I love it when a research paper makes me laugh.
This paper makes me laugh.
It is AWESOME!!
Okay, heres the deal: Prions cause disease by making ‘normal’ proteins fold wrong. When they fold wrong, they clump up together to form amyloid fibrils (wrote about this in the context of HIV-1 a while back). These amyloid fibrils are super stable. They build up and build up… and cause neuronal damage. Now, weve got drugs that work super to stop the formation of amyloid fibrils, thus prion progression, in tissue culture.
Problem is, we put these drugs in animal models (or people)… and the animals still get sick and die.
The drugs we have dont cross the blood-brain-barrier. Well, technically, they ‘could’ cross the BBB, its just that we have receptors in our BBB that actively pump the drugs back out. This is a good thing– we evolved these pumps to help us keep from poisoning ourselves. But its troublesome when the ‘poison’ is a good thing.
So these researchers did an obvious experiment: they created mice that lacked the genes for the efflux pump. If the pump isnt there, the drug gets to the brain (where the prions are causing trouble), and the drug stops the disease.
And thats exactly what happened.
Well, thats exactly what happened… for a while. At ~Day 70, it looked like the mice were ‘cured’– there was hardly any detectable prion around. But by ~Day 90, the mice that got the drug were just as sick, and had just as much prion around as the mice that never got the drug!
What ‘prion’ was in the mice that got the anti-prion drug? Drug resistant prions. *blink*
How the hell does this happen? Well, you know how Creationists are always bawwing about how ‘perfect’ protein structures are? Pretty multi-colored, perfect Lego block machines? Yeah… proteins arent really like that in real life. Im sure Ive written here before, we have a ‘structure’ of HIV-1 envelope, which I study, but we dont really have a ‘structure’. Env is wonderfully floppy and jiggly, reason #1938537943272639203 its hard to make an HIV-1 vaccine.
So this same thing is happening in prions. We dont have TWO STRUCTURES, HEALTHY vs PRION. We have a collection/gradient/kaleidoscope of ‘healthy’ proteins, and ‘prion’ proteins. Just by chance, some of these prion structures were resistant to the drugs. Though this resistant population was initially a minority variant, in the presence of the drug, this ‘less fit’ structure became ‘more fit’, and eventually caused disease, same as regular ‘ol prions.
If you are a regular reader of ERV, this should all sound kinda familiar…
This is exactly the kind of pattern we see with HIV-1 treatment. By chance, there are HIV-1 variants in patients that are resistant to antiretrovirals (QUASISPECIES!!!). The resistant variants are a minority population within the quasispecies, and usually escape from antiretrovirals comes as a fitness cost. So when people take antiretrovirals initially, they work GREAT! Drop in viral load, CD4 counts go up… but HIV-1 can bounce-back from this drop in fitness in the presence of the drugs, and thats when you get antiretroviral failure in patients.
But prions arent RNA viruses. HIV-1 quasispecies is a genotype/phenotype thing. All prions are ‘the same’. So I guess prions might operate as a quasi-quasispecies.
And can you imagine being the researchers doing these experiments?
“LALALALA! Im making a knock out mouse, gonna cure prion disease! LALALA! Wonder if this will work for Alzheimers and such too? DODODODO! Oh look! Day 70! Prions down! YAAAAAAAAY! … Wait… WAIT… DAY 90 WAT? WAT? DRUG RESISTANT PRIONS?? WAT??? FUUUUUUUUUUUUU…….”
Good on them! Good research! Great insight into these kinds of diseases!