BioSystems and Micromechanics (BioSyM)

The BioSystem and Micromechanics (BioSyM) Interdisciplinary Research Group was established under the auspices of the Singapore-MIT Alliance for Research and Technology (SMART) in October 2008 with support from the Singapore National Research Foundation (NRF).

The SMART BioSyM IRG has three major areas of focus. First and foremost is the development of new technologies to address critical medical and biological questions applicable to a variety of diseases. Second, is the further development of these technologies to provide novel solutions for the healthcare industry. Third, is to provide a constant source of new technologies to the broader Singapore research infrastructure.

BioSyM brings together a multidisciplinary team of faculties and researchers from MIT and Singapore's Universities (NUS and NTU) and Research Institutes.

The Group's vision is to o become the focal point for translating cutting edge science into novel technologies for human healthcare.

The mission is to develop enabling biotechnologies that will create the next generation of scientific discoveries and will lead to advances in our understanding of biological phenomena and the development of new diagnostic/therapeutic assays and translation into clinical practice.

One organizing theme of research in the BioSyM program is that mechanical forces and interactions are critical regulators and indicators of molecular, cellular, and tissue functions. It is now widely recognized, for example, that mechanical signaling pathways operate in parallel with biochemical ones in regulating biological function. This mechanical/biochemical coupling in biology offers diverse opportunities to diagnose, intervene, and control biological outcomes from the molecular to tissue levels. The work of BioSyM will have broad impact on many pathophysiological states since there is ample evidence that many mechanical/biochemical coupling mechanisms are ubiquitous in biology. Major goals are to develop novel imaging, manipulation, measurement and control platforms that are applicable from the molecular to the tissue levels; and to apply these platforms for fundamental studies relevant to tissue degenerative diseases, fibrosis and drug screening targets. The integrated research efforts will bridge key gaps between engineering and molecular/cell biology by bringing together technologists in micro- and nanofabrication; single-molecule and single-cell manipulation; 3D molecular, cell, and tissue imaging; and computational biology with engineers, biologists, and clinicians focused on developing new tissue-based disease models, diagnostics, and treatment modalities.

CORE RESEARCH PROJECTS INCLUDE:

Single Molecule Sensors and Sequence Identification -- The aim of this effort is to develop and validate mechanical and optical sensors of intermolecular binding events at the single molecule level. Successful development of our approach – quantitative sensing of kinetic interactions among intra- and extracellular proteins and proteolytic enzymes -- will be critical to the identification of drug targets that are implicated in cell/tissue disease or that significantly affect cell migration and tissue degeneration rates. The experimental and modeling capabilities explored herein will serve as the basis for a new class of mechano-diagnostic sensors. The aim is to engineer generalized sensor platforms to harness single molecule methods for detection and measurement of molecular and cellular interactions and measurements.

Micro/Nanofluidic and Optical Profiling of Cells and Molecules -- It is increasingly evident that the mechanics of biomolecule / cell interactions are critical in the normal operation of many biological systems. Recent scientific advances in cellular and molecular biomechanics revealed many different examples where biomechanical cues and interactions are indeed critically important to normal cell function and molecular / cellular recognition. In addition, such interactions and cellular / molecular mechanical properties could be utilized for diagnostic purposes. It is crucial to develop experimental tools allowing one to manipulate individual cells and molecules mechanically towards further development of this promising field. The aim is to develop platform technologies that provide mechanical, chemical, and immunological information about cells under study. Focus will be on cell-based biomechanical sorters / assay devices, and will be further expanded toward the molecular biomechanical problems.

Multi-Scale Image Informatics Investigation of Liver Fibrosis -- Many diseases have strong mechanical and structural components to their etiology, such as arteriosclerosis, cancer metastasis, and liver fibrosis. Liver fibrosis is particularly prevalent in a number of Asian countries. It arises from chronic insult to the liver with the accumulation of extracellular matrix (ECM) proteins, leading to cirrhosis, portal hypertension, liver failure and hepatocellular carcinoma. Although many molecular pathways are important for liver fibrosis progression, the complex interactions of individual pathways limit the development of effective pharmaceutical intervention. The system biology approach has emerged as an important approach to understand how complex pathway interactions regulate many different cellular biological processes. The specific aims are:

(*) Develop biological models (engineered tissues and animals) and perturbation techniques for systems biology investigation of liver fibrosis.
(*) Develop quantitative, high throughput technologies to characterize tissue molecular, biochemical, morphological and functional states.
(*) Develop data analysis, synthesis, mining, and modeling algorithms for tissue bioinformatics data
(*) Understand and model liver fibrosis progression processes with an emphasis on the effect of therapeutic agents on stellate cell activation and fibrogenesis.

Control of Cell population behaviour in tissue constructs using image analysis and stochastic modeling -- The potential now exists for controlling the growth of tissue constructs by tailored delivery of growth factors and cytokines in combination with controlled physical factors such as shear stress and matrix stiffness. The objective of this project is to advance our understanding of multiple cell interactions with a long term goal of actively controlling collective behavior of cell populations. We view the complex biological processes leading to capillary morphogenesis as a consequence of cell-level decisions that are based on global signals and environment conditions, limited near-neighbour communication, and stochastic decision making with various feedback loops. The aim is to develop both experimental and computational methods integrated into closed-loop control of cell population behavior. Stochastic cell decision models with state transition probabilities modulated by local and global signals will be developed. Micro-fluidic stations equipped with a suite of instrumentation, including state-of-the-art 3-D imaging systems and advanced control of comprehensive physical and biochemical factors, will be developed and used for verification of the stochastic model of cell population behavior. Based on the stochastic model, feedback control will be designed to drive the cell population towards a desired collective behavior.