Drug resistant prions via quasi-quasispecies. LOL.

The world is out to EAT UR BRANES and one day it will.

"Some little bug is going to get you someday,
Some little bug will creep behind you someday,
Then he'll send for his bug friends and all your earthly trouble ends--
Some little bug is going to find you someday."

I feel the same way about diseases and epidemics. Without antibiotics and oxygen and saline solution and vaccination, we have a choice of diseases that circulate often and kill little kids, diseases that circulate once in a while and kill young people, and diseases that circulate once in a long while and kill damn near everybody. Some choice.

Even more fun: if virussesses aren't alive, then prions are even more not alive.

So we have wonderful evolution on something that's decidedly DEAD!

So a great big steaming pile of FU to the people who whine about abiogenesis being in the realm of gods.

I love the fact that tons of proteins have multiple conformations, too. Most proteins actually work because they change conformation upon binding a specific molecule. It strikes me as odd when creationists throw the "proteins are so perfect" card and people actually buy into it. I guess I expect too much science knowledge from the general public.

Wow, natural selection of prions. That's freaking awesome. I mean, not awesome in that it sucks for people, but awesome in the sense of I'd have never have guessed that could happen. That's really neat. It does a really good job driving home that all you need for evolution to occur is imperfect replication.

It is more than a little amazing that something that can be so efficient at killing us, can also have such imperfect intricacy and elegance that within the imperfection there appears to be near perfection...No, I normally don't speak like that...but words fail to describe the sense of wonder that sort of "dance" inspires...

Mildly interesting. But....

This is a good thing-- we evolvedCitation needed these pumps to help us keep from poisoning ourselves.

and

Well, you know how Creationists are always bawwing about how 'perfect' protein structures are?

Any examples of this?

JZ wrote:

Wow, natural selection of prions.

Does that make prions life?

I have a feeling that next we'll be talking about natural selection of radio waves due to your radio reception going to hell in a tunnel, but only for certain frequencies.

Zombie proteins that eat your brain AND can evolve. That's scarier than any horror movie I've ever seen.

I have a feeling that next we'll be talking about natural selection of radio waves due to your radio reception going to hell in a tunnel, but only for certain frequencies.

Well, if people travelled in tunnels a lot and were then only able to listen to certain radio stations that broadcast on the frequencies that got through, and that made the other radio stations go out of business, so that after a while there would only be radio stations transmitting on tunnel-safe frequencies, then I guess that would be natural selection applied to radio stations.

That's a fascinating example of how natural selection works for complex chemicals as well as actual living things. It's not surprising, actually, since the boundary between certain kinds of really complex chemistry and actual life is kind of blurry.

When I first read that title (of the paper) I thought, "Drug-resistant prions? No, no... don't be silly. They must have made a mistake, then I read on and OMGWTFBBQPRIONSIZEVOLVINGS!!!!

Also, when you think about it the only requirements for natural selection is a replicating unit with variation that has a selective force applied to it. So evolution can apply to damn near anything (living, dead, undead <_<) that fit the scheme.

Well...there are more than just the normal and prion variants. Wow. News to me. All I can say is...

CRAP!!!

Willy Wally said

Does that make prions life?

Wow. Just wow. I've been known to ask a dumb question or three around these parts, but did you even bother reading Abbie's entire post? Or are you just being an antagonistic douchebag, as usual?

Shit, there I go asking dumb questions again.

"I have a feeling that next we'll be talking about natural selection of radio waves due to your radio reception going to hell in a tunnel, but only for certain frequencies."

PROTIP: when trying to argue against evolution with analogies, don't resort to something that doesn't reproduce.

PROTIP: when trying to argue against evolution with analogies, don't resort to something that doesn't reproduce.

But those are the only analogies Limp Willy feels comfortable with... since he can't reproduce. (I hope)

He'd have to stop beating his wife first.

lol, that's basically natural selection of CRYSTAL GROWTH, as Prions are "only" complex molecules which can't change their primary structure / structural isomery, only their konformation, which contribues to crystal formation and is the same in more simple crystals.

I have never thought about it that way, but of course it is possible, cause it is a replicating system. If the conditions are turned back to drug-free, the more standart prion crystals would again outgrow the others, and this would go faster than in living populations, as the variation is not caused by genetic changes but konformation changes!

Now I wonder if they should have pushed that into a better journal. They were probably a team of physicists and did not grasp the implications of envolving crystals in quasi-biological systems, or that a successful therapy probably requires a HAART-like approach, for that matter (would be more effective than in biologically envolving systems); they were probably only disappointed their experiment did not give the result they wanted.

When you're a carpenter, every problem looks like a nail.

when trying to argue against evolution with analogies, don't resort to something that doesn't reproduce.

Protiens reproduced? I always thought they were copied. My bad. Turns out that pages coming out of my photocopier are evolving, too.

Just amazing. I hadn't really thought about the possibility of variability among prions and that we could see selection there. Thanks for the great write-up.

Cut William Wallace some slack-his problem is that he can only reason deductively.

Natural selection operates on ANYTHING which gets reproduced, and which has heritable characteristics which influence its chance of reproduction.

If William Wallace ever bothered to learn anything about natural selection, he'd know that. This was even mentioned in "Expelled", he really has no excuse.

If you're that ignorant, you'd re not qualified to argue.

"Turns out that pages coming out of my photocopier are evolving, too."

Only if what's on the paper improves its chances of being copied, and only if all copies are not identical. Then yes, they would be evolving.

You think you're satirizing something, and you're too stupid to know that what you said is actually true.

Willy,

Surely you're joking. That analogy misses the point by such a wide margin that I have to, for the sake of my own sanity, presume you are.

See, Willy doesn't bother to read anything. If he did, he'd know that Dawkins talked evolution of photocopies in his chapter on memes in "The Selfish Gene". Granted that book's only been out thirty years, but I think even someone whose lips move when they read should have got through it by now.

In "The Blind Watchmaker" he talks about evolution of crystals, which was proposed by someone whose name I can't remember.

So we know that Willy doesn't bother to read even popularizations of views he disagrees with.

Prion reproduction is intriguing. I'm going to try to remember to practice my Google-fu on it, but if anyone has any readily accessible materials they can point me at, it'd be much appreciated.

From an eyeball's glance, however, it seems almost that the most proper common chemistry analogy is not crystal growth, but polymerization. Hm.

Didn't know Dawkins had this in the Blind watchmaker, I should read the book at some time.

@ William Wallace: Copied books evolved, the scriptures and bibles the monks in the medieval copied evolved, more popular books or versions were copied more, with all the improvements and mistakes copied by the next monk, who added more improvements and mistakes (both mutations) and some were more popular than others (selection). So the bible and other old text like Commentarii de Bello Gallico evolved since their origin. The different versions of "Of Pandas and People" are another good example.

If you have self-replication and variation, evolution just happens, the same as something you drop falls down.

In this case, the prion proteins are not self-replicating, but the prion aggregates/crystals are, they are growing and breaking apart (the aggregates are "eating" prion proteins).

I think the bigger issue is that when a protein is "copied," errors can occur in that copying process. Copying in this case is not a perfect process, and you are not guaranteed to have a perfect copy every time. This is why you can't compare proteins being copied to making photo copies, because there is no mechanism in the body that ensures that a copied protein exactly matches the original protein.

"Protiens reproduced? I always thought they were copied. My bad. Turns out that pages coming out of my photocopier are evolving, too."

Evolution is the non-random selection of randomly varying replicators. It doesn't matter what kind of replication is involved, as long as there is retention, variation and selection.

For the sake of being pithy I left out the criteria of variation and selection, which I regret, since it simply allowed you to move on to yet another invalid analogy.

This is such an amazingly cool paper! Mind you, since my team was working on a drug which could possibly treat prions, this is very disappointing. However, this may explain why anti-amyloid drugs have been failures in clinical trials.

William Wallace,

Frankly, I don't know why we bother responding to you at this point, because it is painfully apparent that you have close to zero knowledge about what you are talking about and yet manage to be incredibly arrogant. You seem to be a walking incarnation of the Dunning-Kruger effect.

Prions are a type of misfolded protein. They replicate essentially by inducing other proteins to move into the misfolded form (thus becoming prions themselves). So, yes prions do replicate. And the key here is that they are doing so in a variety of different forms, sometimes in different forms. So, there's natural selection going on.

Now, I suggest you read Abbie's piece again and try to actually apply what little brain power you might have.

@28: I just had one of those ten-second reasoning fugues. My first response to your "yes, prions do replicate" was to think "hmmm... they induce proteins (already present in the cell) to assume their shape... is that reproduction?". My next thought was "...but _all_ replicators induce matter (already present in the universe) to assume their shape... so it _is_ reproduction".

I don't think that this is more than superficially like "real" natural selection, owing to the lack of variation and heritability.

If I've understood it correctly, a prion can adopt one of several structures, but the one chosen is essentially random. Selecting for a particular structure - because of the presence of the medicine - doesn't change that. New prions are no more likely to adopt the preferred structure: it's just that the selection is still taking place so if they don't they won't appear. (Sort of like the weak priopic principle.) I presume that if the medicine was removed, the original structure would again dominate.

Regarding the "reproduction" of proteins, there just isn't true variability. Sure: a genetic mutation may lead to a change in the protein, but that mutation is going to be present in the vast majority of cells, right from conception. Proteins are not copied one from another, but cast from the same moulds. (There may be a few cells which have mutated individually, but I doubt that they'd be significant.)

So very interesting findings, but let's not get carried away with comparisons with natural selection.

So the amyloid fibrils cause the diseases. Are the fibrils necessary for prion reproduction? And if not, does the drug actually stop prion reproduction or fibril production? It seems like if it were possible to produce a drug that stopped the fibrils without stopping the prions, they wouldn't evolve resistance to it and wouldn't cause diseases.

Also, has anyone looked for a strain of bacteria or something that could digest amyloid fibrils, so that enzyme could be collected and used as a treatment?

"If I've understood it correctly, a prion can adopt one of several structures, but the one chosen is essentially random. Selecting for a particular structure - because of the presence of the medicine - doesn't change that."

But isn't that exactly the essence of evolution, that variation is random with respect to fitness whereas selection is nonrandom?

But isn't that exactly the essence of evolution, that variation is random with respect to fitness whereas selection is nonrandom?

I think Simon's argument is that the variation in this case is non-heritable; prions convert normal proteins into prions, but prions of a particular conformation (like the drug-resistant ones) don't preferentially convert normal proteins into prions of the same conformation. I have no idea whether that's correct, though; I didn't see anything about it when glancing through the paper.

This is an excellent example of why even negative results should always be published. They didn't get what they were looking for, but they still got something cool.

Anton, #33.
Yep, that's what I was getting at. I don't know why I didn't just talk about heritability.

I think Simon's argument is that the variation in this case is non-heritable

It could be that, or maybe it's a combination of imperfect inheritance and the resistant prions being 'selected against' in the absence of the drug, since they're not as stable? Sort of like the sickle cell trait of prions?

"we observed that PrP(Sc) accumulating in the brains of chronically treated mice had a lower conformational stability compared to that of untreated controls"

No: there is no heritability here.
The non-random aspect of the protein's structure is determined by the producing cell's DNA. That obviously is subject to variation and inheritance, but I don't see how there would be any selection pressure on the gene from the action of the drug on the prions, so there could be no evolution.

One might make a case for saying that there would be some slection for genes for proteins which were less likely to form prions in the first place - always assuming such a protein is actually possible - but if that were so there would be more selection pressure without the drug.

Comparing this with natural selection is an interesting analogy, but it's no more than that and ultimately all analogies are bad.

Looks like Simon's right. I looked through the paper more carefully and found:

The mean incubation periods for MDR0/0 mice infected with untreated and quinacrine-treated inocula were 112±3 and 116±1 days, respectively (n = 8). Analyses of PrPSc in 10% brain homogenates of these ill mice, using GdnHCl denaturation and CDI as described above, showed no significant differences in the stabilities and CDI measurements (Table 3), suggesting that the physically altered, quinacrine-induced PrPSc is not a stably propagating strain.

and later:

Indeed, the PrPSc rebound observed in this study is reminiscent of the failure of antiviral drugs caused by selection of drug-resistant variants. However, unlike resistant viral strains, the quinacrine-resistant conformation formed here was not able to propagate in the absence of the drug and thus cannot be considered a stably propagating strain.

So yeah, this probably isn't natural selection. Quinacrine resistance doesn't "breed true," apparently.

A biological analogy would be, say, breeding border collies for specific coat patterns. If breeders get rid of the puppies with undesirable patterns (which unfortunately they often do), you're going to see a disproportionate number of adult dogs with the preferred pattern. But they'll have as many puppies with undesirable patterns as ever, because this particular trait isn't actually heritable, it's just a random quirk of development. No actual evolution.

Simon, very good catch.

The non-random aspect of the protein's structure is determined by the producing cell's DNA. That obviously is subject to variation and inheritance, but I don't see how there would be any selection pressure on the gene from the action of the drug on the prions, so there could be no evolution.

But that is only if you dismiss the idea of non-genetic inheritance altogether. The whole point of the excitement about prions is that they can transmit the 'prion' conformation to wild-type copies of the same protein, so it's not true that the post-genetic influences are completely random. Of course it's a pretty crude form of inheritance, but nevertheless, that's what the literature usually calls it:

Protein-only inheritance in yeast: something to get [PSI+]-ched about
(science pun, HA HA)

This may be a little better case for variation and selection among prion strains:

Adaptation and Selection of Prion Protein Strain Conformations following Interspecies Transmission of Transmissible Mink Encephalopathy

A biological analogy would be, say, breeding border collies for specific coat patterns. If breeders get rid of the puppies with undesirable patterns (which unfortunately they often do), you're going to see a disproportionate number of adult dogs with the preferred pattern.

But if they were like prions, you would also have dogs that are able to 'turn' the coat pattern of other dogs...

Ahem. LOL, silly children.

Ahem. LOL, silly children.

Wow, what insightful and incisive commentary! Whatever will you do for an encore?

You've already exposed yourself as an illiterate jackass.

windy,

This may be a little better case for variation and selection among prion strains:

You're right, the studies you cite in #40 do indicate distinct "true-breeding" conformations of prions (or just self-replicating proteins in the first study...but a prion's just a self-replicating protein with an effect we find harmful.)

So evidently prions do have some heritable traits (aside from just being prions and not "normally"-conformed proteins in the first place, of course!), and can evolve with respect to them. But quinacrine resistance in the particular study Abbie cites probably isn't one of those traits.

Probably. As you point out, it's still possible that quinacrine resistance is heritable, but is such an otherwise deleterious trait that, even within an initially 99% resistant population, the resistant prions quickly go "extinct" in the absence of quinacrine. I would guess that this is unlikely, though...the incubation period for the resistant strain is only slightly longer than that for the non-resistant strain, so they probably don't differ that much in fitness, no?

But if they were like prions, you would also have dogs that are able to 'turn' the coat pattern of other dogs...

And in some sense they can, only on a much finer level. A pair of border collies can reconfigure available matter into other border collies, and they do have a lot of heritable influence on the coat colors and patterns of their offspring--barring mutation, two blue merles aren't going to produce an orange brindled puppy! It's just that some of the specific coat pattern features, which humans prize, aren't part of the heritable package.

William Wallace is an obnoxious twat. And coming from a guy like me, that means something. He needs to eliminate the scourge of himself for the good of all humanity.

William seems to be trying to be his own microcosm of the creationist approach to science. Follows the following steps:

1) Decide you don't like the science
2) Don't bother learning about it but rather made insulting remarks and misrepresentations
3) After someone who actually has some brains makes an observation that could be construed to help your position claim it as your own.

Granted, Willie's lack of coherence didn't help him do much of the last one. For his next act he will claim that creationists were the real ones responsible for determining that Piltdown man was a hoax.

And in some sense they can, only on a much finer level. A pair of border collies can reconfigure available matter into other border collies

Yesyes, of course, but I meant that the whole prion horizontal transmission aspect was missing in your analogy.

Yesyes, of course, but I meant that the whole prion horizontal transmission aspect was missing in your analogy.

Weeelll, that's because I'm not sure that it should be considered horizontal transmission, as opposed to just being part of the weird zero-sum reproductive system of prions.

IOW, for it to be horizontal transmission of a trait, I'd think that prion A would have to be able to pass it to prion B without also passing on everything else that makes it different from prion B. Otherwise, it's basically just reproducing itself at the expense of prion B, like a parasitoid insect.

By analogy, if merle border collies could turn white bulldogs into merle bulldogs by touching them, that'd be horizontal transmission. But if they could turn white bulldogs into merle border collies by touching them, that'd just be a weird Borg-like method of asexual reproduction.

Weeelll, that's because I'm not sure that it should be considered horizontal transmission, as opposed to just being part of the weird zero-sum reproductive system of prions.
IOW, for it to be horizontal transmission of a trait, I'd think that prion A would have to be able to pass it to prion B without also passing on everything else that makes it different from prion B. Otherwise, it's basically just reproducing itself at the expense of prion B, like a parasitoid insect.

Aargh, you're making this way too complicated, WHYE OH WHYE? Whatever you call it, there was nothing in your analogy that behaved like a zero sum parasitoid insect either, so what are you weeeellling me for?

A prion is just a misfolded protein that can cause the homologous wild type protein to misfold in the same way. It's 'horizontal' transmission since it does not go through a baby protein stage or anything like that. If we find that the same prion exists in different conformations that are 'heritable', it's still the same process. I don't see any reason to divide it into 'parasitoid insect reproduction' and 'heritable traits'.

By analogy, if merle border collies could turn white bulldogs into merle bulldogs by touching them, that'd be horizontal transmission.

Yes, and a prion is more like a merle border collie that turns other border collies to merle. (evil twisted border collies that clump together, but still, the same 'kind').

A prion is just a misfolded protein that can cause the homologous wild type protein to misfold in the same way. It's 'horizontal' transmission since it does not go through a baby protein stage or anything like that.

Weeeeeellllll...sorry.

I just don't think of it as horizontal transmission. That's transfer of genetic material to an organism who isn't your offspring...but the newly misfolded protein is the only kind of offspring the original prion has. If we're going to be using evolutionary terminology at all, that transmission is vertical I think.

And I don't think a "baby" stage is necessary for it to be regular reproduction...it's not like single-celled organisms or viruses go through a infant/larval stage either.

Oh well, I'm disputing semantics and not substance here. I'll retire the dog analogy.

Well, technically some viruses have 'immature' baby states and then a 'mature' infectious state.

Thats how anti-HIV-1 protease inhibitors work-- they keep baby viruses from maturing :)

:P

Oh yeah? Oh yeah? Well, even more technically prions have baby states too, because there are a bunch of intermediate conformations between the native form and the final prion form. And you can block the creation of the final form by, for instance, changing the pH of the medium to make some of the baby states less liable to refold into more mature states. So there!

Jeez, you elitist virologists. Soon as it looks like The Man might be letting your replicators call themselves real living things, everyone else's replicators get thrown under the bus, huh? Sickening.

Wow! Prions actually evolving in one life cycle of a mouse. If we ever have something like that occur in humans, that could be like black plague on steroids.