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Physical approach of biological problems

Group leaders : Pr Jean-François Joanny, Jacques Prost

 Read the scientific activity report. (pdf 31Ko, last update 26th, march 2010)

A rapid inspection of orders of magnitude involved in cell components show that they are very similar to those relevant to “Soft Matter Physics”. There are however two important differences: biological systems are clearly out of equilibrium and molecular specificity can be strongly relevant. These simple remarks convince us that on the one hand Soft Matter Physics can provide a quantitative description of cellular systems, and that on the other hand biological systems raise an interesting number of new and challenging physical questions. For these reasons we concentrate our efforts towards understanding physical features of cell morphology and dynamics. This project is meaningful only with strong interactions with biologists.

Cells contain a very large number of components, but if we focus on mechanical properties, only a few classes of component are relevant: the cytoskeletal networks, molecular motors, phospholipid membranes and the large class of adhesion molecules such as integrins or cadherins. Therefore we study each of these components, keeping in mind the importance of the non-equilibrium behavior. In some cases, this requires the introduction of new physical concepts such as “active” membranes, “active” gels or  “isothermal ratchet”, which is a model to describe molecular motors by the Brownian motion of a particle switching between two different states.

A good physical understanding requires quantitative comparison between theory and experiments by systematically varying controlled parameters: for that reason, we work in close collaboration with the experimental groups both in our laboratory and in the Curie Subcellular structure and cellular dynamics Unit (UMR 144). We contribute to the theoretical description of polymerization-based motion using biological models such as the bacteria Listeria and the keratocytes type of cells, but also biomimetic systems such as plastic beads and oil drops properly treated. We also describe  certain  aspects  of  cell behavior such as phospholipidic nanotube pulling by  molecular  motors,  cell motility, cell division and mechano-transduction. As an additional example, we show on Figure 1 the results of calculations on spontaneous oscillations  of assemblies of molecular motors

 

Fig. 1 Motor oscillations: Oscillations of assemblies of molecular motors obtained from stochastic simulations. The model is sketched in (a) which shows the potentials seen by the motors. The oscillations in the position of the filament interacting with the motors, the power spectrum and the histogram of the positions of the filament are then shown for two sets of parameters.Fig. 1 Motor oscillations: Oscillations of assemblies of molecular motors obtained from stochastic simulations. The model is sketched in (a) which shows the potentials seen by the motors. The oscillations in the position of the filament interacting with the motors, the power spectrum and the histogram of the positions of the filament are then shown for two sets of parameters.

 

We  have  now  reached  a  reasonable  physical  understanding   of   single components and are consequently extending our analysis  to  the  interaction between  components, that is to  the  multi-cellular  level  and  the  mechanical  properties  of tissues. We have for example  performed  numerical  simulations  of  tissues competing for space (see Figure 2 below).

Fig. 2 Tissue competition: Numerical simulation of the competition between two tissues.Fig. 2 Tissue competition: Numerical simulation of the competition between two tissues.

At last, we keep close contact with the evolution  of  statistical  physics. In particular  we  have  derived  a  general  relation  between  the  linear response of a system to any  external  perturbation  and  its  fluctuations. This relation is valid as soon as the system is  described  by  a  Markovian dynamics. It will  be  useful  for  discussing  fluctuations  of  biological systems.

 

Key publications

  • Year of publication : 2011

  • Treating the epithelium as an incompressible fluid adjacent to a viscoelastic stroma, we find a novel hydrodynamic instability that leads to the formation of protrusions of the epithelium into the stroma. This instability is a candidate for epithelial fingering observed in vivo. It occurs for sufficiently large viscosity, cell-division rate and thickness of the dividing region in the epithelium. Our work provides physical insight into a potential mechanism by which interfaces between epithelia and stromas undulate and potentially by which tissue dysplasia leads to cancerous invasion.

  • The magnitude of traction forces exerted by living animal cells on their environment is a monotonically increasing and approximately sigmoidal function of the stiffness of the external medium. We rationalize this observation using active matter theory, and propose that adaptation to substrate rigidity results from an interplay between passive elasticity and active contractility.

  • We study theoretically the shapes of a dividing epithelial monolayer of cells lying on top of an elastic stroma. The negative tension created by cell division provokes a buckling instability at a finite wave vector leading to the formation of periodic arrays of villi and crypts. The instability is similar to the buckling of a metallic plate under compression. We use the results to rationalize the various structures of the intestinal lining observed in vivo. Taking into account the coupling between cell division and local curvature, we obtain different patterns of villi and crypts, which could explain the different morphologies of the small intestine and the colon.

  • The detection of sound begins when energy derived from an acoustic stimulus deflects the hair bundles on top of hair cells. As hair bundles move, the viscous friction between stereocilia and the surrounding liquid poses a fundamental physical challenge to the ear's high sensitivity and sharp frequency selectivity. Part of the solution to this problem lies in the active process that uses energy for frequency-selective sound amplification. Here we demonstrate that a complementary part of the solution involves the fluid-structure interaction between the liquid within the hair bundle and the stereocilia. Using force measurement on a dynamically scaled model, finite-element analysis, analytical estimation of hydrodynamic forces, stochastic simulation and high-resolution interferometric measurement of hair bundles, we characterize the origin and magnitude of the forces between individual stereocilia during small hair-bundle deflections. We find that the close apposition of stereocilia effectively immobilizes the liquid between them, which reduces the drag and suppresses the relative squeezing but not the sliding mode of stereociliary motion. The obliquely oriented tip links couple the mechanotransduction channels to this least dissipative coherent mode, whereas the elastic horizontal top connectors that stabilize the structure further reduce the drag. As measured from the distortion products associated with channel gating at physiological stimulation amplitudes of tens of nanometres, the balance of viscous and elastic forces in a hair bundle permits a relative mode of motion between adjacent stereocilia that encompasses only a fraction of a nanometre. A combination of high-resolution experiments and detailed numerical modelling of fluid-structure interactions reveals the physical principles behind the basic structural features of hair bundles and shows quantitatively how these organelles are adapted to the needs of sensitive mechanotransduction.

  • Year of publication : 2009

  • We propose a mechanism for tumor growth emphasizing the role of homeostatic regulation and tissue stability. We show that competition between surface and bulk effects leads to the existence of a critical size that must be overcome by metastases to reach macroscopic sizes. This property can qualitatively explain the observed size distributions of metastases, while size-independent growth rates cannot account for clinical and experimental data. In addition, it potentially explains the observed preferential growth of metastases on tissue surfaces and membranes such as the pleural and peritoneal layers, suggests a mechanism underlying the seed and soil hypothesis introduced by Stephen Paget in 1889, and yields realistic values for metastatic inefficiency. We propose a number of key experiments to test these concepts. The homeostatic pressure as introduced in this work could constitute a quantitative, experimentally accessible measure for the metastatic potential of early malignant growths.