Basic Concepts: Prions

We've all heard of Mad Cow disease (bovine spongiform encephaly) in the media. A few years back it was as big a sensation as bird flu and twice as scary. The colloquial understanding of the disease was poor: what it was, how humans (or cows) could get it, what should be done to curb its spread, and whether or not there was any treatment. This disinformation led to small-scale hysteria when it came to beef, with some countries (eg Japan) completely banning all beef from nations that were even suspected of having a "mad cow." The beef industry as a whole took a hit, as pubic perception held that beef was now diseased, and could cause them to become demented or crazy.

Scientists rapidly discovered that "Mad Cow Disease" and its human counter-part Creutzfeld-Jacob's Disease was caused not by traditional pathogens such as a virus or bacteria, but something as simple as a protein. Admittedly, this protein---called a prion---is actually anything *but* simple and studying prion diseases has been dangerous and slow to bear fruit. However, it is fascinating that a conformational change in a protein can wreak such havoc on the brain, quickly rendering it as porous as a sponge and its owner gradually more incapacitated.

(Continued below the fold.....)

A prion is an infectious protein which are hypothesized to infect tissues and "reproduce" first by changing its own conformation, and secondly by inducing other benign proteins to do the same. The conformation that is induced is much larger than the normal protein confirmation should be (called an amyloid fold) and following aggregation of these prions, they can cause damage to tissues by expanding within them and causing "holes" to form.

Normal and diseased prions

Prion diseases are particularly nasty as these proteins are very resistant to denaturing or being broken down naturally, and there does seem to be a genetic component which alters the likelihood that someone would spontaneously develop a prion disease. However, the most common way people develop prion diseases is through transmission by infected animal byproducts. Diseases caused by prions (other than Mad Cow) include scapie, fatal familial insomnia, kuru (the laughing disease), and chronic wasting disease in deer.

The protein that prions are made of is found throughout the body normally(called PrPc), although what their non-disease function is is not yet known. These proteins are encoded by the PRNP gene, and mutations in this gene are responsibly for inherited prion diseases. The disease-state prion protein is called (PrPSc) and is resistant to proteases which would normally denature a protein and render it harmless. The theory of how prions become infectious to other proteins is detailed below.


First a disease-state prion (red) is either ingested or spontaneously created. As endogenous (naturally-occurring, shown in green) body prions come in contact with the diseased prion, they are forced to change their conformation to that of the diseased prion. This chain reaction eventually becomes exponential, with more and more diseased prions changing into an expanded conformation and aggregating, causing tissue damage. Note that this theory, while the most widely-held, is suspected, but not confirmed. Another hypothesis (the Protein X hypothesis) suggests that another unknown protein mediates the conversion of normal prion to diseased prion, however this enabler has yet to be found.

As mentioned, sometimes diseased prions are ingested from already-infected tissue. Kuru and Creutzfeld-Jakob disease are both transmitted this way, by eating the meat or brains of infected animals or people. Kuru was identified in a tribe that often ate the brains of defeated enemies as a ritual, however it had the unfortunate by product of spreading this disease. While proteins are usually broken down and digested in the gut, prions resist digestion and remain intact. Furthermore, they are not normally absorbed into the intestinal wall but rather pass into the Gut Associated Lymphoid Tissue (GALT) and then into the body's main lymphatic system. From there, it is a short trip to the brain where they make a lethal home as the chain reaction described above begins.

In regards to Mad Cow, the few human cases that resulted were due to eating beef (or brains) of cows with diseased prions. This transmission event is quite rare, although one of the reasons that diseased prions were able to propagate through cattle populations is due to the practice of grinding up sick livestock for food for other cows. This had the effect of spreading mad cow at a much faster rate than would have been expected. Mad cow/Creutzfeld Jakob disease is always fatal and its symptoms are progressive dementia and loss of motor control.

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It's been awhile since I've discussed prions on here. (Indeed, so long that the last time was on my old blog, but I imported a few of them that can be found here, here, and some background on prions here). Allow me to copy a bit of that to re-introduce the topic: Prions are, of course, the…

It is a big mistake not to mention that organisms that are programmed with the property of motion,have specific ch. reactions for that.This means that if these reactions are not used,the whole organism is facing a serious it is very unhealthy for someone not to exersize.
entropy of life
1)what is the difference between a man that is alive and a man that is dead?In both cases the body is consisted from the same elements and compounds.But in the first case these compounds are reacting with each other and the structure of the body changes every moment.In the second case the chemical reactions of the body are lead to an equillibrium and so the composition of the body remains unchanged.The structure of a dead man cannot change if there are not microorganisms in its environment.
2)The property of reproduction in living beings that are chemical reactions seems to actually be a result of the energy that forces the chemical reactions to continue happening.Life continues because chemical reactions continue.Reproduction seems to be one of the most ancient properties.
3)The relativity of entropy
What happens with the ntropy of living systems that are chemical reactions?The energy that comes externally on earth in the form of light could explain the lowering of entropy.However ,if in the beggining there where 2 or 3 reactions and after a while there are more and more ,and more complicated, seems that the entropy of the whole living system on earth or else nature, is raising.But remember that previously we said that human is not a neutral observer of things, but he is changing together with the system.This confuses him.What impact has that?It means that if humans entropy is raising slower than whole living natures entropy ,he will think that his entropy is lowering.Its something like relativity of motion.One exaple is this :Imagine a large number of birds that are flying one next to other to the same direction.If we tell them to fly one far from the other,so the group will start separating, the entropy of the system will start raising.Imagine also that there are three birds that are very close to each other,somewhere in the group.If they separate with less speed than the others and we consider these 3 birds as a system,the systems entropy will actually lower relatively with the whole system of the birds.

the illusion of life
1)living organisms normally are not dying because the chemical reactions that are composing them are continuing happening.if we analyze all these reactions we will have a very good view to their homeostasis.As we said we are seeing the world from the inside , or else in a mirror like direction, because we our selves are part of things, so we appreciate things from its results.We think that homeostasis is a very magical and perfect mechanism, because we are the result of homeostasis, but the theory that we analyzed says that homeostasis simply is the cataloge of the chemical reactions that are still happening, and just because they keep happening, the organism is alive.

2)the complex organic compounds that are composing living creatures probably are the results of many years of reactions, or else they are the fingerprints of the reactions from the beginning of all the reactions till today.

3)because human is a very complicated system of reactions that all depend from each other, its very loggical to say that it is almost impossible to treat compeletely a chronic disease with a single drug.The human body is not a car that we fix the part that is wrong and everything is ok.Instead, its reactions are so complicated, that (unless the illness is caused by a foreign agent e.g. a microbe, or by that lack of a substance that can be replaced), if there is a problem with a reaction this will lead to a chain reaction way problem to other reactions of the body as well.This mechanism is responsible for chronic diseases.The only way to treat compeletely this disease is to put back the initial reaction with the problem the way it was.Every other method will reduse symptoms, but not heal.Or it may theat a problem and create another.A good example for this is the treatment of high blood pressure or cholesterol.This are much more complicated that we though, that ever with the proper treatment of high blood pressure or cholesterol, we are not talking about healing, but for statistically significant improvement.Some studies also shows that there is no decrease in mortality even with the treatment of the risk factors.Another good example are rheumatic diseases.No complete cure exists.Drugs have many side effects.One hole is closed, and another is opened. Even in major diseases there is a big dissosiation between the pathogenetic mechanisms that are discovered and treatments.This diference will continue growing if we dont realize that the mechanism that organism works is more complicated.
4)lets come now to the position to answer if the spores that some microorganisms forms(e.g. cryptobiosis,anhydrobiosis etc) are living forms.If their metabolism is not zero, if it exists but it cant be detected because it is so weak, then they dont differ in anything from the other organisms.If their metabolism is absolute zero, then the answer gets more complicated.The fact is that it doesnt matter what it is, because the question is useless.Life as we see it is simply the result of the chemical reactions on earth.As we said ,we are part of the system and we dont realize it, but if we were alien forms of life for example, and we were watching the earth from outer space, then we would see only a very complicated network of reactions that are becoming more and more because of the energy of light.This system would have different structural forms, colours, etc.So, what happens with the spores is that because they face very unfriendly conditions ,the certain chemical reactions stop happening or they are lowering their rate.According to our definition, they are not life, but what is life?Life seems to be more an invention of us,or else a term that we use to describe anything that looks like us.There is not such a thing as life, its an illusion.An organism is the reactions that we see, and we think they are something amazing because we see them separately from all the other reactions that are happening in the world.We judge them from their reult, which is that they become like us.We are a part of the reactions that are happening as well, and while we see organisms that look like us, we think they are independent creatures, but actually they cant be separated from the whole soup of reactions.The spores are becoming as they were before because their reactions start happening, and they start looking like us.There is not such a thing as homeostasis.So tthe existence of their reaction gives the illusion that we called life.5)Another implication of the theory is that because the sum of the chemical reactions is a chain, it means that the cause of a disease maybe come from the organ that has the symptoms, but maybe not.An initial problem causes its irregularity, but depends of the vulnerability of each organ to see in which organ the symptom will be seen, because all the reactions communicate with each other, and when a problem exists its like a volcano and we dont know where will it explode.For example a psychic disorder can cause a problem from the liver for example..
continue from previous
Of course, when we are talking about chains of chemical reactions, we do not mean it in the simplistic way, that they are in a chain, and everything is happening in an order, where the formed substance goes to the next position to react with the next substrate etc. Things in nature are much more random, and it is difficult sometimes for us to detect which is the next step.One of the major difficulties are some passive phenomena that happen, such as plasma flow, passive diffusion through membranes because of difference in concentration, or electrical gradients, excretion throught ducts, etc.The latter are phenomena that happen passively ,due to the laws of nature and are not defining life, the way the chemical reactions do. To be more symbolical, they play the role that scientists play in a chemical lab:they transfer the substances from one tube to another, arrarge the conditions, etc.But the chemical reactions are the big difference.
Of course , if these movements that we are talking about were not there, we would not be the way we are.We are the results of all these , and so it is normal to think that if something was not the way it is, WE would not be there, the way we are!So we think that they are essential for us and everything was arranged perfectly, and if something was a bit different ,we would not be there, but as i told everything depends on who is the observer.We are a changing complex, and everything that happens lead to us.We see things from the opposite side though.It is like we are in a moving ship, and so we realize things differentl from someone who is standing in the port.Most of all we dont have a good sence of our own movement.If we were not in the living system, we would not find any reasoning for all the creatures on earth.Even if we were tables for example, we would think that the most perfect creatures are the tables.All depends on what is the observer.
Of course, the most important question is if we could prove or disprove this theory!Here is an interesting option:If we could make a total thyroi..omy to a healthy patient, and then, by giving him the exact amounts of thyroid hormone replacement therapy, that would allow us to have an optional treatment, and we could show that there was absolutely no increase in long term morbidity or mortality, actually we could disprove this theory that we mentioned ,because according to the latter, a disorder in a series of chemical reaction would not be able to be corrected only by administering just a substance that is part of the series of the reactions!The same thing would happen if we resected the hypophysis and after that we were giving the patient the exact amount of the hormones that the organism lacks.One the other hand, if it was proven that long term morbidity is impossible not to be raised, then the theory would either be prooved, or the thyroid gland serves another role in the organism, except in producing hormones, and thats why the health of the body is distracted even though there is no repletion , nor excess of thyroid hormones.Also, the theory says that there is no healthy organ that can be amputated and this would result in no change in the bodys function.Of course we are not talking about causing a disease, because the occurence of a harm in the organism is not synonym with illness, besause somebody can have problems in his body and only after years they will be obvious in the form of symptoms.

Dear Sirs,
We are currently preparing a new policy brief and we need a picture of the prion to illustrate it. Would it be possible for me to use the pic on the top of this web page ?
In advance many thanks for your reply
Best regards,

Sylvie Prosperi
Communication administrator
International Risk Governance Council

how prion can be a genetic disease?

I'm actually not able to give blood since I lived in Scotland in the Early 90's... stupid mad cow scare. I might be stark raving mad in a few years though ;)

Which is when I really might show up at your door in a Star Trek uniform! I'll let you know when I feel the crazies coming on though so you can prepare.

I stopped eating brains when this theory emerged. There was a Lebanese restaurant next the the Daily Variety building in Hollywood which made great lamb brains. No viruses nor prions for me, thanks.

I did, however, eat extremely tasty beef at low prices in Scotland early in the mad cow panic. Did you know that Scottish investors were behind many of the cattle that featured in the "Wild West" American cowboy era? Or that about a third of the cowboys were African-American? Anyway, my wife and I, both professors, can do cost-benefit analyses rationally. We were willing to let the fears of the ignorant subsidize our lifestyle.

In the same way, we got our 11-room house at a good price in Los Angeles county, because it's African-American population drove prices down due to ignorant racist homebuyers and investors.

Sorry, got distracted by a tangent, from the excellent protein/genetics discussion. I have published proteomics and population genetics. I liked your accuracy, clarity, and illustrations. Well done!

I was going to suggest that someone should eat your brains but I realized they would probably catch your Mad Cow disease.

hmm... perhaps - although mad cow might cause the zombie thing...

Recent beautiful model of studying mad cow in mice resulted knockout PrPc have showed very interesting. See (Mallucci et al., Neuron, 2007, Volume 53, Issue 3 , 1 February 2007)

By Bui Chi Bao (not verified) on 11 Feb 2007 #permalink

Could you please provide a reference for your image of "Normal and diseased prions"? The only structural work I know of Alzheimer's-related beta-amyloid was done under highly non-physiological conditions.

You should mention the prion work in yeast, which is a lot more conclusive than the Alzheimer's work in humans.

The reports of cattle engineered to lack the gene for bata-amyloid are very interesting.

By Mustafa Mond, FCD (not verified) on 12 Feb 2007 #permalink

Umm. Alzheimer's is a different condition. And that one, it seems, may actually be caused by a combination of a common mutation in one gene, which leaves the brain susceptable, and the presence of the cold sore version of herpes. Basically, instead of suppressing replication, the faulty gene fails to inhibit growth of the virus, and it spreads into the brain, which then reacts to its presence by trying to protect itself, which unfortunately does the exact opposite. Now, some other stuff is likely involved too, but its not the same thing as Mad Cow. Not even close.

aggregating, causing tissue damage

Reading this, I was reminded of recently seeing a hypothesis that these aggregates are needle like (with an end as conversion surface and growth zone), and then it hit me: this is akin to a popular scenario in old scifi.

I think Harry Harrison did one, with a generation ship returning after an unsuccessful attempt of colonisation due to a mysterious sickness. Here it was caused by the foreign biosphere carrying small amounts of unfamiliar amino acids, which now contaminates life on the ship. One prominent sign is fiber spikes growing through other tissues...

By Torbjörn Larsson (not verified) on 12 Feb 2007 #permalink

Umm. Alzheimer's is a different condition. And that one, it seems, may actually be caused by a combination of a common mutation in one gene, which leaves the brain susceptable, and the presence of the cold sore version of herpes.

A lot of people are working on Alzheimer's, and everyone one of them thinks they have the inside track to what it's really about, so pardon me if I take your pronouncements with a grain of salt.

By Mustafa Mond, FCD (not verified) on 12 Feb 2007 #permalink

You are correct that Alzheimer's and BSE/Creutzfeld-Jakob are distinct. Sorry if I fuzzed that.

By Mustafa Mond, FCD (not verified) on 12 Feb 2007 #permalink

Fred Cohen lab Prion page

Identifying the structural characteristics of the pathological isoform, PrPSc, is central to understanding the mechanism of aggregation and is therefore key to developing potential therapeutics. While a partial three-dimensional structure of PrPC is known, the extreme insolubility of PrPSc makes it difficult to elucidate structure using classical techniques. However, with the help of electron-microscopy (EM) on two-dimensional prion crystals, recent advances have been made, providing low-resolution images of PrPSc.
The Cohen group aims to use molecular modelling to translate the low-resolution EM data into atomic-level three-dimensional models of PrPSc. This process relies on the combined use of experimental information, the analysis of related structures and computational methods. We hope that these approaches can help understand the biophysical mechanisms underlying prion disease, and other pathologies involving protein misfolding.

Please pardon me also for not being impressed by molecular modeling.

By Mustafa Mond, FCD (not verified) on 12 Feb 2007 #permalink

Feel free to be not-impressed all you like, as it is a model, which they concede. The evidence supports it, especially given that beta conformations of proteins are sticky and tend to aggregate as seen in prion diseases (and in Alzheimer's--aggregates of beta amyloid--to draw a similarity).

especially given that beta conformations of proteins are sticky and tend to aggregate as seen in prion diseases (and in Alzheimer's--aggregates of beta amyloid--to draw a similarity).

If this model depends on circular argumentation, I am all the less impressed.

SB: No, you missed the point. Beta conformations have already proven to be sticky (definitively in Alz. and other diseases) That is known. It is also known that when prions change, they aggregate, where before they did not. That is where the hypothesis arises from. Prions are capable of changing conformation, they are benign in alpha, yet become sticky later. Its a good hypothesis that they assume a beta conformation.

By Mustafa Mond, FCD (not verified) on 13 Feb 2007 #permalink

Creutzfeldt-Jakob Disease (CJD) is a spontaneous prion disease unrelated to consumption of infectious materials. The mad-cow analog in humans is known as variant Creutzfeldt-Jakob Disease, or vCJD.

Probably an ignorant question on my part, but why has "studying prion diseases" been dangerous? Are we talking exposure to the contaminated material, collecting the samples from pissed off cattle, or something more sinister?

Jonathan Vos Post said
In the same way, we got our 11-room house at a good price in Los Angeles county, because it's African-American population drove prices down due to ignorant racist homebuyers and investors.

How are the local public schools? Or have you managed to finesse the problem through a university affiliated school, private school, or magnet school? Perhaps your neighborhood doesnt have those problems. But those problems with declining schools as student IQ goes down and aggression/disruption goes up (combined with a great PC fear of doing much about it), combined with the prospect of housing price decline as others leave for schools reasons, why there usually is some tipping point beyond which white (and Asian) flight sets in. Crime is another concern. Real things that most people wish they didn't have to take into account -- but do. Often in "doublethink" kinds of ways best described by Orwell.

By djexplorer (not verified) on 18 Feb 2007 #permalink

For those students like myself, just learning about prions, "The Family That Couldn't Sleep" is a medically authentic book about Fatal Familial Insomnia tracked through generations of a family stricken with this prion disease. I think if you're fascinated with this subject, you'll enjoy the book.

Thanks for a wonderful site.

I liked your article but there is a wee typo in there. The sheep disease is scrapie not scapie. I also think that you need a little more lay description of "conformational change".

Try this: When I describe things I use the "wire frame box" analogy. You know, the thing where you can't really tell if the corner is pointing towards you or away from you. People seem to get it immediately and think about various folding possibilities.

Nice graphics.

By Brian MacLeod (not verified) on 21 Aug 2007 #permalink

When somebody is studying the phenomenon of viruses ,he can see that when viruses are not coming in contact with a host organism, they are a sum of chemical compounds that not fulfill the criteria to be considered as life.While on the other hand they start reacting with a host, or in other words they start making chemical reactions with the compounds of the host,they become alive.The same thing happen with prions ,which are proteinaceous compounds that while they react with proteins of the host, they become alive in a way.

Lets hypothesize that we make the hypothesis that:No living organism is possible to remain unchanged structurally.Lets hypothesize that this rule is principal in nature and nothing could go beyond it or prove that it is untrue.

What would that mean to the way that we see the world?

First of all lets make clear what we mean: An organism that would remain unchanged structurally dyring a very small period of time,would be considered as not living for that period. When we say unchanged we mean of course that there are not taking place chemical reaction inside it.Maybe there is a single cell inside an organism that is unchanged,but the rest of the cells are changing. We say then that this organism has a dead cell.,but the organism as a whole is alive.Maybe this cell would be able to regain life if it react with the appropriate signals. But maybe not.

If we want to see the consequences of our hypothesis in the nature we meet the question:what is the least that can be considered as life?For example, a mitochondrion can be considered life according to what we said, but a simple chemical molecule cannot,unless it reacts with another molecule or substance.At the moment of the reaction these two substances are the least that is considerd life.So, a simple chemical reaction as long as it happens ,is the simpliest form of life, or else, the sparkle of life.That means that the superior organisms as well as all the organism is a summation of chemical reactions.

The advantages of the hypethesis that we made is that we can explain successfully the prions and the viruses.

Another important consequence of the hypothesis is this:Living creatures are the sum of their chemical reactions as we said.While they are getting older,they are suffering a process that is called aging.They are changing especially structurally.Obviously they are getting different.That means that the chemical reactions that are composing their body,are different from that that were before.If the chemical reaction were remaining unchanged forever,then the body would be the same,and that means that the body would stay forever young and forever alive.

Lets see now a simple chemical reaction A+B}C+D.Lets consider that C and D are gases and are expelled from the place of the reaction.The quantity of A and B will get lesser and lesser because they are becoming C and D,Or else they are suffering a chemical transformation.

Lets see now another chemical reaction:A+B---}C+D--}E+F

Lets consider that E and F are gasses.That means that the quantities of A,B,C,D will be lowering unless we put in the mixture exactly the quantities of A and B that is being transformed into C and D every moment.So there is an exact amount, as well as exact rhythm of adding A and B that would keep the reaction unchangeable.Lets consider now a very simple organism that is composed from the reactions :A+B--}C+D--}E+F--}Y+Z.Lets say that A and B are food supplements and Y and Z are compounds expelled from the organism.Of course the real organisms are much more complicated.If that organism eat theoretically a certain amount of food in acertain way, then the reactions of this organism would remained the same forever.[C,D,E,Fare all compounds of the organism.].If we didn't give the exact food ,then the reaction would change ,dependently on the how far we are from that ideal food .In the same manner we can say that all living organisms are a sum of chemical reactions that start with digestion,and end with the waste products of metabolism.

As a result we can say that in a theoretical basis,if an orgasism eated exactly a certain amount,quality and quantity of foods in acertain way,then it could prevent the changing of its reactions and as a result it could prevent the aging process,expanding its lifespan.Of course this is something very difficult to happen in real life because there are numerous things that plays their role and of course things are not that simple.

One important clue that suggests that what we said is true, is the recent discovery that living organisms that follow a calorie restricted diet,can expand their lifetime, in some cases as long as 60 per cent.This is not a proof that what we said is true,but it is positive to find that the changing of caloric menu has as a result a change in the lifespan.Perhaps a certain diet causes an ever greater expansion.It remains to be proved..

The new hypothesis also says that life existed before the first cell,in the form of chemical reactions

Scientists have accepted that life was originated from a single cell,which was the first cell on earth, and composed the first thing that was a form of life. The evolution of this cell had as a result the formation of life the way that we know and see today. A problem with this idea is that, as we know, if we had just a single cell in earth right now, and out of it there was nothing, then not only this would not lead to the formation of more complicated forms of life,but this single cell soon would be dead.Despite of that,most scientists accept the single cell theory.The new theory that we introduced claims tha tit was not necessary to be a first single cell to start the evolutionary process that would lead to life as we know it today, but says that life preexisted , because even a single chemical reaction is a form of life.The creation of the first cell actually is the result of the existence of life.

Lets see now another problem: In the beginning, life on earth was simplier than today. That means that there was a system of chemical reactions that gave its place to a more complicated one.This sounds a bit strange because if a system of chemical reactions does not get energy from outside, leads to an equilibrium state. If we accept that our new theory is true, means that there had to be an external source of energy{probably the large quantities of energy that comes everyday on earth from the light of the sun that lead not only to the survival of the first forms of life, but also to their evolution.

As we said, living organisms are a summation of chemical reactions.What happens now when they die? There is a disorder in a system of reactions (for example brain necrosis, which means that in a large number of neural cells there is a stop in the reactions that happen there) that lead in a chain reaction way to a disorder in other reactions and then in others and so on.The final result is that there is a necrosis in the whole body, in a chain reaction way.

This means that if somebody with a magic way made all the chemical reactions of the body started working simultaneously,(or else there was an arousal of all the reactions and all were working again),we woud not have the chain reaction leading to death again, but the organism would gain life again.The question is with which way we would stimulate all the reactions simultaneously.This means that the source of this energy, would give the appropriate energy to the whole volume of the dead cell, with the right timing.One idea is the use of an appropriate form of electromagnetic waves.

1)Imagine that with the help of a sourse of light we <> in a way,some chemical reactions in a small place.After a period of time,they are getting more and more complicated.Lets hypothesize that someday the whole system becomes extremely complicated.We could not see nothing more but a mixture of colours and shapes.This is life.But human is a part of this complicated system which means that he sees thing in a mirror like way,because he is in the it is very difficult for him to see life in an objective way.2)Nature does not promote a certain form of life,but what we see,is the result of the sum of the reactions that happened through history.