Monday, March 03, 2008

Prions: Viruses Red-Headed Stepbrothers?

Funny how we were just talking about rocks evolving yesterday... Today our guest speaker was a prion guy, Jason Bartz (also incredibly nice!)

omg, you guys.

omg.

Prions, evolve, even though they dont have a genome.

omg.

Say you have a mink infected with a prion. In a few months, your fluffy, fluffy mink will succumb to its disease. So you grind up your fluffy fluffy mink brain and put it in a ferret. A few years later, squeaky ferret succumbs to its prion disease. Grind up its brain and put it in another ferret, and so on and so on.

The prion evolves in the ferret. Eventually, it adapts to the ferrets neurological system, which in turn means it cant infect the mink very well, even though 'mink' is where you got the original prions in the first place!

Holy crap.

How does something with the same amino acid sequence evolve??

The idea I pitched to Dr. Bartz (the idea he was already planning on pitching to the scientific community hehe, I iz smrt) is that prions operate like HIV-1. But instead of exploring sequence space like my HIV, his prions explore structure space. One protein exploring all possible structural configurations. It has an optimal configuration for minks, but needs to explore and find a more optimal configuration for ferrets.

Minor problem: With our current technologies, we can only detect a few configurations (because of the chemical properties of prions, theyre impossible to crystal structure, even though the normal protein is easy as pie). We can detect Normal, Prion 1, and Prion 2 (through some tricks, its not easy), but that doesnt mean that there arent Prions 3, 4, 5, 6... 1,000,000,000 that we just cant see. A cloud in the structure space.

On top of all of this, prions are tough mo-fos. You can autoclave them, freeze them, whatever, and they dont change out of their prion form. So I gave Dr. Bartz my usual schpeal "Okay, so everyone who says 'omg viruses are just devolved cells they arent alive' are idiots, so what about prions? Could they have been around for the past 4 billion years? Could they have been in the soup?"

"Yup."

So Im going to look into this more (as time permits)-- I dont know a lot about prions, but Im intrigued. Theyre more than biological oddities to me now. More than just the occasional news report on MAD COW DISEASE.

They could be my viruses red-headed stepbrothers, and family is family :)

27 comments:

RBH said...

Now that is interesting. And it has some real interesting implications.

ERV said...

It would be better if I could draw a picture-- I was scribbling like a mad woman when I spoke with him after the seminar :) Maybe Ill just scan my scribbles hehehe!

Chris Harrison said...
This comment has been removed by the author.
Chris Harrison said...

I have this awesome little cartoon I drew from a talk I attended earlier this afternoon. Perhaps you can draw something up in MS paint. All blogs could use some half-assed color drawings..

tgibbs said...

Have you ever seen any energetic analysis of prion conformation? The difficulty I have is that by hypothesis, a prion is a normal protein can take on a pathological conformation that catalyzes, perhaps by oligomerization, other molecules of the same protein to adopt the same conformation. However, it is rare for an animal to develop a prion-type disease unless infected by proteins already in the pathological conformation. This implies either that the pathological conformation is very unstable in isolation, or alternatively that the energy barrier for the conformational transition is enormously high--so high that it normally does not occur, even for a single molecule, within the lifespan of the organism.

Now we add in that there is not one, but multiple such pathological conformations, which presumably do not readily interconvert. I suppose that all of this is possible, but it seems a trifle contrived. I'd like to have a better structural understanding of the energy barrier that prevents the pathological conformation from arising spontaneously.

Perfectly Candide said...

"This implies either that the pathological conformation is very unstable in isolation, or alternatively that the energy barrier for the conformational transition is enormously high--so high that it normally does not occur, even for a single molecule, within the lifespan of the organism."

All of a sudden I am suddenly thinking that prions are the protein equivalents of ice-nine though obviously not quite as destructive. (And scanning the Wikipedia article I see some have already used the analogy.)

"Now we add in that there is not one, but multiple such pathological conformations, which presumably do not readily interconvert. I suppose that all of this is possible, but it seems a trifle contrived. I'd like to have a better structural understanding of the energy barrier that prevents the pathological conformation from arising spontaneously."

If I understand correctly we would need would be 1) enough different states in structure space that are prions for evolution to "explore". 2) That energetics barriers between distinct prion states be small enough for "mutation" to another prion state. And 3) that the barrier between the volume of structure space that is prion and the normal proteins to be very large.

Now the question becomes, is that the case. If it is not, would it mean that this interesting hypothesis gets to join the previous ice-nine wannabe, polywater?

Stephen Wells said...

Hang on, hang on, I'm missing a step here. Is the ferret protein really identical in sequence to the mink protein? Or is this a case where misfolded mink protein can catalyse misfolding of ferret protein more easily than the other way round?

For tgibbs: while it's true that there must be a biggish barrier between normal-fold PrP and misfolded PrP', that barrier doesn't have to be energetic, it can be conformational/kinetic. Once you're in a misfolded form, there's again no reason to think that different misfolds have the same kind of barrier between tham as between normal and misfolded.

Perfectly Candide said...

"while it's true that there must be a biggish barrier between normal-fold PrP and misfolded PrP', that barrier doesn't have to be energetic, it can be conformational/kinetic."

Even kinetic barriers are in the end, energetic: the energetic barriers of getting to the intermediate steps between starting and end state. I certainly thought he was referring to the kinetic barriers caused by the need of getting the activation energy needed to change the state between normal and prion states.

S_A_Wells said...

I'm not sure I'd say that a kinetic barrier is ultimately energetic. Consider a marble rolling around the (flat) floor of a large circular chamber, in the wall of which there is a small gap a little wider than the marble. The energy cost for the marble to pass through the gap is zero. The time taken for a marble, launched into the chamber at an arbitrary direction and velocity, to exit through the gap could be anywhere from a very short time to infinity, depending on whether the marble's bouncing off the wall ever leads it to the gap.

For the protein, a better analogy might be a random walk on a very large hyperplane, at one point on which there is a landmine. Whether or not you ever tread on the landmine depends on the outcome of your random walk, but there's no energy barrier to reaching it.

---I should go back to work now.

Bayesian Bouffant, FCD said...

You should take a look at the studies on yeast prions. They are a lot clearer than the mammalian work. You can use the name Susan L. Lindquist as a starting point.

Iron Soul said...

I'm loving the science posts. Thanks

mugwump said...

Prions freak me out.

I had always wondered, wrt Creutzfeldt-Jakob, why cooking wouldn't simply destroy the infecting agent. They I learned about prions. Creepy that they can withstand autoclaving (which shows my presuppositions about what's "alive" and able to "infect").

McDawg said...

@ERV,

Thanks for this blog post.

Yes, Jason is a nice guy and I like his research. Whilst he was one of the speakers at NeuroPrion 2007, I never got a chance to speak to him.

The subject of Prion/ERV's has come up a few times over the last few years and I have a few Papers in my Library that may be of interest to you.

Drop me a note and I'll zap them over to you.

Torbjörn said...

If the pathological conformation adapts (by finding more easily changeable prions to spread by, I take it), I'm certainly willing to modify my yesterday comment to include the evolving conformation as living analogous to viruses. Math freaks will be strangely attracted by this, no doubt.

Oh, and protein soup sounds like a delicious idea.

Mark said...

Do mink and ferrets normally eat each other's brains? How did prions evolve otherwise? Did Mad Cow disease exist before modern food processing procedures? Do prions exist in nature for non-domesticated herbivores, and if so, how? I assume some answer to these was provided at the lecture.

Reynold said...

mugwump said:

Prions freak me out.

I had always wondered, wrt Creutzfeldt-Jakob, why cooking wouldn't simply destroy the infecting agent. They I learned about prions. Creepy that they can withstand autoclaving (which shows my presuppositions about what's "alive" and able to "infect").


What?! Oh crap. Here I am, cruising over here, trying to recover from that brain damage I get from reading Ray Comfort's blog, and I find out THAT!!!

Time for some prion googling...

AIGBusted said...

Here is a speculation that I have:

Could life have begun with something like a prion or virus? It is true that they need a host to survive, and obviously the host would not have been around before life began. But could the primeval soup have provided the materials they needed? I mean, the soup would have contained amino acids and biologically associated molecules.

My question is: Could life have begun with a primordial soup drinking virus?

alison said...

Thanks for a fascinating post, ERV. And thanks too for the way your passion & enthusiasm show through in what you write - you're going to make one great teacher/lecturer/educator (oh heck, you know what I mean!)

Anonymous said...

Great thread, says a dumb taxi driver from Germany

Leeeeee said...

Did Mad Cow disease exist before modern food processing procedures? Do prions exist in nature for non-domesticated herbivores, and if so, how?

Scrapie is one of several transmissible spongiform encephalopathies that affects the nervous systems of sheep and goats. It certainly can exist in non-domesticated populations though the source could be from nearby domestic animals. It's recorded history is over 200 years so it's been around a while.

Torbjörn Larsson said...

@ AIGBusted:

Um, layman here, but how about Koonin et al paper on The ancient Virus World and evolution of cells? They try to place the different domains of related virus, plasmids, introns et cetera emerging from a primordial gene pool. They could indeed be participants and/or products from the different stages on the way to independent replicating cells.

And just for the record, my earlier comment. I just doubted that prion's conformations had an individual evolutionary history and thus could be said to constitute life as consistent with an evolutionary process. Evidently they can.

windy said...

Stephen:
Hang on, hang on, I'm missing a step here. Is the ferret protein really identical in sequence to the mink protein?

The abstract of the second Bartz article says no: "two amino acid changes between mink and ferret: Phe-->Lys at codon 179 and Arg-->Gln at codon 224, respectively."

So, to me it sounds like mink prion catalyzes the conformation change in the first ferret, but once that is done, ferret prion has an easier time infecting other ferrets since the proteins share the same amino acid sequence. Or did they discover some additional evolution within ferrets that isn't explained by this?

mark:
Do prions exist in nature for non-domesticated herbivores, and if so, how?

The non-infective form of the prion protein exists naturally in the body (doing some respectable day job there, before it turns bad and goes prion).

"Our" PrP gene goes back at least to some fish (I assume the yeast prion is not homologous?):

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1456899

Bayesian Bouffant, FCD said...

Do prions exist in nature for non-domesticated herbivores, and if so, how?

Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) of deer, elk (wapiti), and moose. TSEs are caused by unusual infectious agents known as prions...

kezdro said...

Where is it you go to school again? Viruses/HIV, Creationists to play with, and now prions? I'm thinking I'm thinking I might just have to apply there for grad school..

Mark said...

From the wiki article for CWD: "recent research indicates that prions can be excreted by deer and elk, and is transmitted by eating grass growing in contaminated soil... Research has recently shown that an infected deer's saliva is able to spread the CWD prions."
Has anyone studied this method of transmission for BSE, or for a simple way to test cattle for BSE?
I had only previously heard about prions spread by brain material.

McDawg said...

@Mark,

"Dissemination of prions into the environment can occur from several
sources, e.g., infectious placenta or amniotic fluid of sheep. Furthermore, environmental contamination by saliva, excrements
or non-sterilized agricultural organic fertilizer is conceivable."

Source is this Paper in PLoS ONE (open access).


With regards to simple tests for BSE, one of the simplest is a simple "hand-clap" test. A cow that has BSE will be 'spooked' where as a healthy cow will not. Clearly, one would would need to follow up with more scientific methodologies, but it does work.

A much more scientific and effective non invasive method is to use the likes of Heart Rate Variability (HRV). Work here was pioneered by Dr Chris Pomfrett and colleagues at Manchester University.

Related Paper

Anonymous said...

Neurodegenerative Diseases, Prions, And Life Genesis


A. Involvement of misfolded proteins

http://researchnews.osu.edu/archive/targettau.htm

- Alzheimer’s disease is the most common form of dementia among older people. It initially involves the parts of the brain that control thought, memory and language

- In other neurodegenerative diseases, the deposition of aggregates enriched in certain tau isoforms has been reported. When misfolded this otherwise very soluble protein can form extremely insoluble aggregates that contribute to a number of neurodegenerative diseases.


B. Prions, Normal and Pathogenic.

http://blog.360.yahoo.com/blog-P81pQcU1dLBbHgtjQjxG_Q--?cq=1&p=125
and
http://www.the-scientist.com/community/posts/list/122.page#348

- Infectious prions And misfolded proteins. The infectious isoform of normal PrPC, known as PrPSc, is able to convert normal PrPC proteins into the infectious isoform by changing their conformation.

- "Scientists are learning more about the protein behind mad cow and Creutzfeldt-Jakob disease, including how to interfere with the proteins' production in the brains of mice. "

- "It’s also a mystery how prions replicate — they seem to do it without DNA — and they are difficult to kill."

- But, then, it’s also a mystery how at Genesis RNA-related oligomers replicated without DNA!...


C. Again, a phenomenological relationship...

IMO there is a definite, even if yet vaguely understood, relationship between CJ and Life Genesis phenomena parallel to the phenomenological relationship between black-holes and biosphere phenomena.

Black-holes and Biosphere(s?) are both phenomena of constrained energy pockets within a universe of an expanding energy matrix.

CJ and Life Genesis are both phenomena of serendipitous occurrence of 'favourably-directed' energy potential:

- in the case of life genesis, between incoming sun's radiation and RNA-related oligomeric configuration, and

- in degenerating proteins replication, between specific protein-forming-folding-enzymes and enzymes-protein complexes.


musing,

Dov Henis
http://blog.360.yahoo.com/blog-P81pQcU1dLBbHgtjQjxG_Q--?cq=1&p=125

PS: Ease-of-kill is test of lifeness

"It’s also a mystery how prions replicate — they seem to do it without DNA — and they are difficult to kill."

Re the 'uncertainty' about the lifeness of prions or viruses, this is philosophic and factual 'proof' that viruses are alive and prions are not...

DH