> Form II was of sufficiently lower energy that it became impossible to produce Form I in any laboratory where Form II was introduced, even indirectly. Scientists who had been exposed to Form II in the past seemingly contaminated entire manufacturing plants by their presence, probably because they carried over microscopic seed crystals of the new polymorph.
If someone told me this entire article was fabricated I would believe them. I would never have thought that such trace amounts of… everything one has ever shared a room with, essentially follow them everywhere dispersing as they go. Chemistry is wild.
Just wanted to add two things: 1) the so-called mad cows disease is also caused by prions - that's why it is so scary, 2) cannibalism, or any other loop in the food chain, causes retention and amplification of such diseases in a population.
> In Iceland in 1978, a program was implemented to eradicate scrapie, and affected flocks were culled, premises were disinfected, and sheep houses were burnt; after two to three years, the premises were restocked with lambs from scrapie-free areas. Between 1978 and 2004, scrapie recurred on 33 farms. Nine recurrences occurred 14–21 years after culling as a result of persistent environmental contamination with PrPSc.
A human variant transmissible through cannibalism is Kuru (against which the locals have developed some resistance):
> In 2009, researchers at the Medical Research Council discovered a naturally occurring variant of a prion protein in a population from Papua New Guinea that confers strong resistance to kuru. [...] G127 polymorphism is the result of a missense mutation, and is highly geographically restricted to regions where the kuru epidemic was the most widespread. Researchers believe that the PrnP variant occurred very recently, estimating that the most recent common ancestor lived 10 generations ago.
There's a quite decent documentary on the life and work of Mike Alpers put together with a lot of early family footage if you've an interest in the Kuru story.
Technically you could refold the proteins with, say, a vortex fluid device. But that would require... liquefying the proteins... and then re-folding them mechanically. :-/
Squirrel brains, cow brains, human brains ... mammal brains in general.
More interestingly it's rare - you have to eat infected brains that have a variation that side steps not one but two prion defence mechanisms that most humans have ... which suggests that almost all humans have ancestors that engaged in enough cannabalism to develop layered defences against brain transmitted diseases.
Why would we jump to cannibalism if it is merely sufficient to eat a bunch of other mammal brains (which I vaguely remember reading are a "delicacy", though I feel like I hear that about enough extremely dangerous foods that I consider it an anti-endorsement at this point)?
As a general rule of thumb, diseases varients that evolved within mammal type X proliferate the most within mammal type X populations - the varient can jump to mammal type Y but tends to be a relatively rarer occurrence and tends to go with a bit of further evolutionary variation.
FIV is not the same as HIV (Feline, Human, but they're similiar) and so to with prion diseases.
Mad Cow disease came about from feeding large quantities of ground up cow offal from abattoirs mixed up with grains to make 'tasty' feed pellets .. eventually a cow prion disease 'perfected' itself and went on to occassionally(?) affect humans - more common in cows than humans, etc.
With human cannabilism, we know about Kuru from the Fore people in PNG who, like many other groups in the highlands, practiced cannabilism as a mortuary ritual, a funeral practice to retain the essence of someone respected. Kuru was a specific human to human variation that evolved to become more common and overcome the defences against human -> human prion defence I mentioned earlier.
We have other reasons to suspect cannibalism was common elsewhere .. such as the documented European practice of medicinal cannibalism and the fashion of consumming bitumised mummies.
But, ahh, yeah - these days genetics is the thing, markers for defences against human prion diseases are a thing talked about in a group of papers post Kuru.
They're high in fat even in otherwise lean animals so would have been a totally normal thing to eat in much of the world for most of history. In some places & seasons possibly the only ready source of saturated fats, so probably a delicacy for that reason.
Prion diseases https://www.cdc.gov/prions/index.html lurk within brains and nerve stems, with cows it became a big thing when the industry started making mega tonnes of offal waste mixed with grain feed pellets .. so all cows were being feed ground up other cows including brains.
Like most other diseases species -> same species is an easier vector than species -> different species.
> I would never have thought that such trace amounts of… everything one has ever shared a room with, essentially follow them everywhere dispersing as they go.
Everywhere you drive, you leave behind microplastics as particulate. These are washed into waterways and end up in aquatic ecosystems, including the seafood you eat. There's also some small enough to be airborne, thus prone to inhalation by humans and other animals.[1] Particulate production from road wear increases with the fourth power of the weight of the vehicle.[2] One has to assume by Newton's third law that the same is true of tires. Tires and roads are made of petroleum-based materials, i.e., they produce microplastics. This means a car twice as heavy (e.g. EVs vs ICE cars in the same form factor) produces sixteen times as much particulate matter. This also means that typical cars emit a minimum of four million times as much particulate as bicycles. E-bikes emit 10 times as much particulate as bicycles.
Microplastics cling to everything, that's just the nature of particulate. So they follow you everywhere.
> a phenomenon in which a seemingly stable crystal structure is suddenly unable to be produced
The whole intro to this article really undersold to me how significant a phenomenon this is describing. My jaw dropped when I got into the Case Studies section. Apparently there are certain drugs which are nigh impossible to make today because a more stable (but medically ineffective (or still patented)) version of the crystal was once created and now contaminates the atmosphere in microscopic quantities.
> It is hypothesized that "unintentional seeding" may also be responsible for the phenomenon in which it often becomes easier to crystallize synthetic compounds over time.
(Well, to be fair, the only thing that's reversed is the human value judgement. The proposed mechanism is the same.)
The ritonavir story is super-interesting. It's also interesting how the problem got worked around. Initially, ritonavir had to be shipped as a frozen gel, to slow down the conversion. But this was not optimal at all.
The ultimate solution was hot extrusion: molten ritonavir is dispersed in an inert carrier, and then left to cool. The carrier insulates the droplets from outside contact, so it can't get contaminated with the more stable polymorph.
This idea itself is completely obvious. But like pretty much everything in engineering, it took a decade to perfect the process.
If you have a misfortune to get prescribed Paxlovid for COVID, break a tablet and look at it in a microscope. You'll clearly see the ritonavir droplets embedded inside the carrier material. It's super-cool.
(Ritonavir is used in Paxlovid not because of its antiviral properties, but because it inhibits some liver enzymes, thus slowing down the metabolism of the active ingredient)
The article says this is of particular concern to Pharmaceuticals and Computer Hardware industries, but all of the case studies are from pharmaceuticals and food products.
I can imagine how this could present an issue for hardware manufacturing, but are there examples of this occurring in that industry?
While the semiconductor industry does deal in the use of some specialised materials, and do require ultra clean room conditions, I believe their structure is an order of magnitude simpler than those used in the pharmaceutical. It’s the process that is difficult.
I’m just an armchair observer though, and I’m sure something like this has cropped up in some unpublished paper.
This is fascinating, such that I went looking for more information on this phenomenon and found an interesting preprint regarding the polymorphism of ritonavir suggesting that specific milling processes are able to reliably produce each form.
At least I think that's what it says, I'm definitely not a chemist!
It is wild to see disappearing polymorphism appear on the front page of HN! My company, Lavo Life Sciences (W23) is building software to predict polymorphism in drug molecules, happy to answer any questions on this thread :)
Are there any promising paths towards preventing this? Seeding clean rooms with other chiral molecules that can encourage the lost higher energy form of a crystal, maybe?
This feels to me like a repeated “oh, that’s odd” moment. Perhaps this isn’t as simple as “the seed crystals are just everywhere now”, and maybe the explanation is something fundamental about our universe that remains undiscovered.
The morphic resonance guys claim this is proof. And I for one do find it a little unbelievable that these seeds are travelling the world, such that for any cubic foot of air you find a seed. Show me the math on that.
Anyone who's ever had seasonal allergies will quickly and fully understand the implications. And allergens are absolutely enormous. Heck, there's a species of plankton that float through the air, with on average 1 million cells per cubic meter.
The fact that they can make the metastable crystals when they isolate them suggests that contamination is more likely than morphic resonance (which doesn't have any solid evidence going for it). I don't know if the theory behind morphic resonance suggests the mechanism, but if so, would that mechanism be blocked in a similar fashion?
The only problem was that by the time other companies began manufacturing, Earth's atmosphere was already seeded with microscopic quantities of paroxetine hemihydrate from GSK's manufacturing plants
Nobody else's bullshit alarm is going off here? Just mine?
The words “entire athmosphere” and the “plants” might be an exaggregation, but
1) I can readily imagine the _labs_ being contaminated by the reference samples.
2) If the compound is stable, not clumping and not hygroscopic - yes, certainly. “Microscopic” doesn’t do it justice, as there doesn’t seem to be any limit to how small the seed crystals can get.
Since we’re manufacturing literally tons of pharmaceuticals, and carefully manually spreading them over the Earth surface to the pharmacies, so for stable substances it doesn’t seem such an exaggregation to me.
Quite a bit, but Wikipedia provides sources! So I checked [0].
In section 3.3 it says that GSK argued their patent on the new form was being infringed because "there were batches of anhydrate that converted almost entirely into hemihydrate when stored at 40 °C and 75 % humidity within one month."
So "if you keep it wet and warm it will partially convert over the course of a month", and as far as I can tell the "seeding" aspect was not clarified, at least not in the article.
Also it bugs me that the Wikipedia author decided to call the loss for GSK a "technicality". It was decided that it was not relevant that microscopic quantities of the new form were created by accident, I think that is the correct decision and not a technicality.
Sounded totally credible. For me it evoked the situation of GM plants that show up on plots of land of anti-GM farmers, rendering their crops commercially void (and theoretically infringing on the GM licence).
My thought was more: would it not be possible to counter-sue and get damages from them in court. For after all, they "polluted" your lab / plot with something that you never asked for, and that is now causing damages / lost earnings.
> Sounded totally credible. For me it evoked the situation of GM plants that show up on plots of land of anti-GM farmers, rendering their crops commercially void (and theoretically infringing on the GM licence).
Except this almost never happens. But if it does, Monsanto (now Bayer) will reimburse you the cost of contaminated crops.
I was wondering about this too. I get that it's a commonly used drug, but the entire earth's atmosphere? How many molecules per cubic meter of air is that plant letting out? How are the particles travelling around the world exactly?
Sounds like science-fiction or some conspiracy theories indeed... but the phenomenon seems to be scientifically well-described. I'm just wondering, wouldn't a clean room be able to keep out those micro-seeds?
So steel in every smelter on earth can become so contaminated solely via the atmosphere from explosions decades ago it is measurably radioactive, but labs can't be contaminated via the atmosphere with tiny crystals that change nucleation? Walk me through your thought process here.
The crystals (a) weren't deliberately dispersed into the jetstream with hundreds of multi-megaton explosions, and (b) are not radioactive or otherwise capable of affecting unrelated substances from a distance.
Other than that, yeah, I guess it's exactly the same.
Isn't crystal nucleation exactly the kind of process that _is_ affected by impossibly small impurities? One good conference could spread crystal residue over a whole industry.
If someone told me this entire article was fabricated I would believe them. I would never have thought that such trace amounts of… everything one has ever shared a room with, essentially follow them everywhere dispersing as they go. Chemistry is wild.