Kato M, Han TW, Xie S, Shi K, Du X, Wu LC, Mirzaei H, Goldsmith EJ, Longgood J, Pei J, Grishin NV, Frantz DE, Schneider JW, Chen S, Li L, Sawaya MR, Eisenberg D, Tycko R, & McKnight SL (2012). Cell-free Formation of RNA Granules: Low Complexity Sequence Domains Form Dynamic Fibers within Hydrogels. Cell, 149 (4), 753-67 PMID: 22579281
Strap in, friends, because I’m about to tell you about the weirdest pape I have ever read [editor’s note: it’s also fucking SICK]. To help prepare for the emotional landscape that you will traverse as you read it, I suggest starting with the following sentence, which comes at the end of the acknowledgements section: “This work was funded by an unrestricted endowment provided S.L.M [the senior author] by an anonymous donor.”
Out of curiosity, reader, what would you do if a masked stranger gave you infinity money? While most of us are still trying to figure out how much a lifetime supply of Swisher Sweets and a Hovercraft would cost, these dudes took their pile of money to the lab, got extremely freaky deaky and exploratory, and then jotted down their Rashomon-style fever-dreams in two back-to-back Cell papes that will literally soak in through your finger-skin and make you hallucinate if you don’t wear Personal Protective Gear while reading them.
Now ok listen: let’s be clear. Obviously, nasty science can be done with no money at all, or with piles of money. But I just want to point out that having shit-tons of money allows for a certain delightful, jaunty type of inquiry which really puts a spring in your step because you can make a bizarre observation, and then actually follow that weirdo observation down the expensive rabbit hole wherever it leads, regardless of what “scientific field” that happens to be, and ultimately end up making a gnarly contribution to a totally other field than you intended to study. And then the really cool thing is that when you write it up, you can actually describe that tripped-out discovery process in prose instead of pretending you knew what you were doing the whole time, because you never have to impress anyone in your quest for more grants ever again.
What this pape ultimately winds up being about is these mysterious regions in many proteins known, dismissively, as “low complexity” regions. You know how idiots talk about “junk DNA”? Like, how our genomes not only contain genes with known function (i.e. genes code for proteins), but also contain huge stretches with unknown function? Well, the same thing is true within individual proteins. There are parts of proteins called “domains” which adopt specific 3-D shapes and perform known functions - binding DNA, letting ions pass through membranes, detecting light - but there are also these “low complexity” regions in many proteins which have long stretches of totally unknown function that isn’t evolutionarily conserved and is unlikely to adopt specific 3-D conformations. What’s worse, the very fact that they don’t adopt specific 3-D conformations makes them really hard to study because you can’t make crystals out of them for structural analysis and they tend to behave badly in solution for biochemical studies.
What these guys and dolls figured out through their comical misadventures is that regions of low complexity are uniquely suited to forming dense aggregations of proteins and RNA which have been observed in many types of cells, from germ cells to neurons to mamallian cell culture lines, but which have remained mysterious and hard to study (in fruit flies, these aggregations are literally called “nuage” which means “cloud” in French because they look like clouds within the cell and thats basically all we currently know about them). So, if you’ve ever wanted to study nuage in a test-tube (which actually lots of people do), you’re welcome!
But MAN, the way that they ultimately figured this shit out is so hilarious and weird. They were trying to find a drug that would turn mouse embryonic stem cells into heart muscle, but one of their top candidate chemicals caused a “flocculent, white precipitate” to form instantly upon addition to ground-up mouse cells. So, instead of giving up, they figured out every protein in that white goop that forms, repeated this for human cells and fruit fly cells, and realized that all the proteins precipitating were those proteins that are found in these RNA aggregates. Further, all those proteins are enriched for low-complexity regions. Then they start getting REALLY free and making jello-shots out of individual proteins (shown above) to study the biophysics of how these protein aggregations form and function. Spoiler alert: the proteins form heterotypic polymers that, unlike the amyloid plaques found in the brains of Alzheimer’s patients, can reversibly aggregate and de-aggregate.
Ok I’m getting pretty drunk so I’ll stop now but holy shit man - this is the type of pape that makes you want to carry a Dennis-the-Menace sling shot around in your backpocket and just do whatever you want all day.
(Big thanks to Dr. Tripti Gupta and friends help discussing this paper through the tears of joy in our eyes)