Developmental Aspects Of Diseases Of Modern Environments

Developmental Aspects Of Diseases Of Modern Environments

Workshop Summary by

Peter Gluckman¹, Keith Godfrey^2,3, Mark Hanson³ and Chris Kuzawa⁴

¹Liggins Institute, The University of Auckland, Auckland, New Zealand
²MRC Epidemiology Resource Centre, University of Southampton, Southampton, UK
³Institute of Developmental Sciences, University of Southampton, Southampton, UK
⁴Department of Anthropology, Northwestern University, Evanston, Illinois, USA

One of five workshops in a conference on
Evolution and Diseases of Modern Environments
Organized by Randolph Nesse, at the Berlin Charité,  October 13-14, 2009
In conjunction with The World Health Summit
Sponsored by the Volkswagen Foundation

To give focus to the discussion, the workshop primarily addressed the issue of the role of developmental plasticity in contributing to human health and disease, and in particular on the relationship between early life events and the later risks of cardiovascular and metabolic disease. In general a poor start to life, as reflected in maternal conditions, is associated with a greater risk of insulin resistance and hypertension in later life. Increasingly it is also recognised that maternal obesity has consequences for the offspring. It has been known for several decades that gestational diabetes is associated with effects in the next generation – a phenomenon that was originally referred to as developmental programming or metabolic teratogenesis. The word ‘programming’ continues to be used in the biomedical literature to refer to developmental effects with later consequences, but our workshop preferred to avoid such terminology and instead consider the extent to which developmental plasticity can influence chronic disease risk. A key starting point for our discussions was the various conceptual models based on evolutionary principles that have been proposed to explain these relationships. These are built on our current understandings of developmental plasticity and epigenetics.

Most of the discussion centred on conceptual models that posit that developmental plasticity in response to cues in early life has adaptive value, not necessarily just for immediate fetal advantage, but also for advantage that extends postnatally or is only sometimes exhibited postnatally. These have been variously referred to as anticipation, forecasting, prediction or learning models. Anticipation can be incorporated into the genome by genetic assimilation if the exposure is invariable (e.g. the development of the thickened heel pad in infants), but where the exposure is not invariable, plasticity may be more appropriate and under active selection. A general model that has been proposed, with some variations in emphasis, is the learning/anticipatory/predictive model, which states that because there are costs and constraints that limit the capacity to maintain plasticity throughout life, the early offspring alters its trajectory of phenotypic development for potential advantage across its life course.

The nature of the cue and relationship to outcome was discussed at length. In comparative biology cues can be either rather non-specific or have very specific trait-related outcomes. In humans the former appears more likely, with the cues (probably mainly stress and nutrition) involving some degree of inertia integrating the maternal experience. The more severe the cue, the more immediate the response of the developing organism will be (e.g. intrauterine growth retardation, premature delivery). Clearly the outcome will be affected by the developmental period during which the environment is perturbed. The induced advantage may occur early in postnatal life but extend into adulthood. Examples of such posited advantage in response to an anticipated adverse environment cued in utero include increased neonatal insulin sensitivity (and thus adiposity in infancy, which has been proposed to buffer the growing brain against predicted nutritional adversity at or after weaning), an altered life history pattern (including early puberty, which may be interpreted as an appropriate response to a high extrinsic mortality risk), altered appetite control, reduced lean body mass and later insulin resistance to match the organism to an anticipated nutritionally impaired environment. Tradeoffs might include less investment in repair such that longevity is reduced. But as the individual ages, the fidelity of prediction must reduce and indeed its fitness value is reduced once reproduction has been achieved. Thus the appearance of metabolic disease in middle age may be influenced by such processes, particularly given the marked increase in nutritional density in modern environments.

The discussion addressed the extent to which anticipation is an important feature of developmental plasticity and considered alternate models. There are many comparative examples where adaptive advantage of plasticity has been demonstrated or inferred in plants, bacteria and all eukaryotic taxa. In particular a central question was: to what extent are the effects of fetal plasticity adaptive, versus being a failure to buffer? Does it matter that a plastic trait evolved through adaptation? A challenge is how to identify signatures of adaptation in plasticity. If epigenetic changes can be shown to be functional/clustered rather than stochastic, they are more likely a result of adaptation. As yet we have no capacity to identify the signatures of natural selection on epigenetic markings.

Thus the presumption of the adaptive value of plasticity in humans must be based on comparative arguments. Plasticity and canalization are universal features of biota. Clearly it is important to understand how a system evolved irrespective of whether it is adaptive or not, taking account of how the life history and ecological context of the species will have shaped appropriate patterns of response.

A summary of the clinical/experimental evidence was iteratively combined with an evaluation of its theoretical significance. Developmental induction of later metabolic risk is seen in individuals within the normal range of birth sizes and without obvious impact on the fetus or mother, and is affected by physiological stimuli, such as nutritional status before or at conception and during pregnancy, or the nature of infant feeding. This excludes teratogenic effects, suggests a role for anticipatory processes and excludes arguments that have been put forward based on concepts of conflict – namely that the fetal response is primarily for maternal benefit – a concept that gained no traction in the discussion. Adaptive strategies are likely to differ in monotocous versus polytocous species, and maternal benefit may be more likely in the latter. Any disadvantage of such anticipatory induction generally requires a mismatched (high postnatal nutrient) environment and occurs at >35 years of age, and is therefore unlikely to be under negative selection as in evolutionary terms reproductive success has likely been achieved. Indeed, there is little evidence for any adverse fitness effects, bearing in mind that evolution acts to optimise fitness, not health or longevity.

In reviewing the data it was emphasised that complex phenotypes are induced/altered, that at birth in humans epigenetic changes can be seen, and that in late adulthood epigenetic echoes can be observed that in turn reflect the prenatal environment (e.g. the Dutch famine). Preliminary evidence was presented relating the early epigenetic state to later phenotypic trajectory. It was noted that the phenomenon is remarkably easy to replicate in every mammal studied. Several theoretical models have been presented based on a ‘thrifty adaptation’ in utero – however it was pointed out that these have been based on a false premise of fetal insulin resistance; in fact increased insulin sensitivity is a feature of being born small, and insulin resistance does not develop until after infancy. This is also true in several animal models.

An emergent different set of developmental experiences, namely that of the consequences of maternal diabetes and maternal obesity, was discussed. Both are associated with a higher risk of obesity in the offspring. While the effect of gestational diabetes is well recognised and understood in terms of effects of fetal insulin on adipogenesis, less is known about the mechanisms of maternal obesity leading to offspring obesity. Adaptive arguments do exist and it may be that there is no need for a different conceptual framework to explain this phenomenon; however much more research is needed.

Discussion was held as to the significance of epigenetic inheritance, which was distinguished from other forms of non-genomic inheritance. There are several ways in which trans-generational environmental influences could occur, not all involving epigenetic inheritance, and indeed the evidence for trans-meiotic transfer of epigenetic marks is limited except in the case of small RNAs.

This review of the clinical and experimental data informed consideration of the theoretical concepts. We noted that generation length (20-25 years) is the temporal unit of selection and that anticipation is common/universal across taxa. Given this, objections to anticipation models where there is benefit across the pre-reproductive and reproductive phases of the life course based solely on the issue of the time to some potential benefits being measured in years were generally considered ill-founded. Maternal effects are common and generally confer some fitness benefit on the offspring, although the evidence is of variable quality. Conflict theory and imprinting were discussed. It was generally considered that maternal-fetal conflict models were overstated and the evidence for a role of fetal-maternal genomic conflict in humans, unlike some of the better-documented examples in rodents, was weak; in contrast weaning conflicts were assumed to be common in humans.

There are costs and constraints that limit plasticity, and hence the potential role of anticipation is based in part on exposures particularly during critical windows. The fitness costs of mal-prediction are only costs if they occur before and during reproduction, and any fitness benefit of predictions can occur either before or during reproduction. Indeed we favoured a model in which trajectories of development were altered giving potential benefit across the life course. Plasticity theory shows that predictions need not have high fidelity to be selected for, and if the fitness costs of mismatch are asymmetrical then the fidelity of prediction can be very low and yet be under strong selection. For example, if the fitness disadvantage of being developmentally mismatched in a high nutrition/low threat environment is much lower than the failure to predict a low nutrition/high threat environment, then anticipation of a low nutrition environment will be favoured.

Other considerations that merit interaction between empiricists and theoreticians included the role of both spatial as well as temporal environmental variation across the life course, the relative role of adaptive plasticity in generalist and specialist species, and the relative role of non-genomic and epigenetic inheritance in matrilocal and patrilocal populations/species.
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Given the limitations on testing hypotheses regarding fitness and adaptation in humans, the potential value of modelling as well as the comparative approach was emphasised throughout the workshop.