Nucleolus: All life is salad dressing

by Liam Scott, Contributing Writer

Many would claim that salad dressing is what makes a salad worth eating. Diehard fanatics might go so far as to say that salad dressing is what makes life worth living. Still others are opposed to ingesting anything of the colour green, even if you put something yellow on top of it first. Regardless of the camp with which you are aligned, you owe your very existence to the physics instigating the enmity of oil and vinegar: liquid-liquid phase separation. The nucleolus, a component of the cell which has mystified scientists for centuries, has recently been characterized – it is, in fact, a condensate just like oil in vinegar.

Phase separation is a phenomenon which I imagine Italian readers observe daily: the behaviour of oil in water. Simply put, oily liquids will keep to themselves in a container of watery liquid. Bear in mind that you yourself are composed of tiny bags of water known as cells. Those who adhere to an oil-free diet may be disappointed (I digress, not many would choose to read an article ostensibly written on the subject of salad dressing), but each of these cells includes an oil droplet that is absolutely necessary for human life. It is called the nucleolus. It is no coincidence that the word nucleolus resembles nucleus, the so-called “brain of the cell,” as it is often described in high school biology classes – the nucleolus is a distinct structure within the nucleus (you might like to think of it as the brain of the brain of the cell). The nucleus is separated from the rest of the cell by a membrane, but it is still a watery mess, which is essentially the norm for all life. The nucleolus, on the other hand, although easily distinguishable (it was noticed by pioneering microscopists as early as two hundred years ago), does not have a membrane of its own. How is this possible?

The nucleolus’ stable existence is analogous to that of the stubborn droplet of oil in vinegar – it is made possible by liquid-liquid phase separation. A confusing question naturally follows: what makes the nucleolus “oily?” The answer has only recently been worked out – the proteins composing the meat of the nucleolus are intrinsically disordered. By intrinsically disordered, I mean that the proteins making up the nucleolus are unusually, well, disordered. The archetypal protein is folded into a precise 3D structure according to its function, whereas the components of the nucleolus are left forever wiggly. They are essentially submicroscopic noodles that prefer each other’s company over water, and when you put enough of them together, they’ll aggregate into a sphere.

How does one make a wiggly protein, anyway? How do you make any protein, for that matter? That question brings us to the actual function of the nucleolus, which is to produce ribosomes, the “factories of the cell” responsible for manufacturing all proteins. The synthesis of ribosomes involves thousands of reactions, because they are exceptionally large and complicated particles, and it begins in the oiliest, innermost layer of the nucleolus. The beauty of this system is that, as the ribosome-to-be is processed, its solubility in oil decreases and it migrates outward to a less-oily layer of the nucleolus, where the next steps in processing occur. This allows for a proper sequencing of the ribosome synthesis reactions – first you have to build the factory, and then staff it, and then obtain its certification (it must be done in that order!).

There are serious medical implications for the discovery of the physical nature of the nucleolus. Many cancers exhibit overly large and fluid nucleoli, and some neurodegenerative diseases are associated with nucleolar hardening or structural defects. Nucleolar size is already a prognostic tool for breast cancer patients, and our new understanding of the organelle’s structure could lead to game-changing pharmaceutical innovations in the near future.

References:

Lafontaine, D.L.J., Riback, J.A., Bascetin, R. et al. The nucleolus as a multiphase liquid condensate. Nat Rev Mol Cell Biol 22, 165–182 (2021). https://doi.org/10.1038/s41580-020-0272-6

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