Phase Separation

Studying the social interactions of molecules inside the cell

The phenomenon of phase separation explains the social context in which molecules interact in our cells. Consider a village where the people in it perform different tasks in different locations. They might work in the bakery, the construction site, or the power plant. In a similar way, many proteins and nucleic acids in a cell are also located in distinct compartments, where they perform diverse functions. However, most work in cells has focused on the activity and function of individual molecules rather than their collective properties in compartments. Taking an analogy from our village, it would be similar to understanding the behaviour of individuals, without understanding the rules that govern society. Unexpectedly, recent advances show that the mechanisms by which compartments assemble may hold the key to explaining some of the biggest open questions in biology, paving the way for a revolution in our understanding of cellular physics.

The Hyman lab studies how phase separation impacts the formation of membraneless compartmentalisation of macromolecules inside living cells. Stemming from our work on C.elegans in 2009, observations over the last decade have shown that many non-membrane compartments have liquid-like properties (Banani et al. 2017). The liquid-like nature of condensates is ascertained using microscopy in cells by observing fusion events, round shape, rapid diffusion of components, and a predictable response to changes in thermodynamic parameters such as temperature. Phase separation phenomena can be used to describe the formation of P granules (Brangwynne et al. 2009), nucleoli (Brangwynne et al. 2011), stress granules and centrosomes (Brangwynne et al. 2009) and estimates suggest that at least 30% of proteins in the nucleus are in such compartments. To capture the role of soft matter physics in describing these compartments, we have termed them biomolecular condensates (Banani et al. 2017).

Germline P granules are liquid droplets that localize by controlled dissolution/condensation

Condensates Research in Dresden

Research on condensates in Dresden comes in a special flavour. It’s one of collaboration and interdisciplinarity. The Hyman lab collaborates with 8 labs in its vicinity including the Jülicher, Alberti, Grill, Weber, Honigmann, Brugués, Tang, and Toth-Petroczy Labs as well as partner groups on campus and abroad.This collaboration bases its foundation on a marriage of disciplines, namely biology and physics, across multiple scales.

References

Original research

  • Klosin A, Oltsch F, Harmon T, et al. Phase separation provides a mechanism to reduce noise in cells. Science. 2020;367(6476):464-468. doi:10.1126/science.aav6691
  • Patel A, Malinovska L, Saha S, et al. ATP as a biological hydrotrope. Science. 2017;356(6339):753-756. doi:10.1126/science.aaf6846
  • Patel A, Lee HO, Jawerth L, et al. A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation. Cell. 2015;162(5):1066-1077. doi:10.1016/j.cell.2015.07.047
  • Brangwynne CP, Mitchison TJ, Hyman AA. Active liquid-like behavior of nucleoli determines their size and shape in Xenopus laevis oocytes. Proc Natl Acad Sci U S A. 2011;108(11):4334-4339. doi:10.1073/pnas.1017150108
  • Brangwynne CP, Eckmann CR, Courson DS, et al. Germline P granules are liquid droplets that localize by controlled dissolution/condensation. Science. 2009;324(5935):1729-1732. doi:10.1126/science.1172046

Reviews and Perspectives

  • Banani SF, Lee HO, Hyman AA, Rosen MK. Biomolecular condensates: organizers of cellular biochemistry. Nat Rev Mol Cell Biol. 2017;18(5):285-298. doi:10.1038/nrm.2017.7
  • Hyman AA, Simons K. Cell biology. Beyond oil and water–phase transitions in cells. Science. 2012;337(6098):1047-1049. doi:10.1126/science.1223728
  • Hyman AA, Brangwynne CP. Beyond stereospecificity: liquids and mesoscale organization of cytoplasm. Dev Cell. 2011;21(1):14-16. doi:10.1016/j.devcel.2011.06.013

Methods

  • Alberti S, Saha S, Woodruff JB, Franzmann TM, Wang J, Hyman AA. A User’s Guide for Phase Separation Assays with Purified Proteins. J Mol Biol. 2018;430(23):4806-4820. doi:10.1016/j.jmb.2018.06.038