Is our health, over a whole lifespan, primarily determined by our genes or principally conditioned by our living habits and social environment? This debate has gone on for more than a century and has been particularly sharp when the causation of heart diseases, diabetes and cancers is discussed.
About 12 years ago, I was invited to speak at an elite gathering of Indian scientists drawn from diverse disciplines. Asked to profile the growing problem of coronary heart disease (heart attacks) in the Indian population, I described the growing magnitude of the disease as well as the varied levels of associated risk factors in urban and rural populations. I suggested that public health action must focus on the promotion of healthy diets, regular physical activity and avoidance of tobacco while health services must pay attention to early detection and effective treatment of high blood pressure and diabetes to reduce the risk of heart attacks.
In the discussion that followed, leading molecular biologists and biotechnologists faulted me for not identifying genes as a principal contributor to heart attacks, despite very little evidence available at that time to consistently link one or more genes to the risk of heart attacks in Indian or other populations. The disease was considered, at best, a polygenic disorder in which several (as yet unidentified) genes could contribute to susceptibility, which would be expressed only when triggered by environmental factors such as living habits.
In western populations, coronary mortality rates rose steeply and then declined substantially, all in the 20th century. In India, coronary disease rates have risen over the past three decades but still show sharp differences between urban and rural areas. Gene pool changes could not have occurred in these populations, in such a short time, to explain these variations. Further, the risk posed by blood pressure or cholesterol to heart attacks rises incrementally with their levels across a very wide range. The risk is, therefore, spread across the majority of the population and is not confined to a small segment which can be identified by genetic screening.
This explanation did not carry conviction with gene believers, who predominated that gathering. A leading scientist opined that individuals who are genetically predisposed to heart attacks must be identified by genetic screening and only they should be advised a healthy diet. Everyone else should be spared that advice, he said, declaring that personalised health care and prevention based on gene profiling were the future of medicine.
His faith, as of many other scientists, was based on the belief that the Human Genome project would unravel all the genes and enable the linking of different diseases to different genes. Indeed, Francis Collins, who headed the project in the United States at that time, called it “the most important and the most significant project that humankind has ever mounted” and predicted that “it would quickly allow everyone to know the genetic risks for many diseases.”
Where are we now? Reporting on the recent appointment of Dr. Collins as the Director of the National Institutes of Health in the U.S., the New York Times wrote: “Although Dr. Collins was widely praised in 2003 when the effort [Human Genome Project] succeeded, the hopes that this discovery would yield an array of promising medical interventions have greatly dimmed, discouraging many” (July 8, 2009).
Indeed, much of the irrational exuberance associated with the expectation of disease associations with the human genome has subsided, while the undoubted value it brings to the study of life and even the potential for creation of life is recognised and respected. It also offers the potential for several gene directed therapies. Herceptin, which modifies the HER2 gene in a subset of breast cancer, is an example. While genes that have gone awry can possibly be fixed through such scientific advances, the facile assumption that all diseases originate in predetermined genetic patterns yielded to the recognition of gene-environmental interactions as pathways of causation, in many of which the acquired living habits may play a dominant role.
It is in this context that the recently opened up field of epigenetics assumes considerable importance. In 1996, David Allis and Stuart Schreiber described two mechanisms by which gene expression could be modified by chemical alterations in the ‘packaging’ of DNA. These ‘epimutations’ resulting in the alteration of chemicals atop the DNA can turn genes on or off inappropriately, with undesirable consequences. The principal chemical pathways of epigenetic modification are the DNA methylation and histone modification through acetylation, methylation or phosphorylation. RNA-mediated gene silencing is a third mechanism.
Such epigenetic switches play a useful role in guiding developmental transitions during pregnancy, early childhood and puberty. Interestingly, epigenetic modifications can also be triggered by environmental factors such as maternal stress, childhood diet, infection and smoking. The epigenetic effects of our living habits, such as diet and smoking, may lead to disease by disrupting orderly gene function and expression. The culprit in such a case is not the gene, which is normal to begin with, but the environmental exposure which alters its nature and function. Genetic screening in childhood will hardly help to prevent such diseases but giving a healthy diet to a child and preventing an adolescent from smoking will greatly help to reduce the risk of disease.
The concept of developmental plasticity has been gaining greater credence in recent years. The ability of body systems to adapt to environmental challenges, in the womb or during childhood, is increasingly acknowledged. Epigenetic modification of gene function may be a major pathway for such plasticity. Though epigenetic influences have been mostly studied in early life, epigenetic lability could extend across life. Studies on genetically identical twins have demonstrated an association between epigenetic differences and diseases manifesting in later life. Epigenetic modifications can also be transmitted across generations, to children and grandchildren. This occurs without a change in the DNA sequence. Whether such ‘epigenetic imprinting’ is carried across several generations, as an ancestral legacy which helps to cope with certain environmental exposures is under investigation.
Epimutations have been implicated in a diverse set of diseases such as cancer, schizophrenia, bipolar disorder, autism and systemic lupus erythematosus. Research by Waterland and Jirtle suggests that nutrition before and after birth can impact adult predisposition to cardiovascular disease, diabetes and cancer. As Andrew Feinberg remarked epigenetics is now “at the epicentre of modern medicine.” New cancer therapies are emerging which aim to induce or counter epigenetic changes to control cancer growth.
The field of epigenetics is still very young, but the implications are profound. While the term ‘gene-environmental’ interaction was previously interpreted to mean that persons with differing gene profiles may respond variably to an environmental change, it now also means that an environmental agent (such as diet, smoking or toxic chemicals) may alter gene expression and lead to differences of risk levels in people who have similar gene profiles. An Institute of Medicine Report (U.S. National Academies, 2006) titled “Genes, Behaviour and the Social Environment: Moving Beyond the Nature-Nurture Debate” calls for inter-disciplinary research to explore the interactions among these multiple determinants of health.
Till more knowledge accrues in this field, we have to be guided by the knowledge that diseases such as heart attacks, adult onset of diabetes and several cancers have been consistently associated with non-genetic factors such as food habits and tobacco use. Modifying these exposures has reduced the risk of these diseases in individuals and brought down the rates of disease and death. While new knowledge should be avidly sought to explain the mechanisms of disease causation, wisdom lies in utilising the information we already have on the agents that initiate the process. Now that epigenetics has lit up the path of gene-environmental interactions, I hope this rational position would be acceptable to even the most ardent of gene proponents.
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