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Condensates: A New Organizing Principle in Cells?

I wrote a couple of years ago about the idea of “condensates” inside cells – liquid-like droplets of proteins and other biomolecules that associate together in high concentration. That’s an odd idea for most all of us, because we’re used to thinking about cell compartments being membrane-enclosed and cellular anatomy being a bit more. . .defined. Condensates, on the other hand, are just the opposite: there’s no bag around them, and they could be forming, merging, and undoing themselves more or less on their own. These sorts of things have been seen inside cells for many years, and have been given various names (nuclear speckles, Cajal bodies, U and P bodies, paraspeckles, etc.), without there being much of a unifying concept about them.

The field has really been taking off recently – here’s a review from last year – and it’s looking more and more like this could be a fundamental process in cell biology that (up until recently) we’ve totally missed. It could be very important indeed in transcription, for example. As mentioned in that earlier post, it seems that intrinsically disordered proteins are especially likely to form these condensates, and the transcription factor proteins are notorious for this property.

Update: here’s a good news overview on the field that’s recently appeared in Nature.

Thinking in these terms really does open up a lot of possibilities. It’s always been hard to come up with a realistic mental picture of what’s actually going on in the living cell, that near gel-like mass of thousands upon thousands of proteins floating in a soup of ions, small molecules, metabolites and what have you. It may be, in fact, that some of these other species are involved in the behavior of these phase-separated condensate droplets. There’s even a proposal that ATP is not only the key energetic currency of the living cell, but that it has another function as a “hydrotrope”, a molecule that’s actually regulating the solubility of hydrophobic proteins and their condensation behavior. That might explain why it’s present in even higher concentrations than you’d think that cells would need for purely energetic reasons.

Another interesting aspect is the time scale involved. We know a lot about irreversible protein aggregates, which develop in cells over a period of years (amyloid, huntingtin, and many others). Condensates, though, are reversible and could be forming, reforming, and scattering on a time scale of seconds to minutes, which puts them right into the range for a lot of cell biology. This sort of thing also has obvious implications for origin-of-life theories, if you can start to get differentiation of function without necessarily having membranes (although there’s still an obvious role for having a bag around the whole thing at the cell-membrane level). Has there been evolutionary pressure for this sort of behavior in protein sequences?

There are plenty of open questions. As a medicinal chemist, I find myself wondering what the solubility of drug molecules is like in these environments. I was about the say “versus the bulk phase”, but you really have to wonder if there is a bulk phase inside a cell. We blithely say “cytoplasm” to describe that interior, but that might be a case of reification – making a thing where there isn’t really a defined thing to be made. It’s looking more and more like the real situation is a lot more heterogeneous than we’ve been thinking, and that the physicists and polymer chemists might have as much to tell us about what’s going on as the cell biologists do. Definitely an area to keep an eye on.

22 comments on “Condensates: A New Organizing Principle in Cells?”

  1. Me says:

    We chemists do so love to steady-state everything! I suppose we’ve always had this idea in some form with the fluid mosaic model for membranes.

  2. Peter Kenny says:

    Sounds a bit like lipid rafts? Things could get very interesting if two (or more) molecules of a target protein are in sufficiently close contact for one to sense whether or not the other has a drug molecule bound to it.

  3. dearieme says:

    I always enjoy it when a scientific description that sounds a bit odd is replaced by something less odd, even if perhaps more complicated.

  4. pubpeerreader says:

    An interesting pubpeer thread that takes a critical look at the plausibility of ATP as a biological hydrotrope:

    1. Cell Biologist says:

      That pubpeer thread is an unfortunate example of cyber-bullying. The paper was very well received by the field, is already highly cited and will be one of the key topics in the Keystone Symposium on Biomolecular Condensates next year.

  5. Clinical in Austin says:

    I have always thought this was know. In the same way you have a single protein type that aggregate based on concentrations (where are your process development guys to chime in), you can have a chance effect of a bunch of proteins running in yo each other at once in a cell. Proteins don’t have the entropy properties of ions. So these guys happen to be in the same place at the same time and we have a mix of proteins so it possible these other compounds charges, shapes, etc help out and then you get an aggregate, which might be hard to undo depending on how they collect…like power cords in our junk drawer.

    What I want to throw out there is that perhaps diet impacts glucose metabolism, which impacts neural ATP levels, which impacts aggregation, which increases chances of someone developing dementia related diseases. Then someone can simply get us a list of genetic factors that increase the odds of these aggregates staying together.
    Now where do I pick up my Nobel? Or do I need to get some postdocs to earn it for me first?

  6. luysii says:

    Don’t you find it just a bit humbling that all our theory and models of protein and polyNucleotide physical chemistry never predicted their existence?

    1. Anon says:

      But polymer and colloid physical chemistry did, as far as I’m aware

  7. Lil'Joe says:

    Derek – do you think there may be an analogy to (drug-induced) phospholipidosis here – undesirable compound action, in terms of disruption of these “condensates”? I’m not familiar with this literature, but have any “condensate” investigators looked into screening a diverse panel of pharmaceutical-grade compounds (clinical, failed/discontinued, or never made it to the party) to see if there may be significant perturbations?

  8. Barry says:

    We’re still learning all that Hsp90 does, but we’ve long known that it’s one of the most abundant proteins in the eukarytic cytosol. Its role as a chaperone involves providing an environment very different from water (or even from the bulk salt solution of the cytoplasm) in which proteins can fold without burying all their hydrophobic residues in their interior.
    One client bound to its chaperone is less than a Cajal body. But the function of these proteins is often modulated by (if not dependent on) their association and aggregation.

  9. BL says:

    your phD adviser is not good. dont kid yourself otherwise. I too once thought, ” oh, well he is intense, he is good”. He proceeded to destroy my career in the most vial and self serving way possible. trust yourself. if it feels bad, it is bad. there are good advisers out there, but you have to think for yourself and trust your instinct. this is a hard time for PhD students because the gen Xers were raised to be immoral. but, bide your time, and good will come.

  10. Stewart Hough says:

    There appears to be some interesting science here, but, with all respect, any implications to the origin of life are merely speculation and offer nothing substantive for the intractable naturalistic conjecture for how life started.

  11. nano-protoplasm says:

    Gilbert Ling is still alive and might be happy to read about this.

  12. Daniel Rees says:

    I enjoyed this early introduction to such ideas, well written by a physical chemist who won’t lose you in mathematics. Hadn’t imagined that membranes and cytoplasm were any more complex than the standard models taught in undergraduate biology before reading it:

    Pollack, G.H. Cells, gels and the engines of life. (A new, unifying approach to cell function) 1st edn. (2003)

    Can anyone refer me to reviews of more recent work in the field? Who are some of the PIs that I should tune-in to?

    1. Elie Dolgin says:

      Derek beat me to the punch, but I just wrote a lay-friendly News Feature on this topic that ran in the March 15th issue of Nature, if anyone is interested to learn more:

      1. Derek Lowe says:

        I enjoyed that article very much! Just added a link to it in the body of the post – thanks.

        1. Mol Biologist says:

          At the beginning of last century Russian Biologist Timofeev-Resovsky propose that “the main biological problem can be formulated as follows: It is a problem of transferring hereditary information from generation to generation and realizing this information in every generation.” In essence, this formulation covers all the basic problems of biology. ”
          I believe that Guenther Witzany is German philosopher is following his ideas and in the late 1980s he proposed the concept of Life as a communicative structure: cells, tissues, organs and organisms organize and coordinate themselves through communication processes, i.e. sign-mediated interactions.
          I will not agree with you and prefer other view on biology of P-body or P-granules. First, I would debate that proteins play leading role, it is RNAs because it is information. This is an article from very talented group in NYC will give you best clue  All about the RNA after all.
          Proteins may play another role and be conductors of a protein gradient or be mechanical arm to coalesce into liquid droplets. But RNA is not only source of information but also may be sensor of demands. P-bodies always formed as reaction on stress (viruses, heat shock, genome mobile elements or transposons or heavy metals exposition).
          I propose new function for this organelle. IMO formation of such a structure (you can call it as you like it) is a metabolic switch during growing demand. It represents mycelium mechanism for internal growth which is also only having asymmetrical growth. Mycelium (from the Greek mykes – fungus), mycelium, is a vegetative body of the fungus (thallus). It is usually develops inside the substrate, less often on its surface and serves as a resource to absorb nutrients by osmosis

      2. Mol Biologist says:

        Dear Elie, I enjoyed your article as well but it very descriptive and do not have main biological outcome. Here is a good path to start learning.

  13. Richard Bernstein says:

    There is a guy at Penn biochemistry doing really interesting work on this stuff.

    He’s found a protein that efficiently de-gels clumps of intrinsically disordered proteins in an ATP dependent manner.

  14. The requirement for the cell based treatments and researches are essential and that is the reason using the pharma market research firms are to come up with the best reports.

  15. Attentive reader says:

    While there are certainly some cases in live cells where protein liquid droplets and phase separation are important, the recent trend to invoke them at every imaginable occasion (that has more simple, old explanations) seems similar to phlogiston or stone soup to me. In many cases I feel it’s just people subconsciously trying to make themselves a name in our over-competitive time by inventing and over-hyping something novel.

    1. Mol Biologist says:

      Everything new is a well-forgotten old. However, if a polymer mcelles can deliver DNA or proteins to tissues, why can not it be a delivery method in a cell?

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