Breaking the bonds of genetic destiny

The conventional view of genetics is steeped in fatalism. We inherit a unique genetic code from our parents and, for better or worse, this DNA is unalterable. Some diseases run through families like prairie fires — inevitable and unstoppable. High blood pressure, cancer, dementia — inextricably woven into familial double helixes like barbed wire.

Researcher Moshe Szyf and his contribution to Epigenetics
Researcher Moshe Szyf
But what if that thrice-a-week aerobics class and those four-a-day helpings of vegetables that we force upon ourselves do more than just postpone the inevitable? What if, on top of the immediate health benefits, both activities actually modify the expression of our DNA, deactivating the troublesome genes that trip us up and send us stumbling down the path toward cardiovascular disease or Alzheimer's? And imagine if, in so altering that genetic expression, we were able to pass on to our offspring a genetic code that was finally free and clear of the monster lurking in the shadows.

These are among the questions McGill pharmacology professor Moshe Szyf has been asking for 30 years. His pioneering research has proven that although our DNA is pretty much locked and loaded upon conception, exposure to such external factors as toxins and nutrients can precipitate a chemical reaction within our body that can permanently alter the way our genes react. Once triggered, a group of molecules called a methyl group will attach itself to the control centre of a gene, switching it off completely — changing gene function without changing the DNA sequence. Welcome to the world of epigenetics.

Scientific evidence suggests that this environmentally triggered gene expression, or epigenetic imprint, might have repercussions far beyond the immediate host body. This could explain why underweight babies born to malnourished Dutch women during World War II grew up to give birth to underweight children decades after the war and food rationing had ended. Recent studies have demonstrated that the sons of men who began smoking before reaching puberty were more prone to obesity. Clearly, the epigenetic change that took place in both original groups of parents had lastingly adverse effects on subsequent generations. "The trick," says Szyf, "is to be able to control what you activate and deactivate."

As Szyf sees it, if environmental exposure can trigger a chemical change in genes that results in the onset of disease, perhaps researchers can pharmacologically manipulate the same mechanisms in order to reverse the disease. For example, in certain types of cancer, the gene that normally inhibits the growth of tumours is shut down while other genes which promote metastasis, or the spread of cancer, are turned on. Szyf's team is currently testing a pair of cancer drugs that would reactivate this dormant gene as well as drugs that would silence metastatic genes.

Well-groomed rats are happy rats

Researcher Michael Meaney and his contribution to Epigenetics
Michael Meaney, associate director of research at Douglas Hospital
In 2003, Szyf and Michael Meaney, associate director of research at the Douglas Hospital, found that young rats who received a healthy dose of maternal licking and grooming as pups developed into much calmer adults than their less-groomed counterparts. Of course, this in itself is nothing earth shattering - it has long been understood that maternal care has a lasting impact on the development of an individual. "The question then becomes why the change in behaviour?" says Meaney.

Meaney demonstrated that the maternal licking stimulated a chemical change in the glucocortoid receptor in the brain, the very mechanism that regulates how much stress hormone is released by the rats' adrenal glands. The less grooming a rat pup received, the more stress hormones it produced in adulthood.

By administering methionine, an essential amino acid, to the brains of well-adjusted rats, Szyf was able to change the expression of their respective glucocortoid receptors so that they mirrored those of their less nurtured cousins. The result? Production of stress hormones increased and formerly laid back rodents became decidedly more frazzled. Similarly, the McGill team was able to reduce the levels of the same hormones in anxious rats by pharmacologically manipulating the same gene responsible for their production. The implications of these findings are enormous, suggesting that similar interactions could be used to combat the ravages of depression, schizophrenia and other brain disorders.

Med schools revamped

Although creating new drugs for diseases is exciting, the potential of epigenetics extends beyond the pharmacy. "Of course we can think in terms of developing drugs that will produce these effects," says Meaney. "But if the initial effect was laid down in response to social stimulus, is there then a possibility that some sort of social experience might be able to reverse the process?"

In a country propping up an increasingly fragile health care system, epigenetics may force politicians to rethink their economics. Although the field is still developing, evidence is being accumulated that points to the fact that a variety of diverse social and environmental factors such as nutrition, pollutants, housing and childcare will have a significant impact on the health of Canadians now and in the generations to come. "If we really want to strengthen our economy and the health and performance of the individuals within that economy, then we need to focus on early development and the quality of family life," says Meaney.

Perhaps the most radical development that could come about as a result of epigenetic research is the way medicine is taught. Med schools will be required to open their curriculum to include more arts and humanities and interdisciplinary collaboration will be increasingly de rigueur. Abe Fuks, Dean of Medicine, sees the work being done by Szyf the pharmacologist and Meaney the psychologist as emblematic of the new direction of research - a direction that the university has been heading for some time now. "One of McGill's great strengths has always been its ability to combine exceptionally high standards of research with this type of openness and collegiality," he says "This is a wonderful example for others to follow."

This story originally appeared in the McGill Reporter.

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