Scrapie is particularly known, deadly, and long-lived. The toxin proteins can survive for a decade in soil, and infect a new host years after it emerged.
They're all the same in my understanding, just named differently because they have been observed separately before any understanding about PrP existed. And yes, that means they're also all long-lived. These proteins do not decay like more useful molecules or more complex organic matter.
What gets me is why these prions seem to be primarily brain related. Just coincidence or is it something in the nature of mammalian brain biology that leads to prions?
There are already a bunch of prions generated in the body and hanging around neurons; the body can’t sort the invasive prions from the native ones that cause proteins to fold wrong.
Prions are attracted to or at least congregate in and around nerve cells. That's why as they spread around, they always eventually end up in the brain.
The most scary thing about prions is that they're inert. They're not even evil or agressive. They just are.
The mere shape of them causes cascading exponential system failures. And that shape happens to be very stable and requires a lot of energy to be broken up.
Like some kind of rock that falls from the sky or materializes out of thin air, and slowly the whole village turns into identical inanimate rocks.
For some reason this reminds me of the theory of false vacuum decay, where the universe could exist at a local minima rather than an absolute minima and if something ever disturbed that and decayed out of the local minima the whole universe is obliterated. Fun time.
I guess the relation would be that the useful state of being is somehow not the most stable.
To be fair, usually prion disease is not only one misfold away. Cells correct misfolded proteins all the time. Prions only happen once enough misfolded proteins form an ordered aggregate that causes other proteins to misfold too fast for the cells to keep up
Of course it is not common at all, and my fear is probably very ill-founded and irrational. It's just the idea of dying from ... well, the raw form of randomness, scares me. I'm not scared of flying, for example, even though the pilot may very well f up, and they do f up from time to time. But if the pilot is throwing D100's for each flight, and if there is a streak of 50 1's, the next flight will be doomed - I won't be flying at all.
The really scary part is that there's no real testing in our food supply. Wild animals can also spread it over crops and it can stay present in soil for years. If it makes the jump to humans, were screwed. That or dental tools (they may not get sterilized to the point of destroying prions) will be what gets us.
I believe "sterilization" is a bit of a misnomer when it comes to prions, as they can't be reliably destroyed without also destroying the object. Neurosurgical instruments are routinely discarded and incinerated rather than reused due to this risk.
Not just technically. Proteins, and the molecular machinery producing them, are just that. Look at the flagellar motor. It's a marvel of (natural) engineering.
The known cases involve "cannibalism", like feeding sheep with ill dead sheep. It probably requires a lot of prions to cause a the disease. Don't try it at home, but a few would cause no symptoms, unless someone eats our brain and they produce more prions and someone east their brain and after a few rounds of cannibalism the concentration of prions is high and cause problems.
The solution is to avoid tight loops, i.e. use the dead sheep scrapes to feed other animals or as fertilizer. Bacteria and bad luck destroy the prions, so after a while they disappear unless you have tight loops that amplify their number.
Also, I think the bodies of the sheep/cow with symptoms are burned or destroyed, because when the concentration of prions is high enough to cause symptoms they can be bad enough for other species.
"It probably requires a lot of prions to cause a the disease."
There have been researchers who have been exposed and it and developed it pretty quickly. Canabalism isn't the only way, such as with wild deer.
"unless someone eats our brain and they produce more prions and someone east their brain and after a few rounds of cannibalism the concentration of prions is high and cause problems."
That's not really how it works. The prions will continue to replicate without the need for multiple rounds of cannibalism. There is no known safe limit of prions.
I suppose one could go on a wild tangent here and argue that - given they're significantly more stable - prions are the correct-er form of proteins.
They just do not get any work done within how known biological life works, but that could perhaps also be read as said whole tree of life relying on a misconfiguration of that building block?
This is wildly unqualified rambling on my part, but I wonder if life could develop that is based on that prion form of proteins.
From my understanding, no. But maybe "life developing" is the wrong metric for correctness?
FWIW, The universe itself seems to be dead-set on entering the most stable configuration of everything.
That's a little like saying broken pottery is the more correct form of plates. What you're describing is the lower energy/higher entropy state, and yes everything heads in that direction because of thermodynamics. In general, life is a temporary state of higher energy achieved in exchange for waste in the surrounding environment; prions are useless because they are disordered not in spite of that.
I love the hypothesis. It would be interesting if there was research in longevity where proteins that often degrade into unfortunate forms could be slightly modified for self repairing, and bigger resilience to damage. Of course that sounds a lot like a cancer..
I like this take. With its reduction to “survival of the fittest” slogan, it is easy to forget that Evolution can be “subjective”, imprecise in the problems it is solving.
I'm glad they are making some progress partly because my sister has ALS and there may be similar mechanisms - there seems to be some protein folding malfunction at play in that too. So far there's been very little progress with anything like that.
I've seen prion disease up close with someone dear. I couldn't sleep thinking about what could have been going through their minds. It was 6 months of torture, and if I were in the same situation I'd have preferred someone switch me off.
I remember reading about Sonia Vallabh (and their race against time) - I'm so glad they're getting somewhere. Kudos.
Prion diseases are one of the scarier things I've ever heard about. It is transmissible via fluids, but it can also just happen spontaneously in your body, and once that happens, it's basically a death sentence. There is so far still no cure.
It sadly sounds like it targets RNA for the production of all prion proteins (a somewhat important protein for normal brain function, but not essential) and doesn't do anything to clean up existing misfolded proteins. Even if successful, it will probably have side effects.
Looking at the list of observed changes in mice this can be anything from destroying the sleep cycle to general memory problems.
> Even if successful, it will probably have side effects.
> Looking at the list of observed changes in mice this can be anything from destroying the sleep cycle to general memory problems.
Prion diseases guarantee certain death right now though, so the side effects would need to be pretty bad for them to be worse than the disease. Even just delaying death by a few years would be pretty good, since most people die in under a year [0].
(This is somewhat similar to chemotherapy drugs, which also tend to have pretty bad side effects but are still generally accepted as better than the alternative.)
Oh no way is this that Indian origin lady that had this genetically and was essentially guaranteed to die in her 40s/50s so she upended her entire life and pivoted to finding a cure for this? If that’s the case, I am blown away and amazed that they even have a candidate for human testing.
What Sonia Vallabh and Eric Minikel have been working toward since her diagnosis in 2011 is truly inspiring. The drug candidate was developed by Anastasia Khvorova and her lab at UMass Chan Medical School, in collaboration with Vallabh, Minikel, and their research teams.
What makes this effort even more remarkable is their commitment to sharing the drug development process openly, including an IND filing that would typically remain confidential.
Whatever the eventual outcome( I’m optimistic) about the possibilities, the journey, the data, and the knowledge shared along the way will be valuable.
This is not just about developing a drug; it’s about making science more transparent, collaborative, and accessible for everyone working toward the same goal.
In case anyone hasn't seen it, the story behind this couple is interesting:
https://www.cureffi.org/about/
Wired did a great write-up on them years ago (minus everything that's transpired since then, obviously):
https://www.wired.com/story/sleep-no-more-crusade-genetic-ki...
It's been a while, so I'm glad to see this promising update about their research :)
cure foreign function interface before it gets too ubiquitous!
Prion diseases include:
-in sheep, scrapie
-in humans, Kuru and Creutzfeldt-Jacob
-in cows, BSE ("mad cow")
-in deer, Chronic Wasting Disease (CWD)
-in cats, feline spongiform encephalopathy
Scrapie is particularly known, deadly, and long-lived. The toxin proteins can survive for a decade in soil, and infect a new host years after it emerged.
https://en.wikipedia.org/wiki/Transmissible_spongiform_encep...
They're all the same in my understanding, just named differently because they have been observed separately before any understanding about PrP existed. And yes, that means they're also all long-lived. These proteins do not decay like more useful molecules or more complex organic matter.
Some of them are the same, but some aren't. CWD is a prion separate from BSE for instance, but BSE is caused by the same prion as Creutzfeldt-Jacob.
What gets me is why these prions seem to be primarily brain related. Just coincidence or is it something in the nature of mammalian brain biology that leads to prions?
There are already a bunch of prions generated in the body and hanging around neurons; the body can’t sort the invasive prions from the native ones that cause proteins to fold wrong.
Neurons are long lived. Most cells in your body are thrown away often.
Prions are attracted to or at least congregate in and around nerve cells. That's why as they spread around, they always eventually end up in the brain.
Do we know if prions are especially attracted to nerve cells, or if nerve cells are just a typical cause of death by prion disease?
Somehow most of the terms are related to -more or less- the "effects of cattle business" ie. lifestock farming, it seem to me as a layman?
The most scary thing about prions is that they're inert. They're not even evil or agressive. They just are.
The mere shape of them causes cascading exponential system failures. And that shape happens to be very stable and requires a lot of energy to be broken up.
Like some kind of rock that falls from the sky or materializes out of thin air, and slowly the whole village turns into identical inanimate rocks.
Viruses are also not evil, they're just random DNA/RNA strands that natural selection forced to have adverse effects.
Prion proteins seem much less animate, so more scary in this particular way.
For some reason this reminds me of the theory of false vacuum decay, where the universe could exist at a local minima rather than an absolute minima and if something ever disturbed that and decayed out of the local minima the whole universe is obliterated. Fun time.
I guess the relation would be that the useful state of being is somehow not the most stable.
The scariest part for me is: it can just form randomly in one's body, and there's no way to tell until it's too late.
To be fair, usually prion disease is not only one misfold away. Cells correct misfolded proteins all the time. Prions only happen once enough misfolded proteins form an ordered aggregate that causes other proteins to misfold too fast for the cells to keep up
Of course it is not common at all, and my fear is probably very ill-founded and irrational. It's just the idea of dying from ... well, the raw form of randomness, scares me. I'm not scared of flying, for example, even though the pilot may very well f up, and they do f up from time to time. But if the pilot is throwing D100's for each flight, and if there is a streak of 50 1's, the next flight will be doomed - I won't be flying at all.
The really scary part is that there's no real testing in our food supply. Wild animals can also spread it over crops and it can stay present in soil for years. If it makes the jump to humans, were screwed. That or dental tools (they may not get sterilized to the point of destroying prions) will be what gets us.
I believe "sterilization" is a bit of a misnomer when it comes to prions, as they can't be reliably destroyed without also destroying the object. Neurosurgical instruments are routinely discarded and incinerated rather than reused due to this risk.
Most prions can be denatured chemically. Using chemicals can also drop the temperature required when using heat.
Yep, and the US government has sued farmers who *wanted* to test every slaughtered cow for BSE (mad cow disease).
The US gov claimed, you guessed it, commerce clause.
https://www.animallaw.info/case/creekstone-farms-premium-bee...
The solution will be Nanomachines, son.
Technically speaking proteins are nanomachines.
Not just technically. Proteins, and the molecular machinery producing them, are just that. Look at the flagellar motor. It's a marvel of (natural) engineering.
Why are people disagreeing?
I didn't downvote you, but it's too alarmist:
> If it makes the jump to humans, were screwed.
The known cases involve "cannibalism", like feeding sheep with ill dead sheep. It probably requires a lot of prions to cause a the disease. Don't try it at home, but a few would cause no symptoms, unless someone eats our brain and they produce more prions and someone east their brain and after a few rounds of cannibalism the concentration of prions is high and cause problems.
The solution is to avoid tight loops, i.e. use the dead sheep scrapes to feed other animals or as fertilizer. Bacteria and bad luck destroy the prions, so after a while they disappear unless you have tight loops that amplify their number.
Also, I think the bodies of the sheep/cow with symptoms are burned or destroyed, because when the concentration of prions is high enough to cause symptoms they can be bad enough for other species.
"It probably requires a lot of prions to cause a the disease."
There have been researchers who have been exposed and it and developed it pretty quickly. Canabalism isn't the only way, such as with wild deer.
"unless someone eats our brain and they produce more prions and someone east their brain and after a few rounds of cannibalism the concentration of prions is high and cause problems."
That's not really how it works. The prions will continue to replicate without the need for multiple rounds of cannibalism. There is no known safe limit of prions.
Are you referring to a case like this one? Don’t know if 7.5 years counts as quickly. Maybe there are faster ones I couldn’t find.
https://www.researchgate.net/publication/342618008_Variant_C...
A self-replicating asbestos fiber
The ice9 / grey goo of the biological world.
Prions dissolve at 134 °C so climate change will fix that problem for you.
If the atmosphere is past boiling at sea level we have bigger problems.
Yeah it sounds like God hired a malicious freelance programmer who put in a self-propagating backdoor huh.
I suppose one could go on a wild tangent here and argue that - given they're significantly more stable - prions are the correct-er form of proteins.
They just do not get any work done within how known biological life works, but that could perhaps also be read as said whole tree of life relying on a misconfiguration of that building block?
This is wildly unqualified rambling on my part, but I wonder if life could develop that is based on that prion form of proteins.
From my understanding, no. But maybe "life developing" is the wrong metric for correctness?
FWIW, The universe itself seems to be dead-set on entering the most stable configuration of everything.
That's a little like saying broken pottery is the more correct form of plates. What you're describing is the lower energy/higher entropy state, and yes everything heads in that direction because of thermodynamics. In general, life is a temporary state of higher energy achieved in exchange for waste in the surrounding environment; prions are useless because they are disordered not in spite of that.
I love the hypothesis. It would be interesting if there was research in longevity where proteins that often degrade into unfortunate forms could be slightly modified for self repairing, and bigger resilience to damage. Of course that sounds a lot like a cancer..
I like this take. With its reduction to “survival of the fittest” slogan, it is easy to forget that Evolution can be “subjective”, imprecise in the problems it is solving.
I'm glad they are making some progress partly because my sister has ALS and there may be similar mechanisms - there seems to be some protein folding malfunction at play in that too. So far there's been very little progress with anything like that.
There was a youtube recently I think on the same trials https://youtu.be/wuXip1SCJGs
I've seen prion disease up close with someone dear. I couldn't sleep thinking about what could have been going through their minds. It was 6 months of torture, and if I were in the same situation I'd have preferred someone switch me off.
I remember reading about Sonia Vallabh (and their race against time) - I'm so glad they're getting somewhere. Kudos.
Prion diseases are one of the scarier things I've ever heard about. It is transmissible via fluids, but it can also just happen spontaneously in your body, and once that happens, it's basically a death sentence. There is so far still no cure.
If this works, this will be a game changer.
It sadly sounds like it targets RNA for the production of all prion proteins (a somewhat important protein for normal brain function, but not essential) and doesn't do anything to clean up existing misfolded proteins. Even if successful, it will probably have side effects.
Looking at the list of observed changes in mice this can be anything from destroying the sleep cycle to general memory problems.
> Even if successful, it will probably have side effects.
> Looking at the list of observed changes in mice this can be anything from destroying the sleep cycle to general memory problems.
Prion diseases guarantee certain death right now though, so the side effects would need to be pretty bad for them to be worse than the disease. Even just delaying death by a few years would be pretty good, since most people die in under a year [0].
(This is somewhat similar to chemotherapy drugs, which also tend to have pretty bad side effects but are still generally accepted as better than the alternative.)
[0]: https://en.wikipedia.org/wiki/Creutzfeldt%E2%80%93Jakob_dise...
It would be interesting if they pair it with something similar to CAR-T but targeting a specific marker in the misfolded protein.
Oh no way is this that Indian origin lady that had this genetically and was essentially guaranteed to die in her 40s/50s so she upended her entire life and pivoted to finding a cure for this? If that’s the case, I am blown away and amazed that they even have a candidate for human testing.
Prion disease is one of the scariest things I’ve learned about. I’m always careful not to eat meats from shady establishments.
Prions are one of the scariest things to me
What Sonia Vallabh and Eric Minikel have been working toward since her diagnosis in 2011 is truly inspiring. The drug candidate was developed by Anastasia Khvorova and her lab at UMass Chan Medical School, in collaboration with Vallabh, Minikel, and their research teams.
What makes this effort even more remarkable is their commitment to sharing the drug development process openly, including an IND filing that would typically remain confidential.
Whatever the eventual outcome( I’m optimistic) about the possibilities, the journey, the data, and the knowledge shared along the way will be valuable.
This is not just about developing a drug; it’s about making science more transparent, collaborative, and accessible for everyone working toward the same goal.
Let's say her name again! https://en.wikipedia.org/wiki/Anastasia_Khvorova