
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