Hacker News Reader

I've tried to read about prions a few times and never really grasped the mechanism, so this was a really informative explanation, thank you.

In terms of folding, you can imagine a protein as balls on a string, where each ball has some extra stuff on its surface. One may have a bit of velcro hooks here and a small magnet there (N outwards). Another one may have some surface adhesive and a S-outwards magnet. Another one, velcro loops and a blob of adhesive. Etc. You put such a string of balls in a box and shake it for a while. After you're done, you'll have a somewhat stable structure made of various balls connected by their relevant attachment mechanisms. If you were clever at designing the original string of balls, you could make it highly probable that any such string would reach the same connected structure after being tumbled a bit.

Proteins are like that. The connections are chemical bonds; velcro, magnets and glue represent different structures on protein pieces that allow some kids of bonds to form with given strengths, and disallow others. The tumbling/shaking part is matter and temperature - in a living organism, everything mostly keeps bumping into everything else at random, and in particular, there's plenty of water molecules to push things around randomly. Pieces of protein thus keep connecting and disconnecting with other pieces, until the whole molecule reaches a stable state where the constant bumping isn't enough to break any of the bonds. That's how proteins fold.

Somehow, it turns out that any given protein tends to almost always fold into a very specific shape (which is currently impossible for us to compute a-priori, given just an ordered list of amino acid residues). But there are other possible shapes that a protein can sometimes reach, which are also stable but do not let it perform the functions the body needs it to. That's bad - such a protein is at best useless, at worst disruptive, and stability makes it hard for the body to get rid of it. Then there sometimes are stable shapes whose presence cause other similar proteins to fold to that same shape, instead of the one they'd ordinarily do - that's prions. That's very bad news. They reproduce through catalyzing creation of more of them, and their stability means they can just linger around after the host organism has died, and it's not easy to destroy them through boiling or denaturing agents.

I’m not clear on the mechanism by which the prion encourages other proteins to fold the same way. Is the protein interacting with the other protein directly like an Ice IX situation? Is it an interaction between the body and the prion, like the prion causing the body to create an enzyme which interacts which then folds the next protein? Something else?

From what I've read, it seems accepted that the mechanism is closer to Ice-nine - a bad protein shows up next to a good one, and causes the latter to re-fold into a copy of the bad one. The exact mechanism of this is not known.

What are some macroscopic examples where a group of stable things change to match a differently configured stable thing introduced into their midst?

Maybe a stampede, where creatures were stationary until one bolts and then the ones around it start running too?

Or a standing ovation, where people standing in front block the vision of those behind who stand up too until everyone is in their feet?

Or dominos arranged upright in a line and then one is placed lying against a neighboring upright domino?

Zombie apocalypse.

Aren't those usually caused by some sort of a contagion?

Yes! In this case the contagion is the alternate metastable state of the protein that is passed from one to the other on contact. After which, the previously healthy protein quits its job, leaves its family and starts hunting for fresh victims.

Many things. In CS, gossip-protocol based DB systems. In chemistry and physics, phase transitions. Many processes like nucleation/crystallization during freezing are very similar.

When simulated, the code generally resembles cellular automata. Look up Ising model simulation if you want a better understanding.

"There's an argument about whether viruses are 'alive', since they depend on others' cells to make their proteins. Prions are even less considered 'alive' ..."

I have read several proposals for a "viral LUCA" in the past ... does anyone ever suggest a prion LUCA[1] ?

[1] https://en.wikipedia.org/wiki/Last_universal_common_ancestor

> does anyone ever suggest a prion LUCA[1]

Yes, it totally makes sense to talk about a common ancestor!

There's one known prion-disease-causing protein in humans, the "major prion protein".

You can see the gene containing the code for this protein in human DNA, and any mammal DNA has a similar gene that is still very closely related. This suggests that the protein has some important function(s) in mammals, and has a common ancestor before these species existed.

Genes that have a shared history but are less closely related (and don't appear to cause disease) can be found for example also in zebrafish ('Shadoo' gene) and in humans ('Doppel' gene).

https://pubmed.ncbi.nlm.nih.gov/15449459/

That was really instructive, thanks.

Could you develop a bit the last part please? How does it go from "you have accumulating useless proteins in your body" to "you die"? Is it because too many "good" proteins are turned into "bad" proteins and thus you don't have enough anymore to function properly? Is it because the "bad" proteins somehow "clog" the system? Something else?

I'm sure the latter is possible in some way but the common prion-based diseases kill by misfolding functional proteins in the body (or in this case the brain). As the misfolding spreads, the cells in the immediate vicinity are destroyed and ultimately the surrounding tissue.

You can google it if you want, but the end result is a brain that is essentially turned into a sponge with voids throughout.

Either of these theories [not enough good protein/too much bad protein] could contribute to disease, yes.

The correct function of the disease-causing 'major prion protein' in humans is not known, so I think the answer is "we don't quite know which of these factors is more important".

We observe that diseased brains have 'plaques' where they have been turned into sponge, so-called "spongiform encephalopathy". The brain's neurons have simply died, one way or another.

> protein that encourages other proteins of the same type to misfold in the same way.

Gotta wonder if this is a clue about abiogenesis.

I've always understood that viruses are not alive but does the statement "since they cannot reproduce without depending on others' cells..." Not also cover plants that require insects for pollination?

Plants are unambiguously considered alive by this definition, because they do make their own proteins.

I edited to make this clearer.

OP's argument is a little bit unorthodox. Generally maintaining homeostasis is seen as a threshold for life and that's why viruses are often excluded, they cannot really maintain internal state.

I deliberately said it's an argument ;-)

There's no clearly agreed definition of 'life', and in my opinion, scientists are moving gradually towards an idea that viruses should count as life. Hank Green recently posted that he finds it obvious that viruses are alive.

The argument that viruses are not life has become a bit circular - viruses are not life, therefore, we have to come up with awkward definitions of life that exclude viruses.

You've posited a different definition, which I'd suggest is very close to mine - 'maintaining homeostasis' is meant to express the idea that a cell is able to produce its own proteins in order to control its own environment to its own benefit.

[When a virus changes that environment to suit its own needs, we don't want viruses to be considered life, so we don't call that 'homeostasis' any more - at least, we don't when we're talking about the context of what 'life' is. There are plenty of academic papers that do call this homeostasis, considering homeostasis as an interplay between cells and its viral infections.]

What are the consequences of considering viruses to be alive vs not alive?

a reasonable definition for alive is that they carry their own energy production mechanism to reproduce. They can intake materials, produce energy, and reproduce.

If we created robots that could harvest their own raw materials to produce energy and reproduce, then they would be alive too.