Growing pains for field of epigenetics as some call for overhaul

Our genes are not just naked stretches of DNA.

They're coiled into intricate three-dimensional tangles, their lengths decorated with tiny molecular "caps." These so-called epigenetic marks are crucial to the workings of the genome: They can silence some genes and activate others.

Criticism of these epigenetic studies has been growing. Credit: John Hersey/New York Times

Epigenetic marks are crucial for our development. Among other functions, they direct a single egg to produce the many cell types, including blood and brain cells, in our bodies. But some high-profile studies have recently suggested something more: that the environment can change your epigenetic marks later in life, and that those changes can have long-lasting effects on health.

In May, Duke University researchers claimed that epigenetics could explain why people who grow up poor are at greater risk of depression as adults. Even more provocative studies suggest that when epigenetic marks change, people can pass them to their children, reprogramming their genes.

But criticism of these studies has been growing. Some researchers argue that the experiments have been weakly designed: Very often, they say, it's impossible for scientists to confirm that epigenetics is responsible for the effects they see.

Three prominent researchers recently outlined their scepticism in detail in the journal PLoS Genetics. The field, they say, needs an overhaul.

"We need to get drunk, go home, have a bit of a cry, and then do something about it tomorrow," said John Greally, one of the authors and an epigenetics expert at the Albert Einstein College of Medicine in New York.

Among other criticisms, he and his co-authors - Ewan Birney of the European Bioinformatics Institute and George Davey Smith of the MRC Integrative Epidemiology Unit at the University of Bristol in England - argue that in some cases, changes to epigenetic marks don't cause disease, but are merely consequences of disease.

Some studies, for example, have found that people with a high body mass index have unusual epigenetic marks on a gene called HIF3A. Some researchers have suggested that those marks change how HIF3A functions, perhaps reprogramming fat cells to store more fat.

If that were true, then drugs that reverse these changes might be able to help obese people lose weight. But Smith and his colleagues have found that overweight subjects experienced epigenetic changes to HIF3A only after they put on weight.

James Flanagan, a senior lecturer at Imperial College London, agreed with Smith and his co-authors that tracking epigenetic changes over time can be revealing. "It's the best way to go about it," he said.

But these experiments are especially hard to set up, he noted, because scientists have to gather blood or other genetic samples from healthy people and then wait years for some of them to get sick.

In other cases, apparent changes in epigenetic marks may actually be the result of different kinds of cells becoming more or less common in people, Greally and his colleagues also warned. "That's where things get hairy," Greally said.

Smoking, for example, triggers a boom in immature blood cells, which carry epigenetic marks different from those of other cell types in the blood.

Rafael Irizarry, an applied statistician at Dana-Farber Cancer Centre and the Harvard School of Public Health, said new methods could help researchers steer clear of this confusion.

Scientists can sort cells into different types before looking at their epigenetic marks, he said. It's even becoming possible to look at the epigenetics of one cell at a time.

"But it makes the process way more expensive," Irizarry said.

Greally and his colleagues note another source of confusion: Normal genetic variation leads some people to produce different epigenetic marks than others.

If researchers were to find that alcoholics carry an unusual epigenetic mark, for instance, that wouldn't necessarily mean that it resulted from heavy drinking. These people may have a genetic variation that puts them at risk of alcoholism and, perhaps coincidentally, creates an unusual epigenetic mark on their DNA.

Greally said these possibilities have been neglected because scientists have been so captivated by the idea that epigenetic marks can reprogram cells.

"Since you don't talk about anything else, you interpret the results solely through that little sliver of possibility," he said.

He and his colleagues go so far as to claim that no published results on the links between epigenetic marks and disease "can be said to be fully interpretable."

Other experts feel that such an indictment is a bit too broad. Flanagan pointed to several recent studies in which scientists confronted the very challenges Greally and his colleagues wrote about. Last year, for example, a team of European scientists investigated how smoking causes lung cancer. They took advantage of large-scale studies in Australia, Norway and Sweden that collected blood from tens of thousands of people and tracked their health for years.

The scientists found that smokers who got lung cancer tended to lose the same epigenetic marks on a pair of genes.

Greally said that genetic variations the smokers were born with might account for the results. "That's not tested in the study," he said. "It could definitely be the case."

Nevertheless, he added, these reports offer some good starting points for bigger studies in the future.

"There's nothing wrong with an exploratory study, but call it an exploratory study and acknowledge the fact that it may merely be reporting noise," Greally said.

"If you say, 'Look, I'm finding something that's intriguing here,' that's legit."

The New York Times