World's first case of man-made mad mouse disease

[dr. what]

link

Friday, July 30, 2004


When Neil Cashman, perhaps Canada's top expert in prion diseases, learned that his illustrious colleague, the Nobel laureate Stanley Prusiner, had killed mice using prions created from scratch, he was struck dumb.

"It's kind of a slam dunk," Dr. Cashman said yesterday of Prusiner's "spectacular" experiment. "You don't feel like going to work in the morning."

This experiment, he knew, was proof for the radical idea, proposed by Dr. Prusiner in 1982, that prions are nothing more than weirdly twisted proteins. Barring some disastrous flaw in the experiment, science now has no choice but to accept this hotly contested theory, and all it entails: for example, that prions do not require any other infectious agent, such as a virus or a string of DNA, to replicate and spread through the bodies of infected animals.

"No exogenous agent is required for prions to form in any mammal," Dr. Prusiner and his team write in their groundbreaking paper, "Synthetic Mammalian Prions," in today's issue of the journal Science.

Learning how prions become misshapen, then, will not only explain the root cause of mad cow disease, or BSE, and its human form, Creutzfeldt-Jakob. It will also offer insight into other human diseases caused by aberrant proteins, such as Alzheimer's and Parkinson's, the authors write.

Understanding spontaneous prion formation, which seems extremely rare but has been suggested as a cause of Creutzfeldt-Jakob, might also have sweeping effects on the management of BSE in cattle.

"I think Prusiner and his colleagues have solved a very tough problem ... and I think it's a major accomplishment," Dr. Cashman said.

Their experiment took about two years to complete -- roughly the lifespan of a laboratory mouse.

Dr. Prusiner and his team culled proteins from bacteria, twisted them into lethal prions in a chemical solution, and injected them into mice that had been genetically engineered to overproduce that particular type of protein. That way, the team believed the mice would replicate the artificial prions in sufficient quantities to cause disease.

After two years of waiting, they were right. "The brain of the mice created bona fide prions," said Giuseppe Legname, lead author on the paper and a researcher in Dr. Prusiner's lab at the University of California, San Francisco.

Dr. Cashman suggested the team might have "loaded the dice" by using genetically engineered mice, rather than normal ones. These mice, by virtue of their very DNA, could have been overly susceptible to prion diseases, he said. Indeed, Dr. Prusiner notes in the paper that these mice develop neurodegeneration at an early age.

But, Dr. Legname points out, the experiment had a final step. They extracted the brains of the dead mice, noted the ravages of prion disease, ground the brains up, and injected them into healthy, normal mice. (In mice, as in cows and humans, prions are mostly found in the brain.) "And they all got sick," Dr. Legname said.

Dr. Cashman said this paper "is not the complete package tied up in a bow. There are some flaws." But aside from the use of genetically tweaked mice, those flaws are largely hypothetical.

Perhaps, Dr. Cashman said, the mice were inadvertently infected with real prions. After all, the experiment was conducted in the world's top prion lab, where real prions might be lying about alongside the synthetic ones.

Dr. Legname said this was unlikely, and besides, the brain damage in the mice was unlike that from any other known prion disease. What they found was a "unique neuropathological outcome" -- the world's first case of man-made mad mouse disease.

[Admiral Valdemar]

I always considered those that thought prionic diseases had some other element to make them virulent somewhat stupid given the total lack of evidence for anything. Was it really so hard to imagine an evangelizing protein that simply converted other molecules to exact copies of itself?

[Guy N. Cognito]

I found the article really interesting, but I'm guess my grasp on biology isn't nearly enough to fully understand teh significance of this discovery other then the fact that it's just protiens replicating.

[Tzeentch]

I always considered those that thought prionic diseases had some other element to make them virulent somewhat stupid given the total lack of evidence for anything. Was it really so hard to imagine an evangelizing protein that simply converted other molecules to exact copies of itself?

Same here, though as a total layman to bio, I was actually under the impression that this issue had been settled a while ago. Very interesting. My family lived in Britain in the 80s, and they're pretty paranoid about mad cow. It's good to see some progress being made.

[tharkûn]

I always considered those that thought prionic diseases had some other element to make them virulent somewhat stupid given the total lack of evidence for anything. Was it really so hard to imagine an evangelizing protein that simply converted other molecules to exact copies of itself?

The hard part for me has always been wondering how in hell the prion got from the gut to the brain without denaturing or degrading.

I admit it makes more sense than all the alternatives, but it still is a head scratcher, and I've ground up more than my share of cowbrains.

Perhaps, Dr. Cashman said, the mice were inadvertently infected with real prions. After all, the experiment was conducted in the world's top prion lab, where real prions might be lying about alongside the synthetic ones.

Give me the mouse brains and a year at the outside and I can definatively rule this one out. Sythetic, wild, and natural prion should all have different tertiary structure. If you already have backbone frequency mapped give me a couple of weeks.

[Admiral Valdemar]

The prion proteins are resistant to protease activity (the exact nature eludes my memory now, but I recall something about metal ionic bonding), something that has been studied in the PrPSc protein and also been linked, albeit with a certain degree of controversy, to the amyloid plaques formed by beta-amyloid fibrils spontaneously forming in the brain tissue.

This allowes it to accumulate in the brain after passing the blood-brain barrier and avoiding any immune response. The proteins act as seed crystals for the formation of like minded structures and so an exponential spread of the same proteinaceous structure occurs until eventually encephalitis occurs or other side-effects that lead to coma and death, though this can take months to years.

[tharkûn]

The prion proteins are resistant to protease activity (the exact nature eludes my memory now, but I recall something about metal ionic bonding), something that has been studied in the PrPSc protein and also been linked, albeit with a certain degree of controversy, to the amyloid plaques formed by beta-amyloid fibrils spontaneously forming in the brain tissue.

This allowes it to accumulate in the brain after passing the blood-brain barrier and avoiding any immune response. The proteins act as seed crystals for the formation of like minded structures and so an exponential spread of the same proteinaceous structure occurs until eventually encephalitis occurs or other side-effects that lead to coma and death, though this can take months to years.

I am aware of that AV, once it gets to the brain I have less head scratching.

Proteases are not the only denaturant in the stomach, but really the interesting part is crossing the intestinal epithelial cell barrier. The glycine-Cu chelation is certainly interesting but not the end of the story.

It takes an awful lot of evidence to conclude that a protein can withstand denaturing through a dozen different environments, cross mutiple biological barriers, and resist a well honed system for destroying stray protein. Yes I don't doubt that it does, I just required a good bit of evidence before I accepted that it was more likely that all that was true than the alternatives.

[Admiral Valdemar]

Well, it's a conformational change to beta-pleated sheets from typical alpha-helices as I've just re-read. I can't see how that makes it super tough, but somehow it makes it an annoying bastard to get rid of. You think viruses and antibiotic resistant bacteria are bad, at least you can spray trigene on the things and be rid of them. Even cremation doesn't get rid of all prions.

I am interested in how it seeds itself though. There's a story of WWII sonar transducer crystals that were made in a US factory and stored in a warehouse, until one day, a rogue metastable seed crystal got amongst the stuff and before long, their whole merchandise turned to dust and made making anymore crystals in that area futile.

Reminds me of ice-nine.

[tharkûn]

I am interested in how it seeds itself though. There's a story of WWII sonar transducer crystals that were made in a US factory and stored in a warehouse, until one day, a rogue metastable seed crystal got amongst the stuff and before long, their whole merchandise turned to dust and made making anymore crystals in that area futile.

That is a materials science phenomena, known as polymorphism. Start with a supersaturated solution, it is enthalpicly favorable to go to crystal. However there it is not entropicly favorable. So even though you have far more molecules in solution than equilibrium predicts, you have to wait for nucleation to get out. Once nucleation begins it will proceed vigoriously; this is a kinetically controlled process as once you go to crystal it is extremely hard to get back out. So if you start with a matrix that is better enthalpicly than solution, but not the global minima, you can easily seed metastable states. I know a prof who is working on polymer blends be able to systematicly seed differing polymorphs.

Once you have a template it is far quicker to expand than to form a new template, even if a better matrix is possible. Getting the nucleation seed is the biggest entropic hurtle to get over, once you have a ridiciously small particle there it is exceptionally easy to expand it. This is the same phenomena that allows industry to grow single crystal Si dozens of feet long.

[Admiral Valdemar]

Hence why the story Cat's Cradle makes the ice-nine splinters out to be the most valuable things on the planet, no matter how small or readily destroyed by boiling.

But we're dealing with one on a biological level, and given the emergence of nvCJD and the latent period of the disease, it could be argued that another HIV sized pandemic is on the cards.

I probably say it too much, but in this instance I mean it when I say it's the ultimate bioweapon.

[tharkûn]

I probably say it too much, but in this instance I mean it when I say it's the ultimate bioweapon.

What are your criteria? It isn't targetable and the transmission rate is piss poor. I can easily imagine dozens of inhibition measures and the thing has zilch for adaptivity. The soviet already made far superior bioweapons.

[Admiral Valdemar]

What are your criteria? It isn't targetable and the transmission rate is piss poor. I can easily imagine dozens of inhibition measures and the thing has zilch for adaptivity. The soviet already made far superior bioweapons.

Strategic. There are zero treatments right now and it doesn't look all that amazing in the future (I can think of dozens of ways to counter HIV, but it doesn't mean they're practical or doable now). No bioweapon is targetable, so that's a null point and transmission rates don't matter when it gets into a nation's food and health industry and people start going ape after a few years.

Smallpox is good, yes, but we've eradicated it once and can do it again. Though the hampering of that by the lack of any real vaccine today and the use of GM techniques means it'd be harder.

[tharkûn]

No bioweapon is targetable, so that's a null point

Anthrax is, as are any noncommunicable bioweapons. Further out there would be bioweapons which the aggesser could immunize against while the victim would be unable to do so.

I can think of dozens of ways to counter HIV, but it doesn't mean they're practical or doable now

The difference being that HIV is mutagenic as all hell and hence many things which work for one strain fail for others; prions don't have strains and they don't mutate. Finding a cure for a prion weapon is identical to finding the cure; and given the timeframes involved you will have loads of time to develop one.

transmission rates don't matter when it gets into a nation's food and health industry and people start going ape after a few years.

Response rates fall on a modified bell curve, the powers that be will notice the early end of the bell long before the bulk reaches the hump. After which all you really need is a way to break down the plaques in the brain. Granted that is a tall order, but it is a single static order.

Smallpox is good, yes, but we've eradicated it once and can do it again.

Who the hell was talking about smallpox? I'm talking about Soviet superbugs modified for the purpose of training the immune system to attack nerve cells.

All vaccines do is train the immune system to attack the target species, the soviets managed to make bugs that have nerve markers so all your vaccine does is make nerve damage occur faster.

And that is what makes those ones so frikking scary. Symptoms lag communicability by weeks, death lags by even more, and the whole works is a MS mimic so it will be misdiagnosised to hell and back. To "cure" that type of bug you have to prevent the immune system from responding and killing the bug; which I can only see being done with some form of immunosuppression.

Prions are killers, but you need to systematically introduce them into the food supply. The problem is if you expose one cow, only beings which eat that cow end up exposed and in most circumstances those beings are the end of the food chain. How on earth would get enough into the food supply to even approach a good old fashioned pandemic?

[Admiral Valdemar]

Anthrax is, as are any noncommunicable bioweapons. Further out there would be bioweapons which the aggesser could immunize against while the victim would be unable to do so.

Anthrax is also useless and never really been considered a true weapon, despite the media and their fantasies.

The difference being that HIV is mutagenic as all hell and hence many things which work for one strain fail for others; prions don't have strains and they don't mutate. Finding a cure for a prion weapon is identical to finding the cure; and given the timeframes involved you will have loads of time to develop one.

There's nothing to say the disease couldn't form a slightly different isomer or even have a new one engineered. Besides, this is all pie in the sky right now. There are no current effective treatments, hell, we hardly know much about the things as it is. Maybe another couple of decades we may have a better idea, but right now, zilch.

Response rates fall on a modified bell curve, the powers that be will notice the early end of the bell long before the bulk reaches the hump. After which all you really need is a way to break down the plaques in the brain. Granted that is a tall order, but it is a single static order.

Yes, but a single static order that has eluded treatment for a significant time. I won't say it's impossible, but it is unlikely anytime soon without some radical pharm. advances.

Who the hell was talking about smallpox? I'm talking about Soviet superbugs modified for the purpose of training the immune system to attack nerve cells.

All vaccines do is train the immune system to attack the target species, the soviets managed to make bugs that have nerve markers so all your vaccine does is make nerve damage occur faster.

And that is what makes those ones so frikking scary. Symptoms lag communicability by weeks, death lags by even more, and the whole works is a MS mimic so it will be misdiagnosised to hell and back. To "cure" that type of bug you have to prevent the immune system from responding and killing the bug; which I can only see being done with some form of immunosuppression.

Prions are killers, but you need to systematically introduce them into the food supply. The problem is if you expose one cow, only beings which eat that cow end up exposed and in most circumstances those beings are the end of the food chain. How on earth would get enough into the food supply to even approach a good old fashioned pandemic?

What type of bug were those neurone killers though? The only thing I heard about those was pipedream promises and little factual evidence. Smallpox was always the core of their offensive force and that is the one virus you don't want to come back mutated, at least second to Influenza.

And really, the emergence of nvCJD is showing that prions have the potential to become a classic pandemic if left unchecked. Sure, that'd mean years more waiting, but we aren't going anywhere. The concept could still be weaponised, if not in the current form, then in a far more effective way. You can always rely on human ingenuity to add some spanner in the works of a cure.

EDIT: Nevermind, I found it was Legionella they played aorund with. It still sounds like it has far too acute an infection rate. Scary, yes. Practical? Maybe not.

[tharkûn]

There's nothing to say the disease couldn't form a slightly different isomer or even have a new one engineered. Besides, this is all pie in the sky right now. There are no current effective treatments, hell, we hardly know much about the things as it is. Maybe another couple of decades we may have a better idea, but right now, zilch.

Yes there is. If one protein gets misfolded, it is absolutely useless. The rate of nucleation on a single protein is nonexistant (as in age of the universe timeframe), the key here is to start with a crystal already nucleated and expand. A new isomer will just be conformed to fit the packing arrangement. Spontaneously forming a whole new crystal in the new isomer is looking at a massive entropic barrier, ever won the lottery twice?

There are no effective treatments because the level of funding and work done on the problem is relatively small. Remember only a few hundred cases have killed anyone.

Yes, but a single static order that has eluded treatment for a significant time. I won't say it's impossible, but it is unlikely anytime soon without some radical pharm. advances.

Meh it is question of man-hours and time; a slow burning pandemic would provide oodles of both.

And really, the emergence of nvCJD is showing that prions have the potential to become a classic pandemic if left unchecked. Sure, that'd mean years more waiting, but we aren't going anywhere. The concept could still be weaponised, if not in the current form, then in a far more effective way. You can always rely on human ingenuity to add some spanner in the works of a cure.

No they don't. They only spread to that which eats them. Given that the food chain is grain -> cow -> human you have very little room in it for amplification. The reason there ever was a problem was the habit of grinding up organ meet, excrement, and bones and throwing it into cow feed.

The only way you can get the uncontrolled exponential growth of a pandemic is if you have some other vector spreading the prion. The best shot my lab came up with after a few beers was GM mosquitos.

Scary, yes. Practical? Maybe not.

Legionella were just the vector used, I know of no technical reason why you couldn't insert several copies of Popov's gene into the common cold or what have you.

[The Duchess of Zeon]

The prion proteins are resistant to protease activity (the exact nature eludes my memory now, but I recall something about metal ionic bonding), something that has been studied in the PrPSc protein and also been linked, albeit with a certain degree of controversy, to the amyloid plaques formed by beta-amyloid fibrils spontaneously forming in the brain tissue.

Does this article and the results of the experiments detailed in it possibly have any applicability to the treatment of CJD and its variants?

Friday, January 21, 2005 · Last updated 4:41 a.m. PT

Mouse experiment offers Alzheimer's hope

By JIM SALTER
ASSOCIATED PRESS WRITER

ST. LOUIS -- Brain cells in mice recovered rapidly after brain plaques characteristic of Alzheimer's disease were removed, offering hope that plaque-clearing treatments could benefit patients with the disease, Washington University researchers said Thursday.

Results of the study will appear in the Feb. 5 issue of the Journal of Clinical Investigation.

No one knows for sure if the sticky plaque - amyloid beta peptide - is the true cause of Alzheimer's, a brain degeneration disease that eventually robs victims of memory and the ability to communicate and care for themselves. About 4.5 million Americans have the disease.

But the plaque is a prime suspect, and several companies are developing drugs to target the buildup.

Researchers at Washington University injected mice with an antibody that cleared plaque in parts of the brain. Where the plaque was cleared, swelling on nerve cell branches disappeared quickly, the researchers said. They cautioned that while encouraging, more studies are needed to determine if similar effects might occur in people.

Removing the plaque "often led to rapid recovery of normal structure over a few days," said Dave Holtzman, senior author of the study and head of the Department of Neurology at Washington University.

He said that confirmed benefits of plaque-clearing treatments and "also gets us rethinking our theories on how plaques cause nerve cell damage."

Holtzman was among scientists who previously regarded plaque damage to nerve cells as something that happened once and was irreversible. Instead, the results suggest that plaques might not just cause damage but actively maintain it, he said.

Researcher Robert Brendza said he had expected the progression of cell damage to stop once the plaque was cleared. "But what we saw was much more striking: In just three days, there were 20 to 25 percent reductions in the number or size of the existing swellings," he said.

The rapid ability of the nerve cells to regain their normal structure could indicate that the cells are constantly trying to restore their normal structure, the researchers said.

Dr. Sam Gandy, director of the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia and vice chairman of the Chicago-based Alzheimer Association's Medical and Scientific Council, called the finding "a pretty exciting advance."

"It shows that one of the long-standing structural abnormalities that was used to really define the disease is not something that's permanent and in fact it's reversible," Gandy said.

---

On the Net:

Washington University: www.wustl.edu

Alzheimer's Association: http://www.alz.org/

[Admiral Valdemar]

Yes there is. If one protein gets misfolded, it is absolutely useless. The rate of nucleation on a single protein is nonexistant (as in age of the universe timeframe), the key here is to start with a crystal already nucleated and expand. A new isomer will just be conformed to fit the packing arrangement. Spontaneously forming a whole new crystal in the new isomer is looking at a massive entropic barrier, ever won the lottery twice?

There are no effective treatments because the level of funding and work done on the problem is relatively small. Remember only a few hundred cases have killed anyone.

In anycase, there is nothing to stop such a thing right now which is the reason today it could be considered a great weapon in the long term. I'd have to say that work done on the prion isn't as low as you'd expect. The UK at least has put a lot of effort into researching the disease, especially since some suggested a link to Alzheimer's.

Meh it is question of man-hours and time; a slow burning pandemic would provide oodles of both.

True, but that is once again, another advantage to the weapon. They have to expend more resources on one problem leading you to release something else in the meantime, say, smallpox or plague.

No they don't. They only spread to that which eats them. Given that the food chain is grain -> cow -> human you have very little room in it for amplification. The reason there ever was a problem was the habit of grinding up organ meet, excrement, and bones and throwing it into cow feed.

The only way you can get the uncontrolled exponential growth of a pandemic is if you have some other vector spreading the prion. The best shot my lab came up with after a few beers was GM mosquitos.

No, they have been documented to transfer via blood plasma and surgical procedures. The threat alone from that will hamper national infrastructure and cause panic just like BSE, which was amazingly overblown.

And I never ruled out a vector, the mosquito is amazingly good, but depends on area being attacked.

Legionella were just the vector used, I know of no technical reason why you couldn't insert several copies of Popov's gene into the common cold or what have you.

True, they combined many types of bacteria and viruses for better mission profiles, but the prion attack would be to supplement these rather than be a perfect replacement. It can be a good background problem whilst the more immediate threat of plague or nervous system attacking disorders of unknown origin run rampant.

Gotta love the Soviets for their imagination.

[Admiral Valdemar]

*Snip*

Interesting. I'll have to read that when I have more time (got a lot of work on now), but I'm currently researching chronic diseases, Alzheimer's and prion based ones to boot. So I'll ask my professor about this. Thanks for the article.

[tharkûn]

In anycase, there is nothing to stop such a thing right now which is the reason today it could be considered a great weapon in the long term. I'd have to say that work done on the prion isn't as low as you'd expect. The UK at least has put a lot of effort into researching the disease, especially since some suggested a link to Alzheimer's.

Yes but prions take time to accumulate so once the powers that be realize they have a pandemic on their hands and that the hump is going to hit in say 7 years then watch the blank cheques get written.

Currently untreatable pandemic = gold mine for a pharma company. Whoever wins the race of developing a cure for say removing brain plaques would then be able to sell hundreds of millions of doses at premium pricing.

True, but that is once again, another advantage to the weapon. They have to expend more resources on one problem leading you to release something else in the meantime, say, smallpox or plague.

That is the advantage of any bioweapon. Indeed even the US's old bioweapons program operated off the assumption that biological attack would be best using multiple disparate vectors. The truth of the matter is today's prions are far, far from being "the ultimate bioweapon." Tomorrow's prions are going to be nasty crap, but tommorrows superbugs are going to be even worse. There are intrisic limits upon a prion based weapon that just don't disappear.

No, they have been documented to transfer via blood plasma and surgical procedures. The threat alone from that will hamper national infrastructure and cause panic just like BSE, which was amazingly overblown.

In other words HIV-lite, are we even talking class 3? Yes it will cause panic, anything new does, but nowhere NEAR the panic caused of having to quaruntine whole city blocks, shut down airports, etc. The inability of prion to spread person to person makes it far less fear inspiring than the humble massively antibiotic resistant bacterium which can go airborne.

And I never ruled out a vector, the mosquito is amazingly good, but depends on area being attacked.

The mosquito can also be quenched by massive ariel bombardment of DDT. Once it becomes political imperative to trade the ecological enivornment for saving millions of human lives all sorts of options come into play.

True, they combined many types of bacteria and viruses for better mission profiles, but the prion attack would be to supplement these rather than be a perfect replacement. It can be a good background problem whilst the more immediate threat of plague or nervous system attacking disorders of unknown origin run rampant.

Okay so we have gone from "the ultimate bioweapon" to a "background problem". The thing is background problems are a dime a dozen here. Rather than dick around GM'ing complex vectors for prions, you get just as much out of breeding airborne bacteria resistant to everything on the market and dumping them loose at JFK. Or you can generate headaches for everyone by dumping tetradotoxin (which I beleive has been synthesized in kg quantities) into the water supplies of the major municipalities. Even mundane crap like purposefully contaminating the blood supply goes a long way.

Yes someday after much time and research by a state level sponsor somebody will weaponize prions. However prions will always suffer from intrinsic limitations and science will not have waited for this to occur, something else in the bag will own the "ultimate bioweapon" title, if any single bioweapon ever should.

Duchess: I know of a few drugs in the works that are attempting to counteract plaques right now. I would be greatly surprised if at some point somebody didn't find a way to prevent or breakdown plaques.

[Admiral Valdemar]

Yes but prions take time to accumulate so once the powers that be realize they have a pandemic on their hands and that the hump is going to hit in say 7 years then watch the blank cheques get written.

Currently untreatable pandemic = gold mine for a pharma company. Whoever wins the race of developing a cure for say removing brain plaques would then be able to sell hundreds of millions of doses at premium pricing.

Naturally, economics comes into it. But if it's warfare, gov't oppression can come into play. You certainly wouldn't want people going around helping defeat a weapon you've spent ages creating.

Incidentally, I believe there are papers on strains of prions being produced naturally that all create the associated disease. If this means what I think it means, it says the prions are able to differ and therefore, mutate despite being solely made of protein. That makes vaccination and drug treatment suddenly a lot harder if even possible.

That is the advantage of any bioweapon. Indeed even the US's old bioweapons program operated off the assumption that biological attack would be best using multiple disparate vectors. The truth of the matter is today's prions are far, far from being "the ultimate bioweapon." Tomorrow's prions are going to be nasty crap, but tommorrows superbugs are going to be even worse. There are intrisic limits upon a prion based weapon that just don't disappear.

I was thinking more along the lines of smarter proteomic constructs, nanomachines if you will, that allow for a far better mode of attack than a naturally occurring prion particle that has fairly real limits already known.

In other words HIV-lite, are we even talking class 3? Yes it will cause panic, anything new does, but nowhere NEAR the panic caused of having to quaruntine whole city blocks, shut down airports, etc. The inability of prion to spread person to person makes it far less fear inspiring than the humble massively antibiotic resistant bacterium which can go airborne.

If you mean Bio-Safety Level, then HIV itself is only class 3. It's not a true infectious nightmare like Influenza, though if they merged their properties, that'd be a real nightmare.

I'd be wary of saying it is incapable of person-to-person contact. Many documents state it is by the simple fact that it can contaminate surgical instruments, say. But obviously it'd be far superior if it was an actual contagion from simple sneezing which is an amazing way to spread (or vomiting/diarrhoea).

The mosquito can also be quenched by massive ariel bombardment of DDT. Once it becomes political imperative to trade the ecological enivornment for saving millions of human lives all sorts of options come into play.

Well, another point to us. Again, they have to destroy their environment and also potentially poison vast swathes of people with DDT too. It's certainly not on the scale of a cure that is easy to administer and without side-effects. Anything that detracts from the wellbeing of the targeted nation is a mission objective.

Okay so we have gone from "the ultimate bioweapon" to a "background problem". The thing is background problems are a dime a dozen here. Rather than dick around GM'ing complex vectors for prions, you get just as much out of breeding airborne bacteria resistant to everything on the market and dumping them loose at JFK. Or you can generate headaches for everyone by dumping tetradotoxin (which I beleive has been synthesized in kg quantities) into the water supplies of the major municipalities. Even mundane crap like purposefully contaminating the blood supply goes a long way.

Yes someday after much time and research by a state level sponsor somebody will weaponize prions. However prions will always suffer from intrinsic limitations and science will not have waited for this to occur, something else in the bag will own the "ultimate bioweapon" title, if any single bioweapon ever should.

I gave the moniker to the premise, not really the actual examples today. Like I said, protein engineering can produce a whole manner of new obstacles. While a bug can adapt, which is what makes microbes so evolutionary sturdy, they can still take time to attack and can still die without hosts as most pathogenic bacteria require human or similar hosts. If a protein weapon can be made that has an ability to act nearly as quickly as a neurotoxin (or perhaps "tag" host cells for destruction by immune defences) and self-propagate, then you have problems even if you do start looking into a cure. These prion diseases are ALWAYS fatal unlike smallpox which only had a 20% mortality rate, hell, even Ebola Zaire is only 80-90%. There's no real easy way to detect them, they apparently have many conformational forms to use thus negating treatments and they can have rapid or delayed onset. Even when you do find out you have the disease, it's too late by then to reverse major neurological damage. The things are also far more resilient than any other pathogen known. There's nothing saying that a cure won't be found, but equally, nothing else states that simply putting more man hours into the problem will speed a cure up from coming 10 years down the line to 6 months. Especially if it's an entirely new development.

Duchess: I know of a few drugs in the works that are attempting to counteract plaques right now. I would be greatly surprised if at some point somebody didn't find a way to prevent or breakdown plaques.

There are drugs that already do this. The company Elan Pharmaceuticals produced a beta-amyloid vaccination that not only stopped plaque build up, but actively reversed their damage as witnessed in lab mice. The problem was that at Phase 2, the trials were stopped when the antibody response that drove the regeneration caused inflammation of the brain and comas or even death. So the search goes on (though 3 drugs exist I believe, they are all adapted to after 5 years or so of use using a Parkinson's treatment idea).

[tharkûn]

Naturally, economics comes into it. But if it's warfare, gov't oppression can come into play. You certainly wouldn't want people going around helping defeat a weapon you've spent ages creating.

Today every major power is actively researcher biowarfare counters. If you have enough funds to suppress research you have enough funds to invest in nulcear bombs, JDAMs, AP bomblets, chemical warfare, or whatever else meets your needs. Bioweapons are poor mens weapons because they are far less versatile and far less effective than conventional weapons.

The only guy big enough to supress counter research would be the US government and that is debatable, they would never want to undercut the value of the nuclear arsenal and are the biggest losers if biowarfare breaks out. Even the USSR eventually concluded that advanced bioweapons of doom were counterproductive.

lieve there are papers on strains of prions being produced naturally that all create the associated disease. If this means what I think it means, it says the prions are able to differ and therefore, mutate despite being solely made of protein

It doesn't. A protein is no different than any other molecule - there are a handful of conformers that are more stable than anything else. A slight change, such as mutation causes in primary sequence, does squat in terms of tertiary structure - the avialible thermal energy will go back over the hump and fall down the energy well to the nearest avaible well.

Indeed most proteins flex through a myriad of conformers in a second and all we see is a time averaged composite. Forming a stable alternative tertiary structure requires moving so far across the potential free energy landscape that thermal energy can't bring you back. Many proteins which could be "prionized" suffer from the fact that chaperones will simply undo the folding and go on from there.

That makes vaccination and drug treatment suddenly a lot harder if even possible.

No it doesn't. Why is it going to be harder to remove a plaque packed as threemers rather than tetramers to go with an obvious example?

I was thinking more along the lines of smarter proteomic constructs, nanomachines if you will, that allow for a far better mode of attack than a naturally occurring prion particle that has fairly real limits already known.

You are dealing with a real limited number of atoms here. Even triple dipping on functionality you are going to be hardpressed to reproduce, cause damage, evade destruction, and be retained in the body.

All this additional functionality means that your simple rockhard protein has just become a hideously complex machine that is going to be far easier to denature or degrade.

In any event you are talking about designing something which is a quantum leap in computational ability (and you don't have a snowball's chance on Venus to find this via trial and error). We are talking multiple Nobel's increase in our ability to model proteins here, and if you plan on going solid state - hail the biological Einstein - we still can't predict the packing structure of propane.

If you mean Bio-Safety Level, then HIV itself is only class 3. It's not a true infectious nightmare like Influenza, though if they merged their properties, that'd be a real nightmare.

I know HIV is a 3, I was wondering if prions rate even that high. Let's face it we've seen this crap before. You can catch it by blood, it shortens your life, and it is piss hard if not impossible to vaccinate, treat, or cure. However HIV doesn't scare the population near as much as a smallpox outbreak.

Well, another point to us. Again, they have to destroy their environment and also potentially poison vast swathes of people with DDT too. It's certainly not on the scale of a cure that is easy to administer and without side-effects. Anything that detracts from the wellbeing of the targeted nation is a mission objective.

Look when you are dumping billions of dollars into developing a bioweapon you want to get more than they poisoned the environment out of it. Dumping a massively antibiotic resistant bacterium into the system will kill more people, require more draconian responses to contain, and will cost more to fix.

like I said, protein engineering can produce a whole manner of new obstacles.

We have several extremely costly programs that run on parrallel SGIs, they can't begin to predict the tertiary structure from primary sequence. Predicting function is orders of magnitude beyond that.

You also need an acceptional amount functionality to make these suckers. Given the exponential increase in complexity with increasing function, it would be frikking hard to make these with artificial proteins - being limited to the natural proteins which can't be recovered by chaperones makes this inordinately impossible.

While a bug can adapt, which is what makes microbes so evolutionary sturdy, they can still take time to attack and can still die without hosts as most pathogenic bacteria require human or similar hosts. If a protein weapon can be made that has an ability to act nearly as quickly as a neurotoxin (or perhaps "tag" host cells for destruction by immune defences) and self-propagate, then you have problems even if you do start looking into a cure.

I am 99.9999% confidant you can't. In order for a protein to replicate, the protein has to already be present within the body. No wild type in the human body -> no reproduction. Not only that but the wild type has to have an alternative stable tertiary structure (something that is far from garunteed), but that structure has to do what you want.

Even then you need some way to enhance communicability, and using another vector means I target the vector rather than the "prion" on defense. Biodefense is all about nailing the weakest link the chain.

These prion diseases are ALWAYS fatal unlike smallpox which only had a 20% mortality rate, hell, even Ebola Zaire is only 80-90%

So what? Lethality has always been only part of the equation.

There's no real easy way to detect them, they apparently have many conformational forms to use thus negating treatments and they can have rapid or delayed onset.

Detection is a matter of technology, given current trends I could detect them MRI in a few decades. One could make detection fascile if you managed to design a spin or isotopic labeled compound that selectively bound the prion form over wildtype.

Even when you do find out you have the disease, it's too late by then to reverse major neurological damage. The things are also far more resilient than any other pathogen known.

The jury is still out on reversing neurological damage. Far more resilient, yes because they are SIMPLE. The more crap you want a protein to do the more complex it becomes which means that it becomes harder to protect everything from enzymatic degradation.

Let's say you manage to make a prion that tags nerve cell surfaces. Leaving aside everything else, how do you intend to protect the binding site? You can't hide it in the interior of the protein - it can't bind there, you can't have it obscured by chelated metals - those prohibit selective binding. You can't have it adopt a rock solid beta sheet.

There's nothing saying that a cure won't be found, but equally, nothing else states that simply putting more man hours into the problem will speed a cure up from coming 10 years down the line to 6 months. Especially if it's an entirely new development.

The reason why most cures don't come quickly is safety concerns. With a global pandemic watch those go out the window. After safety concerns in clinical trials, the biggest time cost is weeding out the failures. Time is drastically saved if you have more people synthesizing more crap to find the single key admist a thousand rejects. Even crystal structures are had faster when you have more manpower getting them.

There are drugs that already do this. The company Elan Pharmaceuticals produced a beta-amyloid vaccination that not only stopped plaque build up, but actively reversed their damage as witnessed in lab mice. The problem was that at Phase 2, the trials were stopped when the antibody response that drove the regeneration caused inflammation of the brain and comas or even death. So the search goes on (though 3 drugs exist I believe, they are all adapted to after 5 years or so of use using a Parkinson's treatment idea).

I thought I read of 4 that might work, but none had made it past clinicals yet. I know of efforts at several major pharma companies that are further upstream than that.