"How is Load-bearing Tissue Built? A Case for Mechanical 'Allostery' in Animal Structure Formation"
Jeffrey Ruberti, PhD
Chemical Engineering, Mechanical and Industrial Engineering
Director, Extracellular Matrix Engineering Research Laboratory (EMERL)
How is load-bearing tissue built? A case for mechanical “allostery” in animal structure formation Abstract Jeffrey W. Ruberti, Ph.D. Northeastern University Boston Shockingly, there exists no established model that can explain how a cluster of vertebrate cells which are expressing matrix proteins manage to produce, refine and grow load-bearing structures that are organized over much longer length scales than the cells themselves. The current best guess model, which was proposed in the mid-1980s by David Birk and Robert Trelstad (subsequently carried forward by Karl Kadler’s group) suggests that cells extrude formed collagen fibrils into the extracellular space via structures which are termed “fibripositors.” Thus, one imagines that the cells, working together, somehow weave the collagen into the matrix, thread by thread with the necessary exposed loose ends finding each other and fusing to form long-range, organized connective tissue. However, gathering evidence to support this model is severely hampered because it is nearly impossible to observe cells in the act of producing matrix while observing the collagen fibril deposition directly at the nanoscale (but we sure are trying to do that in the lab). In addition, the fibripositor model does not contemplate either matrix refinement or growth. Thus, we are not only in need of experimental evidence to support the fibripositor theory, we are short of a comprehensive testable hypothesis in general for how tissue is built. To address this dearth, we have chosen to make a simple (and risky) assumption: We reject the idea that the cells directly manipulate collagen monomers or fibrils to make tissue. Instead, we assume the cell has spent much of its time (~billion years) refining specific molecular systems (secretomes) that are designed to “settle” into their appropriate configuration simply by “reading” the energetic landscape. To generate load-bearing connective tissues, we suggest that the cells provide appropriate geometry by self-organizing and then produce an appropriate secretome that has been designed to assemble in opposition to the locally and globally applied mechanical forces which threaten to dissipate animal structure. In effect, we predict that mechanical strain is actually a long-range structure producing signal which works via mechanical allostery to modulate both collagen fibril assembly and retention. Because collagen is generally found resisting tension in load-bearing soft-connective tissue, we expect that the mechanical environment directly shifts the molecular energetics such that collagen’s inherent stability and assembly kinetics are enhanced in the direction of applied tensile forces. I will present the current state and limitations of our investigation of this risky assumption and entertain your thoughts, concerns and comments.
Ruberti is a Professor of Bioengineering at Northeastern University and Chair of the Bioengineering Graduate Ph.D. program. He earned a BSE in Biomedical Engineering in 1986 from Tulane University and somehow managed to find work in Industry even though no one knew what a Biomedical Engineer was. After enduring multiple entry level engineering positions at Sikorsky aircraft, the Southwest Foundation for Biomedical Research and Hamilton Standard Space and Sea Systems, he returned to Tulane in the form of a doctoral student. He received his Ph.D. in 1998 in Biomedical Engineering, again from Tulane University, and conducted postdoctoral research at the Massachusetts Institute of Technology through 2000, and at the Department of Biomedical Engineering, Northwestern University through 2001. He has served as an associate consultant at Cambridge Polymer Group between 2001 and 2004, as Lecturer at the Massachusetts Eye and Ear Infirmary at Harvard University and as an Adjunct Scientist at the Schepen’s Eye Research Institute at Harvard University. He has painfully and slowly helped produce a little over 45 scientific papers, reviews and book chapters, as well as over 90 national and international conference presentations. His research has also resulted in the issuance of 12 patents with four more pending. He has participated in the extraction of a total of $8.0 M in research grant funding from the National Science Foundation (NSF), the Department of Defense, and the National Institutes of Health (NIH). He has served as a reviewer for the NIH and the NSF, and as a reviewer for many scientific journals in the areas of ophthalmology, materials, biomechanical engineering, biophysics, and cell and tissue engineering. Ruberti is currently an associate editor for the Journal of Biomechanical Engineering and swims a lot in a futile attempt to slow down the inevitable disassembly of his matrix.