Wednesday, December 1, 2010

Fantastic filaggrin article

I'm genuinely excited today. I found something much more interesting than the usual crop of eczema news. In the magazine The Scientist--which has a tradition of features that have a strong strain of narrative writing--that is, story, rather than just a gaggle of facts and jargon--I found an article written by Irwin McLean, a professor at the University of Dundee in Scotland. McLean is the lead author of the landmark papers that reported, first, mutations in the filaggrin gene that cause ichthyosis vulgaris, a dry, scaly skin disorder; and, second, that the same mutations caused (or greatly increased the risk of) eczema.

Please read McLean's article. It is effin' awesome. It's written by an expert and as riveting a read as you'll find anywhere, if you're interested in eczema science.

Here's McLean's explanation of why filaggrin matters:
Filaggrin is crucial for the formation of the stratum corneum, the layer of dead cells at the surface of the skin, and also for the hydration of this crucial barrier layer. People who have mutations in one or both copies of the filaggrin gene produce dry and flaky skin that is permeable to allergens or chemical irritants. When the barrier is broken, foreign material is able to pass through these skin layers. We think that childhood eczema—which usually first occurs within the first few months of life—is an indication that foreign pathogens and irritants have passed through an abnormally porous skin layer, activating a strong allergic immune response, and thus priming the body to react to antigens that it would not normally encounter by this route. Later in life, when the child’s immune system comes into contact with those same allergens, perhaps through the lungs, it reacts aggressively, causing the inflammation in the lungs that results in shortness of breath. In fact, many children with eczema have multiple allergies to house dust, pet hair, and other substances.
McLean tells the story of how he and his team identified the mutations in the filaggrin gene (FLG). FLG is a remarkably difficult gene to sequence and was one of the last to be conquered by the Human Genome Project. It's very large, and contains 10 (or, sometimes, more) identical subunits, which means that if you start sequencing somewhere in the middle, as is done in a shotgun approach (where you sequence a lot of small bits and join them up like a jigsaw) you can't be sure if you're sequencing just one of the subunits, or more than one, or all of them at the same time. "It was as if nature was having a joke at our expense," McLean writes.

The team managed to identify the two mutations in ichthyosis vulgaris-- but then one of the scientists, Alan Irvine, pointed out that many of the patients in the subject group also suffered from eczema, many more of them than were in the control patient group. (It's this kind of insight that drives scientific discovery.) McLean, Irvine, and colleagues ran a statistical analysis on their patient group, which was very small by epidemiological standards--only 50 affected patients, and 200 controls, instead of thousands--and found that the  measure of significance, the "p-value," indicated beyond a doubt that there was a link between eczema and the mutations.

At the end of the article, here's McLean on what's next.
The question now is how to prevent eczema, asthma, and allergies from occurring in patients with the susceptibility mutations in their filaggrin gene. If it were possible to find a cure for eczema in adults, could we also cure asthma, or would it be too late, with the immune system permanently primed against allergens? I would argue that it might at least help. If the skin barrier is not repaired, then the immune system will constantly produce more antibodies in response to allergens that continue to get past the barrier. Stopping that assault may have some beneficial effects. The alternate possibility is that we may need to prevent eczema in young children before they become sensitized. If the latter proves true, would it be sufficient to curb eczema early in life, as the immune system develops? These are all questions we are gearing up to answer...
...We’ve also started to look for ways to help the body replace filaggrin at the cellular level. We are currently searching small-molecule chemical libraries for new classes of compounds that might induce skin cells to produce more filaggrin protein. Results look promising, and we are hopeful that in a few years’ time, new drugs or creams that enhance skin-barrier function will be available to treat these common diseases.
From McLean's biography we learn that he briefly worked at a biotech company, which is good news for us: he probably has some idea of how cures get from the benchtop to market.

I'm going to argue that HERE is where we need to put our money from philanthropic donors. Now that McLean and his team of leading scientists have found these mutations and laid bare the role of filaggrin in eczema, we need to help entrepreneurial scientists translate this research into startup companies or intellectual property that can be licensed to big pharma or biotech companies such as Genentech. THIS, the proof-of-concept stage, is where funding in the area of $100k can make a difference to an academic lab-- the difference between the science turning into real cures, or languishing in the pages of the scientific literature.

8 comments:

  1. I really hope they can do something with this research. You often hear about these breakthrough scientific discoveries and the possible uses but not so much about them actually being put into practice. (Red, rough) fingers crossed!

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  2. And there's the rub.

    I remain optimistic though. The way the science is going at the moment, it seems that they may find some way to protect kids' skin--a barrier layer--and that will stop or impede full-blown eczema from developing. For those of us who have it as adults, it could be that an improved barrier will reduce the chance of infection. And I do hope someone will discover a way, maybe a drug, to break the itch/scratch cycle.

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  3. I think this is also an interesting article that suggest that the pattern of inheritance is recessive and not semi-dominant, which I've been wondering about.
    http://www.jacionline.org/article/S0091-6749%2808%2900143-7/fulltext

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  4. I am also curious if there is a strong linkage between the various null mutations in fillagrin which impede the production of this protein,how does eczema improve with age in 50-70% of cases given that are genome doesn't generally change bar any exposure to some agent.

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  5. Thanks for the link and interesting questions, Anonymous.

    I hadn't seen that article and I admit I'm surprised. I'm always impressed with how complex a disease eczema is. I have a feeling that known filaggrin mutations account for 20% of eczema cases, so there have to be other factors involved, maybe mutations in other cornified envelope proteins. But I'd think that, given a group of eczema cases, you'd find more people with one mutated copy of FLG than with two. Hmm. (Population studies rarely seem to be definitive-- you need a bunch of them to agree before you can be confident about the results.)

    Re: your last point, although the genome itself doesn't change with age, the pattern of gene expression does change (that accounts for us growing up) and also the immune system gets exposed to pathogens and allergens and learns from the experience. These two factors probably explain why most children usually outgrow eczema.

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  6. I've kept thinking about the question of why most children outgrow eczema even though the disease has a strong genetic component. It's a puzzle, for sure. I bet that if you have two nonfunctional copies of FLG, you're much more likely to suffer eczema as an adult. But there will still be some people with two mutated FLGs who outgrow eczema. That might be because there are other proteins that can, to some degree, perform the same tasks as filaggrin, and they get upregulated in some people. Or there may be mutations in other proteins (such as claudin-1) that increase the severity for the unfortunate few.

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  7. Hello Spanish Key.

    Do you have any news regarding this research? They claim that they have potential drugs in preclinical testing and validation in animal models, so I suppose they´ll will go in to clinical trials in not so many years.

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  8. Wish I was up to date on this. I'm not! All I know is that testing and optimizing drugs and taking them to market is a hellishly expensive process and that very few drugs make it all the way. This is something to check up on when I finally have time to get back to blogging... thanks for asking.

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