Sir Richard Doll LectureDevelopmental origins of chronic disease
Introduction
The search for the causes of chronic adult diseases, and the way to prevent them, has largely failed. For example, there will soon be 250 million people around the world with type 2 diabetes. Hitherto, the search has been guided by a destructive model in which the causes to be identified are adverse environmental influences that act in adult life, and accelerate processes associated with normal ageing, such as hardening of the arteries and rising blood pressure. This model of causation is based on infectious disease, and presupposes that each different disease has a separate cause. It has had limited success. Cigarette smoking and psychosocial stress have been implicated, but these only go a small way to explaining why one person lives a short life and another lives to old age. Genes offer another possibility, but the search for these has been expensive and largely fruitless. Genes are unlikely to explain why coronary heart disease, which was rare 100 years ago, is now the world’s most common cause of death.
There is now clear evidence that people who develop cardiovascular disease or type 2 diabetes grew differently to other people in their early life. They tended to grow slowly in utero, so that their birthweights were toward the lower end of the normal range. In addition, they tended to remain small for the first 2 years after birth1, 2 and throughout infancy. After that, they gained weight and body mass index rapidly.3 These are large effects. If each individual in the Helsinki Birth Cohort had been in the highest third for birthweight and had decreased their standard deviation score for body mass index between 3 and 11 years of age, the incidence of type 2 diabetes would have been halved.4 Fig. 1, based on the original observations in Hertfordshire, UK, shows that the relationship between birthweight and later disease is graded.5 These findings have been replicated extensively.6, 7, 8, 9 They have led to a new developmental model for chronic disease in which the causes to be identified are linked to normal variations in fetoplacental and infant development.
Section snippets
Programming
Like other living creatures, humans are plastic during their development, and adverse influences can permanently change body structure and function; a phenomenon known as ‘programming’.10 In animals, it is surprisingly easy to produce lifelong changes in the physiology and metabolism of the offspring by minor modifications to the diet of the mother before and during pregnancy.11, 12 Malnutrition and other adverse influences during development permanently alter gene expression. They also lead to
Compensatory growth
If the growth of a fetus, infant or child falters because of malnutrition or other adversity, it has the ability, once the adversity has discontinued, to return to its growth trajectory by accelerated growth. The ability to mount rapid ‘compensatory’ growth following growth faltering is common in animals and familiar to farmers.17 If energy is allocated to rapid growth, the allocation to some other developmental activity must be reduced. In animals, compensatory growth has a wide range of
Fetal nutrition
Size at birth is the product of the fetus’s trajectory of growth, which is set at an early stage in development, and the maternoplacental capacity to supply sufficient nutrients to maintain this trajectory. A rapid trajectory of growth increases the fetus’s demand for nutrients.19 This demand is greatest late in pregnancy, but the trajectory is thought to be primarily determined by genetic and environmental effects in early gestation. Experiments in animals have shown that alterations in
Maternal nutrition
The graded relationship between birthweight and later disease (Fig. 1) implies that variations in the supply of food from normal healthy mothers to normal healthy babies have major implications for the long-term health of the babies.23 A baby does not depend on the mother’s diet during pregnancy: that would be too dangerous a strategy. Rather, it lives off her stored nutrients and the turnover of protein and fat in her tissues.24 These are related to her body composition and therefore reflect
The placenta
A baby’s birthweight depends not only on the mother’s nutrition but also on the placenta’s ability to transport nutrients to the fetus from its mother. The placenta seems to act as a nutrient sensor regulating the transfer of nutrients to the fetus according to the mother’s ability to deliver them, and the demands of the fetus for them.40 The weight of the placenta, and the size and shape of its surface, reflect its ability to transfer nutrients. The shape and size of the placental surface at
Conclusion
Under the new developmental model for the origins of chronic disease, the causes to be identified are linked to normal variations in the processes of development, that lead to variations in the supply of nutrients to the baby. These variations programme the function of a few key systems that are linked to chronic disease: the immune system, anti-oxidant defences, inflammation,neuro-endocrine settings and the number and quality of stem cells. There is not a separate cause for each different
Acknowledgements
The writing of this lecture was greatly helped by discussions with Professors Kent Thornburg (Oregon Health & Science University) and Michelle Lampl (Emory University), and colleagues in the MRC Lifecourse Epidemiology Unit, University of Southampton.
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