"long period of uncertainty began on 31 May 2010, when she stabbed her left thumb with a curved forceps while cleaning a cryostat—a machine that can cut tissues at very low temperatures—that she used to slice brain sections from transgenic mice infected with a sheep-adapted form of BSE. She pierced two layers of latex gloves and drew blood"
Later in the article:
""We conduct research only on mouse-adapted sheep prions, which have never been shown to be infectious to humans,” Aguzzi [neuropathologist at the University of Zurich] says."
It sounds like the assumption that mouse-adapted sheep prions can't infect humans may be flawed.
> Emilie is therefore working that day on samples of mice infected with strains of human prions. It is important to stress here that these were human strains and not animal strains, the species barrier no longer protecting, the infectivity of the pathogens handled by Emilie was therefore total.
> Emilie travaille donc ce jour là sur des échantillons de souris infectées avec des souches de prions humaines. ll est important de souligner ici qu'il s'agissait de souches humaines et non de souches animales, la barrière d'espèce ne protégeant plus, l'infectiosité des pathogènes manipulés par Emilie était donc totale.
(In case anyone else wanted to double-check the translation.)
The full section with the Aguzzi quote adds context, including his declining to comment on the French case.
> The scientific community has long recognized that handling prions is dangerous and an occupational risk for neuropathologists, says neuropathologist Adriano Aguzzi of the University of Zurich. Aguzzi declined to comment on the French CJD cases, but told Science his lab never handles human or bovine prions for research purposes, only for diagnostics. “We conduct research only on mouse-adapted sheep prions, which have never been shown to be infectious to humans,” Aguzzi says. In a 2011 paper, his team reported that prions can spread through aerosols, at least in mice, which “may warrant re-thinking on prion biosafety guidelines in research and diagnostic laboratories,” they wrote. Aguzzi says he was “totally shocked” by the finding and introduced safety measures to prevent aerosol spread at his own lab, but the paper drew little attention elsewhere.
This disease was discovered due to an alert translator (most likely translating from Spanish to English) recalling that he had seen patients’ records before that had the nearly the same exact history.
After investigation, it was discovered the patients worked in a slaughterhouse near the pig brain section, where the brains were being aerosolized. Many ended up developing a progressive inflammatory neuropathy.
Keep in mind that the researcher was only 23 years old at the time when the lab accident happened. In some ways, she was basically a kid. As everyone knows, she ended up dying because of this.
A human has a fully developed adult brain around age 25, but for some people it is not until age 30 [1].
I used to mention this to my binge drinking buddies in college when they wanted me to kill more than a few brain cells with them. In general moderation in all things.
I think the point was, if you were injected with the prion in a finger, how long would you have to sever that finger to prevent the prion from entering the rest of your body.
> In a 2011 paper, his team reported that prions can spread through aerosols, at least in mice, which “may warrant re-thinking on prion biosafety guidelines in research and diagnostic laboratories,” they wrote. Aguzzi says he was “totally shocked” by the finding and introduced safety measures to prevent aerosol spread at his own lab, but the paper drew little attention elsewhere.
...
> The government inspectors' report concluded that Jaumain’s accident was not unique, however. There had been at least 17 accidents among the 100 or so scientists and technicians in France working with prions in the previous decade, five of whom stabbed or cut themselves with contaminated syringes or blades. Another technician at the same lab had a fingerprick accident with prions in 2005, but has not developed vCJD symptoms so far, Bensimhon says.
“ vCJD or “classic” CJD, which is not known to be caused by prions from animals. Classic CJD strikes an estimated one person per million. Some 80% of cases are sporadic, meaning they have no known cause, ”
Who knows really. 10 years is a long time to wait and worry, but it can take up to 50 years to express itself. Just imagine spending your whole life worrying about this.
Bear in mind that eating muscle tissue from infected animals is a much lower risk than innoculating yourself directly with brain matter from an infected animal.
The prion protein is expressed in the central nervous system, which isn't legal for human consumption. Also, ingestion of meat exposes it to stomach acid and digestive enzymes before it gets into the consumer's circulation -- enzymes that break down foreign proteins into (harmless) amino acids.
In contrast, accidentally injecting yourself with material from an infected brain is about the most direct possible infection route.
All sales of beef on the bone was banned too. Even Bovril had to change their recipe for a few years.
The ban was introduced on December 16, 1997, after government advisers reported small risks that small nerve endings near beef bones and bone marrow might be infective. The ban included cuts such rib roasts and oxtail, as well as soups and stock cubes made in Britain from beef bones.
The ban was lifted Tue 29 Nov 1999, but other bans on using as food more risky parts of cattle - brain, eyes, tonsils, spinal cord, spleen and intestines - remained in force, as did ban on use of bones in manufactured food and cattle more than 30 months old are banned from the food chain.
Things have been eased further since 1999 but I'm not sure we can get brain on the menu in the UK...
Mammalian proteins don’t differ from each other all that much so it makes sense the prions of any other mammal could potentially infect humans. Though the further away in the evolutionary tree the less likely I imagine.
Émilie Jaumain - the person refered to in your first quoted paragraph - worked at INRAE and the lab there works on prions that can infect humans. She cut her finger, and became infected.
Adriano Aguzzi's lab at the University of Zurich is the one that only works on mouse-adapted sheep prions. Presumably a similar accident wouldn't be possible there.
When lab workers studying the very thing they know best can make lethal mistakes, it's surprising that so many jumped to quell any hypothesis of a covid lab leak.
Scientists make mistakes all the time. They're human.
Imagine all of the mistakes you make in your job. Outages. Stupid bugs. It's the same with any profession.
Scientists (and logicians) avoid saying "shown to never", as it's much harder - almost impossible - to prove a negative[0]. This is also a black swan[1] type situation. The only way you can say something is never something is if you understand all occurrences of it; otherwise you can only report on what you've been shown.
Yes but the problem with "never been shown" is how it's often used to "take advantage" of people's interpretation like what you list above.
For example dropping a 27.4 kg ball on someone's head has never been shown to cause injury. We've dropped a 26.3 and a 29.5, but we've never studied dropping 27.4 kg - and as a result, "dropping a 27.4 kg ball on someone's head has never been shown to cause injury".
Frequently "never been shown" its used as a weasely way of saying "we've never looked at", or "we don't know if"
So one that is almost certain to happen given some time?
>The only way you can say something is never something is if you understand all occurrences of it;
"Understanding all occurences of it" seems like a good criterion for allowing potentially mass murderous work or not. That said, it sounds stricter than what it is. We just need them to know how a thing works and not be doing "sorcerer's apprentices" style peek and poke work.
They don't need to "prove a negative". For example we don't asks scientists to prove that "water can't explode and destroy the earth" to let them work with it casually. It's enough that they know it well. Do they know prion as well as they do water?
Yes but many experts take "never been shown to" to mean that we ought to act as if it doesn't for now. That's an important and useful social mechanism in the laborious process of constructing a solid edifice of truth from the crooked timber of humanity. But it's unwise when considering public health responses.
You're absolutely right, but it's also true that the phrase "never been shown to" most often functions in a sentence more like "doesn't/can't happen" than "we have no idea."
Yeah that’s been constant. There was ‘no evidence that delta variant is more dangerous’ for white a while, until there was actually some evidence to go on.
It seems like gain of function research is going on all over the place. Maybe Alex Jones isn't total conspiracy nut, as the media portrays him. He's just a head of what is commonly disseminated. I watched an interview with him where he claims to read a lot of research papers daily. Literally a dystopian science fiction fantasy of a virus man made in a lab infecting the world has a good likely hood of being true.
"infect" is not the right word. Prions are not viruses, they do not replicate, they ravage other proteins in their surroundings by misfolding them over and over again until it becomes a fatal pathology.
Techynically you are incorrect. Infect is the right word. Worked at the institution that established this. (I do not believe that koch's postulates cover all cases of 'infection').
The word "prion" is actually a contraction of the words "protein" and "infection". (edit: although I agree it's not what one might conventionally think of as an "infection")
A portmanteau word is similar to a contraction, but contractions are formed from words that would otherwise appear together in sequence, such as do and not to make don't, whereas a portmanteau is formed by combining two or more existing words that all relate to a single concept.
"Motel" and "fog" are portmanteaus, because you wouldn't put "motor hotel" or "smoke fog" in sentences that accept the accretions, whereas you could swap "prion" for "protein infection".
Prions are considered infectious, although when they were first proposed it was essentially heresy that something could be infectious without containing any nucleic acid (DNA/RNA).
Whether they self-replicate or not is sort of a semantic issue. They replicate in the same way "fallen-down dominos" replicate.
Prior to being a prion, they are an already complex protein, but by folding a particular way, they become a prion, which causes other proteins of the same type to fold similarly.
Infectious disease is also called transmissible diseases. Infectious microorganism or agent can be a virus, bacterium, protozoan, prion, viroid, or fungus.
Don't forget memes. Not the current pop-culture meaning of the term, but the original Dawkins version, which stretches to cover things like mass-hysteria.
I'm just saying it does reproduce (or replicate to use the exact same word op used). Whether it's correct to use any of the other terms I will leave to others
Prions are weird. I was at UCSF during the time they went from a fringe theory to an established fact and a nobel prize. The professor who studied them (Prusiner) had to overcome tons of resistance and the experiments were heroic (often waiting months for mice to die). It's really funny that everybody resisted it until somebody mentioned that there was a plausible physical mechanism of refolding catalysis.
> everybody resisted it until somebody mentioned that there was a plausible physical mechanism
This is a good instinct IMO. Experiments by one person can easily be nonsense, especially if you don't already know and trust that person. Without a physical mechanism, given extraordinary results, I would certainly remain skeptical.
Is it because many researchers put their ego first over the science?
It's so many times that they ridicule ideas, that often amounts to bullying and then they rarely even say sorry when it turns out they were wrong.
Why won't academia flush out these types of people?
The toxic atmosphere with no way of getting rid of bad apples is what put me off from studying.
It’s because discovering something completely new and unheard of that isn’t even hinted at hy any existing theory is extremely rare. Most people with such claims turn out to be wrong, doing bad experiments, fudging data, or worse.
The scientific community is resistent to such things because 90% of the time they are right to be resistant, the hypothesis is conclusively disproven, and we never hear about it again.
Sometimes, rarely, the claim comes through, survives the scrutiny, and scientists quickly change their minds based on new established fact.
Imagine if someone came out with “I have found a way to run 50 compute cycles per CPU instruction!!”. We would justifiably ridicule that person’s idea as implausible or impossible. It would take a lot of evidence to change the whole computer industry’s opinion on what’s possible.
Exactly, though I would rather put that number at >99%. I would think, its kind of black swan event where in hindsight, everyone thinks its easy to see but it was not.
Recently, we see that here and there with covid research where some single lab (or doctor) comes up with theory that matches some peoples preformed believe. When most scientists then oppose that theory, those people claim that this one of those <1% of cases were all the science is disproven, citing all the cases where it was, failing to see the many more situations where it wasn't.
>Why won't academia flush out these types of people?
Because this behavior is part of human nature. Do you think scientists as a class are are somehow exempt from this, say, by some form of rationalistic purity?
This phenomenon is studied in the history and philosophy of sciences; it is called "paradigm change" ala Thomas Kuhn. Yes, researchers who work in the dominant 'paradigm' tie their psychological identities with the paradigm they are working on. So, this resistance is expected.
'How to overcome resistance' is studied in Sociology of Science.
It's because scientific evidence for a novel theory is often spotty and incomplete, and without any inertia, we'd be jumping from one fad to another, only to discover that the hot new thing is just a statistical anomaly, or a failure in experiment design.
See: the Pons cold fusion nonsense.
Yes, this does sometimes mean that correct novel theories, that don't have an insurmountable body of experimental evidence behind them have a harder time getting adoption. It's a tradeoff. It's the kind of tradeoff that anyone who actually wants to get any work done is constantly making.
No, because the underlying data demonstrated that there was a statistically significant death effect occurring, with a wide range of evidence implicating prions, before there was a mechanism. You shouldn't require a plausible mechanism to trust your experiments (seen this a hundred times, like in RNA enzymes, heart of the ribosome, various dna-is-the-heritable-agent experimetns).
Yes you should: because all you have otherwise is a death rate that could be caused by any number of things. Biological organisms die all the time for all sorts of reasons: there's a difference between showing a series of factors lead to an death rate, and proposing the specific mechanism by which that happens and it's important.
That light behaves like a wave did not summarily prove there was an aether through which it propagated, and not finding it up-ended physics.
Not only did they know the death rate, they had an infectious agent in a tube they knew was protein. If you identify a reproducible agent you can study in the lab, you don't need any plausible mechanism.
Note that aether was the plausible mechanism, and it mislead people for a long time. The experiment that "disproved" aether just showed that the mechanistic proposal was simple, and wrong.
Clearly you do not need to know the mechanism by which light waves propagate to prove that light waves do propagate. It would be ass-backwards to wait until special relativity was formulated to accept the existence of electromagnetic waves.
Not really. Look at how Darwins theory of evolution was published in 1859, while the mechanism wasn't really clear until at earliest 1928, and in some ways it's still not fully understood.
If ancient Romans could have shown correlation & causation between lead pipes & drinking vessels to poor health outcomes, they should have ceased using lead for these purposes even while lacking the capability of understanding the underlying mechanism. There's no voodoo in that.
The article talks about the case of Émilie Jaumain that got contaminated by prion while cleaning a device used to slice mouse brains. She died 9 years later of a prion disease. After several cases of exposure across the world, France decided to block prion research for 3 months to try to study the issue.
They want to make sure that disease did not come from other places than the lab, which would be a concern to the general public. However unlikely, it's a possibility that has to be eliminated.
There are reviews and then there are reviews: Rubber stamp security reviews happen.
I don't know much about this particular case, but I think, in general, a trustworthy review needs to be conducted by an independent body with genuine power (edit. and desire) to order things to halt permanently if they can not be made safe enough (and then there is a separate question of who makes the call "what is safe enough").
>(and then there is a separate question of who makes the call "what is safe enough").
This is hard. If there isn't the right incentive they can decide nothing is safe enough. This ensures safety now, but it means that if a cure is possible it won't be discovered (or anything else useful from the research). The FDA has been accused of needlessly holding up useful drugs on this grounds (I'm not going to comment on if true or not)
That was not the case that prompted this reaction, so I don't understand the reasoning behind your comment?
The case that prompted this reaction is described in the first paragraph of the linked article. The one you refer to in the second one as an older case.
There is no mention of the older case having lead to any shutdowns, making it hard to follow your train of thoughts, since you specifically refer to this older case.
I believe the issue is that the kind of precautions they're using were based on some assumptions (e.g. that mouse prions do not affect humans) which were flawed and need to be re-evaluated. It's not just "don't cut yourself, duh".
Your reasoning seems backwards to me. If she had hurt herself through some unlikely and intricate series of events, a shutdown would have made less sense.
« Prions are misfolded proteins with the ability to transmit their misfolded
shape onto normal variants of the same protein. They characterize several
atal and transmissible neuro degenerative diseases in humans and many
other animals. It is not known what causes the normal protein to misfold, but
the abnormal three-dimensional structure is suspected of conferring
infectious properties, collapsing nearby protein molecules into the same
shape. […] There are no effective treatments for prion diseases. »
Basically, you get infected, you die. See also [2].
Well we don't really know that, because diagnosis is normally confirmed post-mortem. There could be many people walking around infected with prions that show no symptoms at all.
There is evidence that some people have a mutation that prevents them from getting CJD. The mutation causes a small change in the proteins that CJD prions impact (changing a glycine to valine at a certain part of the protein). The working theory is that that structural change prevents CJD prions from being able to re-form healthy proteins, preventing the spread of the disease. I wouldn't be at all surprised if those proteins are eventually broken down by the body and removed.
All that being said, I don't know if you would even consider it an "infection" if the person is immune to the prions spreading. Prions aren't generally transmissible, so if the prions don't do anything and can't be transmitted... is anything actually wrong? You and I are exposed to tons of bacteria every day, but as long as your body can fight it off (i.e. no symptoms and no transmission), we wouldn't usually call that an "infection". In the same light, presence of abnormal proteins that aren't causing an issue doesn't seem like something we would call an "infection".
There's also the fact that some people inherit the disease (as in their body actually makes the prions itself), which doesn't make any sense in the context of an "infection". It's their own body producing the prions, so in those cases it's a genetic disease, not an infection.
Avoid eating British beef in the 1980s/1990s, too.
Apparently 1 in 2,000 people in the UK may be infected.[0]
We still don't know if there's going to be a second wave of disease from infections from that time period due to genetic factors influencing incubation of the disease.
This is why people who were in the UK for longer than a few months during the 80s and 90s aren't allowed to give blood in various places around the world.
I was there with the mad cow disease. Not in the UK, but in Spain, as commerce inside the EU made people truly paranoid on eating meat from "untrusted" sources.
There's still uncertainty about whether or not CJD can be spread through blood transfusions, but if it is spread through blood, and the sneezer also has a bloody nose, well there's the aerosol transmission.
Welcome to the exciting world of duel use microbiology research. There's plenty of people are doing stuff that walks the line between learning new things and creating ways to weaponize germs. It's all a question of good governance.
this is a nitpick, but "negative externality" isn't a synonym for "bad things happening". It describes a market transaction which inherently imposes costs on an unrelated third party.
For instance, a steel mill producing rolling stock to sell me releases sulfur into the air that dirties your property, imposing a cost on you.
Prion research doesn't necessarily impose costs on anyone.
It's not a nitpick, it's just wrong. Bad things happening is a cost which is both negative and external. The use of the term "negative externality" works here.
Negative externality is an economic term which describes a specific market failure. A research lab leak (or nuclear meltdown, or whatever) is a rare accident, not a negative externality.
It would be like me saying the theory of relativity just means a theory about how everything is relative. That's obviously wrong. You can't just break down academic terms into their separate words. It doesn't make sense.
Third parties suffering a disease is the negative externality.
There's no difference between a steel mill leaking sulphur in the course of producing steel and a biotech company releasing prions in the course of producing medicines. Radiation leaks in the course of producing electricity are likewise externalities.
Yes, there is a main difference which changes the entire definition. Sulfur emissions are a core part of steel production. You cannot manufacture steel without using carbon in the reduction process. It is inherent.
However, you CAN research diseases without having accidental lab leaks. Thousands of labs around the world do this perfectly fine year in, year out. That's the way it's normally done. The process of researching diseases does not inherently impose costs on anyone else.
No, sulfur release is not a core part of steel production, and indeed sulphur emmision has been drastically reduced since regulations made steel producers bear the cost of sulphur emmissions, removing it as an externality.
Labs don't continuously spew out diseases, but they very much must impose the risk of such releases upon others. That is the cost. It costs money to insure against risk, even if the disaster never comes to pass. If a biotech company reduces its costs by implementing looser safety policies thus increasing risk to the surrounding population, that cost is borne externally. Hence the name.
What I am arguing is that low-probability events can be treated as effectively certain over large enough sample sizes.
Similarly, dangerous jobs impose a societal health burden via workplace accidents. Each accident is one-off but in aggregate, a non-zero accident rate is a certain outcome.
Containment breaches of contagious diseases, while each a one-off event, are effectively certain over large enough sample sizes- and therefore should be considered as part of the cost of doing research into them.
Also no terrorist is interested in a weapon which takes 10 years to kill their target population, maybe.
The threat of WMD terror hasn't materialized in a meaningful way: intact, state-manufactured nuclear weapons are the only plausible weapons non-state actors can realistically handle without killing themselves with them, and even that's pretty questionable: it's not easy to detonate a nuclear bomb.
Chemicals are even worse: it's pretty easy for a chemistry student to accidentally make organophosphates, but terror groups don't try in any substantial way - you're as likely to poison yourself as anyone else.
Biologicals are the worst: screw up and they infect you and then the rest of your organisation - or you have a power cut and everything dies in the test tube.
>Also no terrorist is interested in a weapon which takes 10 years to kill their target population, maybe.
Not necessarily. If you can somehow pull off a food supply chain attack which creates the perception that a lot of food may have been contaminated with prions, that could potentially very effectively induce a state of mass terror. Symptoms take years to manifest; can't be fully diagnosed until you're already dead; inevitably fatal.
It could potentially turn half of a country into (somewhat rational) hypochondriacs, even if almost no one actually became infected. And if it were confirmed that a lot of people were infected, that'd ramp up the fear much more. Also, the cost of pulling it off is probably much lower than the cost of detonating a dirty bomb or even a full nuclear bomb, while potentially achieving a much stronger effect.
>The threat of WMD terror hasn't materialized in a meaningful way: intact, state-manufactured nuclear weapons are the only plausible weapons non-state actors can realistically handle without killing themselves with them, and even that's pretty questionable: it's not easy to detonate a nuclear bomb.
I kind of disagree. Nuclear weapons seem like they probably won't be viable for terrorism for a very long time, if ever, but I don't think they're the only plausible weapons that can realistically be handled. Look at Aum Shinrikyo and their various planned, attempted, and successful chemical and biological attacks in the 90s. They killed 27 and injured over 6,000 people, but they came very close to potentially killing or debilitating tens of thousands.
There's definitely a risk of being injured or dying in the process, but they took (largely effective) precautions to prevent that. You can also do things like use binary agents which only activate when combined. But, perhaps most importantly, terrorists (regardless of motive/ideology) often fully accept and welcome that they may be harmed or killed in the process, so the risk isn't a big deterrent.
I suspect that within this century, at least one terrorist/cult/lone wolf chemical and/or biological attack is going to come close to, or succeed at, killing a large number of people, and I think the threat of future attacks may paralyze a lot of societies.
It's more dangerous than enriching Uranium. Uranium does not self-replicate, for one thing. It's also very easy to detect and ensure it has stayed contained.
> Jaumain’s family has filed both criminal charges and an administrative suit against INRAE, alleging a range of problems at Jaumain’s lab. She had not been trained in handling dangerous prions or responding to accidents and did not wear both metal mesh and surgical gloves, as she was supposed to, says Julien Bensimhon, the family’s lawyer. The thumb should have been soaked in a bleach solution immediately, which did not happen, Bensimhon adds.
Sounds like a bad lab that wasn't following safety procedures. But even that is in question:
> Independent reports by a company specializing in occupational safety and by government inspectors have found no safety violations at the lab; one of them said there was a “strong culture” of risk management. (Bensimhon calls the reports “biased.”)
Why does every lab have to be shut down for 3 months?
I think the report finding that there were no safety violations is the most damning. You have 100 researchers dealing with a deadly disease, 17 had lab accidents during their work, 5 of them may have suffered fatal exposure with no training how to mitigate this? What are the mandated safety procedures if none where violated? Wear a labcoat and pray that you wont die ten years from now?
Your second quote is the reason why: the administrative controls that are supposed to prevent this sort of incident at any of the labs inarguably failed in this case, and there is no reason to believe they will not fail again.
In addition, these controls may be based on false and overly-optimistic assumptions about the risk these pathogens pose.
For either of these reasons, returning to the status quo ante may not be an adequate response. In general, administrative and procedural controls are inferior to uncircumventable physical barriers.
It's so that they can figure out why the process wasn't being followed and how it can be improved. Nothing is perfect and accidents are a great catalyst for reexamining your procedures.
What could change to make it more likely that the process would be followed? Could we put signs all around places with prion research? Could we implement a buddy system whenever we work with prions? Do metal gloves need to be hung in visible place throughout the lab? Do we keep containers of bleach accessible for when someone pricks their finger? Do we have enough of them and are they visible enough?
The last thing you need is more bureaucracy. If you want the rules to be followed, you punish the people who don't. That's it. It doesn't take 3 months. It doesn't take any audits or committees. If there is a rule following problem, you enforce the rules. People will find a way to comply if they know they will pay the price if they don't.
Part of a process audit is to check compliance, e.g. by counting if there are enough metal gloves per employee - including measuring all hand sizes to check if really every employee even has access to a fitting glove -, by checking if supply orders for PPE match expected consumption, by interviewing current and especially former employees and by checking emails for evidence of staff complaints.
Someone not following a process is a failure of the process. The process should include proper training and regular oversight to ensure that the process is being followed - an audit will reveal if that training and oversight is in place. If you trace any accident back far enough, you'll eventually get to a point where it could've been prevented with better planning.
if we have some dangerous prion, and some person is bypassing procedure, that still is needing some evaluation. prion escape and becoming common in populations would be a large disaster.
> prion escape and becoming common in populations would be a large disaster.
IIRC, all known prion diseases are only transmissible by ingestion of infectious particles - meaning, eating from infected parts of a carcass, urine/feces and blood.
There does not seem to have been any ingestion in these two cases. Still, they do not involve transmission through air or through casual contact, but see the last couple of sentences here with regard to the former: https://news.ycombinator.com/item?id=27984942
Risk management can (and often does) include simply accepting risks and their consequences.
A strong risk management doesn't necessarily mean strong protection of employees, just that lots of risks have been considered, documented and weighed in some form.
Has there been any research on Prions as a bio-terrorism weapon? It sounds like you could infect thousands/millions and have a close to 100% death-rate without anyone noticing until many years after the contamination started.
Imaging contaminating food/drinking water with the Prion which causes Kuru [1] for example.
I've always thought a _very_ effective strategy would be to get a crop-duster and spray a prion-contaminated mist over a major city, basically contaminating every public surface in a large area
I'm also not sure how you would begin to clean up afterwards - do you remove the surface of everything in your city?
To those saying bio-terrorism is ineffective or would not kill a lot of people in any appreciable time-scale, think about the terrorism aspect - imagine not being able to interact with any surface? It would be like a permanent covid lockdown on the area
The psychological effect of a large-scale area-denial would be massive
It's not really effective because it takes years to manifest symptoms of prion disease. Terrorism usually has a message attached to it, and "you're gonna start dying in 10 years" is not conducive to messaging.
It is true that hiding it for many years would make it less attractive for terrorists, however one could imagine another strategy where you wait 12 months before anonymously telling the authorities you did it, without telling them how. (While threatening to do it again)
Having some unknown person(s) spreading Prion diseases around that cannot be detected until way after it happens would be close to the perfect terrorist attack imo. You could probably keep the attack going for at least a year before authorities get their act together, all the while people would be scared shitless as it would be very hard to know how the original group got infected a year earlier if you choose the right product to contaminate. (Not even mentioning the difficulty finding who did the contamination even if the specific product is found)
living with knowing that i probably have 10 yrs before die in a gruesom neurodegeneration, knowing that if i interact much with our world that maybe i spread this to others, seriously terrifying, depressing, would induce misery.
It would make it much easier to get away with than bombs and spread way more fear. If it would work (I have no idea) it would be a very intelligent choice of weapon.
Wouldn't an entire city being sprayed with prions be a fairly apocalyptic event in and of itself? Those prions aren't going to go away, they'll get blown about and distributed by the millions of cars, buses, and trains going in and out of the city. What can you realistically do about that, go full Imperial Inquisition and raze the entire section of the country to the ground?
honestly, I doubt it. Prions do go away, exposure to oxidizing acids (nitrous, sulfuric), oxidizers like car exhaust ozone, sunlight probably damages them, random environmental proteases that are extremely hardy (because they are designed to work outside)... Also we don't really know of a way to make large volumes of prions; IIRC nobody has made a de novo infective prion, you could seed a folded prion protein to become infective prion using a biological source, but that level of biotech requires a significant lab with large-scale fermentation, or I suppose you could just grow flocks of sheep or cattle and harvest their brains, that would probably get noticed too.
We also don't really know what the population penetrance of prion is. It's possible, for something like british mad cow disease, basically everyone got exposed, but only some people got sick due to a random high infectious load, or a weakened capability of the body to clear the prion...
There are proteases in the body that are capable of clearing amyloid forms (insulin-degrading enzyme, e.g.) and it would be hard to believe that for a sufficiently small dose it wouldn't get cleared before it got to the brain.
strange, I just looked it up, but no one has investigated if increasing IDE expression in mice has a protective effect against prpSc infection (when the infection is not administered directly to the brain)... If there are any prion researchers here... Might be an interesting experiment.
Why even bother with terrorism? It sounds like a potentially gruesome and sadistic weapon with which to use against a particularly bitter foe- the terror is only incidental. Maybe it's akin to using a dirty bomb.
> Has there been any research on Prions as a bio-terrorism weapon?
All such research has dual military-civilian usages. Similar to how all nuclear energy research has nuclear weapons implications. All space/rocket research has icbm implications.
As a matter of fact, all nuclear energy, space activity, etc by all nations are tied explicitly or implicitly to the military/defense.
It's why when our "enemies" ramp up on nuclear energy or space research, we ( the government and our media ) complain. It's also why we keep tabs on such research by our "allies" as well.
If any major nation is researching something, my guess is that they are also researching how to weaponize it and defend from it.
The definition of terrorism is "inciting fear", not necessarily "kill thousands". A million people afraid if they caught BSE/cow madness is definitely hitting that definition, especially as the stuff can't be tested for... people exposed to prions will have that sword hanging over their neck for the rest of their lives, and the affected area will be out of order for years.
And killed very few people. That's what we call terrorism (lots of news coverage for very few deaths) - it's not effective in doing anything but news cycles.
> it's not effective in doing anything but news cycles.
"The unlawful use of violence and intimidation, especially against civilians, in the pursuit of political aims" is a definition of terrorism. Death count is irrelevant (outside of spreading fear itself). Zero deaths in a terrorist attack could still be a very effective attack. Spreading something that causes a hideous disease in a city and causing mass hysteria could be an excellent terrorist tactic. Likely better than a bomb that kills a few people.
We need to expand the set of possible actors and goals. The anthrax campaign happened immediately after 9/11. The result of the campaign was the end of effective political opposition to the massive expansion of military and "secret" aspects of the USA government made possible by 9/11. Cui bono? Certainly not the several implausible patsies the authorities immediately had lined up to blame.
Numerous USA calamities make a lot more sense when we study them with an eye toward who benefits rather than who is blamed.
What made 9/11 such a successful terrorist attack was that it made the US live in fear. That is a change (and it hasn't changed back). Terror (fear) is a perfectly fine end in itself for terrorism.
The anthrax mailing caused changes and fear in US society with very little work. That sounds like a very efficient terrorist attack IMO.
For prions specifically, the main "problem" (which is a good thing overall for us) is that they're naked proteins, and they denature relatively quickly when outside of a protective environment. Spray them onto crops? Crops and soil are covered in small bugs and microbes which break down anything too long, including proteins and carbohydrate chains. No, in order to have prions in the food supply, you need something like cannabalistic cow-raising practices or other ways of recycling prions in a wet+hot safe environment.
> For prions specifically, the main "problem" (which is a good thing overall for us) is that they're naked proteins, and they denature relatively quickly when outside of a protective environment.
How does this jive with the seemingly extreme difficulty of effective sterilization of prion-contaminated objects?
That is not how terror is defined though. The amount affected by terrorism is the amount of people that get terrorised by the act, not the amount that gets sick, dies or know someone who did. Using your definition 9/11 only affected aprox. 10.000 people but in reality if cased mass hysteria and fear in the US (and elsewhere) that is still there today.
Can’t you just spray them into a hamburger meat grinder at a meat packing plant to protect the prions in beef? But it’d be a pretty ineffective terror attack if it takes 10 years for people to show symptoms… though that could also mean that attack was already made 5 years ago and we just don’t know yet.
I think and airborne human transmissible prion disease that kill in a few years is the kind of event that can bring our society back to prehistoric living in just a few decades. Hope it never happens.
I find prions unbelievably scary too. What reassures me is that they've had about 3 billion years to wipe out life on earth and haven't done it yet. Which means there must be some natural limits on their spread we don't know about yet.
There's basically one protein which does it (all the variants are just slightly different misfolds or misfolds of a slightly different version of the protein). It's only present in the nervous system and doesn't generally spread from there nor does it very easily make its way there from the skin, gut, or lungs (though of course it does sometimes). It also seems that some people are immune or at least more resistant. This makes a wide spread of it extremely unlikely without some really specific circumstances (like cannibalism, either in humans or in animals, or a deliberate attempt at weaponisation).
Because we have had many population isolated. Indians never got black plague because Europeans isolated, but got smallpox when Europeans show up. Syphilis was deadly until making of penicilin, probably came back with Europeans from Indians. If whole world is connected then disease maybe can go through whole population.
Prions infect animals of all sorts as well, so isolation of human populations is of lesser importance here.
If, say, oceanic fish were susceptible to some easily transmitted prions, you would have a worldwide epidemics in no time. Fish form a crucial part of almost all food chains on the planet.
Is this even possible? By what mechanism could a prion disease become airborne?
Viruses have evolved to more easily infect cells in the respiratory tract for this specific purpose, but prions are much less sophisticated.
It seems there may be some evidence they can evolve, but enough to hijack cellular machinery in such a way that they could increase the concentration in the respiratory tract enough to transmit?
To attenuate fears a bit... Aerosol transmission was proven possible if you're sitting inside a vapor inhalation chamber equipped with a nebulizer spraying out liquid droplets containing >2% w/v brain homogenates from terminally scrapie-sick mice.
Rest assured if you somehow get infected by PrPSc through airborne transmission, someone was trying really hard to make that happen.
>a vapor inhalation chamber equipped with a nebulizer spraying out liquid droplets containing >2% w/v brain homogenates from terminally scrapie-sick mice
I have never been more grateful to be a backend web developer where the worst risk to my health is a headache from flakey libraries. This sounds like a terrifying job!
Prions aren't airborne. vCJD and mad cow spread by a feedback loop involving slaughtered infected animal brains being fed to the same animal stock. This case was a technician who stabbed herself with a tool heavily coated in brain matter from infected animals. It's not like a virus where just a few particles is enough to bootstrap an infection. At least, it's never been seen.
> "Common knowledge is that prions aren't airborne, and can't cause infection that way," said neuropathologist Adriano Aguzzi of University Hospital Zurich, co-author of a study appearing today in PLoS Pathogens. "We were totally surprised and also a bit frightened at how efficient [airborne infections] were."
Prion diseases aren't airborne. Yes, you can aerosolize them mechanically and get them to infect mice in a lab. There has never been a known case of airborne transmission between two animals. The shed load just isn't remotely high enough, being a brain plaque and not a respiratory infection.
> She had not been trained in handling dangerous prions or responding to accidents and did not wear both metal mesh and surgical gloves, as she was supposed to, says Julien Bensimhon, the family’s lawyer. The thumb should have been soaked in a bleach solution immediately, which did not happen, Bensimhon adds.
Does bleach even affect proteins? Isn't that protocol for an organism you're afraid of?
>A 5-minute soak in a 40% solution of household bleach decontaminated stainless steel wires coated with chronic wasting disease (CWD) prions, according to a new study by National Institutes of Health scientists.
Yeah, bleach does affect prions. Most of the studies I could find were tested on metal, not just someone's thumb. It looks bleach doesn't do a great job of penetrating tissue so the hope is to destroy the prions before they get into the cut, which seems more hopeful than effective to me.
That'd be a bold move, considering (1) it may not have helped, and (2) it is possible the thumb incident wasn't how she got infected. It's possible she got infected some other random day in the lab. Maybe she rubbed her eye while wearing a contaminated glove, or breathed in brain flecks through a poor fitting N95, while slicing a particularly dry cryosample.
Yes, though prions are extremely tough by protein standards (surviving extremely high temperatures and acidity, making them difficult to clean away. Prions have been transmitted from patient to patient through sterilized instruments used in brain surgery)
>I am sure those would have been autoclaved and reprocessed at some ridiculous pH value, no?
Probably not until they had reason to do so.
"Hot acidic environment" is hell when it comes to corrosion and the engineering incentive for medical stuff is only to be as corrosion resistant as you need because there are other design considerations and the most corrosion resistant stainless steels are not the bet fit for building a super precise needle you're gonna poke around in someone's eye so you wind up wanting to pick a middle ground alloy. Picking a middle ground alloy puts a hard limit on what you can do to clean your instruments before you degrade them in unacceptably short order.
I don't know how things have changed since. My medical manufacturing experience is out of date and limited.
yeah I wouldn't count on prions being as easily denatured as other proteins. E.g. mad cow disease spread because prions are not killed by simply cooking / boiling it.
Is there some specific reason to think that prions are harder to denature than other proteins? It seems like mad cow disease could also spread simply because meat is not normally cooked to ensure that 100% of the proteins in it are denatured.
Prions are essentially already denatured/unfolded. They are a more stable state of a normal protein that has biological function, and they interact with the "correctly" folded proteins to cause them to denature into additional prions. Often denaturing a prion means actually breaking apart the protein into fragments or amino acids, because it is already at the most stable/denatured state. This is also why they are so persistent in nature and so hard to remove from surfaces. Apparently gas plasma sterilization is a promising possibility. (this seems like an ok overview of the challenges: https://pubmed.ncbi.nlm.nih.gov/21271212/). Current procedures include things like autoclaving in 121C sodium hydroxide for 30 minutes. Definitely not something that fully cooking will inactivate.
In addition prions seem to contain disulfide bonds, which tend to make proteins even more stable. (RNAse for example has them and is notoriously hard to get rid off unless you treat it with essentially H2S).
I haven't found a source for that, but according to my bio teacher mad cow disease started, because they decided to lower the temperature to pretreat animal waste (such as bones and brain matter...) which then ended up in what cows get fed with. Wikipedia mentioned nowadays they simply leave out the bones and brain from the food.
Kinda a morbid question but could you just sever the finger moments after the prick? Or would the blood pump so fast that the prion(s) is already in your body.
My housemate is an organic chemist and from a past conversation apparently there is a cautionary paper regarding a grad student who lost a hand due to delayed amputation of a finger after similarly being jabbed with some nasty chemical. Can’t find the paper unfortunately.
>would the blood pump so fast that the prion(s) is already in your body.
Well, I guess the question is "is it in the blood yet or not". As someone who have had lots of stuff injected into his veins multiple times (cancer treatment) I can state for a fact the from injection until pretty much full body exposure can be counted in seconds on one hand. I'm not a doctor but my guess is it would only work if you cut the finger off pretty much instantly (counting from the time it enters the bloodstream). Of course it would take longer from a small cut than injected into the big pipes. I wouldn't trust it to work after a few seconds though.
They mention in the article that normal protocol is to immediately soak the thumb in bleach. Not sure if that’s actually effective though, or just hopeful.
"This protein, in its healthy, properly-folded state, is, if not trivial, relatively unimportant. Its complete loss is certainly not catastrophic."
I have no idea how to block proteosynthesis of a single protein in humans, maybe more biologically attuned HN:ners can comment what it would mean (I'm totally clueless of cellular biology).
> "This protein, in its healthy, properly-folded state, is, if not trivial, relatively unimportant. Its complete loss is certainly not catastrophic."
If I at my age know anything about how real world works, absence of evidence is not an evidence of absence, and I can bet that this will turn out to be complete bullshit, and it will get known in the future that this protein is important.
Proteins have a half life of ~24 hours. CJD has an incubation period of roughly 10 years. If de novo PrP synthesis was somehow halted, the likelihood of developing CJD would drop to zero.
On the other hand whatever job PrP was doing will also cease getting done, and its downstream pathways will be disrupted. So there are likely consequences.
Now if you could totally shut down PrP synthesis for like a week, then turn it back on, that might work. In theory this is possible using a tet-expression system [1], but I've never worked with a tet system that wasn't leaky. The only sure way would be to KO PrP genes from all cells, then CRISPR it back in a week later. Oh, and I'm talking about cells in a culture dish; this strategy would never work in an adult human.
All of them? I admit that I'm not a biologist, so that's new to me, but this would seem to put our bodies under immense stress if we had to replace half of all our proteins every day. If the average human body has 10 kg of proteins, this would mean the necessity of synthesizing 5 kg per day to prevent your death. Or is this specifically about PrP? If it's true that it doesn't last long, then perhaps stopping its synthesis would be a viable option.
Does the misfolded PrP have a different half-life?
There is certainly a large standard deviation on that 24 hour average. Some proteins might last a few days. But we are talking on the order of days vs. the disease which takes on the order of years to manifest. Anyway I assume that the disease manifests as a result of bad PrP accumulation (much like how tau and Abeta protein accumulation eventually results in Alzheimer's disease; in fact Abeta has been described as having "prion like" properties regarding how Abeta clusters beget more clusters). So as soon as you shut down PrP synthesis, I doubt CJD could manifest, even if the current PrP in your body was immortal.
For anyone unfamiliar, OP is referring to the Kurt Vonnegut novel which has a fictional state of water (ice-nine) that immediately freezes all other water it comes into contact with into more ice-nine.
Edit: I committed a sin and didn't mention the title: Cat's Cradle.
To prion diseases? Mainly in that they're not that common, more like a weird aberration than something that actively fights and adapts for its own survival like bacteria and viruses.
I mean cancer is not contagious, but it still kills millions a year.
This coming so close after the announcement by DeepMind that they're releasing the data on hundreds of thousands of protein folding structures has me with a growing knot in my stomach.
As generous and useful on a human-scale an announcement as that was, my first thought was how it could be abused. So too prion research.
Who'd've thunk that muscle bulk could be so scary? (!)
I just wanted to add a comment about your muscle bulk comment. Protein in protein shakes is usually denatured or rather just a collection of amino acids.
Proteins that are synthesized by the body have a structure to them and Prions are simply misfolded representations of those proteins.
The process of destroying a Prion involves denaturing it by removing its structure.
I don't believe that muscle tissue is anymore related to Prions or structured proteins than any other part of your body as the protein that we eat is simply amino acids or building blocks for creating things like tissues.
It does beg the question though, could some of the advancements by DeepMind help us understand how to unfold Prions more effectively than using Bleach.
Just for clarity - my last line there was me being facetious!
I was under the impression that even boiling or bleaching did little to kill prions? I seem to recall that even autoclaving surgey equipment did nothing to them, so they had to be thrown?
Otherwise, yes - there're lands of opportunity in the science of protein un/folding.. but as much, there's scope for naughtiness too.
Seems to me like this level of tech - or, at least - that which may be available in this domain over the next 50 years, could be one of those existential Great Selector/Filter events that biological civilisations might face over their evolution.
Ah apologies. And Bleach is utilized in the labs to denature the prions appropriately. You're correct that autoclaves are not used as heat unfortunately is not enough to kill them.
I wonder if it would be possible to make a designer protein that latches onto prion “seed crystals” to neutralize it. Some of the recent advances in protein folding and crispr make it so this might be starting to be something in the realm of possibility.
Not sure why she wasn't wearing the proper protection or responded to the exposure correctly (bleach rinse apparently) but this goes to show the importance of following lab safety protocols at all times.
> "She had not been trained in handling dangerous prions or responding to accidents and did not wear both metal mesh and surgical gloves, as she was supposed to, says Julien Bensimhon, the family’s lawyer."
Somewhat off-topic, but what are the chances that new advancements in protein folding research (like AlphaFold) might let us find cures for prion diseases?
The lab leak hypothesis is less plausible than the natural leak hypothesis only if you exclude the fact that gain-of-function research on Coronavirus was being done in the Wuhan Lab. When you include that necessary fact, it becomes the most parsimonious.
If this researcher becomes ill with CJD, we'll know it's because, beyond a reasonable doubt, she was mishandling prions in a laboratory setting, and not because she ate some infected meat from a bazaar.
> When you include that necessary fact, it becomes the most parsimonious.
That's just wishful thinking on your part. That's still not enough evidence in that direction at all. You have large, dense cities in China and people trading wildlife food. There's millions of them in a cramped space. That's a breeding ground for infection, with millions of opportunities for mutations.
That is not an argument. It is extremely plausible because the epidemic started next to the lab. Look at the size of China. Take a map of the country and throw a dart at it. Now consider the probability of it landing within 1 mm of Wuhan. Let's call this dart Occam's fléchette.
> It is extremely plausible because the epidemic started next to the lab. Look at the size of China. Take a map of the country and throw a dart at it.
First of all, that seems to completely ignore the uneven distribution of population. Your fléchette assumes a uniform distribution. Yes, China is large, but Wuhan has a population of...what, ten million people? It's China's ninth largest city as per https://en.wikipedia.org/wiki/List_of_cities_in_China_by_pop... .
The last time something like this happened was in Foshan, thirteenth largest city as per the same page. This does not seem to be a coincidence according to https://health.ucsd.edu/news/releases/Pages/2021-03-18-novel... , where it is argued that in large cities, you have a much greater chance of getting a pandemics from a small number of cases. So if the possibility of emergence of a pandemics of SARS-CoV viruses is heavily weighed in favor of the largest Chinese cities, perhaps your "Occam's fléchette" has actually a ~5% chance of hitting Wuhan or something like that -- maybe more depending on geography and population movement patterns and wildlife trade patterns, who knows? I haven't seen any models of this yet that would predict the most likely locations for the next pandemics. Maybe someone will make those this time.
I'm also not sure what you mean by "next to the lab". Like right outside of it? I doubt that.
Furthermore, some people seem to be clinging for dear life to the first epidemic cluster described and completely ignoring the fact that in general, existence of such clusters means that the disease had already been circulating at that time, perhaps for months. You simply have no idea where the original Wuhan cluster caught the disease from.
Hell, we had no idea where the first SARS came from until over a decade later. Then they found some bats in a cave over 1000 km from the first cluster in Foshan, bats with coronavirus strains the most similar to the original disease than anything else they'd found so far. Surely you're not arguing that those bats were released from a lab?
Those are terrible, terrible arguments. I'm not making a rigorous demonstration, I'm putting forth a Feynman-style back of the envelope approximation. MY argument is about plausibility. You're attacking it for not being rigorous. That is pure strawmanning. But let's address it anyway:
> First of all, that seems to completely ignore the uneven distribution of population
Half of China (the North Western part) is mostly a desert, almost all of its population is located in the South Western half. For my argument, that means you just need to cut my allegorical map in two before you throw my virtual dart. Big deal.
> where it is argued that in large cities, you have a much greater chance of getting a pandemics from a small number of cases.
From that same article: there are 102 cities governed by People's Republic of China with an "urban area" population of over 1 million.
Change my hypothetical map to a square grid of 102 cells. Wuhan is rather large at 11 millions, so make it 10 times bigger than the other ones. Let's not touch Beijing's or Shanghai's square, even though they are bigger. Oh my, that changes everything! Not. Now there is a whopping 10% chance that this happened in Wuhan randomly. Or in other words 90% chance that this is linked to the virology lab.
> I'm also not sure what you mean by "next to the lab". Like right outside of it? I doubt that.
12 km as the crow flies. You can check on Google maps.
Line 7 of the Wuhan metro links the two sites directly.
> Hell, we had no idea where the first SARS came from until over a decade later
There is one way, one sure way, one easy way to disprove the lab leak hypothesis. The way that would have been walked months ago had this happened almost ANYWHERE else in the world rather than an authoritarian communist dictatorship: an independent investigation.
But there is no independent investigation. The Chinese régime won't let it happen. Nobody's stopping them from disproving it. If this were a murder investigation, this would be held as evidence of guilt.
I really don't want to go too far down the rabbit hole but IIRC some of the concern was due to a lack of stringent safety measures in a lab / similar labs.
Nobody is talking about a pandemic here. The risk is for people working directly on those materials (and people eating them eventually, but that would be a edge case).
These mad scientists need to be stopped. How about all research into gain of function, genetic engineering viruses, prions, etc. need to have a moratorium. There is too much risk & not enough transparency on all levels.
We don't hear about all of the problems. I wonder what else is wrong and what happened. Whistleblowers need protection, not punishment.
Look up how fluorine, the "devil's chemical", was found and isolated: https://en.wikipedia.org/wiki/Fluorine#Isolation They blew themselves up, or worse, in pursuit of scientific knowledge. Without their work, semiconductors and electronics wouldn't be possible, and we wouldn't be here on this forum.
You don't have to sacrifice yourself, but don't infringe on those brave folks who are advancing our scientific knowledge by risking their lives. (Although if you're a lab-leak conspiracist, then it's probably too late.)
There's a difference between research on explosives (where the scientist risks their own health) and contagious diseases (where the scientist risks everyone's health).
"long period of uncertainty began on 31 May 2010, when she stabbed her left thumb with a curved forceps while cleaning a cryostat—a machine that can cut tissues at very low temperatures—that she used to slice brain sections from transgenic mice infected with a sheep-adapted form of BSE. She pierced two layers of latex gloves and drew blood"
Later in the article:
""We conduct research only on mouse-adapted sheep prions, which have never been shown to be infectious to humans,” Aguzzi [neuropathologist at the University of Zurich] says."
It sounds like the assumption that mouse-adapted sheep prions can't infect humans may be flawed.