Felicia Low

The role of developmental plasticity and epigenetics in human health

Considerable epidemiological, experimental and clinical data have amassed showing that the risk of developing disease in later life is dependent on early life conditions, mainly operating within the normative range of developmental exposures. This relationship reflects plastic responses made by the developing organism as an evolved strategy to cope with immediate or predicted circumstances, to maximize fitness in the context of the range of environments potentially faced. There is now increasing evidence, both in animals and humans, that such developmental plasticity is mediated in part by epigenetic mechanisms. However, recognition of the importance of developmental plasticity as an important factor in influencing later life health-particularly within the medical and public health communities-is low, and we argue that this indifference cannot be sustained in light of the growing understanding of developmental processes and the rapid rise in the prevalence of obesity and metabolic disease globally.

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.

Developmental plasticity and epigenetic mechanisms underpinning metabolic and cardiovascular diseases

The importance of developmental factors in influencing the risk of later-life disease has a strong evidence base derived from multiple epidemiological, clinical and experimental studies in animals and humans. During early life, an organism is able to adjust its phenotypic development in response to environmental cues. Such developmentally plastic responses evolved as a fitness-maximizing strategy to cope with variable environments. There are now increasing data that these responses are, at least partially, underpinned by epigenetic mechanisms. A mismatch between the early and later-life environments may lead to inappropriate early life-course epigenomic changes that manifest in later life as increased vulnerability to disease. There is also growing evidence for the transgenerational transmission of epigenetic marks. This article reviews the evidence that susceptibility to metabolic and cardiovascular disease in humans is linked to changes in epigenetic marks induced by early-life environmental cues, and discusses the clinical, public health and therapeutic implications that arise.

Epigenetic epidemiology: the rebirth of soft inheritance

Non-communicable diseases (NCDs), such as cardiovascular disease and type 2 diabetes, constitute the main cause of death worldwide. Eighty percent of these deaths occur in low- and middle-income countries, especially as these countries undergo socio-economic improvement following reductions in the burden of infectious disease. The World Health Organization predicts a substantial increase in the incidence of NCDs over the next decade globally. NCDs are generally preventable, but current approaches are clearly inadequate. New initiatives are needed to implement such prevention, and there needs to be greater recognition that early-life interventions are likely to be the most efficacious. Devising appropriate prevention strategies necessitates an understanding of how the developmental environment influences risk. Progress in this field has been slow due to an excessive emphasis on fixed genomic variations (hard inheritance) as the major determinants of disease susceptibility. However, new evidence demonstrates the much greater importance of early-life developmental factors, involving epigenetic processes and ‘soft’ inheritance in modulating an individual’s vulnerability to NCD. This also offers opportunities for novel epigenetic biomarkers of risk or interventions targeting epigenetic pathways to be devised for use in early life. This may pave the way to much more effective, customised interventions to promote health across the life course.

Developmental Plasticity, Epigenetics and Human Health

The unrelenting rise in global rates of non-communicable disease has necessitated a thorough re-evaluation of the current use of adult- and lifestyle-based strategies to curb the growing epidemic. There is a rapidly emerging set of epidemiological, experimental and clinical data suggesting that developmental factors play a considerable role in determining individual disease risk later in life. This phenomenon is known as the Developmental Origins of Health and Disease (DOHaD). Developmental factors, such as maternal and paternal nutrition, gestational diabetes mellitus, and even the normative range of developmental experiences, may evoke the processes of developmental plasticity which enable an organism to change its developmental trajectory in response to environmental cues. However in the event of a mismatch between the early and mature environment, such anticipatory responses may become maladaptive and lead to elevated risk of disease. The evo-devo and eco-evo-devo framework for DOHaD has more recently been supported by mechanistic insights enabled by rapid advances in epigenetic research. Increasing evidence suggests that developmental plasticity may be effected by epigenetically mediated modulation of the expression of specific genes. These mechanisms include DNA methylation, histone modifications and noncoding RNA activity. A growing number of animal studies also point towards the transgenerational inheritance of epigenetic marks, which may have implications for the perpetuation of ill-health. However early-life epigenotyping may find utility as a prognostic marker of metabolic dysfunction for identification and treatment of at-risk individuals.

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.

Developing a Curriculum for Evolutionary Medicine: Case Studies of Scurvy and Female Reproductive Tract Cancers

Most early evolutionary thinkers came from medicine, yet evolution has had a checkered history in medical education. It is only in the last few decades that serious efforts have begun to be made to integrate evolutionary biology into the medical curriculum. However, it is not clear when, where (independently or as part of preclinical or clinical teaching courses) and, most importantly, how should medical students learn the basic principles of evolutionary biology applied to medicine, known today as evolutionary or Darwinian medicine. Most clinicians are ill-prepared to teach evolutionary biology and most evolutionary biologists ill-equipped to formulate clinical examples. Yet, if evolutionary science is to have impact on clinical thought, then teaching material that embeds evolution within the clinical framework must be developed. In this paper, we use two clinical case studies to demonstrate how such may be used to teach evolutionary medicine to medical students in a way that is approachable as well as informative and relevant.

Developmental Epigenomics and Metabolic Disease

Organisms have evolved the processes of developmental plasticity to adjust their developmental trajectory in response to early life exposure to environmental cues. The potentially adaptive nature of such anticipatory responses is aimed at promoting Darwinian fitness; however, a mismatch between the induced phenotype and the later life environment increases the risk of disease, as evolutionary processes act to maximize reproductive success and not to maintain health and longevity. We focus on the developmental origins of later life metabolic disease in humans particularly with respect to early life under- and overnutrition and review the experimental, epidemiological, and clinical evidence implicating epigenetic mechanisms in the modulation of disease risk. There is growing evidence that epigenetic marks—and hence possibly disease risk—may be transgenerationally transmitted via non-genomic pathways of inheritance. This has implications both for the perpetuation of disease risk across generations and for the potential impact on evolution should epigenetic marks become genomically fixed. We also discuss the potential of developmental epigenomics in identifying prognostic biomarkers and therapeutic targets and raise several technical and methodological caveats to be borne in mind when undertaking and interpreting epigenomic research.

Epigenetic and Developmental Basis of Risk of Obesity and Metabolic Disease

The phenomenon whereby an individual’s early life experiences modulate subsequent susceptibility to disease risk is known as the “developmental origins of health and disease” (DOHaD). This chapter focuses on obesity and associated metabolic disease, reviewing this research domain through the lens of an evolutionary developmental biology (evo-devo) conceptual framework. At the molecular level, we use early life nutrition as an illustrative example to review the rapidly accumulating experimental, clinical and epidemiological evidence that epigenetic mechanisms are a key component underlying developmental pathways affecting the risk of obesity and related diseases. Early overnutrition involving evolutionarily novel circumstances such as maternal obesity and gestational diabetes, while potentially representing a non-adaptive pathway to DOHaD, may also be underpinned by epigenetic mechanisms. The evidence that epigenetic dysregulation underlies the pathology of obesity and type 2 diabetes in adults is reviewed, as is the therapeutic potential of developmental epigenomics in improving human health.

Evolutionary Medicine III. Mismatch

Evolutionary processes mediate disease risk via multiple pathways. Evolutionary mismatch arises upon exposure to an entirely novel environment, or to an environment that is beyond the evolved physiology and adaptive capacity of the individual. Developmental mismatch eventuates when the mature phenotype – as influenced by early life cues through the evolved processes of developmental plasticity – is incongruent with the later life environment. The key role of evolutionary and developmental histories in influencing disease risk provides a framework for understanding the etiology of many noncommunicable diseases and for potential preventative strategies.