Monday, October 15, 2012
It’s Not All in the Genes: The Science of EPIGENETICS
In 1953, James D. Watson and Francis Crick proposed the concept of the double helix as the structure of DNA. With this finding, the fields of genetics and biology experienced a monumental shift: seemingly, scientists had finally discovered why we are who we are. The quest began to isolate DNA and map the entire human genome. However, after spending billions and maybe even a trillion dollars unravelling the human genome, researchers have come to the realisation that it is not all in the genes. In recent years, a new idea has come to the forefront of genetics and is the focus of thousands of studies: epigenetics.
Genetic determinism—that is, the notion that “it’s all in the genes,” that everything is determined by our DNA and that we are victims of our hereditary—has been programmed into us since our first high school science lessons. This concept is disseminated by the media and even further propagated in medical school. If one gets a disease, it is deemed “genetic.” However, only a very few diseases—such as Huntington’s chorea, beta thalassemia and cystic fibrosis—can be blamed entirely on one faulty gene. These single-gene diseases affect less than two percent of the population 1. It is estimated that only five percent of diseases are a direct result of gene mutations; the rest are a result of environmental (about which I have written extensively and coined a term, “the DEAL—Diet, Environment, Attitude and Lifestyle”) influences 2. It is now theorised that Alzheimer’s disease, cancers, cardiovascular disease, asthma, autoimmune diseases such as lupus and conditions such as schizophrenia are linked to epigenetic triggers 3. The vast majority of diseases that afflict us today are a result of complex interactions between genes and the environment. Classic genetics alone cannot explain the diversity of disease characteristics in society.
It is true that genes may have an association with a disease, but this does not prove causation. The genes may be related to a disease but are not directing or causing it. Long ago, biologist Jean-Baptiste Lamarck was ridiculed because of his evolutionary ideas when he proposed that the environment, including our diet, can influence our genes. Now science has caught up with Lamarck’s hypothesis. Even Darwin recognized environmental factors outside the hereditary material but that has largely been ignored until now.
Perhaps we need to look at our genes differently. In his book, The Greatest Show on Earth, Richard Dawkins (2009) suggests that our DNA is not a blueprint like that used to build a house, but is in fact a broad recipe from which certain outcomes arise. Tissues and bodily structures are not formed according to set plans or blueprints contained in our DNA, but self-assemble responding to environmental [local] conditions and the laws of chemistry.
Epigenetics provides the missing link between the environment and the development of disease. It goes beyond many of the subtle changes in DNA that explain only a fraction of the diseases humans develop. For the first time since DNA was discovered, epigenetics has encouraged scientists to move from genetic determinism to studying how the environment can shape our lives. Previously, it was believed that DNA would determine the makeup of the person—his or her predisposition to disease, hair colour, metabolic rate, etc. However, not only is “nurture” becoming more significant than “nature,” but also there is a transgenerational property to epigenetics: genes can be turned on and off, and those changes can be passed on for generations 4.
It appears that genes are not our destiny. It is environmental signals that activate the expression of the gene. Environmental factors are capable of causing epigenetic changes in DNA that can potentially alter gene expression and result in genetic diseases, including cancer and behavioural disorders. Environmental influences including nutrition, behaviour, stress, chemicals, radiation and emotions can change how the genes are expressed and can silence or activate a gene without altering the genetic code in any way. These are changes in gene expression that occur without a change in DNA sequence.
Known or suspected culprits behind negative epigenetic changes include agents such as heavy metals, pesticides, plastic compounds including BPA, diesel exhaust, tobacco smoke, polycyclic aromatic hydrocarbons, hormones, radioactivity, viruses, bacteria and deficiencies in basic nutrients. Each nutrient, each interaction, each experience can therefore manifest itself through biochemical changes, which may have effects at birth or 40 years down the track. These epigenetic changes often occur at foetal or embryonic levels, but they set the stage for an adult’s susceptibility to a host of diseases and behavioural responses. There are certain periods of an organism’s life during which it is more susceptible to methylation and epigenetic changes—including gestation, neonatal growth, puberty and old age—but the period in which an organism is most likely affected by methylation is during the formation of the embryo 5.
Detractors have largely ignored epigenetics, and in fact harshly criticised early studies, including one in which researchers used supplements to offset the results of a particular gene in mice. Researchers fed pregnant mice, all of which had an abnormal “agouti” gene, methyl-rich supplements, folic acid, B12, betaine and choline and, as a result, changed the binding characteristics of the regulatory chromosomal proteins. Agouti mice have yellow coats and are extremely obese, which predisposes them to cardiovascular disease, diabetes and cancer 6,7. The pregnant mice that were given the supplements produced standard lean, healthy offspring that lived longer and weighed half that of the yellow agouti mice, even though they still had the agouti gene. These observations suggest, at least in this special case, that maternal dietary supplementation may positively affect health and longevity of offspring.
The research also shows that the epigenetic effects might go on for a number of generations; a disease you are suffering today could be a result of your great-grandmother being exposed to an environmental toxin during pregnancy. Researchers exposed pregnant rats to environmental toxins during the period that the sex of their offspring was being determined. The compounds—vinclozolin, a fungicide commonly used in vineyards, and methoxychlor. Pregnant rats exposed to these chemicals produced male offspring with low sperm counts and low fertility. Those males were still able to produce offspring, however even when they were mated with females that had not been exposed to the toxins, their male offspring had the same problems of low sperm counts and low fertility. The effect persisted through all four generations tested, with more than 90% of the male offspring in each generation affected with no additional pesticide exposures 8. The findings provide a new paradigm for disease etiology and basic mechanisms in toxicology and evolution not previously appreciated.
One study found that over-eating during the SGP (slow growth period of the teen years) by male grandparents led to a higher rate of diabetes and cardiovascular disease in their grandchildren 9. All the results indicated that these potential epigenetic traits were passed down through the male gene line 10. In a later study 11, researchers also induced these alterations through maternal ingestion of genistein, the major phytoestrogen in soy, at doses comparable to those a human might receive from a high-soy diet, and found that they may also cause health problems, via additive or synergistic effects on DNA methylation, when it interacts with other substances such as folic acid. Through these and subsequent studies, it has been revealed that both the mother’s and father’s diets and environment during pregnancy and childhood, respectively, are of paramount importance to the epigenome and development of the offspring 12.
Studies have found that epigenetic effects occur not just in the womb, but also over the full course of a human life span. In a study of 40 pairs of identical twins, ranging in age from three to 74, twins were epigenetically indistinguishable during the early years of life, while older monozygous (identical) twins exhibited remarkable differences in their overall content and genomic distribution of 5-methylcytosine DNA and histone acetylation, affecting their gene-expression portrait. That is, younger twin pairs and those who shared similar lifestyles and spent more years together had very similar DNA methylation and histone acetylation patterns. But older twins, especially those who had different lifestyles and had spent fewer years of their lives together, had markedly different patterns in many different tissues, such as lymphocytes, epithelial mouth cells, intra-abdominal fat and selected muscles 13. As one 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, and the 50-year-old twins with more DNA hypomethylation and histone hyperacetylation (the epigenetic changes usually associated with transcriptional activity) had the higher number of over-expressed genes. The degree of epigenetic change therefore was directly linked with the degree of change in genetic function 13.
Numerous studies have linked epigenetic factors to cancers of almost all types, genetic disorders and paediatric syndromes as well as contributing factors in autoimmune diseases, cognitive dysfunction, reproductive, autoimmune, respiratory disease, neurobehavioral illnesses, mental retardation and aging 14,15. The expression and activity of enzymes that regulate these epigenetic modifications have been reported to be abnormal in the airways of patients with respiratory disease 15.
While epigenetic changes can lead to an increase in diseases it now puts us in control. Not only can we avoid so many diseases that were once thought of as in our genes but research is showing by changing our diet and lifestyle we can also reverse many of these conditions.
1. Lipton 2005
2. Willet 2002
3. Esteller 2008
4. Anway et al. 2005
5. Dolinoy et al. 2007
6. Wolff et al. 1998
7. Waterland and Jirtle 2003
8. Skinner et al. 2005
9. Kaati et al. 2002
10. Kaati et al. 2007
11. Jirtle, April 2006,
12. Morgan et al. 2008
13. Fraga et al 2005
14. Weinhold 2005
15. Adcock et al. 2006