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Journal Club Theme of April 2009: Mechanobiology and Molecular Mechanomedicine

Ning Wang's picture

Professor YC Fung, the widely-recognized father of modern biomechanics, recently challenged the field by asking this fundamental question: “What axioms of the classical continuum mechanics have to be changed for biology?”

Our understanding of mechanobiology and biomechanics at the cellular and subcellular levels is rather primitive.  For example, we do not know if a living cell differentiates a stress from a strain, or stress and strain are equivalent.  In other words, we do not know whether living cells sense and respond to stress or strain.  Nor do we understand by what mechanism a living cell respond to the rigidity of its substrate.  It is clear that laws of physics are obeyed at the molecular levels (e.g., individual protein levels) as studies at molecular biophysics have shown (e.g., stretching a single talin protein, del Rio et al. Science, 2009; http://www.ncbi.nlm.nih.gov/pubmed/19179532).  In this paper it is shown that in vitro a force of a physiologically relevant magnitude can unfold a talin to expose its cryptic binding site for vinculin, consistent with a paper published in 07 by D Discher’s group on forced unfolding of the spectrin molecule.  However, it is not clear at all what classical continuum mechanics theories do not apply to biology at the cellular and subcellular levels and need to be changed.

Over the last decade, my colleagues and I focus on one aspect of this: stress propagation, distribution, and transduction in a living cell.  We have found that stress propagation and transduction occur at a distance in a living cell, representing a major departure from the axiom of neighborhood (local action) of the classical continuum mechanics. See a recent perspective by N. Wang et al., published in Nature Reviews.  In this paper it is explained how a localized stress at the cell surface can be channeled along cytoskeletal filaments and concentrated at distant sites in the cytoplasm and nucleus to induce mechanochemical conversion within the cytoplasm and possibly within the nucleus and alter gene activities.

One could also ask other fundamental questions about other axioms of continuum mechanics on their applicability to living cells and to the nucleus.  For example, we basically know nothing about the role of mechanics in biology of epigenome (information that is carried in the genome and in the nucleus but not encoded in the DNA).  While some view the living cell as a complex material, others view the living cell as a complex machine, but we should ask the question: how could these views/models help understand the unique “living” features of a cell?  No matter what, the underlying governing rules or principles that dictate a living cell’s mechanical behaviors and biological functions remain largely elusive.  For those who are interested in latest advances in mechanotransduction, please read a series of review papers at Nat Rev Mol Cell Biol in Jan 2009.  For those who are interested in the future of biomechanics, it is suggested to read a perspective by some leading experts (D. Discher et al, Ann Biomed Eng. 2009 Mar 4. http://www.ncbi.nlm.nih.gov/pubmed/19259817).

Clearly time is ripe for mechanicians to work together with biologists, chemists, physicists, clinicians, and engineers, in order to make significant contributions to the field of mechanobiology.  In the long term, for the field of mechanobiology and biomechanics to stand out as a striving field that benefits the general public, it should play a leading role in molecular mechanomedicine (application of mechanics/engineering based principles and technologies at molecular and cellular scales in vivo to the diagnosis, treatment, control, and cure of various human diseases).

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Jixiang Huang's picture

Dear Prof. Wang,

The first time when the term “mechanobiology” was said to me was in my graduate course of biomechanics. As far as I know, mechanobiology is a very new and challenging field because the researchers who work on this field have to learn widely the fundamental theories in mechanics, biology, chemistry, physics, medicine and so on. Undoubtly, this interdiscipline is potentially beneficial for the health of human being, and I am very interested in it. I have referred some articles, but I still have no clear understanding about the relationship between mechanobiology and other subjects, such as mechanics, mechanical engineering, and biology, as well as the real role of mechanobiology in biomechanics. Before being clear that what axioms of the classical continuum mechanics have to be changed, I am also very curious about what classic theories that are known to apply to biology at the cellular and subcellular levels, and looking forward to your help.

According to my experience, for example, for better understanding the mechanical properties of composites, on the one hand, I proposed a model to analyze the mechanism based on the theory of mesomechanics at the micro level; On the other hand, I attempted to simulate the local region by molecular dynamics simulation at the nano level. Then, the results from different way were compared with the macro properties of the composites, and the discrepancy was explored and discussed. After this process, sometimes I can have an understanding about what classic conclusions may hold true for the composites. But I do not know whether this idea could do some help for the understanding about what axioms of the classical continuum mechanics that no longer apply to biology. I hope for a more understanding in this interesting field. Could you simply describe the current main difficulty in the research on a living cell?

Thanks.

Best regards,

Jixiang Huang

Ning Wang's picture

Dear Jixiang,

Thank you for your interests in the topic and your questions. Please let me try to answer them to the best of my ability.

The word "mechanobiology" is so new that it is not in the dictionary yet. Therefore there is no "official" definition of the word. Different scientists use their own different definitions.

For example, the Editors-in-Chief G.A. Holzapfel and J.D. Humphrey of the journal " Biomechanics and Modeling in Mechanobiology" describe it this way: "Mechanics regulates biological processes at the molecular, cellular, tissue, organ, and organism levels. The goal of this journal is to promote basic and applied research that integrates the expanding knowledge-bases in the allied fields of biomechanics and mechanobiology".

Gary S. Beaupré of Stanford describes Mechanobiology as "the study of how mechanical stimuli regulate biological processes."

The course description of Mechanobiology and Biomaterials at UCSF states that "The goal here is to understand how physical and mechanical properties such as strain, stress and loading influence naturally occurring biological systems and how the introduction of synthetic material or replacement tissue interacts with the host environment."

When I first started to teach the graduate course of "Mechanobiology for Engineers" at UIUC in 2006, I gave "Mechanobiology" my own definition:

"a subset of biology (science of life or living organisms); a study of mechanical basis of biology, including mechanical force activation, regulation, control, and influence of biology at subcellular, cellular, tissue, organ, and organismic levels."

To some scientists, Mechanobiology is equivalent to Biomechanics; that is to say, they think that mechanics people may call it biomechanics but biologists may call it mechanobiology. Now, what is the definition of biomechanics?

According to Prof. YC Fung (1981), "Biomechanics is mechanics applied to biology. Biomechanics seeks to understand the mechanics of living systems."

I do think that we need to reach a consensus in the field to have a general definition of Mechanobiology. It is NOT just semantics. It has important implications in defining this field in regards to other fields, although this field will continue to evolve. It will be interesting to see what the dictionary definition will be in the future.

Now let us look at your study of the mechanical properties of composites. The question could be, to what degree and when can they be applied to living cells? What are the unique mechanical features of living cells that composite materials may possess and may not possess? Many biophysicists try to understand mechanical properties of living cells at nano, protein, polymer, and subcellular levels (see the work of David Weitz at Harvard, who studies colloids fluids and soft matter physics of those compact materials).

Remember that cells are living and they can respond to stimuli. They also regulate many key physiological variables within a narrow range with feedback loops, although we currently have little understanding what they are and how they are regulated. Living cells also generate their own mechanical forces via myosin motor proteins and other motor proteins for intracellular activities and interactions with their microenvironment. Of course the living cell metabolizes, grows, divides, and adapts to its environment. These features rarely exist in nonliving materials or machines, no matter how complex they may be. All these present tremendous challenges to scientists who work in the field of Mechanobiology. But this is also the fun of working in this area: so many mysteries wait for scientists to solve.

Alejandro Ortiz-Bernardin's picture

Dear Professor Wang,

Very interesting topic. I am starting to get into this topic and I would like to mention two papers that might be pertinent to see how unorthodox can be a mechanobiology application. In a recent study by Dafalias et al., the study of motility of intracellular bacteria like Listeria monocytogenes has been pursued. The main mechanism of cellular motility is the actin polymerization which forms an elastic gel which is growing in very small layers from the vicinity of the cellular membrane surface. In vitro simulations have been performed previously using a simplified spherical geometry (the real problem is in cylindrical coordinates). When one layer is formed, it pushes outward the previously generated layer and at the same time is pushed inward by the previously generated layer. The problem is of mass generation with large deformations hyperelastic material. They have attempted to solve the governing equations analytically and because of the mass generation nature they have faced some complications due to the unavailability of initial configuration. The links to the papers are:

Stress field in actin gel growing on spherical substrate

Stress field due to elastic mass growth on spherical and cylindrical substrates

 
Regards,

Alejandro.

Jixiang Huang's picture

Dear Prof. Wang,

Thank you for your reply. I think I could have a comprehensive understanding about the word "mechanobiology" through the various definitions from different perspectives. As you said, the field of mechanobiology is always mysterious and amazing, and this is just the reason it attracts me so much. I’ll try to combine all the subjects I have ever taken to crack some points of the wide and deep ocean of "mechanobiology". Your guidance is very helpful to me.

Best wishes,
 
Jixiang Huang

Ning Wang's picture

Dear Alejandro,

Thank you for sharing your thoughts and these two papers.  Certainly this is an area that needs lots of people to work on many fundamental issues.  

Best wishes.

Ning

Dear Prof. Wang,

Just now I finish my PhD thesis “Mechanical modeling of cell adhesion and
its mechanosensitivity”, and am eager to post comments in your review. Even
though I have spent 4 years in the topic of cell adhesion mechanics especially
focal adhesion modeling, I’m puzzled by the following two points.

 

1)     The cells are living and dynamics, as a very complex
system.

Focal adhesions are subcellular structures with mechnosensitivity (very
interesting). Focal adhesion modeling, covers integrin, linker proteins (more
than 100), actin stress fiber, cell membrane, microtubules and substrate. Is it
too difficult to model and to explore the underlying mechanism? With
developments in experimental technology, researchers can explore them
gradually. I know it is a hot topic in the scientific area, but I feel puzzled
to face the complex and complicated cells.  I haven't seen any "cells
and focal adhesiosn," for that we  have no experimental condition,
can our modeling work contribute to the human being, even a little?

 

2)     What is the role of physical and mechanical models?

In this review, you said that “we do not know if a living cell
differentiates a stress from a strain, or stress and strain are equivalent. 
Nor do we understand by what mechanism a living cell respond to the rigidity of
its substrate”, but as far as I know, there are many models for these problems.
For substrate rigidity, (a) Schwarz et al 2006 developed a simple two-spring model,
and thought that the stiffer substrate is favored if cells keep a constant
stress; (b) Qian et al 2008 developed an adhesion cluster model, and thought it
more stable above stiffer substrate than soft; (c) Two-layer model for focal
adhesion developed by Nicolas and Safran, also studied the substrate
deformation. I mean, even though these physical and mechanical models proposed
some underlying mechanisms, the true role of substrate rigidity in
mechanotransduction is not understood fully. Someone said that “all models are
wrong, but some useful”, how about perspective of biologists without mechanical
and physical background on the models?

 

Finally, I have a detailed question:

The stretching on the substrate has a central role in focal adhesion
dynamics, how about the magnetic microbeed? Because focal adhesion has
characteristic timescale as cell cytoskeleton, and stress can propagate a long
distance.

 

Thank you very much

 

Kong Dong

(My bachelor and doctoral degrees are engineering mechanics and solid
mechanics, respectively) 

 

 

Ning Wang's picture

Dear Kong,

  Thank you very much for your comments and questions.  I hope that my thoughts below would be a bit useful.

1. You are right that the key is that the cell is living, dynamic, and complex.  According to B. Geiger et al (Functional atlas of the integrin adhesome, Nat Cell Biol, 06), there are at least 156 molecules at focal adhesions (FAs) and the list could increase.  How does one model the physical and chemical interactions among all these components?  What drives them together at FAs?  It would be useful for theorists and modeling scientists to work together with experimentalists to test their theories and models in biology.  I have no doubts that modeling work can contribute to the understanding of biology.

2.  I am aware of the models that you have mentioned above.  However, all these models are yet to be tested rigorously in living cell experiments.  Let me quote the late Harvard professor Thomas A. McMahon: "Theories are always at mercy of experiments".  It might be especially true in biology.  Give you an example.  Recently Dr. Margaret Gardel of Univ. of Chicago showed convincing evidence that when a living cell reforms its focal adhesions after dissipation by myosin II inhibiting drugs, there exists a time when integrins are slipping along the extracellular matrix proteins, even though the cell generates significant tractions at the same time.  How would one explain this with all the existing models?  What is the underlying mechanism?

3.  Stretching a whole cell, either uniaxially or biaxially, has tremendous effects on FA dynamics.  Pulling on a small bead, either optically or magnetically, also has significant effects (see our papers, papers by MP Sheetz et al).  But one is global, the other is local perturbation.  How one is different from the other in FA dynamics is not clear at this time.  It might be an interesting project for someone to work on, since both might occur under physiological conditions in a human body.

Dear Prof. Wang,

I have recently completed my bachelors in engineering and am planning to pursue graduate studies in mechanobiology. I first came across the term 'mechanobiology' while researching for my undergraduate thesis on modeling of cell migration. From the begining I found the paradigm of applying mechanics and engineering principles to better our understanding of the biological systems quite intriguing.

In my limited exposure to mechanobiology, I have found that it is more of a theory driven rather than a application driven field. Or is it that because the field is still in its early stages, its application in diagnosing or treating diseases is still a few years in waiting. Kindly share your views on this.

Also,  can you please suggest an introductory textbook for mecahnobiology.

Thanks,

Mukund

 

Ning Wang's picture

Dear Mukund,

It is not even a theory yet.  It is just at the beginning of experimental stages.  When the field is more mature, various theories might emerge.  It is far from applications to medicine, although I should say that scientists in bone research and clinicians have applied these ideas to orthopedics for some time.  But application of mechanobiology to molecular medicine (molecular mechanomedicine) to other organ systems with micro or nano probes/devices is yet to emerge.  I have not come across a good introductory textbook for mechanobiology, although there are many textbooks on biomechanics. 

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