Are prions truly impossible to destroy?
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- Опубліковано 12 вер 2024
- Prions are some of the most terrifying biological agents out there. Here is a video detailing (almost) everything I could find about these special proteins.
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A note - I refer to the science of prions as being cool multiple times throughout the video. That's not to say that prion disease is cool, because human suffering isn't cool. But the work that went into figuring out what the prion protein does IS COOL.
Corrections:
1) The ION717 antisense oligonucleotide might not have a mechanism to destroy the prion mRNA, instead just blocking the native prion mRNA from being made into protein by blocking the ribosome. I kind of assumed it would result in the eventual destruction, but the way I worded it was kind of imprecise.
Clarification:
2) Some comments have pointed out that evolution does not necessarily prune "useless proteins" - that is correct. However, because the major prion protein is decently well conserved across mammals (and some birds) - and the fact that there are structural elements conserved across these species, could lead one to hypothesize that there is a function for the prion protein. I realize I could have made that point a bit more clear - it does not contradict what these commenters are saying, but rather provides more context as to why I chose to communicate the way I did. Paper referece: www.sciencedirect.com/science/article/abs/pii/S0022283699928310
3) Any reference to "healthy prions" refers specifically to the correctly folded protein product of the Major Prion Protein gene. I shorthanded it which, now I see, can lead to confusion.
** one more correction - ION717 is not a traditional mRNA - I don't think it actually codes for making a protein - it's function is to bind and disable the body's mRNA for the prion protein - oops!
An antisense RNA/DNA is a sequence of nucleotides that is a complementary copy of another sequence of nucleotides; in this case, ION717 is the complementary strand of the diseased prion mRNA. Hence "antisense" - just like how a "codon" in an mRNA matches with the "anticodon" of a tRNA.
Sense and antisense strands combine to form a double helix, and when mRNA forms into a structure (e.g. a double helix), it basically becomes useless - and useless stuff are eventually broken down by the cell.
@@phylumchannel antisense RNA or siRNA?
An antisense oligo-/polynucleotide is a complementary sequence copy of a given RNA/DNA sequence - in this case, ION717 is the complementary strand of the prion mRNA; it's the same thing as the codon-anticodon relationship between mRNA and tRNA respectively. Sense and antisense strands combine to form a double helix. When mRNA forms into a structure (e.g. a double helix), it basically becomes useless; anything useless eventually gets digested by the cell.
@@phylumchannel Phy! Im back! And I'm so glad you touched at least a little bit about the sickness I was talking with you about, best gift i could get after regaining my freedom.... Love you buddy!
I worked in Hospital, repairing medical equipment.
A room on the ICU floor was suddenly closed off..."DO NOT CROSS" tape, Maintenance installed a lock on the door.
Over the course of a month, they stripped out all the dry-wall and flooring before rebuilding.
We were never told exactly why they went 'scorched earth', but prion disease was everyone's guess.
@@pirobot668beta They do all of that to keep prions away? I thought you only get them from eating something
@@genevievewalsh2007 no chances taken, it's something that cannot be cured nor slowed, nor stopped.
@@genevievewalsh2007 Airborne transmission isn't observed in nature but it's been demonstrated in labs so it's possible. Since the onset is so slow and subtle, any possibility, however slight, demands incredible caution otherwise it could be allowed to spread for decades before detection.
@genevievewalsh2007 the moment you get a prion disease, it's a matter of when, not if, you will die.
@@StephenRWilliams I wish I could go back in time and never read your comment to learn airborne transmission is a possibility :(
Honestly the fact Prion disease is so slow acting is scary in of itself. You could have eaten tainted meat years ago and not even know it.
It is actually so slow I wouldn't be surprised if a large outbreak did happen once but everyone involved died of old age or other diseases because the prion wasn't going to act until like way past the average human lifespan of the infected persons so no one ever noticed and because of how prions work, that one community if isolated likely died down entirely without ever knowing the danger they were to the world and sedimentation and other forces probably buried all that dangerous material or it has been scattered so far between samples that the likelihood of a modern human eating that one patch of dirt or grass containing it is borderline ZERO.
@@user-xx7kl7sr6i Dude, learn what a period is
@@user-zn2ub8zs5l you should learn to he nicer.
@@user-zn2ub8zs5l learn to read without them
he used ine
With the prion outbreaks among species of deer in the continental US, I have heard it could take up to 40 years for prions to eventually degrade. The intro mentioning incineration made me wonder if a lack of wildfires correlates to persisting outbreak sites?
That's an interesting hypothesis!
Wildfires do regularly reach temperatures that can incinerate prions, I guess it would depend on how deep into the soil those temperatures go.
Someone ought to look into it
@@bjorntheviking6039 I microwaved a cookie for too long once, I got upset and I looked at the cookie and noticed something awesome. I could see the embers traveling through the inside, I ran the cookie under water and a bunch of steam came out. I have heard root systems act the same, and with how big and spanned they are I imagine those temperatures reach very deep.
The only bad part is that the same phenomena doesn't really happen in human settlements.
I had a brain eating amoeba one, poor fella died of hungry
Oh noes
Took me a little too long to get this😂. Maybe I'm in the same boat as you😅.
greasyRFKjr
My condolences for your loss, sir or madame/in between. I truly hope such a tragedy can be avoided in the future. Perhaps they are in a better place now, beyond the cesspool that is your brain.
(I feel really mean about that last part but i wanted to subvert expectations aaaa-)
OVERUSED JOKE
What surprised me the most about prion proteins is how relatively rare they are.
Given the sheer probabilistic space there is there are a LOT more possible "metastable" states vs fully stable ones.
The fact that only an handful do lead to this kind of "metastability collapse" is extremely puzzling to me.
Probably is an evolutionary trait, if a biological lineage detects a DNA sequence tends to create metastable forms, it will eventually shut it down, while sequences with really low probability of depeloping a metastable form will be kept via natural selection
I think you got them confused... Prion proteins are the more stable ones. The healthy proteins we actually use are the meta-stable. This is the only commonality in all prions. They are more stable(existing in a lower energy state) than the normal folded protein structure. The currently understood hypothesis in how normal folded proteins transform into prion proteins is even based in that.
@@nicholasfigueiredo3171prions have high thermodynamic entropy, as evidenced by their disordered amorphous structure in bulk.
@@KrashFries yes? English is not my first language but in what way what you said differs from what I said?
@@Koroistro They use to be rare, if you look into it there seems to be a recent jump in the number of people with Prion Disease popping up.
If anyone is wondering why strong neural connections can be a bad thing, let me pulm out what I learned in neuropsychology: the stronger a neural pathway is, the harder it is to undo or change. As we grow up and learn as children, our brain makes more and more pathways, but as certain stimuli are encountered more often and as some behaviours are repeated, some of those connections strengthen while others weaken or fade away. As we age, we tend to have fewer and stronger connections. And while this allows us to take shortcuts, go on autopilot and so on, it also means that we are less adaptable.
Does too many strong neural connections lead to results like schizophrenia? Sorry if thats a dumb question. Im just a non doctor curious about prion diseases.
@@lucianaromulus1408 no, there’s no correlation and all he is talking about is simply the plasticity of the brain weakening as you get older. Essentially, your brain maintains and promotes axonal pathways between neurons (the connections between neurons) that are being used and therefore there’s this thing called “long term potentiation”, in which neuron signalling becomes quicker and more responsive. A “strong” connection is like knowing how to play piano after years of practise, or eating or even walking. We all have these neuronal and motor pathways in our brain. Schizophrenia is a complex mental illness with a plethora of causes, involving both a combination of genetic and environmental causes, nothing related to those connections.
@memesix5440 isn't Schizophrenia tied to too much Dopamine? I was just wondering if an overly excited connection could contribute to similar outcomes. If not...how is that expressed in a person? He illustrated in the video that too strong of a connection isn't ideal either.
@@lucianaromulus1408 the monoamine theory has been debunked pretty thoroughly
@@lucianaromulus1408 Schizophrenia is tied to too much dopamine in certain parts of the brain (or so many think at least). If you just have overall stronger neural connections everywhere in your brain, you will probably just be more stubborn, not Schizophrenic.
Ahhh, prion diseases. Nature's angry origami. Another awesome video, by the way.
@@HexLabz underrated comment
😂😂😂 aka the deviant folds
Biological analogue to "false vacuum decay"
The Vallabh and Weismann labs recently published a great paper in Science on a tool they developed, called CHARM, that could silence up to 80% of prion gene (PRNP) expression brainwide in mice - this likely surpasses the therapeutic threshold for delaying and even (maybe) reverse symptoms of prion disease. The tool was introduced to mice brains by a viral vector and they even designed the encoded tool to silence its own expression (to reduce off-target effects) after silencing PRNP. More work will need to be done to show how this affects actual developing prion disease and to show minimal off-target effects, but this is a really amazing new approach that has potential to be applied in humans.
@@cjdabes yes, knockout is very effective in blocking disease. However the lack of normal gene function comes with side effects in humans. If the disease is fatal, then side effects are more likely deemed acceptable.
@@kirby145x I agree. We don't know how PRNP silencing affects humans, but murine studies suggest it's a dispensible gene, though some evidence exists for a function in neurons for the native prion protein. Nonetheless, if CHARM-based silencing were ever an approved therapeutic for humans exhibiting prion disease symptoms, I find it hard to believe that those suffering from the disease wouldn't be completely willing to try this modality, given that prion disease is uniformly fatal and has no other therapeutic treatment to reverse symptoms or stave off the progression.
@@kirby145x Well it's sure fatal.
Truly amazing
@@kirby145x IIRC removing the normal protein in mice has effects on memory, among other cognitive symptoms.
i live in an area where chronic wasting disease is present in our deer population. we've been told that meat from infected deer is safe to eat, but i've avoided it regardless because potential big scary (i know that there's been some research that shows that it's highly unlikely for cwd to be transmissible from animal to human, but i'm overly cautious). one of the things that skeeves me out about cwd is how contagious it is and that it seems to be able to spread through indirect contact. getting into pure hypotheticals, i've spent many a bored moment thinking about how cwd might present in humans, and even more time spent freaking myself out about the general idea of a prion disease that is contagious between humans in the same way cwd is between deer. definite amygdala pressing there. on the other hand, it seems like the spread of cwd has created strong interest in understanding the disease and how to control it, leading to a lot of new and ongoing research. i know that i'm far from the only one eager to see if the research of cwd offers opportunities to better understand and potentially treat other prion diseases. it would be incredible to find more potential options, like ion717, that could open the doors to treating these diseases
My thoughts exactly. A month ago it randomly occurred to me at work what a nightmare human CWD would be. The fact that common disinfectants like sunlight and boiling things don't touch the stuff gives this a perfect 10\10.
Really hits home in what a fragile state we as humanity all are in. Eggs and single basket and all that. Time to settle space already!
if its gone from cows to humans, I wouldn't be surprised if it could go from deer to humans
@@raffishrabbit hey man, keep it up, you may be proven right but you're preventing yourself from being a *potential* patient. maybe you're being paranoid, maybe you're not, never risk getting any disease especially one as potentially deadly as CWD
Idk, I know nothing about the mechanism how it even spreads. I couldn't find clear info on it. For example, do you have to worry if you know someone who had cwd, in your town, at work, someone who lived in the same building as you or the same room ? I get that it's very persistent in the enviroment, but what does that mean ? I touch a door knob after a sttranger who unknowingly has it and Im done, or I have to feast on an infected brain to have a 50-50 chance ? And what is the load you have to get ? just one misfolded is enough or you need to be exposed to a large chucnk of already accumulated gunk directly to get into danger ? How does it enter, how it gets to the brain ? and what with the sparatic cases, genetical disposition might be enough ? I heard that a significant amount of ppl might be infected (especially in Britain) and this could be an unrevealed reason for many case of elderly dementia. This I know very speculative but scary thought indeed.
Work that amygdala!
phy does a good job on being informative while having a personality at the same time
Thats a lot of work, for a single cell.
Agreed, subbed!
Npc comment 🤡
@@auronxnpc moment lmao
@@jakebrouillette8268 wrong comment section, nobody is gonna pay attention to what a pseudoscientist says, good luck
I’ve always been so fascinated by prions back when I played Plague Inc. Prions, thru our lack of understanding, felt like it was someone’s anime OC in disease form. It’s not a bacteria or a virus. It can’t be cooked out. It’s part of our body? But then if it’s a disease then it can take years to form and there’s no cure but only because it’s protein and not a traditional sickness. The more I know the more questions I have. It’s an eldritch horror but it’s real and more research is needed.
fr they’re literally an anime OC. It’s cringey as hell now that you think about it.
Its the biological version of the Strange Matter apocalypse or false vacuum collapse, where the more stable version simply converts anything around it to this more stable but life incompatible state
And much slower. Not sure if that's better or worse tbh.
yo!
The fact that I'm getting the references...
Ah yes, black holes
not life inconpatible actually, as we've seen, most species would survive a prion apocalypse including humans. we would just stop making prion protein as a species until it leaves the enviroment.
prions are so interesting and absolutely terrifying to me. like it’s a miniscule nearly impossible chance but technically a protein could randomly misfold at any moment and then you have to watch your own mind deteriorate until you die and theres absolutely nothing you can do about it. i know mad cow disease outbreaks are extremely rare and they do everything they can to watch for and prevent them but i still get a bit paranoid about eating beef. imagine dying in a slow, painful, deeply upsetting way because you got mcdonalds 😭 (sorry, hope this isnt considered trauma dumping or against any of the rules, please feel free to delete if it is)
@@bugfriend24 yes. And its a disease with a higher mortality than rabies.
Bro i fucking love meat but I dont know if i want to meat ever again. Wtf is this bss
Saaaaame
they don't have an infectivity mechanism, they can't evolve to spread because they didn't evolve at all. the misfold has been possible since the first time the protein was ever folded which was probably millions of years ago, it's a fire that can never spread. probably affected one family at a time throughout most of history, like oh did you hear about the Jorgensens, evil spirits got them and their cattle wandered off - and that would be the end of it. industry's ability to distribute it's mistakes is what's terrifying. what you feel for prions I feel for TCDD and BPA and stuff lol.
@@jgsource552 Don't worry you can still get it from plants that came into contact with infected creatures. Or water downstream from a source, and it persists in environments for years.
this is why I never eat other people's brains
The only reason?? 😰
This video got teased more than gta6,
worth the wait
Prion diseases are more frightening than rabies because they're a slower, more agonizing death, and it doesn't matter when you discover you have one- you're toast. You can't really "vaccinate" in any way either, even if you think you've been exposed. Whereas rabies has a few treatments with negligible but not zero treatments that may help you survive until it passes if you get diagnosed super early but post vaccination stages. Plus the ability to vaccinate if you think you've been exposed within a certain window. Rabies still scares the ever loving heck out of me though. Like holy crap is it bad.
To me, I think rabies is scarier. The long incubation period for prions means you can still live a full life without ever knowing while rabies symptoms start alot sooner.
@@skeletor2994 rabies can take years, it just usually doesn't. Either way, you're more likely to have an idea that you were exposed to it and there's steps you can take if you act in a timely fashion. Not so much with prions.
Disagree. Rabies is much less scary because first, you have to encounter an animal with rabies, and come into contact with it, and then be dumb enough not to see a doctor afterwards because the vaccine is basically guaranteed to save you. Prions, on the other hand, can sporadically happen to anyone at any time (as far as we know). Once you get the first one, your death clock starts. And you could have some inside you right now, slowly but unstoppably making their way to your brain. There is no miraculous chance of recovery. Even the infamous rabies has an infinitesimally small chance of recovery (I believe there are about a dozen recorded cases of recovery in history). Unless Jesus himself descends from the clouds and personally heals you, your fate is sealed if you have a prion disease.
True, and I'm not saying Prion isn't scary. personally, i find rabies scarier.
@@sigiligus not agreeing or disagreeing with anything you said, although there have been cases where people are bitten by bats infected with rabies and not even realizing it. I'm not sure of the specifics of the situations, but I could see situations where that could potentially happen. So, not ALWAYS stupidity, sometimes it's just that someone doesn't know until they start showing symptoms, which by then it's far too late to do anything.
idk why but those sad prion faces are so funny.
Watching this like I haven’t read every article about prions I could find
I’m obsessed with them I wish there was more to read about but obviously it’s great that they are so rare lol
They made me consider switching my line of study from chemistry to biology
11:00 omg i love the fubuki reference. XD didnt expect it at all
@@r1ppl3_13 was looking to see if someone else got it
There is a woman named Sonia Vallabh (she is of Indian descent hence this uncommon family name) who herself has an extremely rare monogenic prion disease that has not gone symptomatic. Despite having no STEM background (Juris Doctor, Harvard Law School), she went to a very unusual way to become a medical researcher and tries to develop a treatment to prevent the onset of symptoms. Her approach is somewhat unconventional: to reduce the amount of normal prion protein in the patient's body as much as possible. I am sceptical of this approach because all we know about the seemly "uselessness" of normal major prion protein come from mice (and you know what a infamous joke of "IN MICE" is in basic research). What if the normal major prion protein does have cruicial biological function in the human body and humans cannot live without it safely? Even if that is not the case, what if there is no safe ways to reduce the amount of it?
Correction:
While Vallabh and her husband did come from the world of law, they DO have a STEM background since they got their PhD's from Harvard in Biological and Biomedical Science.
Also, Vallabh and Weismann just got their recent groundbreaking paper published in Science IM which they developed a compact epigentic editor called CHARM that could be introduced by a viral vector (AAV) and silenced up to 80% of prion gene (PRNP) expression brainwide in mice - this surpasses the threshold for a therapeutically relevant reduction that might delay and even (maybe) reverse the symptoms of prion disease. Truly a cool new tool for scientists at the bench and, perhaps eventually, at bedside, too.
@@cjdabes they didn't have stem backgrounds, they both went back to school after the diagnosis, I believe
@@biggiecheez6879
Going back to school to get a PhD in Biomedical sciences is called gaining a STEM background. I was correcting the original commenter because, as written, they implied that Vallabh and Weismann became medical researchers without any actual STEM background and training - something you cannot realistically do in the modern age of molecular bioscience. They became researchers while acquiring their PhDs and then founded a lab thereafter. I did not omit the fact they changed careers, I clarified their career path.
@@cfromnowhere Okay, but the alternative is dementia and death. Even if the approach doesn't work, it's still testable and a potential solution.
@@biggiecheez6879 having no prior scientific background then? although yeah, I think "getting a PhD later in life as a career change" is enough of a different thing from "no scientific background" to get that separate description
This is a REALLY good video!! I work with other neurodegenerative diseases like Alzheimer's on a molecular scale and the problem is nearly identical (except the fibrils are with a protein called Tau instead).
Love that this video feels like a review paper for a general audience- something sorely needed in science!
That's a perfect way to describe what I'm aiming for! A review paper for the public!
Former anatomist here; I was always terrified of doing brain recoveries or anything that would require us to open up the skull. Not to mention, the countless times we'd have to sever the spine with our scalpels. Cutting myself was my biggest fear of all. Fortunately, I never did, but a few of my coworkers had sharps incidents.
This was INCREDIBLY interesting but I couldn't help but think you sound so much like Saiki's EN voice actor that I just imagined this as being an extra long internal monologue gag from the anime.
Hi phy! Thanks for your video, as always :) I'm one of the many people working on software for TEMs, among which is the team responsible for developing next-gen cryo-EM technology (unfortunately cannot give much details on it). It's great to see some practical applications of what the machine will do, and how it can advance science!
Cryo-EM is wild!!
honestly this video has given me hope so far as it showed how some protein can act as basically prion resistant replacements with the rats
I was not ready for Lichen Roxas..
rocksas
3:31 Netherland jumpscare
Legit
@@tommyatomic222 the verstappening just won't leave us alone
Watching this while waiting for my delicious looking cheeseburger is cooling down from the microwave. Wish me luck guys.
Come back in 12 years if your brain is still working!
Cheeseburger out the microwave?
This is so engaging and informative at the same time. I love these videos!
The "professional hyperfixator" is accurate, you be at least a little crazy to thrive in scientific research fields :p
Also as a current highschool student with no power to develop anti-prion drugs, I've thought of 2 ways to try and cure prion disease and it's nice to know that I'm not the only one who thought of them and that there are still some people working on a cure! (my ideas were a counter-prion that folds all misfolded proteins into a functional state, and molecular machinery that can un-misfold the proteins)
Cool video, you got a new subscriber!
That's probably a lot better then my absolute hail mary idea of figuring out a way to absolutely mess up and you and the problem-prions, and just hope you don't drop first
Essentially a synthetic nano-machine constructed to only bind to the prion and enzymatically force it back into the proper conformation
Potentially start with chaperone proteins, then alter their structure and target sites to generate the desired effect
🙏🏽 I hope you go to school for molecular Biology or biochemistry and follow through on that curious hypothesis
Potentially possible with AI protein design !
@chupacabra304 the solution doesn't have to be some techno nonsense 😭
Not only are you making long form educational content, youre also funny asffffff!!. good shit bro!
I misread your name as "phil the neutroPHILE" and thought it was some clever deep layered chemistry joke i couldnt decipher and then realized it said neutroPHIL
The fact that any of this stuff is how life works is mind bended. Poor mice tho. People should give more tribute to the creatures crushed under innovation and knowledge
I think the thing that scares me is this. There are certanly misfolded prions in our food but we believe they are harmless. But what if they are just mostly harmless.
If everyone that touched lead instantly became stupid we would have known about lead's effects on the brain from antiquity. The fact that it's not fast or dramatic made it hard to realize. By the time we figured out what was going on we had painted our homes with the stuff and were burning in in our gasoline.
The cognitive problems caused by lead were not binary either. We should assume that everyone has had a non-zero cognitive reduction because of environmental contamination.
We may look back and find prions causing small cognitive problems to nearly all humans.
The Flynn effect has reversed in recent decades.
i'm pretty sure we had a non-zero cognitive reduction because of enviromental lead since the dawn of life, lead has always been precent in our enviroment, the gasoline just made it a relevant problem
@@georhodiumgeo9827 The thing with prions is that unlike lead, they induce progressive, irreversible disease. There is no such thing as a small but stable cognitive reduction there.
@@DoveringFifths wat
When he said "domain..." My brain went full autocomplete thought "...expansion".
Go back to bed Gojo, your losing it again
@@lancerhades971 Go/Jo
Flopping same my guy
my dumbass also mentally thought "expansion"
Domain expansion
Rapid multiplication prion !
🙏🏽
@@chupacabra304 domain expansion. Imperfect embodiment of replication!
Thank you for the tism food
Bone apple teeth
super cool how prion disease just keeps increasing among cervid populations in my region and hunters just refuse to test
do they just... not care if they eat CWD venison lol? i know theres never been an instance of it infecting a person but we dont know that its impossible (esp in the future when new variations exist) its just not really worth risking
@@BlisaBLisado you test everything you eat for every possible pathogen?
@@alexmason5521 if you're catching meat and giving it to others it's your ethical responsibility to at least test it
@@alexmason5521 do you think prion disease may be a bit more severe than something like e coli
@@alexmason5521 sending the deer head for testing is pretty normal and if nothing else you should do it because it helps us keep track of CWD rates in different areas. i dont know why you think thats an absurd thing to do lol
We love you man so happy it’s finally out I’m gonna put it in my biology class group chat
Thank you for taking steps to demystify these things!
Awesome video. I love biochemistry and have always had a thing for Prions. Your video is so indepth and up to date, whilst presenting in an pleasant manner and showing cute little animations. Love the video. I will check out more of your channel for sure!!
Ah fubuki truly is influential even science youtube cant escape her
I can totally see fungi adapting their "external digestion" to almost every type of biological material. Makes me want to learn about lichen; they're usually multiple types of fungi and algae living in harmony, breaking down whatever substrate they inhabit and enduring anything that blows or washes into their habitat - very interesting.
I recommend you look into the tau protein. It is a functionally unfolded protein in the brain that can form fibrils in a prion-like manner. It is one of the hypothesized causes of Alzheimer. I learned a little about them in uni and from what I remember, they accumulate when their hydrophobic domains cling to eachother, similar to the beta sheet structures you showed in he video. This can be undone by enzymes, but this ability decreases with age. Once a tipping point is reached, they will form the fibrils in Alzheimer's Disease.
Tau tangles are also seen in other neurodegenerative disorders.
@@PipPanoma enzymes?
Awesome video! Explains prions to even a beginner in microbiology. Pathogenic prions are certainly scary, its a miracle we even discovered them! Astounding work.
8:46 SBEVE :(
sbren sbeve
PRIONS!!! Love those things (well I don't, prions are terrifying and I don't want anyone or anything to have them, but they are really cool to learn about)
I’ve always been curious why regular proteins never “fix” prions by refolding them. In my simple understanding of the issue, if the way a prion folds causes other proteins to fold differently, then that implies our proteins are unstable or not in the lowest energy state. If the prion is a form of a protein in a lower energy state, why wouldn’t *that* state of the protein be the one selected by evolution after billions of years?
Great question! Here's my attempt at an answer (mileage may vary).
It's true that the aggregate misfolded MMPP is in a lower energy state than the "functional" MMPP, but the functional version may be in a "local minimum" - maybe not quite the lowest but decently low. A local minimum might need a bit of an energetic investment to then GET to the final, lowest state. This idea is consistent with something I talk about in my recent yeast prion stream (in my Live tab). One hypothesis as to why chaperone proteins both hurt and help the formation of prion aggregates may be due to providing the means to stabilize the partially unfolded (high energy) prion as a template for misfolding.
This video scratches exactly the itch for Cool Biology Shit that is frequently unscratched since dropping my biology major. If someone can IV drip organic chemistry expertise directly into my veins I might go back and get it someday 😂
when you said this was the perfect time to make this video I got a mini heart attack, expecting you to say there was a new prion outbreak somewhere lol
Its so interesting as much as they are scary like, technically this is THE ultimate evolution, it can creat more of itself while being hard to kill
Yet its deadly to everything that isnt itself
i always considered misfolded prions as a new "ground state" in terms of the energy levels. Pretty much they are highly stable because they are in an energy "trough" and you must add additional energy to break them down.
It's like PFAS but for biology
At this pace I feel like PFAS will be a part of biology too.
15:15 so basically after fixing millons, cell realizes there is now billons and says "f it everyone dies now"(they infact did not all die)
@ 18:20, if the trouble is that misfolded prions have such a large interactivity surface that leads them to interact strongly with healthy prions, and healthy prions have a much smaller interactivity surface, one potential solution would be to simply introduce a weakly-binding molecule that prefers to deposit on the interactivity surface and begins to form crystals above some critical mass. When those molecules come into contact with and deposit onto a sufficiently large surface as presented by the misfolded prion, they would then encase the prion in crystal, reducing the interactivity surface towards zero. Which may be what at least one drug candidate was attempting to do, I have no idea. I'm not exactly a chemical engineer or biologist of _any_ sort.
If prions weren't already discovered, they would be considered too absurd to really exist
Speculation on an alternate reality straight from your ass
It’s also great to check the case numbers at the National Prion Disease Pathology Surveillance Center at Case Western University. Still only 300-400 cases a year, reported.
3:23 domain expansion: gene knockout
@@leomonk974 I wasn't watching at the time he said that. I went back and rewound and expected to find a clip of Gojo schooling some lesser being. Sadly I was disappointed...
At this point the prion could've saved itself, but it didn't know two key things: first is that some lichen species can not only stop, but even reverse the growth of prion aggregates, and second, that the humans can artificially produce temperatures of over 1000°C to incinerate infected organisms.
I first read about prions in 1985 in a science magazine while looking for a topic for a paper for my intro to bio course. Discovering all the different aspects of what prions did and at the time they didn’t contain DNA like a virus, yet was infectious, transmissible, pathological, replicated. It was a very Spock moment for me. It was fascinating! And scary. That course was just to get some credits during the summer to make my senior year in college lighter. In early 2000s I deep dived into prions to see what was the current knowledge. It’s good to see new progress is being made.
16:18: Can I just point out how insane it is that we can work out the crystal structure of proteins? I'm reminded of a physics professor I once had who said something like "we have no business knowing what we know." (I may have tweaked his wording a bit, it's been awhile.)
Amazing videos dude. Your well on your way to becoming a huge name in the science space 😊
Can’t we just create artificial proteins that can unfold the bad proteins or reverse the folding of the ones that got folded wrong?
Not a bad thought, but how would you design one?
as it was said in the video, first we need to understand those proteins, which we don't really. we need more data.
Wow, the timing of this video... I happen to be researching about prions for a group presentation, and was having a lot of trouble getting started because of how little concrete information there was for these proteins. This couldn't have come at a better time, thank you!
I've spent the last 3~4 hours trying to read through a 2008 paper discussing the physiology of the prion protein, and I wanted to share some of my thoughts and takeaways from it (long comment incoming, i'm basically using this to brainstorm somewhere that isn't my group-shared document ;u;)
The paper started off discussing the structure of PrPc, then went into its possible ligands and functions within and beyond the nervous system. There was a lot of speculation, proposals, and contradictory data about what role prions play in motor coordination (hi Doppel), memory, sleep (oh no fatal insomnia), and synaptic activity (yummy Cu2+ ions), but also immune cell development/activation (TCR recruitment? APC maturation?), cell differentiation, apoptosis (triggers it? prevents it?), and a few other body systems and organs (namely neuromuscular junctions, liver, and pituitary) that I ended up skipping because it was no longer related to the topic of our presentation. Then it went into a bunch of signal transduction pathways PrPc may or may not be involved in that I also skipped because by that point my brain wasn't working anymore, and I skipped ahead to the conclusion.
Prions are predominantly expressed in the central nervous system, but in humans they're also found on the surfaces of mature and/or activated lymphocytes and myeloid APCs, along with low levels of expression in other tissues of the body. Prions definitely have a role in the immune system as well as the nervous system, but we don't really know what yet. In the passages leading up to the conclusion, the paper noted that PrPc is sufficiently but not always necessarily involved in a wide range of signal pathways often related to systemic and cellular stressors, but studies conducted on the specifics of these return with contradictory results, and they paint a picture of prions having "seemingly unrelated functions in various cell types."
The paper posited that prions may serve as a "dynamic platform for the assembly of various signalling modules," and that kind of got me thinking. For some reason, prions are a highly conserved feature among animals, most notably mammals but also non-mammals too. They're a key feature of neurons, but also show up in plenty of other unexpected places, yet the role they play in these cells is confusingly subtle, contradictory, and random. Also, maybe this is just me, but the structure of PrPc itself doesn't seem all that impressive to me either? Like, it's just three alpha helices, two antiparallel beta strands, and an unstructured domain filling up the N-terminal half of its ~200 amino acid sequence. I mean, I've never taken a good look at any other protein structure, so I have no basis for the impression I got, but yeah..
This is 100% crack theory speculation now that's completely unbacked by any prior research or knowledge, but I wonder if prions are an evolutionary remnant of animals? They might have been more universally expressed across all tissue systems at one point and played a crucial role in starting signal cascades in response to stimuli, but have since lost that significance as organisms evolved better proteins for more specialized functions. However, since they were so ubiquitous, they still stick around today in unexpected places like in hematopoietic stem cells, leukocytes, and most notably neurons.
TL;DR - I read a 2008 paper and learned that the major prion protein isn't only involved with the central nervous system, but also the immune system and probably elsewhere too, but all data delving into the specifics of that is contradictory and inconclusive. I now have a crack theory that prions used to be really important for signal pathways across many tissue systems, but now only take on subtle roles in the nervous (and immune?) system.
None of this had anything to do with Creutzfeldt-Jakob Disease, which was what my group presentation is specifically supposed to be about, so I decided to drop my rant here :T
The massive unstructured region IS an impressive feature! Flexibility can allow you to interact with a wider variety of stuff. Might be worth seeing the list of things the prion protein binds with!
@@phylumchannel Oh, that's true! I forget that there only exists models of the structured domain, leaving out an entire half of the prion protein. Definitely something I should look into more :p
I've been meaning to do some research about the state of prion knowledge for a while, but haven't gotten around to it. Great video! Prions are truly terrifying. Kinda funny but physics has also theorized prion like "strange" particles that could convert all matter in the universe to "strange" matter
Gotta add something about the mylen sheets, these were recently hypothesized by a study to cause some quantum effects that helps us (or straight up causing) gain consciousness
I love detailed talks about proteins and prions, Thanks for the thorough and informative Video as always 😎
1:23 Ah yes, how could you resist from making 2 gaming references at once 😂
9:10 Ah yes, rookie mistake is assembler code, but it's DNA 😂
New drinking game: every time he says the word "incredible," drink.
I did NOT expect to see Fubuki's glasses rant in this video about horrifying brain diseases but I'm here for it.
Interestingly enough i was diagnosed with a radical protein/prion caused cancer when i was 17 and i was allowed to spend time in labs manned by some of the best oncological geneticists in europe; and it was frankly amazing !
I got to study my very own genes beside them, and witness some of the most experimental treatments in oncological in development.
I just wanted to drop in and comment about the drug resistance, typically when drug resistance occurs in bacteria or viruses, they lose resistance to another drug, so maybe a possible solution is to find another drug that uses another mechanism, and to treat with a combination of drugs simultaneously, since it is unlikely the prion would be able to adapt to both simultaneously. It would at a very least increase the amount of time that an anti-prion drug would work in a patient.
I've been waiting for this for so long
Glasses are also cool because they help me see!
Very good, thank you. Speaking as a (thank God!) retired doctor with an interest in palliative care this is certainly a 'fascinating' subject.
In an attempt to be positive, if one considers prion diseases aren't just infectious but develop spontaneously the question "Why no prion apocalypse?", is a reasonable one. There must be mechanisms that limit the development and spread of prion diseases beyond the death of the host.
If lichens seem to have such mechanisms it's not unreasonable to assume so do all other (effected) organisms, we aren't currently aware of what they are.*
*Finding out:
-Will hopefully yield useful understanding
-It may even lead to useful means of applying those mechanisms
-Maybe prion diseases are naturally self-limiting in ways we don't appreciate, 'we' do have a history of being undeservedly lucky
...but prion diseases are so 'different' the answer(s) may not be as obvious or seemingly simple as "This treatment will do the job." I have no evidence on which to base this speculation, but if prion diseases have been with 'us' for as long as 'we' have been around their seeming control may not be entirely a function of individual self defiance.
-It may be some emergent quality of the ecosystems that have 'evolved' right along with the organisms that make up life on Earth
i) If this is a physical property, what of the proliferation of man-made environments?
ii) Maybe 'higher' organisms have an unrecognized symbiotic relationship with viruses, archaea, bacteria, lichens, controlling prion diseases... who knows?
In the case of i) it's not unfeasible 'we' could be faced with being forced to dismantle our technological world for complex life to survive - a Fermi paradox solution? Or in the case of ii) we may be faced with having to be much more circumspect with the application of modern medicine, imagine:
Doctor: "I'm not going to treat this infection that might very well kill you because it turns out continuing to do so may bring on a prion apocalypse." As I know all too well, people are usually amazingly unreasonable and selfish when it comes to even the illusion of treatment for their own health, never mind the prospect of letting someone die who you might very well be able to help for 'the greater good'.
There is a hereditary form of prion disease and that notion absolutely terrifies me. You can go years and years without even knowing and then you die in less than a year once symptoms start. Thankfully it is fairly rare, but if one of your parents has it you have an over 90% chance of inheriting it. Anyway, thank you for the video.
Both sporadic and generic CJD is extremely rare.
Glasses are very versatile.
I have been aware of and afraid of prions for quite some time, and I did not know about the hidden gene. Very nice video!
great video. didn't expect sbeve to interrupt an otherwise disturbing topic :P
I went from knowing nearly absolutely nothing about prions diseases to being able to understand how they work and how they could be prevented in the future. Thank you for such an informative and interesting video. (I am not a bot)
In French Prions can also mean "We pray/We should pray". Its kinda fitting for this disease
People seek fear in large doses because fear is both a healthy driver for positive attributes and it also acts as an immunization to properly function during flights of real fear.
Anything that exists can be destroyed. I wholly and completely reject the idea that _anything_ is indestructible or incurable.
@@notsae66 He explained in the first few minutes that infected meat can be incinerated, obviously far beyond the realm of cooking it though
@@j-don5228 Note the "Incurable" part. Destroying the host to kill the infectionnis far from optimal, but I'm sure there _is_ a way to safely destroy this thing.
of course nothing is truly indestructible but things are "practically" indestructible like forever chemicals used in fire retardants or things that dont degrade over a very long period of time.
I disagree with you so much I can’t express it without being rude.
@jackismname One could say the same to you, brings 0 constructivity go the table
Ngl, read the title as "Are PRISONS truly impossible to destroy", I was thoroughly confused until you started talking about mad cow disease 🤣
Very high quality video. Informative and entertaining at the same time. Your channel will certainly blow up sooner than later 👍
YES, the ubiquity of solid knowledge available on UA-cam is mind blowing ❤
That cereal scares me.
The thumbnail is definitely a tf2 pyro reference
Dang! Back to the drawing board.
I'm not a nerd or anything I mean I'm 16 but this is super cool and informative and entertaining
8:40 - sbeve
the image of the mad cow disease fire pits are firmly lodged in my brain from childhood. the horror still has a dark corner of my brain all to it's self.
Oh boy! Natural horrors beyond my comprehension! A perfect video for my lunch break.
15:25 almost bro
I thought ingesting prion will make me stronger, but then I remember overexcited neurons may cause seizures.
Jeez, imagine if something like rabies was a prion disease? That's the ultimate nightmare disease!
No, I don't think I will imagine anything of the sort. Brain, conjure up sunshine and rainbows at this instant!
Is it possible the new alphafold AI could help with this given how little we know about the structure of unhealthily folded prions?
You keep saying "the" prion. I thought prions were a whole category. Are they actually a specific molecule only?
For most of human health we talk about "mammalian major prion protein".
Oh boy. Wow. I felt my blood pressure rise when you said drug resistant prion. That would be horrific
Hey I been researching over prions and disease and disorders over these. I’m currently a student and trying to become a neurologist and I want to make something that can combat prions. One of my ideas is trying to make a chemical that can kill the prions however the down side is it will kill the healthy proteins, Kinda like Chemotherapy. Can something like that combat over prions?
try it
Check out Sonia Vallabh’s research
Main issue is getting your chemical to pass the blood brain barrier (ASOs listed in the video cannot do this efficiently) and that previous efforts to have molecules bind to prion proteins have been inconsistent. More research is needed to determine function of cellular prion proteins (regular, non infectious form) so you can target specific steps in the mechanism of the infectious kind.
Imagine if just thinking about prions could cause them to deform.