01.08.2006 Natural Health

The Missing Link

Groundbreaking research is now showing us that, in fact, it's not all in the genes. Dr Peter Dingle introduces us to the science of EPIGENETICS.

After spending billions of dollars unravelling the human genome scientists have come to the realisation that it is not all in the genes.

Darwin himself recognised the importance of environmental factors in the evolution of a species, but until recently, half of the chromosome content, the regulating proteins, have largely been ignored. These proteins, which are chemically attached to the genes, cover them like a sleeve, which means that the gene cannot be "read", making it "inactive". But once the protein sleeve is removed, the gene can be read and duplicated. The sleeve of proteins provides an "extra" layer of transcriptional control and regulates how and when a gene can be expressed. The proteins are much like the driver of a car. The genes are the car, which can't do anything without the driver.

Genetic determinism holds the position that our genes carry the blueprint of life and therefore everything is determined by our DNA. This leaves us the victims of our genetic inheritance. We've had these concepts instilled since our first high school science lessons and they're reinforced by the media and canonised in medical schools. If we fall victim to a disease, it's in our genes. However, very few diseases can be blamed entirely on one faulty gene and those that have a definite and specific genetic cause affect less than two per cent of the population. Only five pent of cancers and cardiovascular diseases can be attributed to heredity. The vast majority of diseases that afflict us today are a result of complex interactions between our genetic makeup and our environment.

The general perception that certain genes have an association with a particular disease does not necessarily mean the genetic component is the cause. Although a gene or genes may be involved in the disease process, it does not necessarily follow that they are directing, or causing, the disease. When a gene product is required, a signal from the environment, not the gene itself, activates the expression of the gene. Genes in themselves do not determine our destiny. We can regain control of our own health. The study of epigenetics (meaning "above genetics") provides the missing link between genes, the environment and the development of disease.

Environmental factors are capable of causing epigenetic changes in DNA, and have the potential to alter gene expression. This can result in "genetic" diseases from cancer to behavioural disorders. The science, although only just over five years old and still in its infancy, is showing epigenetically created changes to be causative factors in cancers of almost all types, genetic disorders and paediatric syndromes, as well as contributing to autoimmune diseases, respiratory disease, cognitive dysfunction, reproductive dysfunction, neurobehavioral illnesses, mental retardation and ageing. As further studies are conducted, this list keeps getting longer.

Environmental influences including nutrition, behaviour, stress, chemicals, radiation, and even emotional states, can change how genes are expressed and can silence or activate a gene without altering the genetic code in any way. That is, even if you have the genes which cause breast cancer, without the environmental trigger that can "turn them on", they are unlikely to cause breast cancer. Conversely, genes for cancer, or those for any other disease, which are dormant or inactive, may be triggered by an environmental factor, resulting in disease. It may be, for example, that the increase in asthma rates in Australia and other developed countries is caused by a combination of factors such as a lack of certain nutrients, such as methyl (which is found in fresh vegetables) in the maternal diet, combined with exposure to certain environmental toxins. There's a growing body of research showing that eating methyl-rich foods along with reduced exposure to synthetic chemicals, reduces asthma rates.

Known or suspected environmental culprits behind epigenetic changes include heavy metals, pesticides, diesel exhaust, tobacco smoke, polycyclic aromatic hydrocarbons, hormones, radioactivity, viruses, bacteria, poor nutrition, emotional states and stress. Each nutrient, each interaction, each experience can therefore be manifested through biochemical changes and may appear at birth, 40 years down the track or be passed onto future generations.

In a groundbreaking experiment, researchers exposed pregnant rats to vinclozolin, a fungicide commonly used in vineyards, and methoxychlor, producing male offspring with low sperm counts and low fertility. The affected males were still able to produce offspring. However, even when mated with females that had not been exposed to the toxins, the next generation of male offspring still had the same problems. Four generations were tested, and more than 90 per cent of the male offspring in each generation were affected, without any additional pesticide exposures. These findings provide a new paradigm for disease etiology and basic mechanisms in toxicology and evolution not previously appreciated - and certainly not considered by our government regulators. Oops we missed it again!

We appear to be most susceptible to these epigenetic changes at the embryonic and foetal stages of development, which then sets the stage for the adult's susceptibility to a host of diseases and behavioural responses.

One of the original experiments in epigenetics used pregnant mice which had an abnormal "agouti" gene. Feeding the expectant mothers methyl -rich supplements, folic acid, B12, betaine and choline, changed the binding characteristics of the regulating chromosomal proteins. Agouti mice have yellow coats and are extremely obese, which predisposes them to cardiovascular disease, diabetes and cancer (sound familiar?). The mice which received the supplements produced standard, lean, healthy offspring which, although they still carried the agouti gene, lived longer and weighed only half as much as the yellow agouti mice.

These and other studies have shown that nutrition is the single biggest factor involved in the alteration and expression of the foetal genome and may have lifelong consequences. A healthy, nutritionally balanced maternal diet will not only ensure optimal foetal development, but will reduce the risk of chronic disease in adulthood.

Studies have also found that epigenetic effects occur not just in the womb, but over the full course of a human life span. Epigenetic studies of identical twins have given interesting results. One study of 40 pairs of identical twins, ranging in age from three to 74, showed that although epigenetically indistinguishable during the early years of life, older, identical twins exhibited remarkable differences in their overall gene expression. Younger twin pairs who shared a similar lifestyles and had spent more years together, had very similar epigenetic patterns. But older twins, especially those who had different lifestyles and had spent fewer years of their lives together, had very different patterns. For example, the researchers found four times as many differentially expressed genes between a pair of 50 year old twins compared to three year old twins (Fraga et al 2005). Recent research has also shown that our susceptibility to epigenetic change appears to increase as we age past 50 years.

Epigenetic changes are gradual in onset and are progressive. Their effects are dose-dependent and are potentially reversible, which increases the scope for the development of "epigenetic therapies". Because of the nature of epigenetics, there is the possibility that the process of methylation itself could be used to either switch on or off, a cancer-carrying gene. These observations present new opportunities in cancer risk modification and prevention, using dietary and lifestyle factors. In this regard, folate, a water-soluble B vitamin, has been the focus of interest because of an inverse association between folate status and the risk of a number of malignancies (in particular, colorectal cancer). Folate has the potential to modulate DNA methylation.

Research has shown that a number of processes (including methylation) which are critical to the normal development and growth of cells, are also involved in controlling epigenetic mechanisms. Methylation is of particular interest because we know folate plays an essential role in one-carbon transfer involving re-methylation of amino acids homocysteine to methionine, thereby ensuring the provision of S-AdenosylMethionine (SAMe), the primary methyl group donor for most biological methylation reactions. That is, folate-rich foods, and as a result SAMe, play a crucial role in the expression of our genes.

Epigenetic changes are not only influenced by our exposure to chemicals and our dietary habits. Studies in rats have shown that licking, grooming and nursing behaviour by the mother can affect the long-term behaviour of her offspring, and can be directly linked to epigenetics in a certain part of the pup's brain, the hippocampus.

Despite the importance of epigenetics, as shown by these studies, there are still huge disparities in funding research - vast sums of money are available for genetic disease research with relatively trifling amounts provided for research into the role of epigenetics and the environment. There is currently a five million dollar, five year grant available from the National Human Genome Research Institute and the National Institute for Mental Health to encourage researchers to develop the tools needed to systematically examine epigenetics and its effects on autism and bipolar disorders. This is only a beginning, and a much broader approach across a much wider spectrum of fields is needed.

Looking at epigenetics from a more personal perspective, we can see that its implications underline the need to eat nutrient-rich foods all our lives - lots more vegetables, fruit, pulses and nuts, as well as avoiding those synthetic chemicals on the supermarket shelves. It should also be causing concern for the regulators, as it raises a whole new set of potential causes of cancer and other diseases they haven't considered. When next you hear about another gene "miracle discovery" linked to cancer or some other disease, just remember, we all have these genes; it is whether or not they are activated that counts, and we have a lot of control over that.

Peter Dingle

Dr Peter Dingle (PhD) has spent the past 30 years as a researcher, educator, author and advocate for a common sense approach to health and wellbeing. He has a PhD in the field of environmental toxicology and is not a medical doctor. He is Australia’s leading motivational health speaker and has 14 books in publication.