From the Physics of the Epithelial-Mesenchymal Transition to Cartilage Formation

• Applicant: Professor Dr. Christoph Weber
• Subject Area: Biophysics
• Term: from 2016 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 299244239

• Final Report Year: 2018

Final Report Abstract

After my arrival at Harvard University the original proposal idea of a mechano-chemical basis for the developing limb of the chicken embryo had been refined to the question whether the undulations in shape may occur prior to the complex chemical signalling cascade of morphogens. In other words, we wondered whether a so called wrinkling instability, as seen when stretching a rubber band or aged animal skin, may occur in a developing embryonic tissue. If such an instability occurs prior to chemical precursors for cartilage and bone forming the future digits, the mechanical instability may represent an example of a mechano-chemical principle in embryonic morphogenesis. Unlike a rubber band where wrinkling is induced by an external load, an instability inside the developing limb bud may occur due to internal stress inhomogeneities arising from differences in cell division rates between the inside of the embryonic tissues and the surrounding epidermal hull. To this end, we developed a theoretical model by which we were able to successfully reconstitute the qualitative occurrence of such a self-wrinkling instability. Moreover, we predicted how winkle size and and number vary with the geometrical properties of the limb bud. However, so far our theoretical predictions could not yet have been scrutinized with the experimental studies. Thus I started further projects going beyond the original question of the proposal. For example I started to investigate the underlying theoretical principle for the mentioned instability in more detail. We could show that in general, differences in active stress lead to a pattern forming instability. The corresponding theoretical study has been recently published in Physical Review Letters and may be relevant for tissues, active gels and mixture of dense active colloids. Moreover, together with PhD students from Harvard University, we refined the underlying theoretical description and applied it to mechanically induced branching systems and also instabilities in active gels. These project are still ongoing. In an other class of projects I got excited about controlling aberrant protein aggregation, in particular the emergence of amyloid fibres forming from miss-folded monomers. Amyloid fibres are stable filamentous structures in the brain believed to be involved in the causative effects of Alzheimer’s or Parkinson’s disease. In the first project we theoretically explored the possibility whether there is an optimal drug dose, an optimal time of drug administration, etc., to diminish the amount amyloid but taking into account that drugs are toxic as well. We could show that optimization of the corresponding drug treatment protocols may significantly increase the life time of an organism. We scrutinized some of our predictions in the model organism C. elegans. In the second project we wondered whether liquid compartments may allow to diminish the toxic action of the amyloid fibres on an organism by spatially organising the aggregates. Recently, a large number of research contributions could show that most cell types have compartments inside the cytoplasm which are reminiscent of liquid droplets. We could show that these liquid phase separated compartments in general have a great propensity to spatially enrich the aggregates even though monomers only weakly partition into the compartment relative to the compartment surrounding. Weak partitioning is expected as interactions inside cells are in general weak with interaction energies in the order of the thermal energy. We could show that there is an amplifying mechanism leading to an accumulation of the majority of all aggregates inside the liquid compartment. Such a spatial organization turned out to be already used inside living cells to protect genetic material for example, or as stress response hosting damaged proteins due to heat shock or other perturbations of the cellular conditions.

Publications

• (2018) Discontinuous switching of position of two coexisting phases. New J. Phys. (New Journal of Physics) 20 (7) 075009
  Krüger, Samuel; Weber, Christoph A.; Sommer, Jens-Uwe; Jülicher, Frank
  
• (2019) Optimal control strategies for inhibition of protein aggregation. Proceedings of the National Academy of Sciences of the United States of America 116 (29) 14593–14598
  Michaels, Thomas C. T.; Weber, Christoph A.; Mahadevan, L.
  
• Physics of Active Emulsions
  Christoph A. Weber, David Zwicker, Frank Jülicher and Chiu Fan Lee
  
• Droplet Ripening in Concentration Gradients, New J. Phys., 19, 5, 053021 (2017)
  Christoph A. Weber, Chiu Fan Lee, and Frank Jülicher
  
• Differential Activity drives Mechanical Instabilities in Active Mixtures, Phys. Rev. Lett., 120, 248003 (2018)
  Christoph A. Weber, Chris Rycroft and L. Mahadevan