Comment by dnautics | Hacker News Reader

Comment by dnautics | Hacker News Reader

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OK, so I worked seven years in this field. Prions (and amyloid diseases in general, like alzheimer's, diabetes, and a ton of diseases you probably haven't heard of [0]) happen when a "normally folded protein" denatures into a flat ribbon [1]. These ribbons become a sheet when you get many of them side-by-side, and this it turns out is an extremely stable configuration. Also, it's autocatalytic (exponential growth), because these sheets will fragment and recruit well-folded proteins (that are of the same molecule) to become ribbons at their ends, extending and growing the sheet.

So, yes, it is protein denaturation. But it's a very specific denaturation endpoint that not all proteins are capable of, and it's such a favored endpoint that even heating won't quantitatively destroy it (and heating could make it worse by fragmenting it into a bunch of smaller sheets).

[0] Incidentally, this denaturation is probably also used by cells in a productive fashion, it's pretty likely IMO that your melanin cells use these sheets to template melanin formation and sequester away the melanin molecule (the melanin precursor is highly toxic). I would link to the paper, but I think all of the data have been essentially cherry picked from shittily-done experiments, even though I think their conclusion is correct -- I have personally repeated the experiments "correctly" and reached the same endpoints in one shot without cherry picking (unpublished for my experiment, also n == 1) -- so I don't want to draw more unhealthy attention to the paper until someone else does the experiment "correctly".

[1] how does this happen? It can happen either due to a mutation that destabilizes the parent, well-folded protein, or, just by bad luck / time. Mutation examples: Fatal Familial Insomnia, non-variant CJD. Bad luck/Time example, insulin in a bottle in a fridge will turn into white flecks (these are sheets). The time at which this happens is highly variable (luck). You can accelerate this by agitating the bottle, and creating an air-water surface that catalyzes the denaturation of insulin. Also note, that insulin is not the protein in sheets in diabetes :biology trollface: (the insulin situation is strictly in vitro, and pH-dependent, as far as we can tell)

I half expect a very scary Black Mirror episode where a militant vegan faction devises a way to spread prions throughout the meat supply chain on a timed release so it hits everywhere at once. Only for the blowback to somehow far exceed their worst dystopian nightmares.

Is there a way to somehow pack chemical or electrical energy into these highly favorable stable endpoint configurations, and release it?

It wouldn't be a black mirror episode unless these militants were able to record the memory of each of the animals before they were slaughtered, record that into the prions to have people experience the entire lifetime of an animal raised for slaughter with every bite... before succumbing to vCJD, of course.

The producers need to add you to the writing staff, brilliant twist. Prions are scary grey goo-reminding nastiness. I've sometimes wondered if they aren't the answer to the Fermi Paradox.

Sounds a bit like the plot of the movie _12 Monkeys_ (a very good movie).

Probably a very ignorant question, but don't protease enzymes break proteins down to the amino acids? Suppose my lab bench is infected with prions or flat protein sheets or something. If I spray it over with a bunch of protease, would I be able to "disinfect" it?

Great question. I'm going to answer in three stages.

1. Theoretically speaking, yes. And there's probably a biological protease that does it in the the body. Last I checked, it's still unidentified; my money is on Insulin-Degrading Enzyme.

2. It's more complicated than that. If you just buy an off the shelf protease, it probably won't work, because those are used to cutting up floppy bits of peptide sticking out of a protein, so to get there you would need to pull the sheet apart ribbon by ribbon first to be effective.

3. Given enough time, though, the ribbons ARE in equilibrium between being on/off of the ends of the sheet, so a protease could randomly catch the ribbon at the right time. But the equilibrium is so low, that your protease would probably self-digest faster than it takes apart the flat protein sheet.

Thanks for the excellent explanation! I feel like I understand, despite my total prior knowledge being merely highschool chemistry/biology and some YouTube videos :)

Thanks for sharing all this Isaac, is incredibly interesting to read!

If you don't mind: what's the most likely source of this new disease? What's the worst case scenario, and how likely is it to play out?

When something is so localized like that I immediately wonder if it isn't a genetic susceptibility. I still suspect that high death rates of covid in northern italy we'll find out was some hereditary susceptibility, especially since the elderly in those communities are less cosmopolitan (less genetic admixing)

Aside from that I think it's irresponsible for me to comment much on it since there is so little information in OP.

Understood, thank you!

Comments like this are why I love HN.

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