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.