The nature-nurture debate is one of biology鈥檚 oldest questions: is it genes or environment that shapes our bodies? But in recent years interest has grown in a third influence, which combines elements of both inheritance and environment 鈥� the environment in the womb.
It was David Barker, a physician and epidemiologist at the University of Southampton in the UK, who first showed that boys born small were more likely to develop heart disease in later life. In a further study, of Dutch women who had been pregnant during the second world war, Barker showed that malnutrition around the time of conception was linked with high blood-lipid levels, heart disease and diabetes in adulthood. Intriguingly, not only did the women who were pregnant through the war-induced famine give birth to smaller children, their daughters also tended to have smaller children. In an important addendum, Barker showed in 1999 that small babies who quickly caught up and eventually overtook their peers in weight tended to have even worse health later in life.
Barker made what seemed at the time a radical proposal: somehow the fetuses were being tipped off that life on the outside was going to be one of deprivation. 鈥淏abies set their metabolism according to the prevailing nutrition in the womb,鈥� says Barker. Their bodies were programmed to hoard energy as fat, particularly in stores around the waist. When the babies grew up in a world of unexpected plenty, that metabolism set them up for an increased risk of heart disease and diabetes. Having fat around the midriff is known to raise blood cholesterol levels.
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This is not the only possible explanation for the so-called Barker hypothesis, or 鈥渇etal origins of adult disease鈥�, however. Perhaps the growing fetus is simply irrevocably damaged by malnutrition so early on in life. If nutrients are scarce, it would make sense for the fetus to preserve supply to the brain at the expense of other organs such as the heart, kidney and pancreas, Barker says. If it comes to choosing between brain damage from birth or ill-health in middle age, there is no contest. The two hypotheses are not mutually exclusive, however; Barker thinks both could be right.
A team of New Zealand researchers from the University of Auckland have been investigating an experimental model of the Barker hypothesis in rats. They subjected pregnant females to a low-calorie diet, and found they gave birth to unusually small pups which put on more weight as they grew up than control animals. And when the deprived pups were given a high-fat diet, they grew much fatter than control rats. 鈥淭hey were eating every time they saw food,鈥� says lead researcher Peter Gluckman. 鈥淭hey were big blobs of lard.鈥�
鈥淣ot only did women pregnant in the famine have smaller children, their daughters did too鈥�
Just as a sedentary lifestyle is considered a factor in human obesity, the rats seemed lazier too. The researchers found that the prenatally starved rats were only about 70 per cent as active as the normal animals.
So how could events that go on in the womb have such long-lasting effects, even through to the next generation of offspring? Recent work has hinted that at least one mechanism operating could be a form of gene silencing known as methylation. This is a system for turning off genes by chemically modifying them, adding methyl groups to the DNA and surrounding histone proteins. Researchers such as Randy Jirtle, at Duke University in Durham, North Carolina, have now shown that in a certain strain of mice, a gene called agouti that affects coat colour can be turned off through methylation. And the extent of methylation is dependent on the mother鈥檚 vitamin intake during pregnancy. The agouti gene is only found in mice, but Jirtle is confident that others like it will be found in humans. 鈥淲e just don鈥檛 know what they are,鈥� he says.