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Tuesday, March 10, 2009

It might drive you mad, but you probably need it.

ResearchBlogging.orgIn the late '90s, everyone started freaking out about their beef products, especially in Europe. Cows in Britain had started falling ill with a strange fatal neural disease. But not only the cows were getting sick - people who ate infected meat were hit too, dying by way of a new variant of Creutzfeldt-Jakob disease. The cow disease became known as Mad Cow for the way in which the infected cows acted. Soon enough it had become epidemic, and people looked for the cause - and found it to be a little protein, called a prion.

Prions are misfolded proteins which cause diseases in animals. But beyond just causing disease in the individual with the genetic or environmental cause for the prion, prions are unique because they can infect healthy individuals like a virus. Somehow they cause normal proteins to misfold and mess up. Theories of how mad cow spread so virulently are varied, but most hinge on cows somehow eating the remains of other infected cows, thus taking in their proteins, including prions. The original source of the prion may have been sheep (whose remains might also have been fed to cows), who have a similar disease called scrapie, but the jury is still out.

But how does a gene that encodes a protein that kills survive in a population? Most theories for how genetic disorders continue hinge on their usefulness in other scenarios. For example, the gene which causes sickle cell anemia, a debilitating and painful disease, is useful if you only carry one copy - you're healthy and you're malaria resistant. But what role do prions play which makes them evolutionarily useful?

The part of the puzzle that had eluded scientists was what these prion proteins (PrPs) were doing in our bodies in the first place. We produce huge amounts of non-infective PrPs, but no one could figure out just why we do. Studies in mice were a dead end - mice who lacked PrPs seemed just as healthy as those who had them. Were PrPs useless? Perhaps evolutionary left overs? Scientists started to wonder. Then, some decided to try the same thing with fish.

Published in PLoS Biology, a new study finds that zebrafish lacking prions during development suffer terribly. Scientists infected fish embryos with morpholinos, DNA-like molecules that prevent PrP production. Infected embryos were unable to create the cell to cell connections which are vital to the development of internal systems. Simply put, the cells couldn't communicate to create the diverse differentiation of cell types for an adult fish. All of those that couldn't make PrP died.

So it turns out that the compounds which drive cows and people mad are incredibly useful. Just how they function in our systems isn't clear yet, but they probably have some role in cell to cell communication during development or differentiation.

This study provides the first clues into the uses and roles that PrPs play in the body. By learning what they do, scientists are one step closer to finding compounds that follow or disable misfolded PrPs that cause Mad Cow and Creutzfeldt-Jakob disease - and one step closer to finding ways to prevent them.

Edward Málaga-Trillo, Gonzalo P. Solis, Yvonne Schrock, Corinna Geiss, Lydia Luncz, Venus Thomanetz, Claudia A. O. Stuermer (2009). Regulation of Embryonic Cell Adhesion by the Prion Protein PLoS Biology, 7 (3) DOI: 10.1371/journal.pbio.1000055

7 comments:

MechApe said...

You should have mention Kuru-Kuru (Papua New Guinea) disease, which is the reason both for the theory of cow cannibalism and the specific "mad" symptopms.

Nice article, thanks.

Max said...

"...cows somehow eating the remains of other infected cows."

As the prion theory first gained prominence, the articles I read indicated that cow parts that weren't good enough for us (organ meats for instance) were recycled back into the feed. It is my understanding that this is still the practice in the U.S., though I haven't dug into this to check it out.

I'm a little confused about the fish study. Doesn't this just proof the value of the PrPs to fish? It seems that mice have developed some other mechanism which doesn't require PrPs. How do we know we haven't as well?

Christie Lynn said...

Max: I don't know about in the US, but in some places that's been banned now. They used to used ground up meats (cow or otherwise) to up the protein content of feed (thus getting the prions into the food). Though there is a little bit of wiggle by people about this (hence why I just said "somehow").

As to your second point, I would say yes, but. Yes, it does only prove that they're necessary to fish. But we do produce a whole lot of them - it seems odd that our bodies would 'waste' the amino acids/etc to make a ton of something that has no use whatsoever. Of course, trying the same trick with human embryos is unethical, so it's hard to be certain how they might be utilized in us. Mice aren't exactly people, and the studies which show a lack of use generally are knockout studies - which means that if they haven't actually IDed the right gene, the mice could still be making PrPs that are different. The fact that such a valuable use in a vertebrate model has been identified suggests that we might still have uses for the PrPs.

Irradiatus said...

I have a couple of critical comments to make on this one (hopefully you wont be offended - their just simple technical criticisms):

Quote: "But what role do prions play which makes them evolutionarily useful?"

One thing that should be made clear is that this study in no way addresses anything at all about actual "prions," from their function to advantages.

The problem here comes from the confusing science terminology (and a horrible nomenclature of the protein itself).

The protein in this study is simply one of hundreds or thousands of normal proteins that are expressed in developing tissues. It just so happens that a pathogenic "disease" form can occur in some animals. Unfortunately, scientists named the normal version "Prion Protein - PrP" - probably because they discovered it through the prionic form (I'm not a PrP expert by any means).

This study ONLY addresses the function of the normal protein, ignoring any implications about the disease form. To do this, they simply did what I spent my entire graduate career doing - injecting morpholinos that block translation of the normal target protein. They found that the normal protein is a developmental regulator - and it does this by modulating cell-cell interactions.

However, it seems likely that there still is no "evolutionary advantage" for the disease form. In cows for instance, in nature they would never be eating other cows' brains. An individual with prionic forms of the protein would just die. But this study does not attempt to address this question.

Quote:"So it turns out that the compounds which drive cows and people mad are incredibly useful."

For the above reasons, this statement isn't really correct (or it's at least a little unintentionally misleading to others who don't understand prions). PrP, the protein studied, isn't the protein that drives cows mad (or at least not the same version).

It's not clear from this paper whether there exists a similar scrapie-like disease in fish.

It's still an interesting paper - but for different reasons.

Christie Lynn said...

Irradiatus - touche.

My phrasing could have been a little more clear.

My point, however, is that before this study, the PrPs (some of which are "bad" some of which are "not") had no function at all - so now we know they might be useful for something other than there being diseased forms which cause Mad Cow.

I guess I misphrased it a little, but my point is that these proteins might have important uses - which might explain how even diseased genes would stay around, as long as both genes aren't bad or if the diseased forms provide an advantage earlier on, and only the disadvantage later - which, now that we know they're important in general, we can investigate further.

And, to be fair - the disease is sheep perpetuated even though sheep don't eat each other, either.

Irradiatus said...

lol

I think you should have ended with "So there!"

Yeah - I didn't know that about sheep scrapie. But now that I think about it, I did know that the deer version propagates...though I don't know how.

I guess a question I want to know is when does the disease present? Is it before or after reproduction?

I hope you know I wasn't trying to knock your post. you know I love ya :)

As far as the paper itself, they hammer the point that the cell-cell interaction appears to be conserved, because 1) homologue constructs from other species have the same effect in S2 cells (based on my cursory reading) and 2) their previous work in T cells (which I haven't read).

Considering that the KO has no developmental effect in mice, I'm not sure that the PrPs have the same function in mammals. Then again, I don't know if there are paralogues in mice that may compensate. Anyone know how many PrP genes there are in mice? In fact, if PrP has a major effect on fish gastrulation, I would be shocked if there wasn't a version of that gene involved in mammalian gastrulation. I mean gastrulation is a pretty ancient process. Fish and mammals aren't that far apart as far as early development is concerned.

In mammals, it could be that the PrPs only function in systems like the immune system (T-cell), in which case you may not see any obvious phenotypes from a knockout until you challenge their immune systems.

I want to be clear that I'm simply thinking out loud here (figuratively). My knowledge of prions doesn't extend much deeper than info from a basic molecular course.

By the way, I was stoked to see you post on developmental AND actually use the word "morpholino." I injected morpholinos into frog embryos weekly for my PhD.

Peter Lund said...

I could have sworn that we knew it was involved in memory function?!?

google search for prion + memory

As an aside: you probably do have mad cow disease in the US. You just don't test for it as much as we do in the EU.

google search for mad cow disease testing