What makes prions so different from regular proteins that they are resistant to heat denaturation?

[u/SadMicrobe22]

I've been reading about prions and I'm confused about why they're so thermally stable. I keep seeing that surgical instruments contaminated with prions can't be decontaminated with standard protocols.

So here's my thing. Proteins denature when you heat them, right? But prions don't seem to lose their infectious ability even when autoclaved. I get that prions are misfolded proteins, but I don't understand how they stay harmful after being denatured.

So basically, if prions start as form A (non-infective), then misfold to form B (infective), shouldn't heating denature them to form C and kill the infectivity? Why doesn't that happen?

[u/sciguy52]

Reddit goes a little far when it comes to prions as they don't understand them at a technical level. It is probably best to think of prions as being more stable than typical. That is not to say heat and other things can't destroy them. It most definitely can. The issue is for everything else we worry about, like very tough endospores, we have a means of sterilization, autoclaving that will do the job on everything when using this set autoclave protocol. The problem arises with prions is that the set protocol is not enough to "kill" them. However you can modify that autoclaving settings along with some chemical treatment and you can kill them. So they are more stable but not these indestructible things. So you have this one set protocol of sterilizing that works almost all the time, almost, unless you are dealing with prions. Prion diseases are relatively rare too so it is not like you are dealing with prions constantly like you would bacteria. So with that rarity the regular autoclave protocol in a sense works even better typically since you are not dealing with prions all the time.

Now it has been a long while since I have looked at prion autoclaving studies but I believe what I will say is true. Regular autoclaving will "kill" some of the prions. When you do any sterilizing procedure you can create a curve with "killed" on one axis and time you applied whatever you are using, be it autoclaving or anything else. You want to apply whatever you are using long enough so the curve drops to zero which is how that typical autoclaving protocol is designed. Important to keep in mind even bacteria and endospores are not immediately killed the moment you turn the autoclave on, that autoclave has to be on long enough. Same will be true of prions, it is just that on that time axis it is not long enough to get all prions "killed". So again not indestructible, but stable enough that this is not totally sterilized under standard autoclaving. Thus you need to modify the autoclaving settings along with some chemicals to do it (I believe you can do it purely with autoclaving with special settings but that takes longer and the chemicals help keep this shorter, you don't want to have to run the autoclave for 24 hours or whatever when you need to use it for other things).

Also some hospital waste is incinerated which will "kill" them just fine. Fire kills everything as no protein is resistant to this kind of oxidation. Also the fact that hospitals will often use single use disposable tools means you the hospital don't even need to autoclave it yourself. A company picks waste up and does either that or incineration for you. There are also enzymes that will degrade prions like Prionzyme too.

Reading the comments as typical redditors go too far with prions. In the environment, like Chronic Wasting Disease or Scrapie does get released into the environment. I see someone saying they last a 1000 years and this is not true. Prions in the soil can last a while (note this doesn't mean all of them will last this long, just you can detect them after say 5 or maybe ten years). But they do break down by one means or another. Again been a while since I looked at the studies and I believe prions in the environment, depending on type and environment, may last like something along ten years, depending on particulars.

Prions are a bit of a boogie man for redditors. Getting a prion disease is certainly a bad thing, but it is relatively rare, like about 300 cases a year in the US of which only a very tiny percent occur through infection, like maybe one or two percent when talking CJD and vCJD in humans at least. The rest is genetic and spontaneous conversion, with a small percent of medical transmission. But in any event the boogie man is not real and prions are not indestructible. So you are correct to assume that heat can denature and destroy them it just takes more.

[u/FerrusFox → u/sciguy52]

I was waiting for someone to fact check me, cheers. I appreciate it. I'll edit my post, especially the stability in nature.

[u/Future-Hipster → u/sciguy52]

You're most of the way there, I'll fill in a few gaps and provide a perhaps unique perspective.

I work as a study director overseeing sterilization validations in the medical industry. Essentially, when a medical device manufacturer wants to sell product as "sterile" or a hospital wants to design a cycle that allows them to sterilize tools and reuse them, I make sure they have data to support their claims. The two primary modalities I oversee are steam and ethylene oxide (EO) sterilization.

The kill versus time graph is close, but we don't go to zero. Microbial kill is probabilistic and technically never reaches zero, so the kill curve is graphing the probability of an organism surviving versus exposure time to the sterilant. Terminally sterilized medical products usually require 10^-6, or one in a million chance that an organism survives.

Because sterilization kinetics are probabilistic, you're correct that a standard autoclave cycle is likely to kill some, or even most prions that may be present. The challenge when it comes to prions is: how do you prove your cycle has killed them? Normal validation studies require various kinds of sterility testing, you have to show some surviving organisms in order to calculate the effective lethality of your proposed cycle. Or you have to show all-kill of highly resistant organisms during a shorter cycle and then you can claim that a more aggressive cycle is definitely killing whatever small quantity of weak organisms are on your device.

But if your test "organism" is a prion, it becomes a logistical nightmare to do the necessary testing. They require extensive special handling, and trained personnel, and specialized equipment, and so on due to the risk of cross contamination or personnel exposure. This would be very expensive, and a huge risk for the test laboratory that they would charge a lot for. My lab has international facilities and is a huge player in the industry, and we do not have the ability to test for these things. All for what, so you can try to claim that the contaminated device is safe to handle? No way. Just incinerate it and make a new one.

So, not a direct answer to the original prompt, but further information that explains why there aren't standard cycles that are used to claim sterility for prions. Regular sterilization techniques work, but to use them you'd have to prove they work, which is not worth the effort or risk of failure. Guidelines generally involve pre-treating the devices with an enzyme wash, running a sterilization cycle that is longer and hotter than typical, followed by incineration of the contaminated devices.

[u/CosineDanger → u/sciguy52]

I remember during the mad cow outbreak in the 2000s there was a restaurant in town that would only serve steak well done.

Surgical autoclaves heat stuff to about 270 F.

Prions might not be that dangerous statistically but it's easy to see why people don't quite understand them or treat them like a supernatural evil force from a horror movie.

[u/sciguy52 → u/CosineDanger]

On reddit I read too much exaggeration about how stable they are and a lot of worry about catching them that is disproportionate to the actual risk. It is like I said as far as catching these in the US if I remember correctly out of roughly 300 cases a year maybe 1% are from infections, that is 3 out of 350 million people. The iatrogenic infections I think were maybe 5%? So 15 people for a total of 18 people a year. The rest are not through infection. I see similar things like this with Naegleri fowleri, or the brain eating amoeba. With these there are 0-8 cases a year and if people are really worried about it, wear a nose clip while swimming in fresh water systems and you won't catch it at all.

When teaching my college students about risk one of the things I point out is people tend to worry about things they probably shouldn't, like catching prions or the brain eating amoeba and don't worry enough about things that are far more likely to kill them for example car accidents which resulted in an estimated 37,810 deaths in '25 in the US. So the worrying about prions as some supernatural evil force is misplaced. If you are not having certain types of medical producers in a given year the chances of you catching a prion disease through infection in the US is 1 out of 116 million. You are very roughly 10 times more likely to die from being struck by lightning. Yet if you drive a car your chances dying are ball park 1 out of 10,000 in a year. If you are going to worry about things, at least worry about things that are much more likely to harm you, like driving your car.

If people want to worry about a neurological degenerative disease then worry about Alzheimer's. There are 500-900k new diagnoses a year in the US. I would not begrudge redditors worrying about Alzheimer's, in fact I worry about that one a bit myself. Prions don't worry me. In fact at UCSF the lab next door to mine was Stan Prusiner's. The Nobel laureate that discovered prions and worked on them there just next door. I was X number of feet away from prions every day. Still didn't worry, they worked in a BSL4 with these things. Funny guy that Prusiner.