One of the examples that I use to show how much we’ve learned about biology (and how much we didn’t know, even in the relatively recent past) is RNA. Who could have predicted that there would turn out to be so many different kinds of the stuff? We all grew up hearing about the basics in school – messenger RNA, transfer RNA, ribosomal RNA if your introductory course got fancy. But short hairpin RNA? Double-stranded RNA? Long noncoding RNA? Circular RNA? MicroRNA? I know that I’m leaving some out, but I’m also sure that there are others that belong on that list that we haven’t even stumbled across yet. Either we don’t know where to look, or how to look (because our existing techniques might not pick them up), or we don’t understand what we’re looking at even if we come across them. And I don’t mean to give the idea that the classes above are all figured out, either. We’re just starting to get the first ideas about what some of these things do in the cell, and how they relate to health and disease. Scientists of 2060 or so will look back on us with some pity, because of all the important things that we just didn’t know yet back in the 2020s.
We might well end up thinking the way that this paper suggests, as a “bag of RNA”. It’s a truism to remind students that “the cell is not just a bag of enzymes”, and it’s a truism because it’s true. But I think that most of us are probably rather protein-centric. I harp on the weirdness of the cellular interior quite a bit, but I think that I still tend to think of it as “mostly proteins”, or perhaps “proteins wrapped up in stuff”. But if you were to take a head count of all the molecules in a living cell (or to be able to take a head count, which is more what applies under the current level of technology), you might well find RNA species way up list, or perhaps even in the lead. I don’t think many people have a mental picture of the cell that corresponds to that. And that’s not even taking into account the incipient discovery of Möbius-knotted double-secret hoodad RNA, or whatever’s coming down the chute next.
Any talk of cellular interiors these days brings up thoughts of biomolecular condensates (which is what I tend to call them, or maybe just “condensates”, although there are many other terms used). These phase-separated droplets inside cells seem (at least at present) to have a lot of RNA species associated with them, for reasons that are only vaguely understood. Indeed, a good number of condensates seem to be mixtures of net-positively-charged proteins and net-negatively-charged RNA species, which would make those liquid droplets, in many ways, cellular kin to the ionic liquids that were so fashionable a few years ago in organic chemistry. More specifically, they’re “complex coacervates“, a term that has spent a good part of its life in the polymer and materials science fields but is now getting a larger turn in the spotlight.
If this condensate behavior really is as important as it’s believed to be, you then start to wonder what makes this so feasible. It’s not crazy to think that the properties of the cytosol (and of other cellular compartments) have been the subject of evolutionary pressure if rapid and specific condensate formation and dissolution have been advantageous. There are an awful lot of phosphorylated species running around in cells – oligonucleotides are of course lined with them, proteins are decorated with them in all sorts of crucial spots, and phosphlipids are crucial membrane building blocks. But there are large quantities of things like adenosine phosphates and inositol phophates (of various types), and while we appreciate the energy-currency role of ATP and the signaling roles of inositol triphosphate, there may well be “bulk property” roles for these and others. For example, there have been suggestions over the years that there seems to be more ATP in a given cell than its energy needs would call for, but it’s not easy to get firm numbers on that.
That takes you to Frank Westheimer’s famous “Why Nature Chose Phosphate” essay (which gets updates here and here). The energetics of phosphate (and polyphosphate) really do make it a clear choice for its many roles in biochemistry, but once that choice was made, evolution was free to make what it could of all those negatively charged groups that were so useful everywhere. You can imagine key cellular processes getting enhanced (or diminished!) by unplanned formation of condensate droplets with these phosphorylated species, with selection pressure then optimizing for such properties. That doesn’t rule out other types of condensates, naturally, nor their own evolutionary paths. But phosphates pretty much have to be a big part of the story, which (you’d think) means that RNA species have to be a big part as well. . .
