As I understand it, prions are just an ever-present rare tiny probability of a cascading malfunction of your physical composition. They are rare because they need to be, in order for a biological system to survive. (any biological system that had a high probability of prions would die off) They can never fully be eliminated because your body is built on probability, not mathematical certainty. Most organisms live less than 100 years, so the probability is good enough not to affect species survival. As long as young organisms don't eat old organisms, the chances remain low.

Another way to look at it is that the combined lifespans of the organisms of a food chain are shorter than the time it would take for one mis-folded protein to be likely to occur and then also cascade to a degree that would affect the health of the top organism. Prion diseases only show up when you introduce a loop in the food chain.

> What is the reason that we can thank for prion diseases not being much more common?

One reason is that we don't eat each other which would spread certain prion diseases like https://en.m.wikipedia.org/wiki/Kuru_(disease)

Another aspect is that a prion disease requires a much more specific confluence of circumstances. It requires a protein, which can be misfolded, and a misfolding that, when in contact with other proteins of that same type, causes the same misfolding to occur.

Indeed, cannibalism is an excellent way to get something like this to the point where it sustains itself.

Yeah we only do that metaphorically in the modern world.

I think it largely comes down to there being no benefit to the prion. It’s more of a lightly continuous sort-of-poison than an actual actor looking for its own reproduction. Viruses and bacterias existence depends on reproduction. Prions just kinda appear naturally from folding errors.

They don’t “want” to exist, even to the minimal extent of a virus, they just happen.

Virus does not "want" to exist either - they just happen. There is no success criteria or will, just a structure that happens to cause self-replication, with variants that cause more aggressive replication being more present and common.

Prions are in that sense no different - they are just less successful.

I definitely see where you're coming from, but viruses do have modes of transmission that evolve over time to counter immune defenses. Unless I'm mistaken, with prions, you either have to ingest infected tissue or apparently prick yourself with a needle with infective material on it.

I don't believe they reproduce in any but the broadest sense either. Don't they just cause other proteins of the same type to misfold as well? It's not really a transfer of genetic material, it's a change in the emergent structure of the protein.

It is all a matter of definition. They are both merely a physical structure, they both have to interact with very specific tissues in very specific ways to do anything, they both make our own matter replicate into additional copies of itself, they both have "preferred" areas of attack which are simply areas that they are more successful in, they both tend to "accidentally" cause behaviors that make us assist in spread (e.g. biting), and they both cause various bad things to happen as a side effect of their means of operation.

The prion's mode of operation isn't just "bump into stuff". It reaches the brain, causes other materials (DNA aptamers) to clump together, and causes other prions to be created.

That one happens to have a part that looks like genetic material and the other looks like a misfolded protein is merely a small implementation detail to me.

(Disclaimer: I, like everyone else I'm this thread, is not a qualified source of medical information.)

There's a lot we don't know about prions and a heck of a lot I don't know, but I would be surprised if prions turned out to be something substantially different from a misfolded protein.

I've never heard of prions targeting certain tissues. I need to do some reading, as it's been a while since my last bio course. Do you have an article that explains how that works? In order to have that ability, they would have to be more complicated than I understand them to be.

The major difference is that prions do not evolve from selective pressure.

That we know of - which seems to be more due to the ‘being less successful at wide spread replication’ part. Which we can all be thankful for.

But there is a difference between e.g. crystals and viruses. Both "want" to exist under some conditions. Crystals will even "evolve" to a small extent that more stable/lower-solubility polymorphs will dominate, and there have been cases of polymorph "infection" (ritonivir) between production facilities. Prions are like crystals in this aspect.

The difference is that viruses have many more tools available in order to evolve and adapt. Prions, like crystal polymorphs, merely have the configuration space of the molecule. Viruses have the configuration space of dozens of proteins, and complexity can increase, so in theory there is no upper bound.

So I guess yes, they are all replicators that differ in extent by the amount of phase space available to their lifecycle. But the complexity jump between prions and viruses is huge, and prions are inherently bounded.

https://www.pnas.org/content/100/5/2180.

Comparing a crystal to a prion or virus is a fun exercise, especially as they all appear in the body and causes health issues. Kidney stones, sugar crystalization around nerves, etc.

One main "behavior" difference between crystals, prions and viruses is that a crystal only forms by recruiting its equals when in high concentration - growth, but no replication.

Most virus is way more complicated than prions as you say, but a blue whale is also more complicated than a single-celled myxozoa and yet they are both animals. I do not think a comparison of complexity is meaningful in this debate.

One should also consider that there are countless proteins to misfold in any number of ways, so the prion space is not necessarily that limited. Virus do have the upper hand by using our well-oiled evolutionary machinery though.

I think it’s debatable as to the meaning of “want” of non-thinking/non-living things. Viruses continued existence depends on reproduction however, which they’ve been doing for billions of years. That’s a “want” in my book as far as something seemingly inanimate can want.

Viruses that don’t “want” reproduction fail to do so and disappear.

I'm not sure it's entirely correct to refer to this instance by the term of "anthropic reasoning" too, but:

The viruses we see are common because they reproduce, it's not that they reproduce because they have some drive to become common.

Thus prions are less common because they aren't as successful in spreading (for some reason(s) I don't know either).

Still not sure I get the distinction with prions that you're making.

The essential idea is roughly "we end up with more of the things that replicate more". Despite the redundancy, there is a crucial idea in here. If we allow the use of the word "want" metaphorically then anything that replicates "wants" to reproduce including memes, crystals, prions and computer viruses.

Maybe you're just saying that a prion isn't as good at replicating as a virus? It seems like a difference of degree rather than kind.

> Maybe you're just saying that a prion isn't as good at replicating as a virus? It seems like a difference of degree rather than kind.

They are qualitatively different.

A virus infects a cell, and critically, can quickly adapt (through random mutations) in an unthinking war between the various forces of the immune system and transmission mode efficacy; A prion does not evolve, it's a misfold of a single type of protein. If you want to compare it to a virus, it's like a virus that is incapable of replicating anything other than an exact copy - and can also only replicate itself using a particular cell (one type of protein).

Why the human body cannot effectively defend itself against particular propagating misfolded proteins is a mystery to me though... perhaps it's too low level to be identified by the immune system as something to attack, much like a poison.

A protein can misfold in countless ways, and there are countless of proteins to misfold.

That a virus can be a big and complicated structure does not mean that smaller and simpler structure is fundamentally different.

Viruses themselves also have many different modes of operation, with things like virophages, satellite virus and giant virus showing just how unclear the term "virus" is.

> A protein can misfold in countless ways, and there are countless of proteins to misfold.

They are countable, but yes there are many ways, but that alone doesn't mean it's capable of meaningfully evolving. It's a search space multiple orders of magnitude smaller than a piece of DNA, so it's easy to see how a different successfully propagating misfold will be significantly less likely when starting from an existing propagating misfold.

If you are suggesting one propagating misfolded protein can, by chance, misfold into another propagating misfolded protein at a rate fast enough to become adaptive... then it's qualitatively the same as a virus, but I don't see this as likely given the significantly smaller search space.

The largest protein we produce is about 27k amino acids, more complicated than most virophages. That is merely the biggest we produce. I know of no upper limit on protein complexity, and that is before even taking folding options into consideration.

The space of possible proteins - and thus prions - is not at all limited, neither figuratively nor literally. It is most certainly not "countable" without some Nobel-prize inducing discovery.

> The largest protein we produce is about 27k amino acids, more complicated than most virophages

The only known human prion proteins seem to be a few orders of magnitude smaller than that though, and they don't appear to adapt.

Are you saying it's possible for prions to emerge from large proteins with the ability to adapt?

They may be suggesting that prions don't have a large space to evolve within through random mutation

By that metric, everything just happens though. Humans just happened, we didn’t will ourselves into existence. Human free will cannot be proved and may very well just be an illusion in our perceiving of a cosmic causal chain. Are our “desires” for reproduction any different? Or are they artifacts of our internal calculations of the future? When we are optimistic, we reproduce. When we are pessimistic, we don’t. That seems more like opportunism than free will to me. And that seems very much like what a pathogen would encounter: favorable or unfavorable conditions.

I guess what I am saying is that either you are right and that can be extrapolated all the way up the chain to humanity. Or that you are wrong and you can apply free will all the way down the chain.

I think another way to state this without getting into philosophy or semantics is that viruses are capable of evolving methods of being more successful at infection. Prions are not, because their method of operation involves remaining single molecules.

I like to tell people that early humans lived in close contact with animals for hundreds of thousands of years, and until a few generations ago, when most people were still farming for a living. If prions had the potential to end the human race, they would already have.

I think prions are a bigger problem in crowded single-species environment than in comparatively sparse mixed-species pre-industrial world.

In particular when you feed cows proteins made from dead cows it's making it more likely to create prion problems than when wild animals live in small herds in forests (and the ones that are sick are killed by predators or starvation before they can infect others more than likely).

Feeding the output back into the input definitely makes it a bigger problem, however Chronic Wasting Disease in Elk and Dear in North America is becoming a huge problem and is a prion disease, and they’re living wild.

So it doesn’t require it, it just increases the odds (and they don’t eat each other to spread it - it’s highly infectious and demonstratively infects if they share browsing/grazing land).

It doesn’t appear to spread between them and humans, but it definitely makes me nervous.

The advent of agriculture and animal husbandry is generally thought to be much more recent than your comment makes it sound. More like ten thousand years ago.

The slight problem there is, prions probably did end a bunch of tribes which were sufficiently local - and then left the area alone long enough that the prion contamination in the environment broke down.

Today we have international animal shipping and trade, and global distribution. Prions are able to spread from exposure to shared pastures. A couple years of contamination used to be no big deal - today, if missed, it can spread all through the food supply.

I always wonder how much more truth there is to haunted houses and forbidden lands than we think. Just superstition? Maybe, but maybe not.

It is hypothesised that Kuru (and vCJD) in some individuals (due to genetics) might take 40-50 years to develop if introduced through intestine. Well after the individual had a chance to reproduce.

We're actually having a worse situation re/ animals than our ancestors. We nowadays cram farm animals in stables so tightly that without antibiotics and medical treatment the animals would almost immediately perish. Our farms and our animal "care" practices have been the breeding ground for all recent global pandemics (swine flu, bird flu, SARS/MERS/SARS2). Not to mention the conditions that farm and slaughterhouse workers have to work and live in (as evidenced by massive COVID outbreaks).

The chance of any infectious agent "jumping the species" due to cramped conditions or because of exposure of workers to contaminated animal parts in unclean slaughterhouses is immense - the current SARS-CoV-2 pandemic in my opinion is a warning signal of something much worse to come, and no matter what kind of agent it will be, we're pretty much screwed. Half the population or more of the world doesn't believe in vaccination, a quarter or more don't have access to vaccines or any kind of modern medicine at all, we are already running out on reserve antibiotics...

Not a biologist, so this is just a guess, but I imagine their simplicity is their weakness.

Viruses rely on the machinery of nucleic acids to replicate. That machinery is complex and robust and the result of some long period of continuous evolution, which means viruses exists in a fairly smooth fitness space where mutation and recombination are effective means of improving fitness.

Prions by contrast seem more like isolated spikes in a much sparser fitness space. Presumably the equivalents of mutation and recombination for prions lead to molecules that almost never retain the capacity to replicate, so they have limited potential to become fitter over time.

They are super, super-specific.

Prions can't self replicate from raw resources: they depend on inducing conformational change in other proteins. The host has to produce, and use, the specific protein they can target in an accessible location.

The upshot of this for prions is that lacking genetic code, or a need for replication machinery, and being a variant of the protein they target, they are perfectly adapted for their environment and host and currently impossible to destroy without also damaging the normal correct protein form.

No ready vector for spreading. It needs to come into direct contact with your proteins to affect them

Doesn't that just mean physical contact? Our skin is made out of proteins, is it not?

Not all proteins can exist as prions. (In fact, it's amazing that some can even exist: think about it: a protein that exist in two stable shapes where the shape that does not normally exist in the body can cause the other shape to make the switch!)

Like a seed crystal causing super cooled water to suddenly freeze in seconds?

Yes, like that

The outer layer of your skin is mostly made of dead cells. It's cold, dry, exposed to the elements, constantly discarded, and has the wrong pH for most biochemical processes that are optimized for the inside of your body. It takes a fairly invasive pathogen to break that barrier.

“Protein” isn’t just one thing.

I’m far from knowledgeable in this area, but the model in my head is: the $foo_protein can be folded in at two important ways, $foo_v1 is what you want, $foo_v2 is a catalyst for refolding $foo_v1 into $foo_v2 but doesn’t refold much (or anything?) else.

Anything expressed by DNA is a protein, but not all proteins are the same. Prion infections are caused by proteins that change the same proteins in the same way, like how crystals replicate.

A human analogy might be a disgruntled but charismatic worker who starts spreading a disruptive attitude until morale and productivity plummet in their department. As long as one of that team remains, the issue can still spread. Coincidentally, both the potted plants and highly compensated leadership are unaffected.

> less defensible against than viruses, and at the same time [...] so much more common (easier to appear).

Not really on both parts. It's only transferred by eating meat so the defence is as soon as prion infection is detected all possibly infested livestock is culled and severe bans on trading are placed. Cannibalism in animal feed is also disallowed which makes transmission rare. Being vegetarian is also a complete defence.

They're also rare to appear, otherwise eating livestock would have regularly wiped out humans already. They're basically non-existent if you don't eat humans and livestock isn't fed to livestock.

> Being vegetarian is also a complete defence[sic].

Tell that to deer dying of CWD.

"defence" is one of the correct spellings for the word.

Your condescending sic is, ironically, misplaced.

>Being vegetarian is also a complete defence.

Lady in the story could have been a Vegetarian yet still died from a Prion. As others have pointed out swimming in bodies of water is possible vector for prions.

Swimming in water was pointed out as a vector for amoebas (some of which can be ‘brain eating’ in some areas), not prions.

Second part is incorrect, first part is a nitpick. She got it from working in a lab. If I say abstinence make you immune from HIV are you going to "counter" that by saying you could get it from being transfused or pricking with infected blood?...

That they don't spread through the same mechanisms that viruses and bacteria use. You'd have to have much more direct contact between the organisms to transfer prions from the one to the other, they are internal and don't self-replicate in the way that bacteria and viruses do. The lack of selection pressure on prions is what keeps them in their lane.

But: consuming bush meat, brains, feeding dead animals to other animals, being careless with sharps and so on are all excellent ways to contract them.

> What is the reason that we can thank for prion diseases not being much more common?

We kinda take this for granted, but it may be the case that our deeply-rooted psychological disgust and aversion to eating human flesh is a product of prion disease killing populations of ancestors who did. Or perhaps, even our tendencies to ceremonies of death helped us: those that feared the bodies of the dead, or were more likely to create rituals of destruction and avoidance, were more likely to persist and pass on their genes :)

I suspect the issue is that, prions require a fairly large series of coincidences to be viable, so the biological niche is a pretty small one. I think they're much more specific conditions than that required of viruses.

In addition, your body probably has evolved to use proteins that aren't particularly susceptible to misfolding AND accumulation. (Perhaps a long time ago, it WAS quite common?)