Friday, 27 January 2012

Epigenetics 101 and autism

Just relaxing @ Paul Whiteley
Ladies and Gentlemen. In the red corner, several million/billion years in the making, the current champion, genetics. In the blue corner, weighing in at several billion/trillion pounds, the challenger, environment.

[OK fellas, a good clean fight].

Ladies and Gentlemen... lets get ready to rumble!

Dramatic opening to post finished as I offer one of my more descriptive entries on the emerging field of epigenetics and some of the research already carried out with specific regards to autism spectrum conditions. I admit that I am sailing on the waves of current interest in this field with this post, being brought to it by the news that we may be seeing a lot more of the word 'epigenetics' in autism research circles soon as per this announcement on funding for Prof. Margaret Daniele Fallin based at Johns Hopkins Bloomberg School of Public Health and an accompanying 'what is epigenetics' post by Autism Speaks. The news that poverty might also have an epigenetic angle also took my interest (take note Politicians the world over).

Epigenetics has been mentioned before on this blog; normally posting a link to this piece in Time magazine about why your DNA is not necessarily your destiny. In short, epigenetics is the study of changes to gene activity without alterations to the genetic code passed down at least one generation. Epigenetics is quite an intellectually satisfying approach for lots of reasons; primarily perhaps because instead of pitting genes against environment in some kind of grudge match boxing contest, it actually suggests that our environment - our diet, our various stresses and exposures right from our earliest days - can affect gene activity by switching genes on or off. Synergy in action.

Another interesting article on epigenetics recently appeared on the Scientific American blog. I don't want to plagiarise what is a very good article, but there are some interesting data and concepts discussed which I do want to mention.

  • I can't pretend to be an expert in this area so I won't try. Instead I refer you to quite a good introduction which presents the terms chromatin (the stuff of chromosomes), the DNA-protein mix nicely packaged up to fit into a cell nucleus, and histone, the scaffold around which DNA is wrapped to form nucleosomes.
  • There are various ways that histone can be 'modified' including acetylation, methylation and phosphorylation. Such modifications have onward effects which have been described in a 'histone code' which seems to be growing all the time.
  • The concept of Lamarckism is gaining in popularity as a consequence of the epigenetics tide. Lamarckism basically states that certain characteristics acquired by a parent can be passed to offspring. So coupled to epigenetics, parental (or grandparental) nutrition for example, might alter gene expression which then gets passed down to successive generations. I'm thinking Barker hypothesis and thin-fat bodies.
I've talked before about genetics on this blog and how whichever way you look at it, genes, mutations, etc. we are all very much a product of mutation and the emerging view is that genetics in relation to autism is a very, very, very complicated thing. I would hasten to add that concepts of Lamarckism are not to be viewed as another 'blame game' idea given that exposure events are likely to be multiple and complex and, as per the wartime famine studies related to the Barker hypothesis, events are not always likely to be under our control.

Very interesting, I (hope I) hear you say. But what about autism?

Well, epigenetics is obviously quite a new area for autism simply because a quick search of PubMed (26/01/12) only reveals 37 entries for the words 'autism and epigenetics'. That's not however to say that there isn't some interesting data already available to look at as I hope I will show.

This overview paper by N. Carolyn Schanen* (full-text) is as good a start as any. It is quite a long paper and not exactly easy to follow unless you are a molecular biologist, but nevertheless it offers some interesting discussions not least forecasting where we are today in terms of lacking any significant, universal genetic markers for autism.

This paper by Mehler and Purpura** (full-text) also has some interesting discussions about epigenetics. Appreciating that there is some degree of speculation in the text on their theory "of a functionally impaired locus coeruleus-noradrenergic (LC-NA) system", I find myself also drawn to their ideas on fever potentially affecting the presentation of symptoms in some cases of autism as per other research among the literature and the possible involvement of antipyretics in some cases.

Finally, this paper by Grafodatskaya and colleagues*** I think sets the tone for where genetics research might be heading in autism research with epigenetics at the helm. Noting that the authorship list includes Peter Szatmari who commented on the twins study published last year (the game changer!), it is difficult to argue against the notion that genes and genetic research is in the midst of a revolution. A revolution where the boxing match between nature and environment might just be replaced by an altogether more understanding relationship.

Cue the candle-lit dinner and (b)romantic music... (for my non-UK audience, read more about the background to this song here).

* Schanen NC. Epigenetics of autism spectrum disorders. Human Molecular Genetics. 2006; 15: R138-R150.

** Mehler MF. & Purpura DP. Autism, fever, epigenetics and the locus coeruleus. Brain Research Reviews. 2009; 59: 388-392.

*** Grafodatskaya D. et al. Autism spectrum disorders and epigenetics. Journal of the American Academy of Child and Adolescent Psychiatry. 2010; 49: 794-809.

2 comments:

  1. Again you prove yourself a man of great wisdom and foresight. Most autism commentators are still scratching their collective heads saying "epige-what?"

    Many answers to the autism mystery will be discovered by finally asking the right questions--particularly, what novel exposures could have, via epigenetic mechanisms, so horribly impaired gene expression in our children?

    IMO, the elephant in the room is the prenatal pharmaceutical craze which started after the war and ended (kind of) in the late 1970s.

    Millions of us were exposed, via then-accepted wacky obstetric practice, to heavy doses of toxic, teratogenic, endocrine-disrupting chemicals marketed as drugs--many packing a powerful epigenetic punch. During this time the FDA and medical profession gave no thought to the potential vulnerability of fetal germ cells (or much to the the fetus itself for that matter, as we know through the thalidomide and DES catastrophes). To this day -- incredibly -- the FDA has never required any testing of pharmaceuticals for potential impact to fetal germ cells.

    One estimate found that in the US in the period 1958-65, half of pregnant women were on two or more medications, for anti-miscarriage, nausea, sleep, weight loss, hypertension, and more. Many of these drugs, particularly the multitude of anti-miscarriage fake progestins, estrogens, and corticosteroids, were injected or taken weekly from the very start of pregnancy through the end of the second trimester. (Oh, medical history, how little we know you. By the way, those endocrine-disrupting drugs, which were largely untested, didn't actually work.)

    It's not genes v. environment, as you rightly point out. It's in many cases about a highly abnormal chemical/pharmaceutical environment changing genes, or at least gene expression. In what can only be described as a massive departure from evolutionary norms, pharmaceutical practice in those Wacky Mad Science Years permanently, if inadvertently, poisoned millions of otherwise robust germlines.

    With this in mind, one can see why transgenerational epigenetic research will be key moving forward. I'm hearing the romantic music already! Thanks for your excellent column.

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  2. Many thanks for the comment. I am blushing...

    Epigenetics is gaining some pretty fast momentum at the moment and opens up a whole new area for studying autism and quite a few other conditions. I'm not one for predictions, but I would wager a few pennies that some interesting things will eventually turn up from this area...

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