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How epigenetics is changing our fight with disease

Sequencing the human genome was supposed to answer our questions about the genetic origins of disease but the burgeoning science of epigenetics is telling us it's a whole lot more complicated.

Decoding the human genome was supposed to answer all our questions about the genetic origins of disease.

But six years after the complete genome was sequenced, more evidence than ever suggests it's not just our genes that affect our susceptibility to disease but also our environment. In our battle against disease could we be fighting the wrong adversary?

Epigenetics is the science that describes all modifications to genes other than changes to the DNA sequence itself. Epigenetic marks can switch particular genes 'on' or 'off', and this process can have major implications for health.

Although epigenetics is a normal part of human development, things can go badly wrong when the marks switch off genes that we need to remain healthy, such as those that fight cancer or regulate our metabolism.

While we don't yet fully understand how or why most of the marks operate, scientists believe they are often a response to environmental factors, particularly those we were exposed to in the womb, such as our mother's diet or her exposure to toxins or diseases.

With research suggesting a role for epigenetics in conditions as varied as asthma and schizophrenia, some experts believe epigenetic changes may turn out to play an even bigger role in human health than our actual genes.

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Epigenetics and our genes

Our genes are like the instruments in an orchestra, says Dr Jeff Craig, a researcher in developmental epigenetics and disease from the Murdoch Childrens Research Institute in Melbourne.

The particular combination of instruments — the DNA — we inherit from our parents determines the kind of music that can be played.

But the thing that's missing from this picture is the musicians, Craig says.

Just as the instruments remain lifeless until somebody plays them, our genes need to be 'played' by the series of molecular changes known as epigenetics.

"Epigenetic marks are molecular beacons that land on the DNA and turn genes on or off," explains Craig, who is looking for such marks in childhood leukaemia in the hope this will lead to better diagnostic tests and more targeted therapies.

While the particular genes we carry can influence our susceptibility to a certain disease, whether we get the disease will often depend on whether those genes are switched on or off.

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Cancer at the forefront

The first disease to be studied epigenetically was cancer and it is still the best understood.

Earlier this year, scientists at Sydney's Garvan Institute announced they had identified one epigenetic process that appeared to be implicated in breast cancer.

When researchers compared normal and malignant cells, they found the cancer-fighting gene, P16, had been switched off in the malignant cells through a process called DNA methylation, where molecules are added to the DNA backbone affecting its function.

By monitoring methylation changes in very early stages of breast cancer, the group hopes to develop a set of markers that will indicate which women are at risk of going on to develop invasive cancer, helping with decisions about how aggressively an individual cancer should be treated.

Even more exciting is the prospect that it might be possible to reverse the epigenetic changes leading to a range of cancers, says Professor Susan Clark, who heads the Garvan's epigenetics research group.

"With genetics, you can't actually fix it, whereas with an epigenetic change it is potentially reversible," she says.

"The dream of every cancer researcher is that one day we will be able to turn off the cancer switch."

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Miracle cures?

For his part, Craig believes epigenetics may ultimately hold the clue to understanding how a very small number of cancer patients experience 'miracle cures', leaving doctors mystified by the complete disappearance of a tumour.

It may be these patients' tumour suppressor genes have somehow become reactivated after initially being switched off by epigenetic marks, he says, allowing their bodies to fight and defeat the cancer.

We are trying to mimic that process," he says of the research into childhood leukaemia he is conducting with colleagues from Melbourne's Royal Children's Hospital and Peter McCallum Cancer Centre.

The group is already using drugs designed to reverse epigenetic marks, such as DNA methylation inhibitors, although these are still pretty "blunt instruments", Craig says.

The challenge now is to develop drugs that will act only on the relevant genes in cancer cells, rather than system-wide.

The researchers are also mapping the epigenetic variability or epigenome in children with leukaemia.

Monitoring epigenetic changes in these children will give doctors access to markers that can predict the progression of the disease and determine which treatments are most likely to be successful in a particular child, Craig says.

"Cancer treatments are pretty toxic," he says. "So, if we can say this kid's more likely to respond to drug x or drug y, it could save a lot of suffering."

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Environmental effects

So, how do the epigenetic marks come to be placed on our genes and can they, as has often been reported, be passed from one generation to the next?

Dr Catherine Suter, who heads the epigenetics laboratory at Sydney's Victor Chang Cardiac Research Institute, is one researcher attempting to answer these questions.

Her work with groups of genetically identical mice has shown that changing the diet of pregnant females causes epigenetic changes in the offspring that dramatically affect their future health.

When the mothers were given a protein-restricted diet, for example, their offspring experienced epigenetic changes that interfered with satiety signals, the brain's ability to know when the stomach is full. The baby mice overate, became fat and went on to develop diabetes.

However the process could be interrupted by feeding the baby mice a combination of micronutrients, including vitamin B12 and folate.

Although Suter believes the causes of diabetes in humans are likely to rely on a complex interplay of genetic and epigenetic factors, this is an exciting finding in the long-term search for a cure.

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An evolutionary challenge

The implications of epigenetics may be even bigger than the potential to find cures for intractable diseases, Suter says.

As our understanding of the science improves, it may require us to rewrite the theory of evolution itself to include a role for environmental effects.

The epigenetic changes in Suter's mice have been found to persist through at least two generations, with her current research aiming to show whether they can continue to be passed on beyond that.

It is even possible that epigenetics could make the process of evolution more responsive to environmental challenges, she says.

"It is plausible that natural selection could act on environmentally-induced epigenetic changes," Suter says. "If the environment turns off certain genes, that could make them more vulnerable to mutation."

And so the dance between genetics and epigenetics continues.

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