Disclaimer & Corrections! > > > > > 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.

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.

I had a brain eating amoeba one, poor fella died of hungry

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.

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?

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.

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.

Ahhh, prion diseases. Nature's angry origami. Another awesome video, by the way.

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.

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

phy does a good job on being informative while having a personality at the same time

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)

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

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!

This video got teased more than gta6, worth the wait

idk why but those sad prion faces are so funny.

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.

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!

11:00 omg i love the fubuki reference. XD didnt expect it at all

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.

Watching this like I haven’t read every article about prions I could find

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.

I was not ready for Lichen Roxas..

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?

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.

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

3:31 Netherland jumpscare

This is so engaging and informative at the same time. I love these videos!

When he said "domain..." My brain went full autocomplete thought "...expansion".

Watching this while waiting for my delicious looking cheeseburger is cooling down from the microwave. Wish me luck guys.

this is why I never eat other people's brains

Not only are you making long form educational content, youre also funny asffffff!!. good shit bro!

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!

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.

super cool how prion disease just keeps increasing among cervid populations in my region and hunters just refuse to test

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.

If prions weren't already discovered, they would be considered too absurd to really exist

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!!

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

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)

We love you man so happy it’s finally out I’m gonna put it in my biology class group chat

Thank you for the tism food

Very high quality video. Informative and entertaining at the same time. Your channel will certainly blow up sooner than later 👍

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 😂

Can’t we just create artificial proteins that can unfold the bad proteins or reverse the folding of the ones that got folded wrong?

8:46 SBEVE :(

Thank you for taking steps to demystify these things!

it would be great if yeast could be developed as a delivery mechanism for anti-prion strategies. Especially if the yeast that did it was S. Cerevisiae. I would love to have a doctor yell out GET THIS PATIENT A PINT O' GUINNESS, STAT! That would go a long way toward fostering trust between patient and doctor.

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

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.

Thank you so much for the video, I have tried to keep up with development around prion diseases, but I learned several new things here. Awesome work, thank you.

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.

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

Glasses are very versatile.

loved the experience as a first time viewer, but as a biology student the bit about evolution eliminating a useless & potentially harmful gene made me actually gasp and skip back to see if I'd misheard. Bestie NO. Even putting aside the assumption that an average animal's DNA isn't overwhelmingly junk and leftovers, prion diseases are not common enough by far to be under much selection pressure. Even more importantly, as far as I know most of them would never even be subject to selection pressure as their symptoms are delayed enough that most organisms affected would have offspring before being killed by prion disease. Thank you for coming to my TED talk

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.

New drinking game: every time he says the word "incredible," drink.

I've been waiting for this for so long

Anything that exists can be destroyed. I wholly and completely reject the idea that _anything_ is indestructible or incurable.

It's like PFAS but for biology

I love detailed talks about proteins and prions, Thanks for the thorough and informative Video as always 😎

Glasses are also cool because they help me see!

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.

Amazing videos dude. Your well on your way to becoming a huge name in the science space 😊

I thought ingesting prion will make me stronger, but then I remember overexcited neurons may cause seizures.

Ah fubuki truly is influential even science youtube cant escape her

Imagine if just thinking about prions could cause them to deform.

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)

Always reminds me of a certain book I read (won't say which one for spoilers) where at one point a team of explorers lands on a new planet. Everything there looks good for complex life, there just isn't any, yet. But there are a whole absolute shitload of prions! And by the time the people down there figure this out, it's far too late for anyone who even made contact with anyone who went to the planet. It's bruuuuuutal. Anyway this video was great to explore a little more in depth what's actually going on. I don't know but it makes it a little less freaky?

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!

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

I wonder if the existence of the prion doppelganger is related to why the brain is so sensitive to prion missfolding to begin with

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.

great video. didn't expect sbeve to interrupt an otherwise disturbing topic :P

Ngl, read the title as "Are PRISONS truly impossible to destroy", I was thoroughly confused until you started talking about mad cow disease 🤣

"I am pausing here to allow you to pick up the pieces of your surely shattered brain" Wow this is an mind blowing discovery!

YES, the ubiquity of solid knowledge available on KZfaq is mind blowing ❤

studying histopathology which just saw amyloid stained slides a couple of weeks ago, i cannot imagine what would brain tissue loaded with prion look like, already seen the scary signs of metastatic cancer and that is already confising for me to figure what the tissue is supposed to be

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.

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 thought that it said ‘prisons’ and I was like ‘tf yes u can destroy prisons?’

I think it’s important to note that it has such a long incubation period and such a strange way of spreading, it could just show up and can lay dormant until you’ve reproduced. So people wouldn’t necessarily die out fast enough. So any benefit of it seems to be just accidental

Oh boy! Natural horrors beyond my comprehension! A perfect video for my lunch break.

I thought this was going to be about deconstructing prisons

What about just boosting the ER's fixing output to negate the exponential effects of a prion disease?

I'm not a nerd or anything I mean I'm 16 but this is super cool and informative and entertaining

Nowhere near impossible to destroy, they’re just more resilient than your brain, which basically means your brain will be toast by the time whatever you’re doing affects the prions.

The Nagasaki mouse sounds almost exactly like what happens when you fix a bug in a program after double checking what you could have sworn was everything, only to find you've spawned three far worse errors which you understand even less.

Jeez, imagine if something like rabies was a prion disease? That's the ultimate nightmare disease!

reminds me of huntington disease where the DNA goes CAG an inordinate amount of times and there is a delayed brain issue (Though many other diesases are also delayed like hepatitis or TB or whatever) However thankfully it's only transmissible genetically

Just subbed for a 1000yrs of life!!!

I am quite surprised that nobody has tried to make an armor(figuratively) out of prions given how strong their beta sheets are

Wow, functional prions!!! That's incredible!!!

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?

A NEW VIDEO LETS GO!

The brain is the most important organ in the body, according to the brain.

You keep saying "the" prion. I thought prions were a whole category. Are they actually a specific molecule only?

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.)

Have computational groups looked at predicted structures for the misfolded prions?