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Artificial Prion Created
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."
I've not read the article.. but a little synopse of how BSE works... Everyone already has the protein for BSE in their brain. Except in its natural form in the brain.. its meta-table.. Meaning it can unfold and refold into its original shape. The interesting thing about BSE is its super-stable fold of the protein. What makes this dangerous is proteins can learn new and unique ways of folding.. so if in contact with a BSE protein it'll learn to fold the BSE way. Meaning.. it'll learn to fold superstable.. which is basically a knot you can't untie. Proteins are the messengers of the body.. and if they can't unfold to be read.. its basically dead weight. After a couple years too many proteins have been retrained, leading to loss of cognitive abilities.. tada... your cow has the mad shakes!
The abstract for the original Science article is here. However, you need to register(free to see abstracts) first. You can also pay to see the fulltext.
X-Has-Sig: yes
This was done at UCSF, not UCSD. Read the article
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)
"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?"
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 affecting protein folding in the brain.
-n
Yes, I am a microbiologist, and I've done research on prions.
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).
Visit the Game Programming Wiki!
Ooooooo... Another "When I first read this" joke on slashdot... How incredibly original. How do you come up with this stuff?
Slashdot gets worse every day... Pipedot: News for nerds, without the corporate slant
There are some rumors that the prions which cause mad cow disease were developed as part of the extensive biological and chemical weapons programs of the former Soviet Union. Agencies such as: Biopreparat, the FSB (formerly the KGB), and the Soviet Military were all involved.
In another chilling development, Vozrozhdeniye Island 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...
ucsd link
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."Real knowledge is to know the extent of one's ignorance" -Confucius
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.
Not by cooking heat, no, but you can destroy *any* material given enough heat.
The problem is that if you apply enough heat to destroy the prions you also destroy any nutrition in the food (Thus, the "crisp" comment).
Creutzfeldt-Jakobs disease (spelling?) is not highly contagious. Far from it. The risks of a person contracting it from tainted meat are blown out of proportion by politicians looking for reasons to hinder imports of meat from other countries. Even among cattle, where it is *most* common, it is still rare. The entire North American herd has only had, I believe, 2 confirmed cases of BSE in something close to 50 years. I would hardly call that common.
One more reason to stop eating meat
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.
"...always new atoms but always doing the same dance, remembering what the dance was yesterday." -Richard Feynman
Sorry about posting this again, I wan't logged in before *noob*
The disease takes at least 2 years to manifest in other animals as well. It's part of the insidious nature of all BSE / Kuru related diseases.
Kuru is a human form of this disease which was researched in the 50s and 60s by Carlton Gadjusek, who won the Nobel Prize in medicine for showing that a disease can incubate in an otherwise healthy / asymptomatic animal for several years before acute onset of symptoms.
He (with collaborators) inoculated many different species with the brain tissue of dead kuru victims, and waited to see if they would develop symptoms. The study found the human form of the disease could infect chimps and that there was no sign at all of infection until the extremely rapid onset of symptoms several years after exposure to the human form.
Pretty interesting guy I might add. He was truly a genius, but had some quite odd personal habits. (Many of which I feel were picked up as he assimilated into the native new guinien culture to study this disease in that population.)
Cheers, SpencerWhat makes this dangerous is proteins can learn new and unique ways of folding.. so if in contact with a BSE protein it'll learn to fold the BSE way. Meaning.. it'll learn to fold superstable.. which is basically a knot you can't untie. Proteins are the messengers of the body.. and if they can't unfold to be read.. its basically dead weight.
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.
Let's try not to let fact interfere with our speculation here, OK?
For those of you who don't study biochemistry, here is some background information regarding the importance of this discovery:
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
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.
Yes, but there have been 150 *human* deaths (so far) from vCJD due to the BSE outbreak here in Britain. Of course, the reason it spread through cattle here is because we put the remains of dead cows in their feed as a protein supplement. As long as they don't do that in the US then there won't be any problem.
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
Oh, you're not stuck, you're just unable to let go of the onion rings.
Life at the molecular level is a very interesting topic. It's mysterious, it's a great unexplored frontier, and understanding it has direct consequences on our lives. I think you'll feel the same way if you read the following article. It's written specifically to be more accessible to the average reader but I assure you as a biochem major it is not a trivial explaination. You'll really understand what prions are and just how protein mis-folding is responsible for mad-cow and alzheimers.
Unraveling the Mystery of Protein Folding by W. A. (Bill) Thomasson
http://www.faseb.org/opar/protfold/protein.html
Enjoy!
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
Oh, you're not stuck, you're just unable to let go of the onion rings.
-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.
"FDA staff reviewers expressed concern about the number of patients who were left out of the study because they died."
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
Oh, you're not stuck, you're just unable to let go of the onion rings.
In the UK, mad cow Disease only started becoming prevalent when the government at the time relaxed the centuries old bye-laws preventing the re-use of nervous tissue (cow brains). This was all part of the program to "cut the red-tape of beauracracy".
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.
Vintage computer adverts: http://www.vintageadbrowser.com/computers-and-software-ads
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 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.
There are 2 types of diabetes (called type 1 and type 2 - clever, huh?). Cutting down on sugar intake has nothing to do with the development of type 1 diabetes - this is caused when someone's immune system attacks the cells in their pancreas that make insulin. In type 2 diabetes, cutting down on sugar would be beneficial only if it reduces your caloric intake and you don't get overweight. Maintaining a healthy body weight and moderate physical activity are probably the best ways to reduce your risk of developing type 2 diabetes. Once you *have* it, eating a consistent amount of carbohydrates (such as sugar) will make it easier to control your disease.
If you have type 1 diabetes, you can eat as much sugar as you want - BUT then you need to use more insulin. Many people find that it is easier to not gorge on candy bars and then have to chase it with extra shots, but there is no physiologic reason that either group needs to avoid sugar or that doing so in the first place has any impact on the development of the disease.
How long does a slab of luncheon meat last in the wild? Protiens degrade, troll.
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.
Just a Tuna in the Sea of Life
Thankfully, Nature provided the reference to the original report printed in Science. Since this thing's right up my alley (I'm a biochemist), and since I know few people will read the real article, and since I'm a karma whore anyway, here's a summary of the original report. It assumes you know a little about prion diseases (BSE, CJS, GSS) already -- see other posts in this thread, or Wikipedia, for more info.
First: some background. There is a gene in mice that, if a certain mutation occurs, causes the mice to develop a neurodegenerative disease (hereafter abbreviated NDD) at an early age. If brain extracts from the diseased mice are transferred to healthy mice, the healthy mice contract the same disease. We're talking about an extant, previously-known prion-like disease in mice. Previous work by Kaneko, et al (see article if you really want the reference) took a short amino-acide sequence from the mouse protein believed to cause the NDD, and folded it into two different conformations: a non-beta-rich and a beta-rich (beta-rich structures are believed to be the NDD-operative part of other prion diseases such as BSE and CJD). They then injected the two different conformations into two different groups of mice. The non-beta-rich-protein group was fine, but the beta-rich-protein group developed the NDD anywhere between 1 and 2 years after injection. All this was work published previously, before the current paper in Science.
Okay, now we get to what Legname's paper is about. Taking the previous knowledge into account, Legname, et al took a similar beta-rich segment of the possibly infectious protein (called MoPrP -- roughly moprion protein) and made two preparations of it: one MoPrP which was just separate strands (called "unseeded"), and one MoPrP which was clumped in amyloid fibrils (called "seeded" -- basically an abnormally polymerized clump of protein, the presence of which correlates with NDD's like BSE and Alzheimers). Note that the critical difference here between the current work and the previous work is that the previous work folded the MoPrP protein into a known beta-rich (infectious conformation), whereas the current work just polymerized it into an amyloid plaque. The former doesn't necessarily happen spontaneously in vivo, whereas the latter certainly can. Anyway, the two preparations, unseeded and seeded, were injected into mice. Two years later, the seeded mice had a much higher rate of NDD than did the unseeded mice.
So, some of the conclusions that come from this:
- Strong evidence that prion diseases are in fact caused by misfolded proteins -- generally believed to be true, but some people thought otherwise.
- "amyloid fibrils harbor detectable levels of prion infectivity"
- "PrP [prion protein] is both necessary and suffienct for infectivity"
- "spontaneous formation of prions, which is thought to be responsible for sporadic forms of prion disease in livestock and humans, can occur in any mammal expressing PrPC" and "no exogenous agent is required for prions to form in any mammal" (though an exogenous agent can certainly help).
My own conclusion from the last point: it's possible that Alzheimers is just like a prion disease, just one that starts spontaneously. The issue of infectivity (as far as we know, Alzheimers isn't communicable) is still unsolved, but Legname's work is an interesting addition to the prion work.If you want information on a conspiracy related to Prusiner, the following link is just the ticket:/ CarolASTh ompson/prions.htm
http://ourworld.compuserve.com/homepages
Prusiner's comment that he is "flabbergasted" that it has taken people 22 years to accept his hypothesis, makes me wonder why it has taken so long to get convincing results, if that's what they are. Just because you have synthesized a protein, unless it is chemically and not biologically synthesized, does not mean that the problem of contamination with RNA and DNA is solved.
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 diseases. We aren't really sure how he got it (they raised sheep, who get a version of BSE/vCJD called "scrapie"), but after seeing the effect, you wouldn't even want to be in the same building as him. It is very easy to understand the terror and fear folks had when AIDS first came out.
Yes, scientists will need this kind of thing to understand how and why it works, as well as how and why a cure will work.
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?
+++ATHZ 99:5:80
...are an idiot.
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
Slashdot, where armchair scientists get shouted down and armchair theologians get modded up.
Control mice that received a brain injection without the lab-made prions did not develop prion disease after 670 days
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?
+++ATHZ 99:5:80
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 fairly concentrated hydrogen peroxide would probably also take care of mild prion contamination.
If you've got time to spare, prions will break down on their own. Exposure to open air and sunshine will do it. I would expect that soil microbes would be able to digest the stuff, albeit slowly. Sure, they'll remain the ground for a little while, but they're by no means indestructible. Formalin-formic acid treatment will also inactivate prions; I believe this is what is usually done with tissue samples.
Your body can probably cope with a small exposure to prions--your cells have mechanisms that are designed to recognize and digest misfolded proteins. (It happens fairly regularly; if the body couldn't cope with the occasional oops we'd *all* have CJD. My own area of study is a family of so-called protein chaperones which carry out these folding, refolding, and disposal tasks.)
If that's true, the followup question is what do the do with the remains of the study rats?
In general, I would expect the study rats to be disposed of in the same way as most other experimental animals: incineration. It gives you a nice, clean, essentially guaranteed destruction of pathogens, including prions. My understanding is that a lot of the cattle corpses in the UK and elsewhere were actually burned, rather than buried.
~Idarubicin
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 kill a patient, but let's not go overboard.
It's bloody difficult to eradicate--we don't have any techniques to do so yet. Perhaps something antibody based would work--something that will recognize the uniquely misfolded prion. I can also see this being a potential application for gene therapy. Regardless, it's a tough nut to crack. On the other hand, it is by no means alone in being an incurable, progressive, degenerative illness. Are the drug companies actually suppressing cures for all of cancer, diabetes, Alzheimer's, MS, ALS, etc.?
I'll leave the full debunking of the conspiracy theories to someone else. The notion of a pharmaceutical company deliberately murdering people to quiet them is appealing, but this is a dumb way to go about it. If you're trying to silence someone, you don't give them a disease that takes years to manifest--you hire a hit man. They'd also need to get your physician on side, unless you're in the habit of accepting injections from random individuals.
Incidentally, one of the symptoms of CJD can be paranoia. Hm.
~Idarubicin
There are technical hurdles to using mouse models to study prion diseases. Ideally a researcher would take a completely healthy mouse and induce a prion disease with the administration of a misfolded protein. Unfortunately for researchers most healthy mice don't have a lifespan long enough to develop a prion disease from scratch. The best that the researchers are able to do is take a transgenic strain of mice (Tg196), which are known to have a DNA defect which leads to prion related disease, and administer additional amounts of the prion in order to antagonize the disease state.
/. who can answer it. The authors of the article note that Tg196 mice exhibit spontaneous disease in 30% of their population at ~550 d. The status of the control group is fairly glossed with only a single line which meantions that, as of 670 d, the control mice were still healthy. If that means _all_ the control mice why is there a deviation from the known standard? If that means _some_ of the control mice why did the peer reviewers not ask about it?
/. headline reads "Artificial prion created". That's true. The researchers brewed a batch of MoPrP(89-230) which is a truncated form of the natu
The researchers in this case leave too many questions unanswered that could have been easily addressed.
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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)?
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I keep pointing this out and apparently there aren't enough scientists on
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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.
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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.
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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>.
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The
+++ATHZ 99:5:80
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) convert existing harmless prions into the harmful type, or (b) force the body to produce the harmful type instead of harmless type by blocking or modifying the body's normal metabolic pathway. We're not entirely sure which.
These researchers have shown that you can actually create the harmful prions by simply "shaking up" the harmless ones and getting them to deform.
They didn't "create a new disease" -- the disease was already there. They just proved that the disease is as simple as some had theorized it was. Some scientists had though that the prions where just a byproduct of some traditional infection, which would explain how it spreads. This research shows that is definately not the case.
There is actually no "disease" involved in the classic sense. No bacteria, no virus, no microbes of any sort. Nothing with any sort of RNA or DNA. Just a piece of protein. That's what these researchers have proved. Note that "prion infection" is completely unlike any other contageous condition ever discovered, which is why some scientists have been so slow to accept the idea. This research is a sort of wake-up call to the scientific community.
Now we know that sterilization (cooking, burining, chemicals, etc.) can't protect you because there's nothing to kill. Your immune system won't protect you because it's lived with (harmless) prions all your life, and sees no threat.
This reasearch helps in the search for a cure because it shows *where* you have to look. They've shown that traditional methods can't help you because this isn't a traditional disease. Instead, you have to try to somehow denature these proteins without killing the patient. Either that, or somehow stop the harmful prions from being produced.
Make no mistake, this discovery is a major step in the right direction.
"With sufficient thrust, pigs fly just fine. However, this is not necessarily a good idea...."
RFC 1925