View Full Version : Mechanobiology and diseases of mechanotransduction

03-16-2010, 02:09 PM
This article may blow peoples minds on the typical medical model or as the Oracle states in the Matrix "What's really going to bake your noodle..."

Annals of Medicine 2003;35(8):564-77. 2003:

Donald E. Ingber, M.D., Ph.D

Mechanobiology and diseases of mechanotransduction.


1) “Mechanical forces are critical regulators of cellular biochemistry and gene expression as well as tissue development.”

2) Many “unrelated diseases share the common feature that their etiology or clinical presentation results from abnormal mechano-transduction.”

3) There is an “undeniable physical basis of disease.”

4) Abnormal cell and tissue responses to mechanical stress contribute to the etiology and clinical presentation of many important diseases.

5) There is a “strong mechanical basis for many generalized medical disabilities, such as lower back pain and irritable bowel syndrome, which are responsible for a major share of healthcare costs worldwide.”

6) Physical interventions can influence cell and tissue function.

7) “Altered cell or tissue mechanics may contribute to-disease development.”

8 ) “Mechanical forces are critical regulators in biology.”

9) Because of the recent advances in the molecular basis of disease, there has been a loss of interest in mechanics.

10) “Mechanical forces serve as important regulators at the cell and molecular levels, and they are equally potent as chemical cues.”

11) Tissues are composed of groups of living cells held together by an ExtraCellular Matrix (ECM).

12) The surface membrane of cells is mechanically attached to all of the cells organelles, to its nucleus and its chromosomes, and to its synaptic vesicles, by a “filamentous cytoskeleton.” [“Filamentous Cytoskeleton”]

13) Because our bodies are hierarchical structures, mechanical deformation of any tissues results in structural rearrangements in many tissues.

14) Mechanical loads anywhere in the body can affect many tissues and cells because they are physically interconnected.

15) “Forces that are applied to the entire organism (e.g., due to gravity or movement) or to individual tissues would be distributed to individual cells via their adhesions to the ECM support scaffolds that link cells and tissues throughout the body.” (WOW!)

16) If the ECM is less flexible, then stresses will be transmitted to and through the cell. (WOW!)

17) Living cells contain a cytosketeton that generate and transfer tensional forces, known as “tensegrity.” (Tensegrenous Matrix)

18) Changes in the cytoskeletal force balance alter tissue homeostasis.

19) “The physicality of the ECM substrate and degree of cell distortion govern cell behavior regardless of the presence of hormones, cytokines or other soluble regulatory factors.” (WOW!)

20) “Cell-generated tensional forces appear to play a central role in the development of virtually all living tissues and organs, even in neural tissues.”

21) “Mechanical forces directly regulate the shape and function of essentially all cell types.”

22) Many of the enzymes and substrates that mediate cellular metabolism (e.g., protein synthesis, glycolysis, RNA processing, DNA replication) are physically immobilized on the cytoskeleton and nuclear nucleoskeleton matrix. Consequently, mechanical stresses through the cytoskeletal and nucleoskeletal matrix can alter physiology by physically altering biophysical properties, which in turn alter chemical reaction rates.

23) Mechanical stress stimulates rapid calcium influx in the neuromuscular synapse, again altering function.

24) “All cells also contain ‘stress-sensitive’ (mechanically-gated) ion channels that either increase or decrease ion influx when their membranes are mechanically stressed.”

25) “The global shape of the cell dictates its behavior (e.g., growth versus differentiation or apoptosis), and these effects are mediated through tension- dependent changes in cytoskeletal structure and mechanics.”

26) “These new insights into mechanobiology suggest that many ostensibly unrelated diseases may share a common dependence on abnormal mechanotransduction.” (WOW!)

27) Local mechanical changes in tissue structure may explain why genetic diseases, including cancer, often present focally.

28) Manual type therapies, physical therapy, massage, muscle stimulation, Etc… have known the therapeutic value because they alter mechanotransduction. (WOW!)

29) Most of the clinical problems that bring a patient to the doctor’s office result from changes in tissue structure and mechanics.

30) Abnormal cell and tissue responses to mechanical stress may actively contribute to the development of many diseases and ailments. Consequently it may be wise to look for a physical cause for disease.

31) Mechanics must be reintegrated into our understanding of the molecular basis of disease.

Donald E. Ingber, M.D., Ph.D-The current focus of medicine on molecular genetics ignores the physical basis of disease even though many of the problems that lead to pain and morbidity, and bring patients to the doctor’s office, result from changes in tissue structure or mechanics.

The main goal of this article is therefore to help integrate mechanics into our understanding of the molecular basis of disease.

This article first reviews the key roles that physical forces, extracellular matrix and cell structure play in the control of normal development, as well as in the maintenance of tissue form and function.

Recent insights into cellular mechanotransduction–the molecular mechanism by which cells sense and respond to mechanical stress–also are described.

Re-evaluation of human pathophysiology in this context reveals that a wide range of diseases included within virtually all fields of medicine and surgery share a common feature: their etiology or clinical presentation results from abnormal mechanotransduction.

This process may be altered by changes in cell mechanics, variations in extracellular matrix structure, or by deregulation of the molecular mechanisms by which cells sense mechanical signals and convert them into a chemical or electrical response.

Molecules that mediate mechanotransduction, including extracellular matrix molecules, transmembrane integrin receptors, cytoskeletal structures and associated signal transduction components, may therefore represent targets for therapeutic intervention in a variety of diseases.

Insights into the mechanical basis of tissue regulation also may lead to development of improved medical devices, engineered tissues, and biologically-inspired materials for tissue repair and reconstruction.

Donald E. Ingber, M.D., Ph.D., has made major contributions to cell and tissue engineering, as well as angiogenesis and cancer research, systems biology, and nanobiotechnology. His research group is interested in how living cells and tissues structure themselves so as to exhibit their incredible organic properties, including their ability to change shape, move, and grow. His team strives to identify design principles that govern the formation and control of living systems, and to use this knowledge to develop novel therapeutics, devices, and robotic systems. By combining approaches from molecular cell biology, chemistry, physics, engineering, computer science, magnetics, and optics, Ingber has helped to develop multiple new experimental nano- and micro-technologies, as well as engineered tissues and cancer therapeutics that have entered human clinical trials. His pioneering work demonstrating that tensegrity architecture is a fundamental principle that governs how living cells and tissues are structured at the nanometer scale has inspired a new generation of cancer researchers, bioengineers, and nanotechnologists. It also has resulted in the discovery of the molecular mechanism by which living cells sense and respond to mechanical forces. His contributions include more than 290 publications and 35 patents in areas ranging from anti-cancer therapeutics, tissue engineering, medical devices, and nanotechnology to bioinformatics software.

Ingber received his B.A., M.A., , M.D., and Ph.D. degrees from Yale University before completing his postdoctoral training with Judah Folkman at Harvard University. He holds the Judah Folkman Professorship of Vascular Biology at Harvard Medical School and Children’s Hospital Boston, and he is a Professor of Bioengineering at the Harvard School of Engineering and Applied Sciences. Ingber served as Co-Director of Harvard’s Center for Integration in Medicine and Innovative Technology at Children’s Hospital from 2005-2007.

He helped to found two biotechnology start-ups, and has consulted for multiple pharmaceutical, biotechnology, venture capital and private investment companies, as well as the Department of Defense, Office of National Intelligence and National Public Radio. Among his many awards and distinctions, Ingber received the Biomedical Engineering Society’s top award for 2009, the Pritzker Distinguished Lectureship, was named one of the world’s “Best and Brightest” in 2003 by Esquire magazine, and is a recipient of a Breast Cancer Innovator Award from the Department of Defense.

Ingber is the Founding Director of the Wyss Institute for Biologically Inspired Engineering at Harvard University, which was launched in January 2009 with a $125 million dollar gift — the largest single philanthropic gift in the history of Harvard University.