Twins tackle puzzle of gene change

 

Could what your grandmother ate while she was pregnant with your mother be affecting your health? Scientists think so, Lynnette Hoffman reports.

 

Identical twins Imogen and Tennille Purton grew up in the same outer western suburb of Melbourne. They were both breast-fed for more than two years. They took swimming lessons together and attended the same child care centre.

But just days before their 5th birthday Imogen began to feel achy and pale; she had a fever and became vague and lethargic. Six weeks and two lots of antibiotics later, Imogen was still unwell, but Tennille didn’t seem to have caught the illness.
That’s when doctors sent Imogen for a blood test and subsequently diagnosed her with leukemia. She started intense treatment the very next day.

Meanwhile Tennille’s blood test showed no signs of any problems. So how do two little girls with identical DNA who grew up in almost exactly the same environment end up in such polarized circumstances?

Researchers say the answer may lie in epigenetics— a term that describes genetic changes that don’t involve mutations to the DNA sequence.  What’s more, the diseases a person develops are influenced not only by the DNA code in their genes, but also by the amount of activity in each gene.

In other words, genes have a metaphorical "dimmer switch" beside them that can turn the gene up or down, or on or off. Diet, smoking, exposure to toxins and chemicals and other environmental factors have the potential to activate or deactivate genes, and the changes can be inherited across generations.

"Every egg that a woman has is developed in her ovary while she is still in utero. Therefore, your individual health is potentially dependent on the lifestyle and diet of your grandmother while she was pregnant with your mother," says Dr Richard Saffery, a researcher at the Murdoch Childrens Research Institute Epigenetic Laboratory in Melbourne.

Factors such as the amount of nutrients a baby gets in the womb could impact the epigenetic state of their cells.

Last year when Spanish researchers looked at 40 pairs of identical twins who ranged in age from 3 to 74, they found the genes in the younger twins were expressed in almost exactly the same way, while the way genes were expressed in older twins was “extremely different.” The differences were more distinct in twins who had spent more time apart or had greater differences in their lifestyles (PNAS 2005;102(30):10604-10609).

To that end a great deal of research has looked at ways lifestyle factors may be affecting epigenetics—for example smoking is well known to have damaging effects on the smoker’s health, but it seems the habit can affect even unconceived offspring.

A study published in the European Journal of Human Genetics found that 9-year-old boys whose fathers had begun smoking in their pre-teens had significantly higher body mass index—a measure of body fat— than those whose fathers had either never smoked or hadn’t started until they were at least 16 (2006;14: 159–166).

But understanding epigenetics may have wider ramifications than explaining ‘unsolved mysteries’.

“Epigenetic markers,” such as a chemical change to genes called methylation, have been linked with a number of rare diseases and cancers that are typically difficult to diagnose and treat.

It’s for that reason that governments around the globe have begun to make research into epigenetics a higher priority.

In 2004 the European Union allocated 12.5 million pounds to set up the Epigenome Network of Excellence—a collaboration of established and new research groups and research associates from 10 countries— with a mandate to “advance epigenetic research” through 2009.

The US is initiating a similar effort. Meanwhile the Korea Human Epigenome Research Center is set to launch in early 2007 and will form a consortium with epigenome research teams in Japan and China.

On the homefront, the National Health and Medical Research Council has spent $5.8 million on research into epigenetics since 2000, covering diseases such as cancer, cardiovascular disease, diabetes, asthma, arthritis and inflammatory and autoimmune diseases. The funding has increased each year but researchers at Melbourne’s Murdoch Childrens Research Institute and the Garvan Institute of Medical Research in Sydney say it’s a trickle in comparison to what other countries are doing.

“There’s been a huge increase in funding and research internationally, but we haven’t gotten anything like that in Australia. In Australia there has been no special initiative or dedicated funding,” says associate professor Sue Clark, an epigenetics researcher at the Garvan Institute.  

“Japan, China and Korea have all made epigenetics research a special part of their scientific agenda. But we’re very much at the tip of the iceberg in Australia—we have the expertise here—for example we developed a new technique that allows us to analyze the epigenome, but there’s not as much resources dedicated as other countries have.”

One reason for the hope in the research is that epigenetic changes differ from changes to DNA code in an important way: they’re reversible. If they’re just left on their own the epigenetic changes are generally stable, which is why they can be transferred from one generation to the next.

“But if you push them,” either through major environmental changes or medication, you can change the expression of the gene, says Jeff Craig, also a researcher at Murdoch Childrens Research Institute Epigenetic Laboratory.)

Last year researchers found they could predict the likelihood of tumors recurring in patients with low-grade prostate cancer by looking at changes in patterns on histones (proteins that bind to DNA), regardless of other predictors such as the stage of the tumor (Nature 2005:435(7046);1172). But the implications of the epigenetic link stretch beyond predicting prognosis.

Currently if your doctor suspects you may have prostate cancer he or she will test your levels of prostate-specific antigens. If they’re high you may have cancer—but it may also be the result of a prostate infection, damaged blood supply or other problems. And unfortunately there’s no easy way to find out without invasive and sometimes risky tests, Clark says.

A number of other cancers such as ovarian or pancreatic cancer are rarely diagnosed until they’ve reached advanced stages, Clark says.  

“There are no good tests, and by the time we detect the symptoms it’s really too late,” she says.

But experts say that could change as researchers develop diagnostic tests to look for epigenetic markers.

Cancers don’t happen overnight and changes in activity in genes occur in the early stages, even before the cancer has begun developing, so diagnostic tests designed to pick up on those changes could have a big impact on survival rates and prevention.

A study by the Garvan Institute found that in colon cancer cases large regions of DNA that contain genes that normally work to prevent tumors were “switched off.”

“Our cells become cancerous when the normal controls over cell growth and death go awry,” Clark says.

In the past scientists thought that only happened because of DNA mutations of single genes or sections of chromosome being deleted.  But DNA methylation also causes “gene silencing”—even genes that haven’t actually gone through the chemical change, but happen to be near others that have, also become switched off in colon cancer. “It’s a case of being in the wrong neighbourhood at the wrong time,” Clark says.

Current cancer treatments such as chemotherapy work by stopping cells from dividing— but they can’t differentiate between cancer cells and healthy cells, so they kill or damage both.

In America the Food and Drug Administration has approved clinical trials of at least two drugs designed to inhibit the chemical changes that switch off the genes that suppress tumors and return the genes to their normal state.

Ideally that would mean the treatment would be far less toxic than chemotherapy and therefore have fewer side effects, says professor Emma Whitelaw, head of the epigenetics lab at the Queensland Institute of Medical Research.

Whitelaw says there’s still a long way to go before epigenetic therapy produces the ‘miracle drugs’ some researchers are predicting.

Scientists are still trying to determine exactly how different epigenetic changes will affect people’s health, and develop ways to target only the “problem” genes. Studies on drugs being tested so far have found they can turn on hundreds of genes that should be off, and vice versa, which can lead to serious side effects, Whitelaw says.

“The technology we have is very crude right now,” she says.

 

Epigenetics 101

 

 

Code Breakers

 

Research funding for Epigenetics      

  
2000        $176,720           Actual Expenditure        3 grant
2001        $409,421           Actual Expenditure        5 grant
2002        $556,913           Actual Expenditure        6 grant
2003        $683,266           Actual Expenditure        5 grant
2004        $665,251           Actual Expenditure        6 grants
2005        $1,618,393        Actual Expenditure        11 grants
2006        $1,691,033        Forecast Expenditure    16 grants
Total        $5,800,997

 

Source: NHMRC

 

First published The Australian, October 7-8 2006.