Diagnosing cellular nanomechanics

Researchers at Singapore-MIT Alliance for Research and Technology (SMART) and MIT’s Laser Biomedical Research Center (LBRC) have developed a new way to study cells, paving the way for a better understanding of how cancers spread and become killers.

The new technology is explained in a paper published recently in Nature Communications. A new confocal reflectance interferometric microscope provides 1.5 microns depth resolution and better than 200 picometers height measurement sensitivity for high-speed characterization of nanometer-scale nucleic envelope and plasma membrane fluctuations in biological cells. It enables researchers to use these fluctuations to understand key biological questions, such as the role of nuclear stiffness in cancer metastasis and genetic diseases.

“Current methods for nuclear mechanics are invasive, as they either require mechanical manipulation, such as stretching, or require injecting fluorescent probes that ‘light up’ the nucleus to observe its shape. Both these approaches would undesirably change cells' intrinsic properties, limiting study of cellular mechanisms, disease diagnosis, and cell-based therapies,” say Vijay Raj Singh, SMART research scientist, and Zahid Yaqoob, LBRC principal investigator. “With the confocal reflectance interferometric microscope, we can study nuclear mechanics of biological cells without affecting their native properties.”

While the scientists can study about a hundred cells in a few minutes, they believe that the system can be upgraded in the future to improve the throughput to tens of thousands of cells.

“Today, many disease mechanisms are not fully understood because we lack a way to look at how cells’ nucleus changes when it undergoes stress,” says Peter So, SMART BioSyM principal investigator, MIT professor, and LBRC director. “For example, people often do not die from the primary cancer, but from the secondary cancers that form after the cancer cells metastasize from the primary site — and doctors do not know why cancer becomes aggressive and when it happens. Nuclear mechanics plays a vital role in cancer metastasis as the cancer cells must ‘squeeze’ through the blood vessel walls into the bloodstream, and again when they enter a new location. This is why the ability to study nuclear mechanics is so important to our understanding of cancer formation, diagnostics, and treatment.”

With the new interferometric microscope, scientists at LBRC are studying cancer cells when they undergo mechanical stress, especially during extravasation process, paving the way for new cancer treatments. Further, the scientists are also able to use the same technology to study the effect of “lamin mutations” on nuclear mechanics, which result in rare genetic diseases such as Progeria, which leads to fast aging in young children.

The confocal reflectance interferometric microscope also has applications in other sectors. For example, this technology has the potential for studying cellular mechanics within intact living tissues. With the new technology, the scientists could shed new light on biological processes within the body’s major organs such as liver, allowing safer and more accurate cell therapies. Cell therapy is a major focus area for Singapore, with the government recently announcing a S$80 million (US $58 million) boost to the manufacturing of living cells as medicine.

About BioSyM

BioSystems and Micromechanics (BioSyM) Inter-Disciplinary Research Group brings together a multidisciplinary team of faculties and researchers from MIT and the universities and research institutes of Singapore. BioSyM’s research deals with the development of new technologies to address critical medical and biological questions applicable to a variety of diseases with an aim to provide novel solutions to the health care industry and to the broader research infrastructure in Singapore. The guiding tenet of BioSyM is that accelerated progress in biology and medicine will critically depend upon the development of modern analytical methods and tools that provide a deep understanding of the interactions between mechanics and biology at multiple length scales — from molecules to cells to tissues — that impact maintenance or disruption of human health.

About Singapore-MIT Alliance for Research and Technology (SMART)

Singapore-MIT Alliance for Research and Technology (SMART) is MIT’s research enterprise in Singapore, established in partnership with the National Research Foundation of Singapore (NRF) since 2007. SMART is the first entity in the Campus for Research Excellence and Technological Enterprise (CREATE) developed by NRF. SMART serves as an intellectual and innovation hub for research interactions between MIT and Singapore. Cutting-edge research projects in areas of interest to both Singapore and MIT are undertaken at SMART. SMART currently comprises an Innovation Centre and six Interdisciplinary Research Groups: Antimicrobial Resistance, BioSystems and Micromechanics, Critical Analytics for Manufacturing Personalized-Medicine, Disruptive & Sustainable Technologies for Agricultural Precision, Future Urban Mobility, and Low Energy Electronic Systems.

SMART research is funded by the National Research Foundation Singapore under the CREATE program.

About the Laser Biomedical Research Center (LBRC)

Established in 1985, the Laser Biomedical Research Center is a National Research Resource Center supported by the National Institute of Biomedical Imaging and Bioengineering, a Biomedical Technology Resource Center of the National Institutes of Health. The LBRC’s mission is to develop the basic scientific understanding and new techniques required for advancing the clinical applications of lasers and spectroscopy. Researchers at the LBRC develop laser-based microscopy and spectroscopy techniques for medical applications, such as the spectral diagnosis of various diseases and investigation of biophysical and biochemical properties of cells and tissues. A unique feature of the LBRC is its ability to form strong clinical collaborations with outside investigators in areas of common interest that further the center’s mandated research objectives.

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