We take measures now, for tissues where prions are a possible transmission risk. The article mis-represented that. But:

(1) there are only so many resources to go around. Should we be devoting them to vanishingly rare things rather than things that might actually affect you?

(2) prions will never be a wildfire plague. They have little or no tranmissive ability, by nature of being absolutely naked protein. One step up from that - encoding the protein for space constraints and encapsulating it - is called a virus.

> (2) prions will never be a wildfire plague. They have little or no tranmissive ability, by nature of being absolutely naked protein.

Chronic wasting disease (CWD) (affects deer) can be transmitted by infected saliva. One of the symptoms of symptoms of CWD is excessive saliva production. It is very transmissible, and is devastating captive populations of deer, although it is relatively rare in the wild.

I think if a similar TSE affected humans, spreadable by infected saliva, it would absolutely be a wildfire plague.

https://en.wikipedia.org/wiki/Chronic_wasting_disease

Is there any mammalian prion disease not linked to the PRNP gene (which is fairly conserved across mammals)?

At first I assumed that 'prions' came in many flavors, like virus. However from my brief lit search, it seems like people are talking about (p)rion proteins as if they were't all (P)rion proteins (PRNP). If all mammalian 'prion' disease can be traced to a single conserved gene, I think the risk of another 'prion-like' disease cropping up is pretty low.

But then again, who knows? Prion disease still seems shrouded mystery, which I find odd given (1) how inherently interesting this topic seems, and (2) we've gotten really, really good at molecular biology.

I feel like we are missing a key piece of the puzzle when it comes to understanding prion disease. The literature seems to want people to conceptualize the disease etiology as such: an alternately folded (disease causing) variant of PRNP protein (PrPs) bumps into a normal version of PRNP (PrPc), causing a normal copy of PrPc to also misfold into PrPs. Rinse, repeat. So you can basically think of it like an enzyme that catalyzes a conformational change on versions of itself, in a feed-forward cascade. I feel like an alternative hypothesis however, could be one of an autoimmune response. The mammalian immune system, particularly the antibody system, is mind blowing. This system can recognize virtually any foreign protein -- it can even recognize specific sub-moieties and conformations of proteins (antigens). It must, do this while never mistaking an endogenous protein to be foreign; if it does, you get an autoimmune disease. My idea is basically that PrPs is just slightly different enough from PrPc to get tagged as foreign by the antibody system (which it absolutely can do, given that we can perform western blots to detect the PrPs variant), but also just similar enough for the antibody system to mistake some endogenous PRNP for the foreign version.

Scrapie, a prion disease of goats and sheep, is severe enough that there are national efforts to combat it.

What if this were suddenly transmissible to humans?

https://en.wikipedia.org/wiki/Scrapie

"In the United Kingdom, the government has put in place a National Scrapie Plan, which encourages breeding from sheep that are genetically more resistant to scrapie. This is intended to eventually reduce the incidence of the disease in the UK sheep population."

That is interesting, and new to me. I’ll have to read up on it more. Thank you for the link.

Nitpick but the step between virus and prion is a viroid; a naked piece of RNA. They mostly exist in plants to my knowledge and are basically the smallest possible infectious disease. The smallest viroids clock in at around 120 base pairs (240 nucleotides).

Prions are like gamma-induced bit flips, Viroids are like small code patches, and Viruses are self-deploying code patches.

What blows my mind is these aren't really analogies, they are in fact mostly truth.

To be precise, these aren’t really analogies, they are in fact similes. :)

To be precise, similes are a type of analogy

What's a virion?

https://www.theguardian.com/society/2018/dec/10/mysterious-p...

A virion is the singular noun for a viral particle. The viral genetic material plus capsid equal an individual virion.

Virion and Viriod are two different things. The former is about 10 to 100 times larger than the later.

> (2) prions will never be a wildfire plague. They have little or no tranmissive ability

Mad Cow Disease was caused by a prion[0].

[0]:https://en.wikipedia.org/wiki/Bovine_spongiform_encephalopat...

And it was spread by the livestock industry.

The example in the article has very little transmissive ability because it grows in the brain and eyes. If there were a respiratory prion disease that could be much different. By nature of being a protein they are simpler and harder to eliminate than bacteria or viruses:

> In a particularly vexing twist, prions are also nearly impervious to destruction, even when attacked using a strenuous combination of disinfectants, heat, and pressure.

> If there were a respiratory prion disease that could be much different.

Not really. The point your parent is making is that prions themselves don't reproduce like viruses and bacteria. Its basically impossible for a large scale breakout to occur and spread.

Can you explain why? I'm not saying this is wrong, but they definitely replicate (by encountering and warping other proteins), so are you (and grandparent) saying that the replication rate is too slow? If so, why? Are you saying we have no means of transmitting proteins? (that sounds wrong, though I've been wrong before)

From my (ignorant, despite being interested in prions for decades now) perspective, you have something that (1) can replicate, (2) is durable (3) is harmful, and only the relative rarity of prions in general (because 1 and 3 are physically unusual to combine) have kept them from being a general problem. As we tinker with DNA and thus look into creating new proteins and factors that would influence protein-folding, I'd think it's worth taking the matter seriously (though not fear-mongering), certainly as part of our need to understand proteins better anyway.

What are my faulty assumptions?

A prion can't arbitrary replicate from "food" or "host", its replication is more like a damaged version of protein X that can damage that same protein X if it encounters it. In many aspects it stays the same protein - the exact same DNA, the exact same sequence, just folded differently.

A virus can overtake a cell and mobilize its resources to create a bajillion copies of that virus. A prion can transform only as much copies of that protein as that cell has made in its normal processes.

A bacteria replicates at a much smaller rate than a virus.

A virus requires a cell to replicate, bacteria require a much more limited range of hospitable environments.

Both bacteria and viruses "attempt" to create exact copies, just as a prion does. Admittedly prion replication probably has more accuracy, but that prions occur at all indicates the process allows for natural selection.

These don't seem to put prions outside of the "replication" category - they replicate by encountering other proteins, so they are in a body. Their rate of replication is limited (or boosted) by the rate of encountering these proteins. They attempt to create copies of themselves with the chance of failure or different end result.

But they do reproduce, by causing other proteins to misfold. If they didn't reproduce at all, then ingesting a few prions wouldn't cause any problems.

They can't reproduce outside of the body, but neither can viruses.

Yes but they can only warp their own specific kind of protein not take over an entire reproductive ability of the native cell.

It’s orders of magnitude less reproduction.

How is this at all a "twist"? The reason you cannot deactivate prions using these methods is that they are meant to denature protein. Prions are "amyloids"/beta-sheets, which means they are already in the lowest-energy state. This lowest-energy-state is exactly why the presence of prion can serve as a nucleation point for other proteins to denature into beta-sheets.

I don't care whether or not it's a "twist". I care that there is an entire class of pathogen that we don't know how to sterilize a surface of.

It’s been said a few times in this thread that that is a misrepresentation by the article. Allow me to quote at length from an article on the topic by Brown and Lee:

One of the characteristic features of prions is their resistance to a number of normal decontaminating procedures. These pathogens are resistant to processes affecting nucleic acids, such as hydrolysis or shearing [9]. However, agents that digest, denature, or modify proteins do have activity against prions [7]. The PrP purified from the brains of scrapie-infected animals (PrPSc) can be inactivated by prolonged autoclaving (at 121ºC and 15 psi for 4.5 hours), or immersion in 1N NaOH (for 30 minutes, repeat three times), or immersion in concentrated (>3 M) solutions of guanidine thiocyanate [10]. However, certain cautions prevail; it appears that inadequate autoclaving can establish heat-resistant subpopulations that fail to diminish with a further cycle of autoclaving [11]. Stainless steel instruments also may retain infectivity even after treatment with 10 percent formaldehyde [12,13].

Newer decontamination techniques are being investigated. There has been some success in sterilization using a combination of sodium dodecyl sulfate (SDS), proteinase K, and pronase [14]. A radio-frequency gas-plasma treatment has been shown to effectively decontaminate surgical instruments [15]. Another group has tested a decontamination formula combining copper metal ions with hydrogen peroxide [16].

OK, but how do ophthalmologists typically decontaminate their instruments?

You just use bleach and then autoclave:

>"combining autoclaving (even at 121 degrees C) with a sodium hydroxide treatment is extremely effective." https://www.ncbi.nlm.nih.gov/pubmed/10658760

Bleach is sodium hypochlorite; sodium hydroxide is lye/caustic soda.

Yea, sorry. Earlier in the abstract it mentioned sodium hypochlorite then I didnt read closely: "Strong sodium hypochiorite solutions achieve inactivation but other chlorine-releasing compounds are less effective"

Usually there is some sodium hydroxide in standard sodium hypochlorite bleach solution as well though, perhaps that explains why they reported it is the most effective of the chlorine bleaches.

If any of the proteins involved in respiration were susceptible to lower free energy confirmations (different foldings that were entropically favorable in vivo) then they likely would already be present, there would be such a prion and life that used those proteins would be highly selected against. Respiration is very common in animals.

As it is, very few proteins in humans have alternate favorable form (by luck or selection?). The exception appears to be the extremely complex and relatively new nervous system of mammals. I'd guess that our immune systems might be another place to look, but that is very highly tested.

Frankly, this seems like a susceptibility that is rare because it is chemically odd not that there is a lack of potential exploitation. Luckily, the range of creatures that share our respiration system far exceeds the range of creatures which share our recently evolved nervous system.

Is there someone advocating that we don't take measures now? Because we do take measures now. Example: there are a bunch of rules about what you can feed cows, and how to keep their nervous tissues out of meat at slaughter time.

The fear may be rational, but the response to it needs to be rational as well. That means treating the things that are known to do the most damage currently, while maintaining containment procedures that can handle your black swan epidemics.

Your “next prion disease” is entirely hypothetical. Given that, it is pure speculation how to prevent its transmission. Why would you assume specific precautions taken would apply?

The same way standard protocols are used to prevent transmission of viruses & bacteria. Apparently they don't work on prions:

> In a particularly vexing twist, prions are also nearly impervious to destruction, even when attacked using a strenuous combination of disinfectants, heat, and pressure.

I don't think that's true. Prions aren't bacteria or viruses that evolve and transmit. They're mostly just a misfolded protein that occurs spontaneously. (They can then be transmitted.)

I'm not sure there will ever be a prion that hasn't already existed, whereas I am sure there will be new viruses and bacteria.

If they can replicate imperfectly, they're subject that evolutionary processes.

They don't replicate. Prions can't themselves make more prions like viruses do.

I think the main difference is an imperfectly-replicated virus or bacteria might still be viable.

A prion only makes itself. Even if it replicated imperfectly, the odds of a slightly different misfolded protein becoming another prion are vanishingly small (otherwise we'd all be dead) because there probably just are very, very few configurations possible. The vast majority of misfolded proteins just do nothing.

There are several billion humans who are each replicating millions of copies of each of the 20,000 or so proteins during their lifetimes. It seems pretty unlikely that there are many misfolds that haven't occurred. It's just that only a handful become prions. And even if they do, prions are thankfully very hard to communicate (again, we'd all be dead if they weren't).

They can induce correctly-folded proteins to misfold, effectively replicating.

But shouldn't the number of misfolds be very limited or just one so that evolution cannot occur? It almost sounds like fearing that fire will evolve.

> fearing that fire will evolve.

Well now I have new nightmares... :)

But in seriousness, I don't know much, but I believe that protein-folding is a hugely complicated problem that still lies at the edge of our understanding, therefore I conclude that we can't really conclude that the options for a replicating, harmful prion are basically harmless.

I mean...we don't even really know how common prions are, right? We only have noticed a handful because they have dramatically bad symptoms. A large number of replicating but harmless prions could exist (right?).

Obviously there's no reason to panic, but considered caution and study seems a better reaction than overconfident dismissal.

I don't know how many conformation changes could plausibly be caused by a prion or how many of them would be stable (and I'd imagine it depends heavily on the protein), but the number of possible conformations is incredibly large for any reasonably large protein.

Viruses can't replicate themselves either. Cells replicate viruses. And prions replicate by deforming healthy proteins.

Whether that replication can be incorrect and produce a different kind of prion, I don't know. If it can, evolution will do its work.

Not exactly. Presumably almost all imperfect replications lead to dead ends (or we'd all be dead). Also, because they transmit poorly from host to host, even if one did evolve, which might be impossible, it'd probably die when it's host did.

Given that each human replicates each protein many millions of times over the course of their life, and that there have been several billion humans alive, if that were possible we'd probably have experienced it by now and again all be dead.

With the same effect I can argue that viruses and bacteria are just misarranged RNA :)

I think this underestimates the complexity of proteins.

It is also an are where our innate fears, fears that modern society tells us are unacceptable, might have a place. There is a deep-seated fear of diseased people that once kept us healthy. Modern science has given us an understanding of disease that means there is often no need to physically separate paints where we know the disease is not easily transmitted. The shunning of an aids victim, or a child with cancer, is totally unacceptable in polite society. But prions, and especially research into possible links to various forms of dementia, suggest some dark futures. Maybe it isn't a great idea for the kids to visit grandma in hospital.

As stated in the parent comments that the likelihood of prions spreading in an infectious disease like fashion is very slim. Articles like this, ironically from a science-oriented publication, really don't help the conversation. Luckily modern medicine is fact based and not fear based.

Given that I have been exposed to the BSE prion, and so can never donate blood in north america, this is not a theoretical issue. The transmission of prion diseases are the subject of policy debate.

Is your username… related?

"Prions no threat, nothing to worry about," says Prions. Hmmmmm. :P

Nitpick note:

The phrase is actually “deep seated.”

You are correct. I've heard it both ways and ascribed slightly different meanings, but deep-seated was what I meant.

It's an eggcorn!

Oxford, Cambridge and Merriam-Webster say no.

Why do you say this? And why phrase it so tersely?

Merriam-Webster at least (the only one I've checked) says that "deep-seated" is the only correct version:

  Definition of deep-seated 
  1 : situated far below the surface
  2 : firmly established
  https://www.merriam-webster.com/dictionary/deep-seated

  “deep-seeded”
  The word you've entered isn't in the dictionary.
  https://www.merriam-webster.com/dictionary/deep-seeded

I was trying to make it clear that whiddershins was wrong to say that ‘deep seated’ is the correct usage in contrast to ‘deep-seated’ when Oxford, Cambridge and Merriam-Webster say that ‘deep-seated’ is indeed a correct usage.

P.S. Inconsistency: I assumed that whiddershins was complaining about the hyphen, rather than correcting ‘seeded’, which had been changed to ‘seated’ by the time I first saw it.

I see. You were pointing out the hyphenation or lack thereof? I think you might have missed that the earlier discussion was regarding "seated" versus "seeded". Thus your brevity made it looked like you were claiming that the "seeded" form was correct. I don't think anyone else was concerned about the hyphenation.

Now we have three variants in the wild. The correctly folded "deep-seated" and its harmless but slightly anomalous "deep seated". Worryingly, there's this new configuration "deep seeded" that a significant but unknown number of HN readers may have been exposed to. Although the original infection source has been neutralised, we must remain vigilant against sporadic recurrence in future.

Yes, I was indeed concerned by my wrongly perceived concern of whiddershins over the parent’s usage of the hyphen.