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Dr. Michael Sheetz is currently Director of the Mechanobiology Institute at the National University of Singapore and his recent work has defined the molecular mechanisms of rigidity sensing and matrix control of cell growth. In 2012, he was the recipient of the Lasker and Wiley Prizes for Biomedical Sciences for work done on in vitro motility assays and the discovery of kinesin. He has had an appointment at Columbia University since 2000 and prior to that he was Chair of Cell Biology at Duke University Medical Center (1990-2000).
Mechanobiology: How Do Small Cells Create Large Living Creatures
All life is created by cellular units smaller than grains of sand. The challenge of Mechanobiology is to understand how forces and growth at the cellular level are created and controlled to shape the organs and ultimately the organism. What is emerging is the realization that cells use a standard set of tools to create tissues just like you and I use a standard set of tools to build a house. The major difference is that at the length scale of cells there are only very rapid diffusional processes that need to be averaged over time for cellular functions. Thus, similar to your hand phone that has chips with billions of And/Or gates to perform the critical functions, cells have billions of protein motors and enzymes that act on the sub-second time scale to produce the emergent property of a cellular function. We will discuss one cellular device, a sensor of matrix rigidity that is critical for cell differentiation in development and cancerous cell growth. It has a complexity that gives us a window into how other cellular functions can work to create the diverse biological systems that we see every day.
Engineering Regeneration and Cancer
An important aspect of higher organisms is the ability to heal wounds through regenerative processes. This poses a number of problems because cell proliferation is needed for regeneration; however, unwanted cell growth can cause death as in cancer. It is perhaps not surprising then that repeated damage and inflammation of a tissue correlates with increased risk of cancer in that tissue, e.g. smoking or asbestos exposure correlates with lung cancer. One way that cells appear to activate proliferation is to upregulate expression of microRNAs that cause the degradation of mRNAs encoding for specific proteins that normally suppress cell growth. This could enable the cell chromatin to remain differentiated during proliferation toenable the rapid reformation of the tissue. For example, miRNA-21 is highly expressed during brain, skin or liver regeneration, particularly in the proliferative phase.
Plus, it is expressed during amphibian limb regeneration. Not surprisingly, miRNA-21 is also highly expressed in most severe cancers where it correlates with the transformed cell state.
This raises questions of how are cell states controlled. Many recent studies indicate that sensing of the cell microenvironment is critical for controlling cell behavior. For example, the most efficient
way to produce pluripotent stem cells is by culturing differentiated cells in the right matrix environment. In the case of regeneration and cancer, the cells are less sensitive to the microenvironment. Transformed cancer cells lack mechanosensors that test the matrix rigidity and components of the rigidity sensor are major tumor suppressors. Thus, understanding the mechanobiology of cellular systems provides a different perspective on wound healing and cancer that can stimulate new approaches to improve healing and block cancerous growth.