Friday, February 17, 2006

A Role for Prions in Inheritance?

The most recent issue of Seed (I think) has an article online by Dr. Alain Bussard, titled The Prion Anomaly.

The thesis of this piece is that as we learn more about prions, we are starting to realize that they have endogenous activities. Furthermore, since prions are resistant to degradation, they are heritable and thus can transfer heritable information from one generation to the next. This leads to him predicting an imminent paradigm shift as the evolutionary synthesis is forced to account for the role of prions in inheritance. Or, as he puts it:

More recently, prions were found to have a role in another sacred domain of biology: the transfer of hereditary information in a non-Mendellian fashion from parents to offspring. It was in yeast that researchers first found evidence that prions could alter the expression of enzymes from one cell to another. Far from being pathologic, this form of protein-based information flow was an adaptive mechanism, conferring evolutionary advantages onto recipients. And recently, Susan Lindquist at the Whitehead Institute in Cambridge, MA (who has been working on prions with her group since 1993) has found a notable example: a molecular chaperone, the prion Hsp90, that strengthens the hereditary evolution of drug resistance in diverse fungi. But it is the evidence that prions play an important role in the formation and maintenance of long-term memory—discovered by Eric Kandel at Columbia University in New York—that seems to me of greatest importance.

Scientific revolutions concern the replacement of an old paradigm by a new, incommensurable one. However, the conflict of paradigms often does not end with the death of the old one. Rather, the new theory is incorporated into the older framework so as to make it more universal. Physicists have become quite used to this and have been quick to adapt their common views to new theories. But I wonder if we are not, today, in a new epistemological situation in which two apparently incompatible paradigms can exist simultaneously: in this case, the classical (molecular biology) paradigm and the prion paradigm. After all, is it not the case in physics that Albert Einstein attempted for 40 years to reconcile the relativity and quantum paradigms, with no success?

Now, I think this is an incredibly cool idea if only because I like to see people stir things up. Furthermore, as Dr. Bussard is a Professor at the Department of Cellular Immunology at the Pasteur Institute, it seems probably that he knows more than me. Nonetheless, I think he's jumping the gun a bit.

First off, here's the article about prions in yeast (Nature: subscription required) that I think he's referring to, Epigenetic regulation of translation reveals hidden genetic variation to produce complex traits. And here's the article I assume he's referring to about Hsp90 (Science: subscription required), Hsp90 Potentiates the Rapid Evolution of New Traits: Drug Resistance in Diverse Fungi. I'm really just linking to these so you can make up your own mind.

Next, I should point out I'm way out of my area of expertise here. But nonetheless: this is not the first epigenetic phenomena we've encountered. As an example off the top of my head, cellular organelles (such as the endoplasmic reticulum or the mitochondria, to use two contrasting examples) must be reproduced independently during cell division. In the case of the mitochondria, it has its own genetic information that must be duplicated. In the case of the ER, it's required for protein synthesis; if the daughter cells had no ER, how would they build a new one? So although inheritable prions that play a role in heritability is an intensely interesting idea, it's not quite as novel as he makes it sound.

Also, Hsp90 is not a prion. It's a molecular chaperone, albeit one that they claim in the article from the Lindquist lab is acting in a prion-like fashion. But exactly what that fashion is, is far from clear.

And although I find the work by Eric Kandel (who's certainly not the Nobel Prize winner I would choose to mess around with) suggesting prion involvement in formation of long-term memory fascinating, it doesn't yet seem at the point that we know where this is going for sure. But, I must admit I'm less familiar with it than I could be.

But ultimately, my argument is this. Referring to the current paradigm as the "classical (molecular biology) paradigm," sort of makes my point for me. The current paradigm already has room in it for protein, and I see no reason why it can't make more. One demonstration of yeast prions, another of a heat shock protein, and an involvement of prions in memory does not convince me that in five years we'll be in the middle of a revolution demonstrating the ubiquitous involvement of prions in all things inherited. It's possible that this could occur, but it seems to me that we're just continuing to find out that things are a little more complicated than we might have thought a decade ago. Which I firmly place in the category of "science as usual."

EDIT: No sooner do I get this up than I discover Seed has just posted a much more interesting article about prions, including a potential role in early neuronal differentiation. Nothing revolutionary (aside from continuing evidence that prions have an endogenous role in animals), but interesting nonetheless.


At 18 March, 2006 03:20, Blogger Impatient Patient said...

How can there be two outcomes for prions? I have read/heard that prions might be implicated in Alzheimers- I have no idea if this is true or possible, and now I read that the opposite- that they are beneficial in memory and learning- may be true. Since I am by NO means a scientist, just a curious person, I am perplexed.

Next- could prions cause inflammation? If you have cow prions in your brain, could this cause problems with the immune system?

At 18 March, 2006 20:44, Blogger The Neurophile said...

Alright, we're officially in over my head when it comes to prion-related knowledge. But I can pretend I know what I'm talking about for a few, and truck on ahead.

First off, I think part of the confusion is because the current definition of prions is expanded from an original definition, making me unclear where the current definition ends and begins.

Originally, a prion referred to a proteinaceous particle capable of infection. This was novel at the time, because all other forms of infection involve bacteria or viri, all organisms (or pseudoorganisms) which require at least some minimal semblance of cellular metabolism and at some point replicate via DNA. A prion, on the other hand (under this definition) is merely a specific protein which causes an infection entirely on its own.

This occurs because prions are proteins that have misfolded and have the ability to force other proteins to similarly misfold. This leads to an accumulation of these proteins that can grow over time: this is a type of amyloid plaque. Of note is that classical prions are highly resistant to degradation: they will not denature even at temperatures that kill most bacteria, which is why meat from cows with BSE isn't safe even when cooked.

Now, originally, the term prion referred to a specific class of proteins, those involved in the related diseases of scrapie, Creutzfeld-Jacob Disease, and mad cow disease.

However, it seems to have expanded since then in a few directions. First, it seems that the term "prion" can now be used in reference to the wild type versions of these proteins, which are not virulent and do not interfere with cellular processes. Secondly, it seems to sometimes get used to refer to other diseases caused by misfolded proteins, even in a noninfectious manner.

So, to address your questions:
One, Alzheimer's involves the accumulation of amyloid plaques in various parts of the brain. Although these plaques are different proteins than those involved in CJD, there's a similar pattern involved: large-scale accumulation of misfolded protein deposits leads to neural degeneration. Does this count as a prion under a modern science definition? I honestly dunno.

Second, I haven't read any of Kandel's work implicating prions in memory. I would assume that this either involves the WT version of the protein involved in CJD, or somehow involves a protein which forms a conformation resistant to degradation. The fact that there is an inverse correlation between complicated mental activities (playing chess, doing crosswords, dancing) and development of Alzheimer's, and whether or not it may somehow relate to a role of prions in memory is interesting to muse upon but completely beyond my ability to register an opinion on.

Third, it would be safe to assume that prions should be capable of evoking some sort of immune response: they're foreign proteins, and should be recognizable as such by the immune system. Does this actually happen? I don't know, but I would assume it would. And if you have cow prions in your brain, you have a lot more to worry about than immune problems. As I understand it, vCJD (variant Creutzfeld-Jacob Disease--the version caused by cow prions) is highly fatal.

Some wikipedia links that might help:

Alzheimer's disease

Again, this is way beyond my area of expertise, and somewhat beyond my realm of knowledge (which I think is already pretty clear). That said, was that helpful?

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