If you put any cell under the microscopy, with some fluorescent proteins and RNAs, you will see it light up with mesmerizing constellations. Just like oil droplets in water, they find each other forming a sort of mini environment amid all the crowded cellular space.
A long standing problem in the field of cell biology is “how are cells able to organize and compartmentalize the numerous complex biochemical reactions in space and time”. In other words, how can cells enhance and favor certain reactions over others, with millions of molecules floating around. If you ask any high school student they will directly think of classical membrane bound organelles (the nucleus, golgi apparatus, or the endoplasmic reticulum (ER)) as separators, yet, these compartments are impermeable due to their lipid bilayer, and thus cannot orchestrate everything. Over the last decade or so, research has shown that the cell uses numerous non-membranous compartments to orchestrate the different reactions taking place.
These non-membranous organelles, or condensates, are formed through the process of phase separation; a relatively recent concept in cell biology, whereby certain proteins and/or RNA demix from their surroundings.The field of phase separation is relatively young, it started around 2008 when Cliff Brangwynne and Anthony Hyman described a p-granules in C. elegans as liquid droplets with liquid like properties, after they were thought to be solid like, and since then a door was opened for studying and discovering different condensates in almost every model and non-model system used, with many definitions, approaches, and boundaries being decided by the community on a regular basis. Condensates are described to be formed of nucleating factors without which they cannot form, followed by client molecules that could play a role in the different biophysical properties of these organelles that range from liquid, to gel, to solid-like ones and all what is in between. Biomolecular condensates could be either nuclear (like the infamous nucleolus, paraskeckles, cajal bodies), or cytoplasmic (namely stress granules, p-bodies, or germ granules), and are described to be hubs of gene regulation. Interestingly, the majority of these granules present an internal organization, whereby they are not formed of one big macromolecule , but rather of a heterogeneous distribution of different components.
Since the scientific community started poking into the different properties and functions of these condensates, two main approaches to study condensates have been followed. The first would be the theoretical school that explains the different aspects of condensates based on physical and chemical properties. This approach is mainly led by physicists and mathematicians, with a noteworthy mention of Rohit Pappu at WashU, however this perspective hasn’t quite yet integrated into the reasoning of classical biologists who often shy away from the mathematical aspect of biological phenomena. The other approach would be the classical wet lab approach led by biologists, and mainly relies on either building these condensates in the test tube to understand the impact of their different components, or observing condensates in vivo in physiological conditions and analyzing their behavior to different stimuli. Over the last few years, these two “schools” came hand in hand to unravel numerous condensates and their biophysical properties, noting how they behave under different conditions. Of note, an interesting approach worthy of putting forward is the work on generating artificial condensates, and integrating them into in vivo systems, providing even more manipulation potential with numerous molecule, biophysical, imaging, and computational tools available.
Nevertheless, a fundamental question, mainly raised by scientists outside the field, remains “so what” or, put precisely, “what is the biological relevance of these condensates”. Indeed, the next step that followed unraveling the biophysical behaviors of different condensates was understanding their role inside cells. This topic was brought forward in this year’s Phase Separation meeting “Cellular mechanisms driven by phase separation” in EMBL-Heidelberg, where fascinating science demonstrated the involvement of condensates in cellular processes including aging, neurodegenerative diseases, fertility, stress control, translation regulation, and so forth. This congress showed a great shift in focus of the phase separation community towards understanding the biological impact of condensates, and the actual mechanisms used to drive, or be driven by physiological and disease phenomena.
Certain skeptics still oppose the direction the field of phase separation is taking. They consider that condensates have no real biological function and are not worth the fuzz. Yet, it is only fair to let the scientific community be the judge of that, especially after the recent dives into the function of biomolecular condensates, and the emergence of several start-ups that work on turning these condensates into therapeutic solutions for previously unsolvable problems.
How does condensate structure affect their function ? Are there dispensable condensates ? Does structure drive the function or vice versa ? Are condensates worthy druggable targets ? and many more questions are still open for investigation to better understand much of what is going on inside our cells, but it seems that biomolecular condensates play a major indispensable role in that.
References
Banani, S., Lee, H., Hyman, A. et al. Biomolecular condensates: organizers of cellular biochemistry. Nat Rev Mol Cell Biol 18, 285–298 (2017).
Brangwynne, C. P. et al. Germline P Granules Are Liquid Droplets That Localize by Controlled Dissolution/Condensation Science 324, 1729–1732 (2009)
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