A major metabolic disturbance during early pregnancy, such as the dramatically decreased availability of food during the Dutch Hunger Winter, would significantly alter the epigenetic processes occurring in the foetal cells. The cells would change metabolically, in an attempt to keep the foetus growing as healthily as possible despite the decreased nutrient supply. The cells would change their gene expression to compensate for the poor nutrition, and the patterns of expression would be set for the future because of epigenetic modifications to the genes. It’s probably no surprise that it was the children whose mothers had been malnourished during the very early stages of pregnancy, when developmental programming is at its peak, who went on to be at higher risk of adult obesity. Their cells had become epigenetically programmed to make the most of limited food supply. This programming remained in place even when the environmental condition that had prompted it – famine – was long over.
Recent studies examining DNA methylation patterns in the Dutch Hunger Winter survivors have shown changes at key genes involved in metabolism. Although a correlation like this doesn’t prove cause-and-effect, the data are consistent with under-nutrition during the early developmental period changing the epigenomic profile of key metabolic genes[37].
It’s important to recognise that even in the Dutch Hunger Winter cohort, the effects that we see are not all-or-nothing. Not every individual whose mother had been malnourished early in pregnancy became obese. When scientists studied the population they found an increased likelihood of adult obesity. This is again consistent with a model where random epigenetic variability, the genotypes of the individuals and early environmental events, and the responses of the genes and cells to the environment combine in one great big complicated – and as yet not easily decipherable – equation.
Severe malnutrition is not the only factor that has effects on a foetus that can last a lifetime. Excessive alcohol consumption during pregnancy is a leading preventable cause of birth defects and mental retardation (foetal alcohol syndrome) in the Western world[38]. Emma Whitelaw used the agouti mouse to investigate if alcohol can alter the epigenetic modifications in a mouse model of foetal alcohol syndrome. As we have seen, expression of the Avy gene is epigenetically controlled via DNA methylation of a retrotransposon. Any stimulus that alters DNA methylation of the retrotransposon would change expression of the Avy gene. This would affect the colour of the fur. In this model, fur colour becomes a ‘read-out’ that indicates changes in epigenetic modifications.
Pregnant mice were given free access to alcohol. The coat colour in the pups from the alcohol-drinking mothers was compared with the coat colour of the pups from pregnant mice that didn’t have access to booze. The distribution of coat colours was different between the two groups. So were the levels of DNA methylation of the retrotransposon, as predicted. This showed that the alcohol had led to a change in the epigenetic modifications in the mice. Disruption of epigenetic developmental programming may lead to at least some of the debilitating and lifelong symptoms of foetal alcohol syndrome in children of mothers who over-use alcohol during pregnancy.
Bisphenol A is a compound used in the manufacture of polycarbonate plastics. Feeding bisphenol A to agouti mice results in a change in the distribution of coat colour, suggesting this chemical has effects on developmental programming through epigenetic mechanisms. In 2011 the European Union outlawed bisphenol A in drinking bottles for babies.
Early programming may also be one of the reasons that it’s been very difficult to identify the environmental effects that lead to some chronic human conditions. If we study pairs of MZ twins who are discordant for a specific phenotype, for example multiple sclerosis, it may be well nigh impossible to identify an environmental cause. It may simply be that one of the pair was exceptionally unlucky in the random epigenetic fluctuations that established certain key patterns of gene expression early in life. Scientists are now mapping the distribution of epigenetic changes in concordant and discordant MZ twins for a number of disorders, to try to identify histone or DNA modifications that correlate with the presence or absence of disease.
Children conceived during famines and mice with yellow coats have each clearly taught us remarkable things about early development, and the importance of epigenetics in this process. Oddly enough, these two disparate groups have one other thing to teach us. At the very beginning of the 19th century, Jean-Baptiste Lamarck published his most famous work, Philosophie Zoologique. He hypothesised that acquired characteristics can be transmitted from one generation to the next, and that this drives evolution. As an example, a short-necked giraffe-like animal that elongated its neck by constant stretching would pass on a longer neck to its offspring. This theory has been generally dismissed and in most cases it is simply wrong. But the Dutch Hunger Winter cohort and the yellow mice have shown us that startlingly, the heretical Lamarckian model of inheritance can, just sometimes, be right on the money, as we are about to see.
Chapter 6. The Sins of the Fathers
For I, the Lord your God, am a jealous God, punishing the children for the sins of the fathers to the third and fourth generation of those who hate me
The Just So stories published by Rudyard Kipling at the very beginning of the 20th century are an imaginative set of tales about origins. Some of the most famous are those about the phenotypes of animals – How the Leopard Got his Spots, The Beginning of the Armadillos, How the Camel Got his Hump. They are written purely as entertaining fantasies but scientifically they hark back to a century earlier and Lamarck’s theory of evolution through the inheritance of acquired characteristics. Kipling’s stories describe how one animal acquired a physical characteristic – the elephant’s long trunk, for example – and the implication is that all the offspring inherited that characteristic, and hence all elephants now have long trunks.
Kipling was having fun with his stories, whereas Lamarck was trying to develop a scientific theory. Like any good scientist, he tried to collect data relevant to this hypothesis. In one of the most famous examples of this, Lamarck recorded that the sons of blacksmiths (a very physical trade) tended to have larger arm muscles than the sons of weavers (a much less physical occupation). Lamarck interpreted this as the blacksmiths’ sons inheriting the acquired phenotype of large muscles from their fathers.
Our modern interpretation is different. We recognise that a man whose genes tended to endow him with the ability to develop large muscles would be at an advantage in a trade such as blacksmithing. This occupation would attract those who were genetically best suited to it. Our interpretation would also encompass the likelihood that the blacksmith’s sons may have inherited this genetic tendency towards chunky biceps. Finally, we would acknowledge that at the time that Lamarck was writing, children were used routinely as additional members of a family workforce. The children of a blacksmith were more likely than those of a weaver to be performing relatively heavy manual labour from an early age and hence would be likely to develop larger arm muscles as a response to their environment, just as we all do when we pump iron.
It would be a mistake to look back on Lamarck and only mock. We no longer accept most of his ideas scientifically, but we should acknowledge that he was making a genuine attempt to address important questions. Inevitably, and quite rightly, Lamarck has been overshadowed by Charles Darwin, the true colossus of 19th century biology – actually, probably the colossus of biology generally. Darwin’s model of the evolution of species via natural selection has been the single most powerful conceptual framework in biological sciences. Its power became even greater once married to Mendel’s work on inheritance and our molecular understanding of DNA as the raw material of inheritance.