Dutch genes still bear scars of a famine


In September 1944, trains in the Netherlands ground to a halt. Dutch railway workers were hoping that a strike could stop the transport of Nazi troops, helping the advancing Allied forces.

But the Allied campaign failed, and the Nazis punished the Netherlands by blocking food supplies, plunging much of the country into famine. By the time the Netherlands was liberated in May 1945, more than 20,000 people had died of starvation.

The Dutch Hunger Winter has proved unique in unexpected ways. Because it started and ended so abruptly, it has served as an unplanned experiment in human health. Pregnant women, it turns out, were uniquely vulnerable, and the children they gave birth to have been influenced by famine throughout their lives.

When they became adults, they ended up a few pounds heavier than average. In middle age, they had higher levels of triglycerides and LDL cholesterol. They also experienced higher rates of such conditions as obesity, diabetes and schizophrenia.

By the time they reached old age, those risks had taken a measurable toll, according to the research of L.H. Lumey, an epidemiologist at Columbia University. In 2013, he and his colleagues reviewed death records of hundreds of thousands of Dutch people born in the mid-1940s.

They found that the people who had been in utero during the famine — known as the Dutch Hunger Winter cohort — died at a higher rate than people born before or afterward. “We found a 10 percent increase in mortality after 68 years,” said Lumey.

The patterns that Lumey and his colleagues documented are not disputed, but scientists still are struggling to understand how they come about.

“How on earth can your body remember the environment it was exposed to in the womb — and remember that decades later?” wondered Bas Heijmans, a geneticist at Leiden University Medical Center in the Netherlands.

Heijmans, Lumey and their colleagues published a possible answer, or part of one, on Wednesday in the journal Science Advances. Their study suggests that the Dutch Hunger Winter silenced certain genes in unborn children — and that they’ve stayed quiet ever since.

While all cells in a person’s body share the same genes, different ones are active or silent in different cells. That program largely is locked in place before birth.

But scientists have learned that later experiences — say, exposure to a virus — can cause cells to quiet a gene or boost its activity, sometimes permanently.

The study of this long-term gene control is called epigenetics. Researchers have identified molecules that cells use to program DNA, but how those tools work isn’t entirely clear. One of the best studied is a molecular cap called a methyl group.

At millions of spots across our DNA, genes may carry a methyl group. They seem to silence genes — at least, researchers have found that silenced genes often have a collection of methyl groups lurking nearby.

Many researchers have speculated that prenatal conditions can influence people’s health across their lifetime, and some have speculated that methyl groups or other forms of epigenetics put this so-called fetal programming into action.

But it’s hard to put that idea to a firm test. The Dutch Hunger Winter might offer an opportunity, Heijmans and Lumey realized.

When Lumey first started studying the Dutch Hunger Winter cohort in the 1990s, he took blood samples from thousands of middle-age subjects. He also took samples from their siblings, born before or after the famine.

Over a decade later, he and his colleagues were able to take advantage of powerful new technology for detecting methyl groups in blood cells. They retrieved DNA from the samples and placed it in a device able to find methyl groups at nearly 350,000 spots on the genome.

Next, the researchers looked for odd patterns. They searched for methyl groups that were common in the Dutch Hunger Winter cohort, for example, but missing from their siblings.

Then they turned their attention to the health of their subjects. They sorted people according to their body mass index, for example, and looked for methyl groups that were unusually common in overweight people.

Finally, the researchers merged the results — and found a few methyl groups that were linked both to the famine and to health conditions later in life. “We were able to connect the three dots,” said Lumey.

Lumey and his colleagues propose that these methyl groups disrupt how cells normally use genes. One methyl group that is linked to a higher body mass index may be able to quiet a gene called PIM3, which is involved in burning the body’s fuel.

So here’s the theory: Perhaps the Dutch Hunger Winter added a methyl group to fetuses born to starving mothers, which made the PIM3 gene less active — and continued to do so for life.

The result? “Maybe your metabolism is in a lower gear,” Heijmans said.

Dalton Conley, a biosociologist at Princeton University who was not involved in the new study, said that there might be other explanations for the results. Perhaps putting on extra weight as you age triggers an epigenetic change to PIM3, rather than the other way around.

And the Dutch famine probably led to many miscarriages and early deaths. It’s possible that the survivors had some genetic variant that made them resilient and gave them a distinctive epigenetic profile not captured in this study.

John M. Greally, director of the Center for Epigenomics at Albert Einstein College of Medicine, noted that blood is made up of many different types of cells, each with its own epigenetic profile.

Maybe the Dutch famine made some types of cells more common, he said, rather than altering the epigenetics.

But Heijmans and his colleagues studied the same methyl groups in muscle cells, fat cells and other tissues they got from cadavers. In any given person, the pattern was roughly the same.

Still, Heijmans said that the new study would need to be followed up — for example, with carefully controlled experiments on animals that can shed more light on how a pregnant mother’s food supply affects the epigenetics of her offspring.

If scientists can solve the Dutch Hunger Winter’s lingering mysteries, they might also get some clues to how other kinds of stress can reprogram children’s health even before they’re born.

Lumey speculated that epigenetic profiles might someday allow doctors to detect changes that would lead to problems much later in life. “You don’t have to wait for 60 years,” he said.


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