The Epigenetics Revolution

Audrey Hepburn was one of the 20th century’s greatest movie stars. Stylish, elegant and with a delicately lovely, almost fragile bone structure, her role as Holly Golightly in Breakfast at Tiffany’s has made her an icon, even to those who have never seen the movie. It’s startling to think that this wonderful beauty was created by terrible hardship. Audrey Hepburn was a survivor of an event in the Second World War known as the Dutch Hunger Winter. This ended when she was sixteen years old but the after-effects of this period, including poor physical health, stayed with her for the rest of her life.

The Dutch Hunger Winter lasted from the start of November 1944 to the late spring of 1945. This was a bitterly cold period in Western Europe, creating further hardship in a continent that had been devastated by four years of brutal war. Nowhere was this worse than in the Western Netherlands, which at this stage was still under German control. A German blockade resulted in a catastrophic drop in the availability of food to the Dutch population. At one point the population was trying to survive on only about 30 per cent of the normal daily calorie intake. People ate grass and tulip bulbs, and burned every scrap of furniture they could get their hands on, in a desperate effort to stay alive. Over 20,000 people had died by the time food supplies were restored in May 1945.

The dreadful privations of this time also created a remarkable scientific study population. The Dutch survivors were a well-defined group of individuals all of whom suffered just one period of malnutrition, all of them at exactly the same time. Because of the excellent healthcare infrastructure and record-keeping in the Netherlands, epidemiologists have been able to follow the long-term effects of the famine. Their findings were completely unexpected.

One of the first aspects they studied was the effect of the famine on the birth weights of children who had been in the womb during that terrible period. If a mother was well-fed around the time of conception and malnourished only for the last few months of the pregnancy, her baby was likely to be born small. If, on the other hand, the mother suffered malnutrition for the first three months of the pregnancy only (because the baby was conceived towards the end of this terrible episode), but then was well-fed, she was likely to have a baby with a normal body weight. The foetus ‘caught up’ in body weight.

That all seems quite straightforward, as we are all used to the idea that foetuses do most of their growing in the last few months of pregnancy. But epidemiologists were able to study these groups of babies for decades and what they found was really surprising. The babies who were born small stayed small all their lives, with lower obesity rates than the general population. For forty or more years, these people had access to as much food as they wanted, and yet their bodies never got over the early period of malnutrition. Why not? How did these early life experiences affect these individuals for decades? Why weren’t these people able to go back to normal, once their environment reverted to how it should be?

Even more unexpectedly, the children whose mothers had been malnourished only early in pregnancy, had higher obesity rates than normal. Recent reports have shown a greater incidence of other health problems as well, including certain tests of mental activity. Even though these individuals had seemed perfectly healthy at birth, something had happened to their development in the womb that affected them for decades after. And it wasn’t just the fact that something had happened that mattered, it was when it happened. Events that take place in the first three months of development, a stage when the foetus is really very small, can affect an individual for the rest of their life.

Even more extraordinarily, some of these effects seem to be present in the children of this group, i.e. in the grandchildren of the women who were malnourished during the first three months of their pregnancy. So something that happened in one pregnant population affected their children’s children. This raised the really puzzling question of how these effects were passed on to subsequent generations.