Phase Separation

On the left, watch Louise explain Phase Transitions in her Two Minute Talk! On the right, watch Tony’s 2011 iBiology lecture on phase separation in P granules.

In addition to utilizing vesicles bound with a membrane, cells can segregate their internal material into drops or compartments that do not possess a membrane or other physical barrier. Such non-membrane bound compartments can contain a large number of proteins as well as RNA, and they play a crucial role in many processes during development, as well as other processes in vivo. We are interested in understanding the physical mechanisms that control the formation of these compartments and how cells regulate this process. In some instances, the process of segregation appears similar to the de-mixing of two liquids, analogous to oil de-mixing from water. In other instances, the segregation results in more solid-like aggregates or fibers.

One particular segregation of cell material into liquid-like droplets is observed during development of C. elegans, where non-membrane bound compartments called “ P granules” are important for germ cell specification. These P granules condense out of the cytosol when the solubility of P granule components decrease owing to the absence of MEX-5 (Brangwynne et al, Science 2009). Once condensed, the drops are spherical, undergo coalescence, and show many other characteristics of a liquid. Similar compartments, called “stress granules”, form in response to stress in yeast and HeLa cells.

Click above to watch a short movie clip of protein droplets landing on and coalescing with a surface

Click above to watch a short movie clip of protein droplets landing on and coalescing with a surface

We study the process of protein segregation into non-membrane bound compartments through a variety of methods that bridge many research interests in the lab. Using TransgeneOmics BAC cell lines, we can identify proteins that form non-membrane bound compartments in HeLa cells and test which stress-conditions induce their condensation. We also observe this process during development in C. elegans, and use measures of P granule growth rate, size distribution, and mechanical properties to test possible physical models that could underlie this behavior (Lee et al, Phys Rev Lett 2013, and Brangwynne et al, Science 2009). Lastly, we purify proteins known to form non-membrane bound compartments to assess how these proteins behave under different conditions in vitro and test how they interact with other proteins and RNA.

Reviews and Perspectives:

• Hyman AA, Weber CA, Jülicher F. Liquid-liquid phase separation in biology. Annu Rev Cell Dev Biol. 2014 Oct 11;30:39-58. [PDF]
• Hyman AA, Simons K.  Cell Biology. Beyond oil and water–phase transitions in cells. Science. 2012 Aug 31;337(6098):1047-1049. [PubMed]
• Alberti S, Hyman AA. Are aberrant phase transitions a driver of cellular aging? Bioessays. 2016 Oct;38(10):959-68. [FullText]



ATP as a biological hydrotropeAmyloid-like self-assembly of a cellular compartmentA Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation


Members of the lab working on Phase Separation are:
Edgar Boczek, Titus Franzmann, Anatol Fritsch, Louise Jawerth, Ceciel Jegers, Amayra Hernandez Vega, Adam Klosin, Kate Lee, Avinash Patel, Martine Ruer, Shamba Saha, Stephanie Spannl, Jie Wang, and Xiaojie Zhang


Other Associated Publications

  • Hernández-Vega A, Braun M, Scharrel L, Jahnel M, Wegmann S, Hyman BT, Alberti S, Diez S, Hyman AA. Local nucleation of microtubule bundles through tubulin concentration into a condensed tau phase. Cell Reports. 2017 Sep 5; 20(10):2304-2312. [FullText]
  • Patel A, Malinovska L, Saha S, Wang J, Alberti S, Krishnan Y, Hyman AA. ATP as a biological hydrotrope. Science. 2017 May 18;356(6339):753-756. [PDF] [Video Abstract]
  • Mateju D, Franzmann TM, Patel A, Kopach A, Boczeck EE, Maharana S, Lee HO, Carra S, Hyman AA, Alberti S. An aberrant phase transition of stress granules triggered by misfolded protein and prevented by chaperone function. The EMBO Journal. (2017) e201695957. [FullText]
  • Boke E, Ruer M, Wühr M, Coughlin M, Lemaitre R, Gygi SP, Alberti S, Drechsel D, Hyman AA, Mitchison T. Amyloid-like self-assembly of a cellular compartment. 2016, Cell 166, 637-650. [PDF] [Video Abstract]
  • Patel A, Lee HO, Jawerth L, Maharana S, Jahnel M, Hein MY, Stoynov S, Mahamid J, Saha S, Franzmann TM, Pozniakovski A, Poser I, Maghelli N, Royer LA, Weigert M, Myers EW, Grill S, Drechsel D, Hyman AA, Alberti S. A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation. Cell. 27 August 2015. [FullText] [Video Abstract]
  • Lee CF, Brangwynne CP, Gharakhani J, Hyman AA, Jülicher F. Spatial organization of the cell cytoplasm by position-dependent phase separation. Phys Rev Lett. 2013 Aug 23; 111(8):088101. [PubMed][PDF]
  • Hyman AA, Brangwynne, CP.  Beyond Stereospecificity: Liquids and Mesoscale Organization of Cytoplasm. Dev Cell. 2011 Jul 19;21(1):14-6. [PDF]
  • 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 Mar 15;108(11):4334-9. (Epub 2011 Feb 28) [PubMed]
  • Brangwynne CP, Eckmann CR, Courson DS, Rybarska A, Hoege C, Gharakhani J, Jülicher F, Hyman AA.  Germline P granules are liquid droplets that localize by controlled dissolution/condensation. Science. 2009 Jun 26;324(5935):1729-32.  [PubMed]