I’ve always thought about it as something similar to what happened with Ritonavir, i.e. disappearing polymorphs. But inside your own body and with proteins instead of a drug.
tl;dr
tl;dr of the above: basically, in the beginning, there was no ritonavir, an antiretroviral drug, anywhere in the world. Then someone synthesized it for the first time, and it produced a form of ritonavir which was highly water soluble, making it ideal for an oral liquid capsule, which they proceeded to manufacture and sell for some time. However, this form of ritonavir existed at a high “potential energy”, let’s say (I don’t think this is technically the right term for it in here, but I can’t remember what is), and could transition to a different form of ritonavir. This second form of the drug was even more stable than the first, existing at a lower energy level, but it was nowhere near as water soluble, crashing out of solution as crystals, and thus vastly less bioavailable. Once you got to this more stable crystal form of ritonavir, you couldn’t go back, the crystals were useless as medicine. Worse still, the first time a molecule of this second form was created (some years into production), it spread like a virus, ruining every batch manufactured, and temporarily halting all production of the oral formulation worldwide until an alternative solution was found.
It might be that normal proteins, while optimal in their function with their shape, might be more stable or have a lower potential energy when misfolded as prions. They don’t do the job they originally did, anymore, hence why they cause disease; but they certainly seem to be a lot more stable (given they require significant time in an autoclave to fully denature them…) and there doesn’t seem to be a way to make them go back to the way they were before. It’s just our luck that they’re not easily transmissible the same way tiny crystals of ritonavir were, else we’d be really fucked.
I’ve always thought about it as something similar to what happened with Ritonavir, i.e. disappearing polymorphs. But inside your own body and with proteins instead of a drug.
tl;dr
tl;dr of the above: basically, in the beginning, there was no ritonavir, an antiretroviral drug, anywhere in the world. Then someone synthesized it for the first time, and it produced a form of ritonavir which was highly water soluble, making it ideal for an oral liquid capsule, which they proceeded to manufacture and sell for some time. However, this form of ritonavir existed at a high “potential energy”, let’s say (I don’t think this is technically the right term for it in here, but I can’t remember what is), and could transition to a different form of ritonavir. This second form of the drug was even more stable than the first, existing at a lower energy level, but it was nowhere near as water soluble, crashing out of solution as crystals, and thus vastly less bioavailable. Once you got to this more stable crystal form of ritonavir, you couldn’t go back, the crystals were useless as medicine. Worse still, the first time a molecule of this second form was created (some years into production), it spread like a virus, ruining every batch manufactured, and temporarily halting all production of the oral formulation worldwide until an alternative solution was found.
It might be that normal proteins, while optimal in their function with their shape, might be more stable or have a lower potential energy when misfolded as prions. They don’t do the job they originally did, anymore, hence why they cause disease; but they certainly seem to be a lot more stable (given they require significant time in an autoclave to fully denature them…) and there doesn’t seem to be a way to make them go back to the way they were before. It’s just our luck that they’re not easily transmissible the same way tiny crystals of ritonavir were, else we’d be really fucked.