Thursday, 6 September 2012

The Dutch Winter Hunger

I've recently finished reading The Epigenetics Revolution by Nessa Carey, and what a triumph it is.  I find biology, like chemistry, can be a little 'dry'.  I like Dawkins' books - all very accessible but as a general rule (and outside of sport science), dull!  A school-life spent growing watercress in blacked-out jam jars, or splitting the stem of a rose so that each half of stem was in different coloured water, didn't really set my imagination on fire.

Skip forwards to 2012 and we are now in the neo-paleo period and biology is where it is at!  Epigenetics has made biology cool.  In turn The Epigenetics Revolution has made epigenetics understandable to the layperson.  Specifically, Nesse addresses how epigenetics can influence outcomes decades after the fact. (And today's news about 'junk DNA' being no such thing would be old news to you had you read Carey's work.)

Nesse gives a great example of this by reference to one of the most famous examples of epigenetics in action:
  • The Dutch Hunger Winter - One of the first aspects they studied was the effect of the famine on the birth weights of children who had been in the womb during that terrible period. If a mother was well-fed around the time of conception and malnourished only for the last few months of the pregnancy, her baby was likely to be born small. If, on the other hand, the mother suffered malnutrition for the first three months of the pregnancy only (because the baby was conceived towards the end of this terrible episode), but then was well-fed, she was likely to have a baby with normal body weight. The foetus 'caught up' in body weight.

    That all seems quite straightforward, as we are all used to the idea that foetuses do most of their growing in the last few months of pregnancy. But epidemiologists were able to study these groups of babies for decades and what they found was really surprising. The babies who were born small stayed small all their lives, with lower obesity rates than the general population. For forty or more years, these people had access to as much food as they wanted, and yet their bodies never got over the early period of malnutrition. Why not? How did these early life experiences affect these individuals for decades? Why weren't these people able to go back to normal, once their environment reverted to how it should be?

    Even more unexpectedly, the children whose mothers had been malnourished only early in pregnancy, had higher obesity rates than normal. Recent reports have shown a greater incidence of other health problems as well, including certain tests of mental activity. Even though these individual had seemed perfectly healthy at birth, something had happened to their development in the womb that affected them for decades after. And it wasn't just the fact that something had happened that mattered, it was when it happened. Events that take place in the first three months of development, a stage when the foetus is really very small, can affect an individual for the rest of their life.
A quick (simplified) primer: Epigenetics work in two broad ways; by turning genetic activity on or off through a process called methylation (like a switch), or through expressing a gene upwards or downwards (like a volume control), using histone modification.  

This certainly puts a bit of nail in the simplified ELDM model.  It also means that the obesity and health researchers of tomorrow are going to have a hell of a time unravelling confounders present in the life of some 40 year old, obese, heart-attack victim in 2112, given that his/her grandparents are alive today subsisting on box of Twinkies and Pretzles in front of the TV.  As modern foods (like margarine), quickly change their nutritional profile with ease, to reflect the prevailing dietary wisdom of they day, this problem is two-fold. Histone modifications are different to DNA methylation in a very important way. DNA methylation is a very stable epigenetic change. Once a DNA region has become methylated it will tend to stay methylated under most conditions. That's why this epigenetic modification is so important for keeping neurons as neurons, and why their are not teeth in our eyeballs.

Back to Nesse:
  • Although DNA methylation can be removed in cells, this is usually only under very specific circumstances and it's quite unusual for this to happen. Most histone modifications are much more plastic than this. A specific modification can be put on a histone at a particular gene, removed and then later put back on again. This happens in response to all sorts of stimuli from outside the cell nucleus. The stimuli can vary enormously. In some cell types the histone code may change in response to hormones. These include insulin signalling to our muscle cells, or oestrogen affecting the cells of the breast during the menstrual cycle. In the brain the histone code can change in response to addictive drugs such as cocaine, whereas in the cells lining the gut, the pattern of epigenetic modifications will alter depending on the amounts of fatty acids produced my the bacteria in our intestines. These changes in the histone code are one of the key ways in which nurture (the environment) interacts with nature (our genes) to create the complexity of every higher organism on earth.
These epigenetic effects mean that what your parents and grandparents did, from where they sourced their energy (how they ate, what they ate), and how they expended energy (activity levels), have affected you and your current physiology. And more relevant to YOU is that your source of nutrition today (how you eat and what you eat), and how you expend energy (your current activity profile), will affect the physiology of your children and grandchildren!

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