Prions are a crazy, crazy phenomenon. From wikipedia:
> A protein as a standalone infectious agent stands in contrast to all other known infectious agents such as viruses, bacteria, fungi, and parasites, all of which contain nucleic acids (DNA, RNA, or both)
In my layman's understanding, they're like this bizarre edge case in the way proteins interact. Of all the myriad way a protien can fold, it happens to find one that induces the same malformation when it interacts with another protein. To me, it almost seems like as much of a mathematical/geometrical problem as a biological one. In any case, very interesting from the perspective of emergent behavior in complex systems.
Right--as I understand it, it's not that different than Google's "Meeting Room Hardware Virus":
"I imagine it started with all of the adapters which were thrown around in every meeting room. Everyone with a Macbook of some flavor needed a DVI to VGA adaptor in order to use the projectors, so they were plentiful. Somehow, someone probably damaged one of them and smooshed a couple of pins into places where they should not have gone.
"Then, someone else forced this into their Mac. Perhaps two pins tried to go into just the one socket. At any rate, it would now break the socket and get it all out of whack. That socket, used with another adapter in another room, would then break that adapter. This new broken adapter would then go on to break even more Macbook DVI connectors.
I was thinking that Prions remind me of biological Ice-nine and sure enough there's a mention of it in the wikipedia article for Ice-nine:
Ice-nine has been used as a model to explain the infective mechanism of mis-folded proteins called prions which are thought to catalyze the mis-folding of the corresponding normal protein leading to a variety of spongiform encephalopathies such as kuru, scrapie and Creutzfeldt–Jakob disease.
>"Of all the myriad way a protien can fold, it happens to find one that induces the same malformation when it interacts with another protein."
It doesn't really "just happen", amyloids consist of peptides folded into beta-sheets and aggregates of these seem to be the most thermodynamically stable structures it is possible for polypeptide chains (regardless of sequence) to form:
"From a wide range of in vitro experiments on peptides and proteins we now know that the formation of amyloid structures is not a rare phenomenon associated with a small number of diseases but rather that it reflects a well-defined structural form of the protein that is an alternative to the native state — a form that may in principle be adopted by many, if not all, polypeptide sequences
[...]
These observations, therefore, have led to the remarkable conclusion that, at the concentrations present in living systems, the native states may not always represent the absolute free energy minima of the corresponding polypeptide chains — the native form of a protein could in some cases simply be a metastable monomeric (or functionally oligomeric) state that is separated from its polymeric amyloid form by high kinetic barriers"
http://www.ncbi.nlm.nih.gov/pubmed/24854788
Edit:
I realized some people might not be aware of the connection to prions. Here it is from the same wikipedia page as cited by the parent:
"All known prions induce the formation of an amyloid fold, in which the protein polymerises into an aggregate consisting of tightly packed beta sheets."
https://en.wikipedia.org/wiki/Prion
What's also wild to me is that, conversely, RNA can have enzyme-like behavior [1], including catalyzing their own synthesis [2]. Both types of molecules are amazingly versatile.
You can break it down further into two separate surprises:
1) The normal form (PrPc) is mostly helical, while the diseased form (PrPsc) is mostly beta-sheet.
2) PrPsc catalyses the switch from helix to sheet.
I find the first to be more surprising. After all, chaperones (https://en.wikipedia.org/wiki/Chaperone_(protein)) exist to catalyse folding of proteins - although that is from partly folded to fully folded.
The most terrifying thing about prions is that since they're not reliant on the usual processes for reproduction, they're not susceptible to our usual weapons for dealing with disease (e.g. cooking, antibiotics/antiseptics, vaccines).
plants can be a vector for prions. When researchers fed hamsters grass that grew on ground where a deer that died with Chronic wasting disease (CWD) were buried, the hamsters became ill with CWD, suggesting that prions can bind to plants, which then take them up into the leaf and stem structure, where they can be eaten by herbivores, thus completing the cycle. It is thus possible that there is a progressively accumulating number of prions in the environment
It makes sense that we find this on occasion (once you accept that there exists some combination of folding that produces this). Once one protein folds in a way that can induce the same modification, it will replicate rather quickly.
Are there proteins that cause looping multiple-step reactions as well? Maybe that's what this is and I need to read more :p.
The most terrifying thing about prions is that they are infectious but not alive: they can't be "killed" in the normal sense by sterilization. The proteins must literally be dissolved to neutralize them.
When I was a teen I was so freaked out by this fact during the mad cow episode in England that I never ate beef since. I would not for a few years even eat anything prepared in close proximity to where beef was being prepared.
I lived in the Caribbean at the time...
Spores formed by bacteria like C. botulinum or B. anthracis are also very difficult to neutralize. The key is knowing if there is an exposure risk and taking added precautions.
The good news is that some people are "immune" to developing an infectious prion disease. Turns out that certain mutations prevent normal proteins from interacting with a complementary prion in a way that would cause them to become misfolded.
Yes, it can not be "killed" but, as other dangerous/infectious particles (like viruses), it can be destroyed. The immune system is able to naturally develop defenses against both live and inert foreign bodies, but only if the given body is over a certain size. The small objects (relative to cell size) do not trigger antibody creation and that is why this abnormally folded protein is so dangerous. There are, however, methods in which the organism is trained to recognize and develop natural defenses against bodies as small as a molecule, say, to prevent relapse in drug addicts:
This method may be a little bit costly (relative to promised returns of solving a problem that does not directly affect humans) and with limited effect, but still, it may be a way worth investigating.
"You Can't Kill What's Not Alive: Prions cannot be destroyed by boiling, alcohol, acid, standard autoclaving methods, or radiation. In fact, infected brains that have been sitting in formaldehyde for decades can still transmit spongiform disease. Cooking your burger until it is well done will not destroy the prions!"
http://learn.genetics.utah.edu/content/molecules/prions/
So there's no cure, no vaccine, and you can't kill them. Terrifying. An outbreak of this thing would have free pass to eradicate entire species, including us.
>>Although the disease is not known to be transmissible to humans
This is not quite correct, the disease is believed to be transmittable to humans, but we're not in the practice of eating deer brains, so there are no confirmed cases. All of the states with CWD have advisories on reducing the risk with consumption. Eg: http://www.dgif.virginia.gov/wildlife/diseases/cwd/deer-carc...
Given that we don't really know how CWD is transmitted among animals it is still pretty worrying.
Prions are both beautiful and terrifying. One of my favorite science fiction stories is Kim Stanley Robinson's "Aurora". He makes great use of the prion concept, and its consequences for human life, in relation to space exploration. Fascinating read if you're interested in the topic.
Prions are fucking scary. They survive all regular decontamination procedures - alcohol, boiling, even autoclave. Patients had been infected through the sterilized scalpels and endoscopes.
Could a prion have been the precursor to life? Seems simpler for a protien to accidentally come into existence and start replicating than a string of rna?
Possibly, but the modern age has considerably more vectors for exposure to these misfolded proteins, and the last statement of what logfromblammo said[0], these misfolding proteins don't always affect core processes of the body.
To be fair, this doesn't have to have originated via animal-to-animal infection, but could be an example of sporadic CWD.
As far as I know, sporadic CWD is relatively uncommon, but given CWD is caused by the PrP protein, and there are a number of known mutations in PrP which can increase its likelihood of undergoing prion-conversion, I'd hope they're going to sequence this animal's PrP gene to see it it shed's some light on the etiology.
Irrespective, this could still mean that CWD is now endemic in Europe.
>>>
Updated for clarity and extra info/context (thanks pbhjpbhj!)
>>>
CWD: Chronic Wasting Disease (deer-based prion disease - main topic of article)
PrP: The specific prion protein involved here. Note that (confusingly!) prions are both a 'class' of proteins but also refers to a specific protein (PrP).
Prions (class) are proteins which can exist in one of two states. In their soluble form they're happy-go-lucky proteins that are monomeric (i.e. exist as a single unit). However, these soluble-form prions can undergo a conformational change (re-arrange their shape) into a different conformation (the infectious form). The infectious form of the prion can do two specific things: 1) Aggregate (so all the previous soluble prion proteins get stuck into a big wad of protein) 2): Catalyze the conversion of soluble-form prion into the infectious form. Herein lies their infectivity - you get an exponential growth in the number of proteins in the infectious state.
Prions (PrP) is a specific protein found in many higher-order multicellular organisms that is the SPECIFIC protein that causes a range of prion diseases (Creutzfeldt-Jakob Disease (CJD), BSE [mad cow], CWD, Scrapie etc). There are species barriers to these diseases, even though the proteins are pretty similar (i.e. humans cannot catch CWD from deer, even though the PrP protein misfolds in CWD and the same human version misfolds in CJD). These species barriers are convenient (!!) but very poorly understood, which is somewhat concerning.
Finally - it's worth point out prions aren't always bad. Fungi use them as a mechanism to facilitate non-genetic heritability/diversity [1], and we're increasingly finding examples of prion-like mechanisms that facilitate fast and irreversible signalling in cells (e.g. in the inflammation response [2])
[1] True, H. L. & Lindquist, S. L. A yeast prion provides a mechanism for genetic variation and phenotypic diversity. Nature 407, 477–483 (2000).
[2] Cai, X. et al. Prion-like polymerization underlies signal transduction in antiviral immune defense and inflammasome activation. Cell 156, 1207–1222 (2014).
Too bad DNA doesn't stick around more than a few million years [1]. It'd be interesting to research the possibility of prions wiping out the dinosaurs from Mad Herbivore Disease.
[+] [-] shmageggy|10 years ago|reply
> A protein as a standalone infectious agent stands in contrast to all other known infectious agents such as viruses, bacteria, fungi, and parasites, all of which contain nucleic acids (DNA, RNA, or both)
In my layman's understanding, they're like this bizarre edge case in the way proteins interact. Of all the myriad way a protien can fold, it happens to find one that induces the same malformation when it interacts with another protein. To me, it almost seems like as much of a mathematical/geometrical problem as a biological one. In any case, very interesting from the perspective of emergent behavior in complex systems.
[+] [-] matthewmcg|10 years ago|reply
"I imagine it started with all of the adapters which were thrown around in every meeting room. Everyone with a Macbook of some flavor needed a DVI to VGA adaptor in order to use the projectors, so they were plentiful. Somehow, someone probably damaged one of them and smooshed a couple of pins into places where they should not have gone.
"Then, someone else forced this into their Mac. Perhaps two pins tried to go into just the one socket. At any rate, it would now break the socket and get it all out of whack. That socket, used with another adapter in another room, would then break that adapter. This new broken adapter would then go on to break even more Macbook DVI connectors.
Thus, we had a hardware virus." [1]
[1] https://rachelbythebay.com/w/2012/09/24/dvi/
[+] [-] po|10 years ago|reply
Ice-nine has been used as a model to explain the infective mechanism of mis-folded proteins called prions which are thought to catalyze the mis-folding of the corresponding normal protein leading to a variety of spongiform encephalopathies such as kuru, scrapie and Creutzfeldt–Jakob disease.
https://en.wikipedia.org/wiki/Ice-nine
[+] [-] nonbel|10 years ago|reply
It doesn't really "just happen", amyloids consist of peptides folded into beta-sheets and aggregates of these seem to be the most thermodynamically stable structures it is possible for polypeptide chains (regardless of sequence) to form:
"From a wide range of in vitro experiments on peptides and proteins we now know that the formation of amyloid structures is not a rare phenomenon associated with a small number of diseases but rather that it reflects a well-defined structural form of the protein that is an alternative to the native state — a form that may in principle be adopted by many, if not all, polypeptide sequences
[...]
These observations, therefore, have led to the remarkable conclusion that, at the concentrations present in living systems, the native states may not always represent the absolute free energy minima of the corresponding polypeptide chains — the native form of a protein could in some cases simply be a metastable monomeric (or functionally oligomeric) state that is separated from its polymeric amyloid form by high kinetic barriers" http://www.ncbi.nlm.nih.gov/pubmed/24854788
Edit:
I realized some people might not be aware of the connection to prions. Here it is from the same wikipedia page as cited by the parent:
"All known prions induce the formation of an amyloid fold, in which the protein polymerises into an aggregate consisting of tightly packed beta sheets." https://en.wikipedia.org/wiki/Prion
[+] [-] acjohnson55|10 years ago|reply
[1] https://en.wikipedia.org/wiki/Ribozyme
[2] https://en.wikipedia.org/wiki/Autocatalysis
[+] [-] gilleain|10 years ago|reply
1) The normal form (PrPc) is mostly helical, while the diseased form (PrPsc) is mostly beta-sheet. 2) PrPsc catalyses the switch from helix to sheet.
I find the first to be more surprising. After all, chaperones (https://en.wikipedia.org/wiki/Chaperone_(protein)) exist to catalyse folding of proteins - although that is from partly folded to fully folded.
[+] [-] ryandvm|10 years ago|reply
[+] [-] Kristine1975|10 years ago|reply
plants can be a vector for prions. When researchers fed hamsters grass that grew on ground where a deer that died with Chronic wasting disease (CWD) were buried, the hamsters became ill with CWD, suggesting that prions can bind to plants, which then take them up into the leaf and stem structure, where they can be eaten by herbivores, thus completing the cycle. It is thus possible that there is a progressively accumulating number of prions in the environment
Are you afraid yet? ;-)
[+] [-] Joof|10 years ago|reply
Are there proteins that cause looping multiple-step reactions as well? Maybe that's what this is and I need to read more :p.
[+] [-] Brakenshire|10 years ago|reply
[+] [-] omegaham|10 years ago|reply
[+] [-] activee|10 years ago|reply
[+] [-] kordless|10 years ago|reply
Sounds like a kill switch to me.
[+] [-] danieltillett|10 years ago|reply
[+] [-] rdtsc|10 years ago|reply
[+] [-] jcromartie|10 years ago|reply
[+] [-] Grazester|10 years ago|reply
[+] [-] ekianjo|10 years ago|reply
[+] [-] esm|10 years ago|reply
The good news is that some people are "immune" to developing an infectious prion disease. Turns out that certain mutations prevent normal proteins from interacting with a complementary prion in a way that would cause them to become misfolded.
[+] [-] restalis|10 years ago|reply
http://www.doctortipster.com/11968-new-vaccine-against-metha...
http://www.livescience.com/21132-cocaine-vaccine-cure-addict...
http://www.voanews.com/content/scientists-develop-experiment...
This method may be a little bit costly (relative to promised returns of solving a problem that does not directly affect humans) and with limited effect, but still, it may be a way worth investigating.
[+] [-] unknown|10 years ago|reply
[deleted]
[+] [-] hodwik|10 years ago|reply
[+] [-] nxzero|10 years ago|reply
"You Can't Kill What's Not Alive: Prions cannot be destroyed by boiling, alcohol, acid, standard autoclaving methods, or radiation. In fact, infected brains that have been sitting in formaldehyde for decades can still transmit spongiform disease. Cooking your burger until it is well done will not destroy the prions!" http://learn.genetics.utah.edu/content/molecules/prions/
"Eating human brains helped Papua New Guinea tribe resist disease, research shows." https://www.theguardian.com/science/2015/jun/10/brains-helpe...
Original name for the prions was "trembling in fear" - or Kuru: https://en.m.wikipedia.org/wiki/Kuru_(disease)
[+] [-] Mahn|10 years ago|reply
[+] [-] ckinnan|10 years ago|reply
This is not quite correct, the disease is believed to be transmittable to humans, but we're not in the practice of eating deer brains, so there are no confirmed cases. All of the states with CWD have advisories on reducing the risk with consumption. Eg: http://www.dgif.virginia.gov/wildlife/diseases/cwd/deer-carc...
Given that we don't really know how CWD is transmitted among animals it is still pretty worrying.
[+] [-] martian|10 years ago|reply
[+] [-] Kristine1975|10 years ago|reply
[+] [-] exhilaration|10 years ago|reply
Apparently it's been shown that spiker monkeys can contract it but it hasn't (yet) been shown to be transmitted to humans.
[+] [-] imaginenore|10 years ago|reply
[+] [-] drunken-serval|10 years ago|reply
[+] [-] azazqadir|10 years ago|reply
For someone who had an endoscope recently, that's really scary.
[+] [-] Balgair|10 years ago|reply
If anyone knows any other good resources or intros, please share as well.
[+] [-] mrfusion|10 years ago|reply
Or am I misunderstanding?
[+] [-] debacle|10 years ago|reply
[+] [-] gilleain|10 years ago|reply
There is a paper roughly in this area (polyphosphates and peptides in an autocatalytic cycle) here :
http://cosmology.com/Abiogenesis100.html
[+] [-] technological|10 years ago|reply
https://www.youtube.com/watch?v=vw_tClcS6To
[+] [-] Grazester|10 years ago|reply
[+] [-] jcfrei|10 years ago|reply
[+] [-] FilterSweep|10 years ago|reply
[0] https://news.ycombinator.com/item?id=11534177
[+] [-] alexholehouse|10 years ago|reply
As far as I know, sporadic CWD is relatively uncommon, but given CWD is caused by the PrP protein, and there are a number of known mutations in PrP which can increase its likelihood of undergoing prion-conversion, I'd hope they're going to sequence this animal's PrP gene to see it it shed's some light on the etiology.
Irrespective, this could still mean that CWD is now endemic in Europe.
>>>
Updated for clarity and extra info/context (thanks pbhjpbhj!)
>>>
CWD: Chronic Wasting Disease (deer-based prion disease - main topic of article)
PrP: The specific prion protein involved here. Note that (confusingly!) prions are both a 'class' of proteins but also refers to a specific protein (PrP).
Prions (class) are proteins which can exist in one of two states. In their soluble form they're happy-go-lucky proteins that are monomeric (i.e. exist as a single unit). However, these soluble-form prions can undergo a conformational change (re-arrange their shape) into a different conformation (the infectious form). The infectious form of the prion can do two specific things: 1) Aggregate (so all the previous soluble prion proteins get stuck into a big wad of protein) 2): Catalyze the conversion of soluble-form prion into the infectious form. Herein lies their infectivity - you get an exponential growth in the number of proteins in the infectious state.
Prions (PrP) is a specific protein found in many higher-order multicellular organisms that is the SPECIFIC protein that causes a range of prion diseases (Creutzfeldt-Jakob Disease (CJD), BSE [mad cow], CWD, Scrapie etc). There are species barriers to these diseases, even though the proteins are pretty similar (i.e. humans cannot catch CWD from deer, even though the PrP protein misfolds in CWD and the same human version misfolds in CJD). These species barriers are convenient (!!) but very poorly understood, which is somewhat concerning.
Finally - it's worth point out prions aren't always bad. Fungi use them as a mechanism to facilitate non-genetic heritability/diversity [1], and we're increasingly finding examples of prion-like mechanisms that facilitate fast and irreversible signalling in cells (e.g. in the inflammation response [2])
[1] True, H. L. & Lindquist, S. L. A yeast prion provides a mechanism for genetic variation and phenotypic diversity. Nature 407, 477–483 (2000).
[2] Cai, X. et al. Prion-like polymerization underlies signal transduction in antiviral immune defense and inflammasome activation. Cell 156, 1207–1222 (2014).
[+] [-] djsumdog|10 years ago|reply
Where does alzheimer's disease fit into this? Are there instances where plaque build up is caused by protein misfolding, or are there other causes?
[+] [-] pbhjpbhj|10 years ago|reply
I'm guessing it's in the article, but, well, y'know ...
[+] [-] amorphid|10 years ago|reply
[1] https://en.wikipedia.org/wiki/Ancient_DNA
[+] [-] braderhart|10 years ago|reply
http://www.pbs.org/wgbh/nova/next/body/phage-alzheimers-cure...
[+] [-] nsajko|10 years ago|reply
[+] [-] danielsiders|10 years ago|reply
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3020930/
[+] [-] tinix|10 years ago|reply
[+] [-] unknown|10 years ago|reply
[deleted]
[+] [-] mrkgnao|10 years ago|reply
[+] [-] unknown|10 years ago|reply
[deleted]