Artificial Prion Created 496
jabberjaw writes "Nature is reporting that researchers at the University of California San Diego have created a synthetic prion which, when injected into mice will bring about symptoms similar to those displayed by cattle suffering from bovine spongiform encephalopathy, aka mad cow disease. The researchers first crafted healthy prion proteins using bacteria. They then shook these proteins until they resembled the tangled structure of an unhealthy prion. Afterwords, these prions were injected into the brains of mice who fell ill two years later. Perhaps someone who is more familiar with this field of research would care to fill us in on the details as the article was rather light."
whoo hoo? (Score:5, Funny)
This is the first step, I'm sure, to giving it to politicians.
On perhaps a bit more serious of a note, what does this do for us? Is this highlighting that we now know HOW the disease is created, so we can start developing a cure? Or am I wrong. Again.
Re:whoo hoo? (Score:5, Insightful)
There are all sorts of protocols like this already... ie, EAE (Experimental Allergic EncephaloMyelitis) where they give mice... um... artificial MS, then test drug canidates out on them to see what the effect is. It's not very nice to watch.
That's why I'm glad that I'm in molecular studies. However, it's done to help people with these diseases, and animal reseach is really the only way to conduct some of these tests.
Peace...
Re:whoo hoo? (Score:3, Interesting)
Am I way off base here?
Re:whoo hoo? (Score:3, Informative)
Re:whoo hoo? (Score:3, Informative)
You Sir (Score:5, Informative)
Current research believes that 50% or more of Alzheimers patients are really a form of prion degredation of the brain. It has nothing to do with politics. It is not most common in cattle, it is most seen sheep. And the entire US herd has zero cases of BSE (Bovine Spongiform Encephalopathy). Canada has had 1, and one is unconfirmed. This however is trival. BSE is already in the food supply, of this there is no doubt. Current testing ability cannot find BSE in low levels. The only question is - are you at risk? I dunno, but -
Eat all the beef you want to, I only hope that you don't get an infected cow. A Neurosurgeon I heard speak(who has treated CJD personally) said it is the worst way to die he has ever seen - this from a guy that sees brain damage every day.
Sera
Re:You Sir (Score:3, Insightful)
No... No one has ever conclusively demonstrated that you can take a prion from one species and use it to induce a prion state in another species. The current article fails to show any significant effect on mice using sheep scrapie Sc237 in mice. There have been one or two other research groups who have practically saturated one species with the prion of another and then claimed to find evidence of interspecies cros
Re:You Sir (Score:3, Insightful)
Hey, that's the same standard of proof we have for MDMA neurotoxicity.
Re:You Sir (Score:4, Funny)
Re:You Sir (Score:3, Informative)
Cross-infection is only taken for granted by those pitching it to politicians or who were in favor of the mass wholesale slaughter of every cow in UK and Europe several years ago.
The vast majority of sane scientists hold out that cross-infection for prions is technically possible but yet to be clinically proven. Look even at the current article in question. They did subject some of their mice to Sc237
Re:You Sir (Score:4, Funny)
Re:whoo hoo? (Score:5, Informative)
Yes.
Prion diseases (to oversimplify a bit) are caused by incorrectly folded proteins that induce "correctly" folded proteins to assume the prion form. They are typically communicated by ingestion of meat (or meat products) from infected animals.
Bubonic plague is a bacterial infection by Yersinia pestis.
Re:whoo hoo? (Score:3, Informative)
Am I way off base here?
Completely.
Prions are proteins that are found (in at least their harmless, unfolded, flexible state) in most (if not all) plants and animals on the planet. If the harmful (folded and rigid) prions are introduced into an organism, they either (a) conv
you're right (Score:3, Informative)
It is the most scary thing I have ever seen or experienced in my life. I've seen folks with advanced AIDS and other fatal di
Re:Another Brick For Bio Weaponary (Score:3, Informative)
Besides, Toxins are already contraband, so a protein that causes a disease is by definition, toxic. You would get better results from dumping E. Coli into the food supply or dump soluble lead into the water supply.
Re:Another Brick For Bio Weaponary (Score:3, Insightful)
Re:whoo hoo? (Score:2, Informative)
Acording to a genetic biologist that I briefly "dated", there has been a long standing debate over whether prions are the cause of or end result of brain wasting type diseases. So I believe the answer to your question is yes.
Which is fairly ironic since her masters research was based on searching for hiden viri that could posibly be af
Re:whoo hoo? (Score:5, Informative)
ucsd link [ucsd.edu]
As for your question of how the disease works. Theories were made about how this was possible, dealing with stereochemistry of the prion proteins causing your natural protein to switch its stereochemistry to the unnatural state found within the Prions in a cascade effect resulting in death. It appears this group may have verified this theory.Re:whoo hoo? (Score:4, Informative)
This isn't _that_ huge.
The transgenic mice being studied are already susceptible to this genetic defect and the researchers antagonized it by adding the purified product of the genetic defect. Is there any surprise that more mice became more sick more quickly?
Additionally one must look closely at the graphs on page 674. I can't locate in the article what "RML" is, but apparently administering RML caused conditions and antagonized the CNS of the mice even more than the purified MoPrP(89-231). 100% of the RML group experienced CNS dysfunction after less than 200 days. On top of that the researchers haven't proven that there's a clear prion effect. Immunoblot analysis of a brain tissue puree is hardly a characteristic identifier of MoPrP(P101L). The RML and PBS lanes are nearly identical to the lanes of mice which received the bacterial broth.
The authors acknowledge that 30% of their mice will develop spontaneous disease at ~550 days but they try to pooh-pooh that fact when they begin to discuss their findings
Then, on page 675
That's probably because Sc237 is the prion protein for sheep scrapie. While Europe was busy killing ever cow in sight, sane scientists were trying to tell them that the chance of a prion crossing the interspecies barrier is minimal. Conveniently, there is no immunoblot of the Sc237 inoculated mice. I wouldn't be surprised if it looks the same as the 9949 and RML lanes.
Does anyone else read these things critically?
Re:whoo hoo? (Score:5, Insightful)
Well, seeing as that it's in Science, it probably was reviewed. RML is a purifed prion preparation (made by Rocky Mountain Labs), and is a common positive control in prion studies. To the grandparent: the scientists that still dismiss prion disease are few and far between. The majority of the scientific community accepts the prion mechanism of transmission now. This was not the case a few years ago, but it's an accepted mechanism now.
All that said, I do think it's a bit of a stretch to call these "synthetic prions". I only skimmed the paper so far, but as far as I can tell, they state that these are only infectious in mice that already overexpress an aberrant protein (16 fold!) in the CNS.
The big thing that gets me is the lack of controls. This is a Science paper; where is the CD1 mouse infected with the 'synthetic prion'? My guess is that it didn't get disease, so they excluded the data. Fig 1C starts to show this a little, but still lacks proper controls. Here, they show that brain homogenate from 9949 mice hit with seeded protein can induce disease in normal (FVB) mice. They still don't do complete controls, though. Where is the homogenate + CD1 mouse? The FVB + vehicle mouse? Heck, where are the loading controls? Come on, a Science paper without loading controls???? It's not exactly the kind of thing that belongs in "unpublished data".
The positive side is that they seem to have confirmed the role of beta-rich regions in prion disease, and the importance of crystal/amyloid formation (which has been downplayed recently due to gross pathologic findings; this suggests that micro-plaques will also cause disease). Hammering out the structural domains responsible for disease is an important step.
Re:whoo hoo? (Score:3, Informative)
The prion proteins tend to be fairly durable, but extended exposure to high temperatures or harsh chemicals will eventually degrade or digest them. (Hospital guidelines for decontaminating instruments exposed to prions involve autoclaving at >130 degrees Celsius or soaking in 1.0 N sodium hydroxide. Hospitals tend to be pretty conservative, however.) Full-strength bleach or fairl
Re:whoo hoo? (Score:5, Funny)
The lesson is clear. If someone comes at you with a big long needle, and wants to stick it in your brain, don't let him!
Re:whoo hoo? (Score:3, Funny)
the bottom line (Score:5, Funny)
Re:the bottom line (Score:2)
two years?? (Score:5, Funny)
A solution ... (Score:2, Funny)
Re:two years?? (Score:3, Funny)
Re:two years?? (Score:5, Informative)
Is that "all control mice" or just "some control mice"? The original publication doesn't say. The authors note that the transgenic mice that they use are known to develop spontaneous CNS dysfunction at about 30% of the population ~550 days. The difference between the 550 d empirical timepoint and the 670 d endpoint is 120, or about 20%. Given that the variation for the animals which were injected was about between 25-35% (380-600 d for unseeded and 500-660 d for seeded) I don't find there lack of CNS dysfunction in the control group to be statistically significant at 670 days.
To summarize:
-Control mice are historically known to be 30% dysfunctional at 550 d.
-Some/few/all control mice in this study were functional at 670 d. This fact is insignificant in that it deviates from the known behavior of this strain of mice AND in that it doesn't statistically quantify the control group.
-At 550 d, mice which received a purified form of a malevolent protein were about 60% dysfunctional. At best this shows that administering a toxin to a strain known to be susceptible will antagonize the toxic effect.
-At 670 d, all mice which had received the malevolent protein were CNS dysfunctional. Some/none/few of the control mice were CNS dysfunctional.
Why are the statistics for the control group not in the publication? If we assume that the control mice all stayed completely healthy then why are they not exhibiting the expected 30% spontaneous illness rate?
Artificial Beef Patties? (Score:2, Funny)
this is truely scary (Score:5, Insightful)
Re:this is truely scary (Score:2)
More scary (Score:4, Interesting)
Suppose some not-so-nice people find a way to medicate the symptoms away(needing injections/pills/treatments) to make you functional, do you think they(he-who-would-profit) would create a cure? Look at diabetes. Nasty. If there was money in a cure, nobody would need insulin shots. Truth is, cutting down on sugar intake is a better preventative.
This(BSE) however, is insidious. It takes years to manifest, and by that time, you could be done for. Another worst case-if you have a treatment for the condition, if you displease someone who wants you gone, all it takes is for them to MAKE the prion fold wrong(tampering with the treatment to cause it) instead of mitigate the bad folded ones, you would be none the wiser, and it wouldn't show for years. Not saying that Pharmas have ethical problems...*cough*
I see it as a tool, and how this tool will be used will determine what the outcome is.
And a short blurb about Alzheimers. It appears some of the people diagnosed with it actually have CJD(human equivalent). I'll leave it up to newsies/linker types to Google it.
Oh, FYI-the prion 'dies' at around 1000 C. You'd kill any patient you try to 'clean'. Perhaps it resonates at a different frequency than the normal folded sequence. Detection(absorption) and irradication(more power) might be possible.
Yeah, it creeps me way out. Appologies for bad grammar, spelling-it's late. Sweet dreams...
Ah, the mandatory fscking stupid conspiracy theory (Score:5, Insightful)
Never mind that:
1. There _is_ money in a cure. If you had a cure for, say, Cancer and a 20 year patent on it, you could sell it for any sky-high amount of money you'd want to. It's the perfect extortion scheme. You pay up or you die a slow painful death.
2. Lo and behold, they did make cures and vaccines for a metric buttload of diseases.
3. Most importantly: there are doctors, pharmacists, managers at pharmaceuticals corporations, etc, who die of Cancer every year. Or have a bad case of diabetes. Or whose _child_ is dying of some disease.
Now you're telling me no less than they'll rather patiently wait for their own death -- or the death of those they love -- rather than break the conspiracy oath and divulge the cure. Doesn't that strike you as a completely retarded idea? If _you_ could make a cure, and you'll _die_ if you don't, wouldn't you just make the stupid cure already?
4. We're talking millions of doctors, pharmacists and researchers world wide. Some in countries where they don't even have private enterprise as you know it. (E.g., until recently the USSR and to some extent still China.) Or where it's not even easy to keep in touch with a western conspiracy. (E.g., the USSR block was pretty much isolated and guarded by a paranoid secret police.) And which invested hundreds of billions in researchs. (E.g., in developping their own nuclear weapons, sattellites, chemical weapons, biological weapons, ICBMs, etc.)
Yet you'd want me to believe that _all_ those are part of the same global conspiracy to keep some diseases untreated.
You know what? There's a medical name for that. It's called "Paranoia".
Re:Ah, the mandatory fscking stupid conspiracy the (Score:5, Funny)
There are treatments for paranoia, but I know the world government is keeping the best of them hidden from us...
Re:Ah, the mandatory fscking stupid conspiracy the (Score:3, Interesting)
1. There isn't money in a cure. 20 years of drug therapy and pills that cost $800/month = $192,000. Unless you can convince people and insurance companies to shell out $192K per patient cured, you can't sell the cure. Take into consideration again that a good number of the people who have cancer can barely afford their monthly medication, and unless medicare/social security/etc were willing to pay for curing people, the d
Re:More scary (Score:3, Informative)
It doesn't take a thousand degrees to eliminate a protein. Diamond will ignite at less than that temperature.
Extended autoclaving at 135 C or immersion in 1.0 N sodium hydroxide will positively disinfect prion-contaminated objects. Granted, those conditions would also kil
protein folding! (Score:3, Informative)
Re:protein folding! (Score:2)
Re:protein folding! (Score:4, Informative)
In the case of prions, it seems they can act as templates for each other. As they bump into each other, they will tend to act as a mold, effectively lowering the barrier between the two states. The new state is "narrower" but "deeper", so it is easier for one of the normal prions to slip over to the rouge state when molded than the other way around.
Re:protein folding! (Score:2, Informative)
Close, but backwards... Proteins have many functions, and their folded shape is what helps determine their funtion. The way a protein folds creates areas that like water (hydrophilic) and don't like water(hydrophobic), etc. These regions help determine which chemical compounds are structurally compatible with the protein, and lead to all kinds of reactions...
Check out Folding@home http://www.stanford.edu/group/pandegroup/folding/s cien [stanford.edu]
Ice 9? (Score:2)
so if in contact with a BSE protein it'll learn to fold the BSE way.
So this sounds very close to an Ice 9 [barnesandnoble.com] like scenario, with this particular molecule in a brain. Is that the kind of model you're describing?
Not really. (Score:5, Informative)
I'm not sure what you think you mean by "messengers of the body", but proteins are not information storage devices. They are products of genes, which are encoded by DNA, which is the information-carrying molecule of living organisms.
Proteins are functional or structural objects -- they act as scaffolding, motors and chemical reaction centers. They can be modified in ways that allow the transmission of information (e.g. phosphorylation), but that's a secondary responsibility.
That said, your description of BSE is incorrect. Proteins are not unfolded for "reading." They fold to assume their functional shape, and unfolding destroys their function. It's not something that happens to healthy, useful proteins. In fact, the cell has mechanisms to hunt down and destroy unfolded proteins, lest they do some sort of damage.
BSE is the result of a rarity in the protein universe -- a protein that has two stable folds. Most proteins have only a single, naturally stable conformation, but the protein responsible for BSE has another. What's more, this oddball protein fold can actually catalyze the folding of other proteins into it's own shape, thus destroying their previous function. What ultimately causes the disease, however, is the propensity of these misfolded proteins to aggregate, forming solid clumps that kill the cells in which they accumulate.
BSE has nothing to do with proteins "learning" of new ways to fold. Proteins don't learn. Proteins fold correctly, or they don't -- and in this case, failing to fold correctly has a nasty consequence.
Re:protein folding! (Score:4, Informative)
Re:protein folding!-I forget. (Score:3, Interesting)
This is not a 'troll' despite its rating and that it was posted by an AC. Prion diseases are actually quite similar to Alzheimer's in that both are caused by aggregation of proteins in the brain, resulting amyloid plaque formation.
Ok so now... (Score:2)
Was it a problem trying to replicate it in a lab or was it too costly to have a lab full of mad cows, just easier with mice?
of course the Mad cow Link [funnyjunk.com]
Explanation (Score:2)
Re:Explanation (Score:4, Funny)
When thing it will show... (Score:5, Interesting)
Mad cow acceptable level of risk to big businesses (Score:5, Interesting)
"Those representing the U.S. meat industry say the U.S. government's testing program is more than adequate."
-CNN
One more reason to stop eating meat [goveg.com]
Re:Mad cow acceptable level of risk to big busines (Score:4, Informative)
If you want to avoid food that contains beef by-products, you'll need to stop eating more than just meat. For example, most cheese is made with animal-based rennet. Its source is the stomach linings of mammals like cows.
Link to abstract (Score:3, Informative)
2 yrs later? That's when mice get Alzheimer's... (Score:3, Interesting)
Re:2 yrs later? That's when mice get Alzheimer's.. (Score:2)
The mice developed BSE-like symptoms one to two years later, the team report in Science1. They became weak and shaky, and post-mortem analysis revealed that their brains were full of holes and rogue prion proteins.
Critically, when the mouse brains were ground up and injected into healthy rodents, they too became ill. This is the acid test for any prion disease, says Legname.
Note that the mice didn't just die. They developed BSE-like symptoms and the
Wrong university...butu you've got it mostly right (Score:5, Informative)
There are still a few people the dis-believe the prion theory of disease put forward by Pruisner. For those who aren't familiar with the subject, prions are essentially misfolded proteins that can induce their mis-folding by interacting with copies of themselves. So, if protein A become randomly misfolded into A', it can bump into other copies of A and induce them to form A'. In many of the disease cases, these misfolded proteins can form plaques or tangles which then disrupt or rupture and kill cells.
While Pruisner's evidence for such a mechanism is more or less overwhelming there were still a couple people who didn't buy the story. The experiment talked about here (and I haven't seen the actual paper yet, but look forward to reading it) is rather difficult to do and is pretty much the last nail in the coffin of those disagreeing with prion theory. They do complain that the protein activities of the mutants were really low and that the mice used were not of the ideal strain buut this is missing the forest through the trees. As far as all of us whose opinions matter are concerned, the case is no more than closed and the pro-Pruisner side has won.
BTW, I've heard Pruisner say that a lot of neurological diseases are really prion based...but that case is far from being closed...so keep your ears open for such discussions in the future.
-Devon (who should disclose that he's a neuro grad student at UCSF, but works on neurogenetic diseases and not prions)
Zombie Proteins (Score:5, Funny)
A brief lesson on prions... (Score:5, Informative)
Basically, prions are proteins which are able to act upon other proteins and thereby create functional copies of themselves (identical copies are not needed). BSE (mad cow disease) and CJD (essentially the human version) are caused by 'rogue' prions which destroy tissue by converting large quantities of protein into more prions. Prions are basically the most elementary form of an infectious disease (as they are simply protein, no genetic material required).
Now, what these researchers have done is to prove that prions can spontaneously develop, without the need for viral or bacterial infection. Random changes in protein structure MAY result in prion creation. You needn't eat some mad cow (nor cannibalize some CJD gray matter) to contract CJD or some other prion-induced malady. Nor is a viral/bacterial infection required; the disease may develop spontaneously.
Hopefully this makes sense... I've had a few too many Schooners (beer).
So... (Score:2)
Re:A brief lesson on prions... (Score:2)
Re:A brief lesson on prions... (Score:4, Informative)
HIV isn't a disease either, but AIDS is.
This answers a major question (Score:3, Interesting)
So direct synthesis of a prion, and demonstrating that it was disease-causing, was a useful research project. Now we know.
No more amusement park rides for me! (Score:2)
Right. Won't catch me dead on this protein-shaking carnie ride, then: The Zipper+Roller Coaster [thrillride.com]. Sweet jesus, you'd be sure to develop mad cow disease!
The TRUE source of Mad Cow Disease? (Score:3, Informative)
In another chilling development, Vozrozhdeniye Island [mhhe.com] in the Aral Sea, where much testing of biological agents including anthrax, bubonic plague, glanders, and other extremely infectious agents occurred supposedly contains massive amounts of anthrax hastily buried by Russian scientists amidst the collapse of the Soviet Union in 1989. More fodder for the conspiracy theorists out there...
Re:The TRUE source of Mad Cow Disease? (Score:4, Informative)
And even before BSE, it was known through the work of Carleton Gajdusek and others (www.nobel.se/medicine/laureates/1976/gajdusek-le
that the prion disease kuru in humans could be transmitted by eating infected tissue.
So it's all natural, in a sense. Which doesn't make it any less scary.
Kluge
Re:The TRUE source of Mad Cow Disease? (Score:5, Insightful)
Re:The TRUE source of Mad Cow Disease? (Score:5, Interesting)
Those prions are nothing special, they have always been there, but not in enough quantity to do any (as far as we know) harm. Those species at the end of the food chain receive some more prions through their diet, but still not in hazardess quantities.
When we started feeding cows to cows(yes, money makes prople do strange things), we created a loop in the food chain, in effect stretching the food chain infinitly. The species in the loop (cows) and those at the end of the food chain developed a new disease because of the overdose of prions.
Probably not realistic but... (Score:2)
Does this have the potential to develop into a weapon?
Re:Probably not realistic but... (Score:2)
Re:Probably not realistic but... (Score:2)
Sure does. All they gotta do is strap you down, inject it into your brain, then wait a couple of years for your brain to degenerate..
What a weapon!
Oh no, now wait for the War on Prions FUD to begin.
Like Ice-Nine (Score:4, Interesting)
Shaking (Score:5, Interesting)
The guy in charge of the project wasn't interested in pursuing the results because the intersection of protein dynamics and hydrodynamics wasn't somewhere he wanted to go.
It will be interesting to see if they can develop anything more than handwaving explanations for how the shaking is causing the prions to change structure. Standard molecular dynamics simulations of proteins don't model mixing behavior of the water molecules surrounding the protein. Part of this may be due to the different time scales of the two phenomena.
Re:Shaking (Score:3, Funny)
Re:Shaking (Score:2)
Does anyone know if prions are quaternary structure protiens? i.e. complexes of tertiary folded proteins, for instance hemoglobin.
Great! (Score:3, Insightful)
An off-the-wall theory? (Score:4, Informative)
As has been hinted at in other entries here, a prion is an alternate, stable, but nonworking and here's the kicker *infectious* conformation of a normal brain protein.
Proteins fold and twist, combine, etc., into little functional specially-shaped nuggets, sheets, strands, etc. What's strangely intuitive about functional proteins is how many of them function based on their shape. No obscure chemsistry or quantum effects here; they make little socket wrenches, funnels, motors, lock-and-key assemblies, etc.
However, that's not to say that because their core function doesn't have to do with their electronic properties, that these aren't important. Since their individual atoms do still have charge effects, they can be deformed, ("denatured",) reshaped, etc. They can also do this to each other. E.g. certain enzymes have two "sockets": the one that would normally work on a target molecule is bent out of shape and inactive until some other "cofactor" atom or molecule snicks into the back of the enzyme, bending it differently and opening up the active area.
So proteins are a little flexible, and can affect each other's shapes if they're close enough. As previously mentioned, the kicker: you can take certain sheet-like molecules in the brain and mutate them so that not only do they no longer work right, but they generate a charge field around themselves that will eff up other, similar molecules that encounter them, *and so on*
So you end up with this Night of Living Dead effect where as soon as you make a legit molecule of this kind, it goes off all peppily into the brain, doing its deal, until it encounters a zombie prion, and hey, you don't look right...but...somehow..seductive...yes! I will join you in your plaque pile! I must tell others! So you get scrapie or CWD or mad cow or some others.
What I have always thought strange is that no one seems to have looked at prions as a possible cause of Alzheimers', another poorly-understood neurological disease marked by pileups of nonfunctional protein plaques in the brain.
The reason this is significant? Folks, I thought this was one of your core beliefs! The only way to really truly understand something complex (a cake, a compiler, a neuropathic protein) is to build one that works.
Re:An off-the-wall theory? (Score:4, Informative)
There's more than enough chemistry and quantum mechanics in the folding of proteins. Hydrogen bonds, the sharing of electrons between electron-rich atoms and electron-poor hydrogens, is the key element holding proteins together. Actually, 'forcing' them together is rather more accurate since the "hydrophobic effect" that is the reason most proteins collapse into a structure is really just due water preferring to interact with itself rather than non-polar portions of a protein, thus forcing those portions to, in-effect, "hide" from the solvent.
That proteins denature or deform has more to do with subtlety of their arrnagement than to the "charge effets" of "individual atoms" that you refer to. Proteins may be denatured (unfolded) in a variety of ways: by heat, (which induces so much kinetic energy that stabilizing structures are overcome), by polar salts (which screen stabilizing charge interactions), by using a different proteins (some large proteins are thought to help 'fix' misfolded proteins by engulfing them and exposing them to a non-polar environment), or even by pressure.
That they "generate a charge field around themselves" is an especially worrisome comment. A better description of the way a prion protein could cause another to misfold is that it presents a surface with a series of hydrophobic and charged patches that the 'healthy' protein could interact with and catalyze the formation of its misfolded state.
As for the relation to Alzheimer's, the curiousity of prions is less that they form amyloid plaques in the brain and more that they act as an infectious agent for this type of disease. I'm not aware of any evidence of Alzheimer's spreading like a communicable disease, making the need to find an infectious agent minimal. That said, any treatment designed to block or reverse plaque formation in the brain will likely be able to treat Alzheimer's or prion-induced diseases.
More fun way to make prions.... (Score:3, Funny)
Hmm anybody want to fund my experiment, just need $80 for some mice, a paint can, and a paint mixer.
koch's postulates & why this study is cool (Score:4, Insightful)
That being said, in this prion story, we have an some example of postulates 2-4. The Prusiner team synthesized an artificial agent that's implicated in disease, and used it to infect and create new diseased organisms. This is a scientific step forward. Previously, the prion agent itself correlative with disease, but as to whether it is the causative agent, it was unclear.
The brief criticisms in the NY Times articles may have some merit though. It's still possible that the disease has some other underlying cause, and the artificial prion only hastened onset. This is an important point, because the signs of aggregate prions (the amyloid plaques) are found in BOTH healthy and diseased animals, thereby violating the first Koch postulate in some sense. However, I warn the reader that my knowledge is deficient here. Perhaps the amyloid plaques are composed of misfolded variants of other proteins also.
This is a rough summary of what I know. I hope I haven't offended any experts who know the details. Please feel free to correct what I'm sure are numerous mistakes.
Some background information (Score:3, Informative)
For starters, an enzyme is a protein which specializes in catalyzing a specific reaction (lowering the amount of energy input needed to allow a reaction to occur). Proteins/enzymes are synthesized from DNA/RNA templates. The synthesis occurs in a linear fashion producing a long chain of amino acids which will eventually fold to become the protein/enzyme. The structure is classified according to proximity (primary, secondary, tertiary, quaternary). The primary structure is the amino acid sequence. Secondary structure is folding that occurs over short distances due mostly to polar attractions; this includes alpha helices and beta barrels. Tertiary structure is more of the overall shape that results forming a subunit. Quaternary stucture is the association of the subunits to create the overall protein/enzyme. Hemoglobin, for example, consists of 2 alpha subunits and 2 beta subunits around a heme (iron) core to create the complete enzyme.
The interesting thing about prions is that they are not malformed proteins due to a mutation in the primary structure as is seen in most diseases (sickle cell anemia, cancer). A prion has the exact same amino acid sequence as its healthy and properly formed counterpart; the prion simply folded in the incorrect way. When amino acid sequences are processed through molecular modelling programs to determine their final 3D conformation, often times there are multiple conformations which are thermodynamically equivalent.
When a prion is present it causes enzymes with the same primary structure within proximity to adapt its misfolded shape, thus spreading itself. The concept is similar to "ice nine" that Kurt Vonnegut Jr. describes in "Cat's Cradle" where a single crystal of ice nine is the seed which causes all other water molecules to crystalize into ice.
The significance of artificially creating a prion is that medicine may one day be able to create prions to correct enzymatic problems rather than create them. This could lead to a cure for vCJD/BSE and other undiagnosed disorders due to prions (although I do not know if it could ever correct primary structure mutations such as sickle cell anemia).
Matt
Unraveling the Mystery of Protein Folding (Score:3, Informative)
Unraveling the Mystery of Protein Folding by W. A. (Bill) Thomasson
http://www.faseb.org/opar/protfold/protein.html [faseb.org]
Enjoy!
A few things to remember.... (Score:5, Informative)
A lot of people have heard of "Mad Cow". Some of them have even heard of BSE or CFD. And most people don't realize that this is nothing novel, nothing new, and not at all limitted to cows.
The result of these prions in the brain is spongiform encephaly - literally, holes being eaten in your brain by the prion's interaction. Not a very fun thing!
Now, prion-caused sponfigorm encephalies have been found in a good number of animals. At a minimum, humans, goats, sheep, cows, squirrels, deer, elk, etc..
In cows, the condition is called "BSE" ("Bovine Spongiform Encephaly"). In humans, it's usually called Creutzfelt-Jacob's Disease (I'm sure I murdered the spelling). Those are merely terms for the resultant condition from the prion infection.
Now, the prion responsible for BSE isn't all that bad, as far as infectious prions go. First, it's not really transmissible in cows without the direct ingestion of infected nervous tissue. That means that if we just didn't feed cows ground up cows or ground up sheep, a very large part of the problem is solved.
However, there are other prion agents that are a bit nastier. In the case of CWD and scrapie, the prions have been shown to be transmissible to other individuals through the environment if (a) a n infected carcass or (b) excreta from an infected animal is in the area. Even better, even after all of the animals have left the area, CWD and scrapie agents have been shown to remain and still be contagious to other individuals years later.
Here's the good part: Researchers have already found genes that cause resistance to prion infections, or at least to certain types of them. The genes are found most commonly (and most heavily) in populations that practiced (or still practice) cannibalism. On the down side, it's not something as nice as getting infected and developping an immunity - we're talking about the cannibalistic societies being mostly wiped out by prion-based diseases, leaving only those (luckily) able to resist as the sole survivors, to pass along the genes to their offspring.
steve
Ok... (Score:3, Funny)
Scientific problems with these results (Score:3, Informative)
Anyway, while these results from Prusiner and colleagues go a long way toward demonstrating the infectivity of prions, there are still some problems with the experiment before one can conclude that Koch's postulates [wsu.edu] have been satisfied.
I've listed some of the problems (potential and real) with the experiment here:
BTW, my scientific background is not in prions. I direct a lab that works on Epstein-Barr virus [northwestern.edu].
Artificial Pr0n? (Score:3, Funny)
Reasonable science, bad reporting (Score:5, Informative)
The researchers in this case leave too many questions unanswered that could have been easily addressed.
1>
The Tg196 transgenic mice express a low level of MoPrP(P101L) which is said to cause the CNS dysfunction. The researchers brew E. coli to produce a large amount of MoPrP(89-230) which they will use to spike the mice. To ensure that the additional disease effects are really attributable to the E. coli produced MoPrP(89-230), why do they not use a control group of mice which receive an extract from an E. coli broth which does _not_ produce MoPrP(89-230)?
2>
I keep pointing this out and apparently there aren't enough scientists on
3>
The bottom line worry is that a prion disease in your cow or sheep will end up in your supermarket and cause a mass plague in humans. The researchers in this study did administer Sc237 (sheep scrapie prion) to some of their mice and saw no ill effects. Paranoid people and others with a political agenda need to give up on the hype.
4>
The results are statistically fuzzy. While the authors note that 30% of a population of Tg196 mice are known to be dysfunctional at ~550 days they don't have any expected dysfunctional population % for 670 days. Their own experimental groups have a range of 380-600 and 500-670 d for unseeded and seeded groups, respectively. Additionally, at the 550 d point, both experimental groups were exhibiting about 60% CNS dysfunction in the population. The researchers have shown that administering a prion, for which the mice are known to be susceptible, will hasten their illness. It may be a good bit of lab work but it's not a surprise.
5>
The immunoblots are pretty but don't say much. The control group lacks many of the spots that the test groups have, but even the experimental group which received nothing more than the extraction/folding broth (PBS? PBH? I left the PDF on my desk) shows some of the additional bands present in the animals which received actual prions. Additionally there's the RML group. I couldn't find the definition for RML in the paper but noticed that the RML group exhibited 100% population CNS dysfunction by about 180 days. Is this really a prion effect if "RML" is more effective than the prions? Finally, where are the immunoblots for the Sc237 subjects? Ideally they would look like the control group immunoblots since the Sc237 subjects did not exhibit CNS dysfunction. My better sense tells me that the immunoblots for the Sc237 subjects would look more like the mice that received the blank extraction/folding buffer or even closer to the 9949. This would raise some obvious questions about the specificity of the immunoblot for active, MoPrP and inactive PrP from another species. This ties in with <3>.
6>
The
Details? Chase down the references. (Score:3, Interesting)
Legname G., et al. Science, 305. 673 - 676 (2004).
Look for university libraries in your area. You don't need a library card to go to the current journals and photocopy pages. If you are at a university and your university has subscribed to the electronic journal, go to http://www.sciencemag.org and find the link.
It is full of a lot of details that most of us (certainly not me) don't need. Read the abstract, the introduction, and the conclusion. If your interest is piqued, you might read the body and chase some references.
I doubt that anybody will read this. The comment count has exceeded 400 (thanks to the WMD discussion--really people, they INJECTED IT INTO THE BRAINS OF THE MICE). I also like to shout at airplanes.
Re:WMD (Score:2, Insightful)
That seems to suggest there were other WMDs. Coulda sworn they haven't found any...
Terrorists don't need weapons of mass descruction. The States has been mired in fear for the past three years and all the terrorists had were box cutters.
Re:WMD (Score:2)
Only nukes are true WMDs (Score:5, Funny)
Great, now we have yet another form of weapon of mass destruction.
Artificial prions are chemical weapons, just like VX, sarin, and other nerve agents. Unlike nuclear weapons, chemical weapons are technically not weapons of mass destruction because only a nuclear reaction can destroy mass.
Re:WMD (Score:3, Insightful)
Re:What's the point again? (Score:3, Interesting)
Though their exact mechanisms of action and reproduction are still unknown, it is now commonly accepted that they are responsible for a number of previously known but little-understood diseases generally classified under transmissible spongiform encephalopathy (TSEs) diseases
IANAMB(I am not a microbiologist) but I'm assuming if scientists can replicate how something works, they can counter that process and develop a cure. Pretty neat stuff.
Re:What's the point again? (Score:3, Insightful)
It seems to me that the scientists figured out a way to develop a prion and show t
Re:artificial pr0n (Score:3, Informative)
Re:Important because (Score:2)
Or more germanely, it may be advisable not to inject your next Big Mac straight into your brain...
Re:Ugh (Score:2)
So what exactly would artificial pron be? The mind boggles!
MMmmmm... hentai... [reference.com]
. o (Oh crap... was that my outside voice again?)
-Twilight1
Re:But how is it transmitted? (Score:4, Informative)
Well, your line of thinking isn't all that unsound. But here's what we do know:
1. Prions do exist, and do infect the nervous tissue of cows (and a lot of other animals, actually.)
2. Prions are rarely (if ever) able to be found outside of the nervous tissues.
3. Consuming infected nervous tissue does appear (quite strongly, in fact) to infect the consumer.
So, our classical line of thinking about digestion and protein absorbtion doesn't quite fit what we're seeing. What does that mean, class? That's right, we'll have to keep researching both what's really going on with the digestion (or lack thereof) of prions, and the absorbtion/transmission.
Note that while BSE doesn't appeaar to be transmissible in cattle without the cannibalistic ingestion that results from human intervention, there are other related prion diseases such as CWD and scrapie that do appear to be transmitted through environmental factors. In fact, in scrapie epidemics, it has been shown that scrapie agents may remain in the local environment for years after the outbreak.
steve
Re:But how is it transmitted? (Score:5, Informative)
-Flesh of creature A, including malformed protein, is consumed by creature B. (Consumption is apparently part of the mechanism of infection.)
-Malformed protein avoids chemical breakdown in digestive system. This is quite possible as prions are acid and protease resistant.
-Malformed protein is taken up by Peyer's patches, sites of lymphoid tissue in the intestinal lining (Heppner, et al. in Nature Medicine, Transepithelial prion transport by M cells.) These patches normally "sample" substances from the intestinal lumen, and are instrumental in triggering an immune response if you eat something you shouldn't.
-However, your immune system doesn't find the malformed protein too threatening, possibly because it mistakes it for the very similar properly folded protein hanging out on GPI anchors all over your body's neurons. If it were recognized as dangerous, the usual method of dealing with a misfolded protein, degradation in a lysosome, wouldn't work, once again on account of prions being highly resistant to the sort of enviroment that disintegrates most proteins.
-The misfolded protein is taken up by the vagus nerve, which ennervates the gut (and does many other important things). Now, the vagus nerve may be familiar to some of you as the Tenth Cranial Nerve. So the prion rides up the long axons of the vagus to the brain.
-The prion gets to the brain, bad stuff happens and you die in a horrible manner.
Now, I can't completely assure you this is the mechanism by which prion uptake occurs, it is currently the Best Idea We Have, and I think there is evidence that it certainly could happen this way, though no guarantee that it actually does. I just wanted to mention that the gut isn't exactly an impenetrable barrier for antigens, and that it's quite possible for stuff you eat to make its way to the brain surprisingly intact. Also, how exactly do you believe the South Fore and those Britons contracted spongiform encephalopathy? They didn't stick syringes of brain matter into their heads, you know. Even a "slow virus" theory of TSE would have to take oral transmissibility into account. The studies of the Fore, for instance, note that only those who took part in funeral feasts, and then only those who ate certain parts, contracted kuru. When the feasts ended, so did the disease. Likewise, the bans and herd destructions were accompanied by a sharp dropoff in vCJD cases.
I understand that correlation does not imply causation, but I see tremendous circumstantial evidence that something these people orally ingested gave them a TSE- I mean, the natural rate for CJD is about one in a million, and then there was this sudden outbreak among people half the usual age for victims, whose only commonality was the consumption of beef, beef from cows which had consumed sheep offal...- and this experiment offers highly suggestive evidence that the agent in question was a prion.
Re:Half way there! (Score:3, Insightful)
Re:Some points that a lot of people miss (Score:5, Informative)
One more thing that you've missed is that the variant that does appear very strongly to be transmitted through the consumption of cows is not the classical CJD, but a new variant called (uninterestingly) vCJD.
The new variant occurs at a MUCH higher rate than normal CJD, and strikes much younger people. The median age for CJD is around 68, the median age for vCJD is around 28.
Furthermore, of all diagnosed vCJD to date, virtually all of had multi-year expose in Britain during the peak of the BSE epidemic.
There has never been a single vCJD case in a country where cows did not have BSE.
It's not like there's one single prion disease. There are a lot of them. And what's more, even within one prion disease, there are many different variants. Within scrapie alone, there are at least 15 different variations.
vCJD is a little worrisome in that it does appear (very strongly!) to jump from cattle to humans. On the other hand, it appears to require direct consumption of the infected animal. Stop eating beef, problem completely solved.
steve
Re:Some points that a lot of people miss (Score:3, Informative)
Once a ban was put back in place, the number of new cases in people started to decline (although a great many people also stopped eating beef), although nobody is sure if there is going to be a epidemic in the future or not.