Alan S. Beedle

Towards a new developmental synthesis: adaptive developmental plasticity and human disease

1focusing mainly on short-term outcomes such as infant survival and stunting. 2 However, the longer term eff ects on adult health 3 of a poor start to life suggest a further perspective. Developmental eff ects have been viewed traditionally in the context of major disruptions such as caused by teratogens, prematurity and growth retardation, but there is increasing appreciation of the role of developmental plasticity, which provides individuals with the fl exibility to adjust their trajectory of development to match their environment. Plasticity operates across the entire range of environment, from undernutrition to excessive nutritional environments associated with gestational diabetes or maternal obesity, 4,5

Metabolic plasticity during mammalian development is directionally dependent on early nutritional status.

Developmental plasticity in response to environmental cues can take the form of polyphenism, as for the discrete morphs of some insects, or of an apparently continuous spectrum of phenotype, as for most mammalian traits. The metabolic phenotype of adult rats, including the propensity to obesity, hyperinsulinemia, and hyperphagia, shows plasticity in response to prenatal nutrition and to neonatal administration of the adipokine leptin. Here, we report that the effects of neonatal leptin on hepatic gene expression and epigenetic status in adulthood are directionally dependent on the animals nutritional status in utero. These results demonstrate that, during mammalian development, the direction of the response to one cue can be determined by previous exposure to another, suggesting the potential for a discontinuous distribution of environmentally induced phenotypes, analogous to the phenomenon of polyphenism.

Fetal and Neonatal Pathways to Obesity

Evolutionary and developmental perspectives add considerably to our understanding of the aetiology of obesity and its related disorders. One pathway to obesity represents the maladaptive consequences of an evolutionarily preserved mechanism by which the developing mammal monitors nutritional cues from its mother and adjusts its developmental trajectory accordingly. Prediction of a nutritionally sparse environment leads to a phenotype that promotes metabolic parsimony by favouring fat deposition, insulin resistance, sarcopenia and low energy expenditure. But this adaptive mechanism evolved to accommodate gradual changes in nutritional environment; rapid transition to a situation of high energy density results in a mismatch between predicted and actual environments and increased susceptibility to metabolic disease. This pathway may also explain why breast and bottle feeding confer different risks of obesity. We discuss how early environmental signals act through epigenetic mechanisms to alter metabolic partitioning, glucocorticoid action and neuroendocrine control of appetite. A second pathway involves alterations in fetal insulin levels, as seen in gestational diabetes, leading to increased prenatal fat mass which is subsequently amplified by postnatal factors. Both classes of pathway may coexist in an individual. This developmental approach to obesity suggests that potential interventions will vary according to the target population.

Low birthweight and subsequent obesity in Japan

The Lancets World Report (Feb 10, p 451)1 rightly highlights the growing epidemic of obesity in Japan—a pattern that is also seen in other Asian countries and which might be of concern for future patterns of disease, given that susceptibility to the metabolic consequences of obesity seems to be higher in some Asian populations. There can be no doubt that this increasing prevalence of obesity is driven by changing patterns of nutrition and exercise, but there might also be other factors worthy of consideration. We have suggested that a mismatch between intrauterine constraint, arising from small maternal stature and suboptimum fetal nutrition, and a nutritionally rich postnatal environment might explain the high levels of metabolic compromise seen in some developing populations.2 Observations of social trends in Japan suggest that such a mismatch might also occur there. In Japan, birthweight has fallen rapidly (figure).3 and 4 This has been associated with a reduction in family size, increased maternal smoking, decreased maternal prepregnancy body-mass index resulting from dieting, and aggressive management of weight gain in pregnancy (mean weight gain in pregnancy has fallen by 2 kg in the past two decades, largely as a result of a zealous and unsupported obstetric belief that reduced weight gain is protective against pre-eclampsia5). The reduction in birthweight of more than 150 g represents a significant increase in maternal constraint and much reduced fetal nutrition. Thus if the developmental mismatch pathway has a role in the development of obesity in childhood and increases the risk of metabolic compromise,2 PD Gluckman and MA Hanson, Living with the past: evolution, development, and patterns of disease, Science 305(2004), pp. 1733–1736. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (282)2 then the developmental component is another factor in Japans obesity epidemic and a further point for intervention. Japans next 10-year public-health plans might have to include nutritional recommendations for pregnant women.

Predictive adaptive responses in perspective

In a recent opinion article, Wells accepts our fundamental claim that early metabolic plasticity in humans can contribute to later disease if there is a disparity (‘mismatch’) between nutritional experience at different phases of life, but he revives a debate and about the nature and function of the cue directing such plasticity. As in that earlier exchange, Wells argues that (i) the interests of mother and offspring are distinct, (ii) the only traits of interest are nutritional and metabolic and (iii) modern humans are in some way ‘special’ because of their extended lifespan and reproductive strategy. He argues that in humans prediction has been abandoned for a backward-looking strategy that operates solely for maternal benefit. We have explained elsewhere why we do not believe this to be the case. We suggest that a broader approach is needed because (i) evolution maximizes inclusive fitness, requiring optimization of the outcomes of the set of maternofetal dyads produced across the mothers reproductive life, (ii) plasticity cued by early-life information operates through trade-offs among the whole suite of life-history traits, and it is misleading to concentrate on a single trait and (iii) as in other species, humans use the mechanisms of developmental plasticity cued by information from the past and the present to prepare for the future.

How evolutionary principles improve the understanding of human health and disease.

An appreciation of the fundamental principles of evolutionary biology provides new insights into major diseases and enables an integrated understanding of human biology and medicine. However, there is a lack of awareness of their importance amongst physicians, medical researchers, and educators, all of whom tend to focus on the mechanistic (proximate) basis for disease, excluding consideration of evolutionary (ultimate) reasons. The key principles of evolutionary medicine are that selection acts on fitness, not health or longevity; that our evolutionary history does not cause disease, but rather impacts on our risk of disease in particular environments; and that we are now living in novel environments compared to those in which we evolved. We consider these evolutionary principles in conjunction with population genetics and describe several pathways by which evolutionary processes can affect disease risk. These perspectives provide a more cohesive framework for gaining insights into the determinants of health and disease. Coupled with complementary insights offered by advances in genomic, epigenetic, and developmental biology research, evolutionary perspectives offer an important addition to understanding disease. Further, there are a number of aspects of evolutionary medicine that can add considerably to studies in other domains of contemporary evolutionary studies.

Leptin Reversal of the Metabolic Phenotype: Evidence for the Role of Developmental Plasticity in the Development of the Metabolic Syndrome

Events in early life are associated with changes in the risk of disease in later life. There is increasing evidence that these associations are mediated by permanent transcriptional changes in metabolic pathways, in some cases linked to epigenetic alterations. We have proposed that this phenomenon of ‘developmental induction’ is not a manifestation of pathophysiological processes but rather represents the consequence of developmental decisions made during fetal and early postnatal life to maximize subsequent fitness. However, this fitness advantage is lost if the early and later environments are mismatched. Rats undernourished in utero by maternal underfeeding develop features of the metabolic syndrome, especially if fed on a high-fat diet, but transient neonatal treatment with leptin reverses induction of this adverse metabolic phenotype. This observation demonstrates that developmental programming is reversible and provides strong support for the match-mismatch or predictive model for the origins of developmental programming.

Developmental Perspectives on Individual Variation: Implications for Understanding Nutritional Needs

Genetic research has focused on identifying linkages between polymorphisms and phenotypic traits to explain variations in complex biologies. However, the magnitude of these linkages has not been particularly high. Conversely, the ability of developmental plasticity to generate biological variation from one genotype is well understood, while interest has emerged in the clinical significance of epigenetic processes, particularly those influenced by the external environment. Environmental cues in early development may induce responses that provide adaptive advantage later in life. The benefit of such responses depends on the fidelity of the prediction of the future environment. Life history and physiological changes mediated through epigenetic processes then follow, determining the later phenotype. Developmental mismatch, leading to disease, can arise from discordance between the fetal environment, which is relatively constant across generations, and the postnatal nutritional environment, which can change drastically within and between generations. Metabolic disorders represent the outcome of an individual living in an energetically inappropriate environment. Experimental and clinical evidence suggests that individual capacity to live in a given energetic environment is influenced by developmental factors acting through epigenetic mechanisms. Epigenetic biomarkers may be able to identify a risk of developmental mismatch and thus offer the opportunity for nutritional or other intervention.

Migrating Ovaries: Early Life Influences on Later Gonadal Function

The authors discuss a new study of Bangladeshi migrants to the UK, which found that adult women who had migrated before the age of 8 years had greater luteal phase progesterone secretion than those who had migrated after that age.

Human growth: evolutionary and life history perspectives.

Evolutionary and life history perspectives allow a fuller understanding of both patterns of growth and development and variations in disease risk. Evolutionary processes act to ensure successful reproduction and not the preservation of health and longevity, and this entails trade-offs both between traits and across the life course. Developmental plasticity adjusts the developmental trajectory so that the phenotype in childhood and through peak reproduction will suit predicted environmental conditions - a capacity that may become maladaptive should early-life predictions be inaccurate. Bipedalism and consequent pelvic narrowing in humans have led to the evolution of secondary altricialism. Shorter inter-birth intervals enabled by appropriate social support structures have allowed increased fecundity/fitness. The age at puberty has fallen over the past two centuries, perhaps resulting from changes in maternal and infant health and nutrition. The timing of puberty is also advanced by conditions of high extrinsic mortality in hunter-gatherers and is reflected in developed countries where a poor or disadvantaged start to life may also accelerate maturation. The postpubertal individual is physically and psychosexually mature, but neural executive function only reaches full maturity in the third decade of life; this mismatch may account for increased adolescent morbidity and mortality in those with earlier pubertal onset.