THE SINS OF THE FATHER (AND MOTHER...)

So how’s today looking diet-wise, skipped lunch and now snacking on biscuits?  Or already on your second packet of fags?  That’s a shame.  Not just for you but for your kids and grandkids too.  Yep, those descendants who perhaps don’t yet exist may be affected by the health choices you make today. 

S Vuono

Hang on.  This sounds a little inflammatory, akin to the type of claims I was criticising only yesterday? Admittedly it’s still early days, but this one may actually stack up...

To understand why, we need to look at the molecular origin of 'why we are the way we are'.  I’m talking about DNA and specifically a field of research catchily entitled ‘epigenetics’.

 In short, epigenetics is the link between the environment and the human genome - the missing jigsaw piece in the nature versus nurture debate.  Environmental exposures, such as diet and smoking, can alter a pattern of chemicals attached to the DNA sequence (which contains the genes themselves) and the way the DNA is wound up and packaged inside the cell – collectively the epigenome. Often this involves adding chemical groups (tiny clusters of carbon and hydrogen atoms called methyl groups) to sections of the DNA and larger clusters (called acetyl groups), to its structural proteins (histones)*. These rather simple and unassuming molecules have an incredibly influential role within the cell, functioning to switch some genes on and turn others off. For example, your liver cells contain exactly the same DNA sequence and genes as your heart cells. The only difference is the liver cells have all the ‘heart’ (and every other type of cell) genes turned off, so the only proteins being made inside the cells are the ones you need – liver.

A moment on the lips, a lifetime on the DNA strips…

But this neat molecular switch isn’t just the preserve of development biology.  A quick search on Google reveals that epigenetics is burgeoning into one hot subject – there are over 17 international conferences devoted to this area of genomics this year alone. (I’ve offered my services to various telly execs to report from the epigenetic frontline – Miami, Boston, Aruba (yes please!) - but it’s “too niche” apparently. Humph.) 

Why all the interest? Well, epigenetics appears to be involved in much more that just basic cellular determination; it is thought that it plays a role in some of the biggest killers of the modern age – cancer, heart disease, diabetes and ageing itself.



M Meiklejohn

For example, most of us would assume that a mother’s diet during pregnancy would impact the health of her child. But what’s interesting is the effect lasts long after the duration of pregnancy, affecting the child’s susceptibility to adult-onset disorders such as insulin-resistance and obesity.  It appears that the mother’s diet actually alters the child’s epigenome – a process known as metabolic imprinting.  This reprogramming of the genome is thought to have enabled the foetus to survive under conditions of poor nutrition.  But if later in childhood, the paucity of nutrition is removed, the child is less able to deal with the increased calorie intake and is more likely to become overweight.¹

More importantly for those of us raiding the kitchen cupboards, this mechanism for turning some genes off and others on doesn’t just function while we languish in the womb: it’s a dynamic system that is highly susceptible to environmental triggers in the big wide world too. And while most epigenetic modifications get wiped during fertilization (effectively resetting the genetic code to time zero), there is increasing evidence from mouse models that not all are.²  So crucially, it appears to matter what your mother ate and did BEFORE she was even trying to conceive.

All you would-be fathers had better take note too. Swedish and UK researchers investigating the relationship between periods of famine and the onset of disease in a remote community in northern Sweden found that the paternal grandfather’s food supply during mid-childhood was linked to the cardiovascular disease, diabetes and mortality risk of their grandsons³ (similar findings also occurred between maternal grandmothers and their granddaughters). This supported data from an early ‘90’s UK study showing that fathers who started smoking early (around 11 years of age), increased the chances of their sons being obese⁴.   

In both cases, the genetic reprogramming appears to have happened before the parents even hit puberty (a particularly fertile period for male epigenetic reprogramming). This is 'transgenerational epigenetics'.  Here the epigenetic modifications occur in the germline (sex cells) as opposed to somatic cells, enabling any changes to be passed onto multiple generations.  This remains a nascent field of research,  so it goes without saying that these claims need to be treated with caution.  Data sets covering large populations over decades are difficult to find and unsurprisingly the results take some time to appear.  It’s also challenging, although not impossible, to strip out the social factors involved.

However one of the awesome things about epigenetic reprogramming is that, unlike the DNA sequence, it’s not set in stone. If some of the modifications have been damaging and confer a disease, drugs can be targeted to reverse them.  And this is much easier than splicing out chunks of faulty DNA and popping in a ‘good’ sequence (the aim of gene therapy). One such drug is Dacogen, approved by the FDA in 2006 for the treatment of acute myeloid leukaemia. It works by stripping off the incorrectly placed methyl groups attached to tumour suppressor genes, in a precise, malignancy-specific fashion.

Food as medicine?

K. Atsawintarangkul

Fortuitously perhaps, this type of research taps into the current zeitgeist to ‘science-up’ food.  A trend that is not lost on food manufacturers, who spend a fortune to convince us of the health benefits of their products.  There appears to have been a fundamental shift in our relationship and understanding of food - from a basic building block for energy and growth, to a mechanism of information transmission and molecular signal.  

So if diet can contribute to a disease in the first place, might it be possible that it can prevent disease too, reversing the epigenetic rewiring? The idea of food as a drug isn’t new -  those with metabolic disorders know the importance of diet in alleviating their symptoms (e.g. sufferers of phenylketonuria can't process the amino acid phenylalanine, a component of protein, so need to consume a diet low in this compound) - however here the genetic mistakes aren't being corrected, only the negative effects of them in the body. 

Currently, the significance and impact of preventative nutrition is under very keen investigation.  Probably the most common example is the supplementation of folic acid during pregnancy.  This B vitamin is a core component of the embryonic DNA methylation pathway.  Disruptions to this pathway causes incorrect levels of gene expression leading to a variety of disorders, including neural tube defects in the foetus.⁵

The increasing speed and decreasing cost of genome sequencing means that each individual’s genetic profile could soon be more readily accessible.  This would give us an unprecedented account of our genetic strengths and weaknesses.  Potentially changing our diet could prevent the ticking time bomb of adult-onset disease later in life, when treatments may be severe or non-existent.  This opens up the possibility of personalised nutrition based on scientific data (unlike the ‘eat right for your blood type’ diets and their ilk that come into vogue with alarming regularity).

Personally, I find this all really encouraging.  Research in this field will potentially create new, tailored opportunities to prevent and cure disease, and improve the quality and duration of life.  Knowledge that we are no longer shackled by our genetic make-up, but can alter and improve it, is a phenomenal prospect, however it comes with the awareness that we are not only responsible for our own health, but that of future generations. Together they make a pretty awesome and humbling proposition.

*non-coding RNAi molecules also play a role, but for simplicity I’ve left them out here.  Generally I’ve tried to keep in all the important stuff without getting too bogged down in the precise molecular processes.  If you want more detail on anything I’ve mentioned, message me and I’d be happy to fill you in.

1. Waterland RA, Garza C. Potential mechanisms of metabolic imprinting that lead to chronic disease. Am J Clin Nutr. 1999; 69:179-197.

2. Rakyan VK, Chong S, Champ ME et al. Transgenerational inheritance of epigenetic states at the murine Axin(Fu) allele occurs after maternal and paternal transmission. Proc Natl Acad Sci USA 2003; 100: 2538– 2543

3. Kaati G, Bygren LO. Cardiovascular and diabetes mortality determined by nutrition during parents’ and grandparents’ slow growth period. European Journal of Human Genetics. 2002; 10, 682 – 688

4. Pembrey M, Bygren LO, Kaati GP et al: Sexspecific, sperm-mediated transgenerational responses in humans. Eur J Hum Genet 2005; 14: 159– 166.

5. Stover PJ, Caudill MA. Genetic and Epigenetic Contributions to Human Nutrition and Health: Managing Genome–Diet Interactions. J Am Diet Assoc. 2008; 108:1480-1487.