A model for phenotype change in a stochastic framework

some species, an inducible secondary phenotype will develop some time after the environmental change that evokes it. Nishimura (2006) [4] showed how an individual organism should optimize the time it takes to respond to an environmental change ("waiting time''). If the optimal waiting time is considered to act over the population, there are implications for the expected value of the mean fitness in that population. A stochastic predator-prey model is proposed in which the prey have a fixed initial energy budget. Fitness is the product of survival probability and the energy remaining for non-defensive purposes. The model is placed in the stochastic domain by assuming that the waiting time in the population is a normally distributed random variable because of biological variance inherent in mounting the response. It is found that the value of the mean waiting time that maximises fitness depends linearly on the variance of the waiting time

Prenatal factors contribute to the emergence of kwoshiorkor or marasmus in severe undernutrition: evidence for the predictive adaptation model

Severe acute malnutrition in childhood manifests as oedematous (kwashiorkor, marasmic kwashiorkor) and non-oedematous (marasmus) syndromes with very different prognoses. Kwashiorkor differs from marasmus in the patterns of protein, amino acid and lipid metabolism when patients are acutely ill as well as after rehabilitation to ideal weight for height. Metabolic patterns among marasmic patients define them as metabolically thrifty, while kwashiorkor patients function as metabolically profligate. Such differences might underlie syndromic presentation and prognosis. However, no fundamental explanation exists for these differences in metabolism, nor clinical pictures, given similar exposures to undernutrition. We hypothesized that different developmental trajectories underlie these clinical-metabolic phenotypes: if so this would be strong evidence in support of predictive adaptation model of developmental plasticity

Pathogenesis of adolescent idiopathic scoliosis in girls - a double neuro-osseous theory involving disharmony between two nervous systems, somatic and autonomic expressed in the spine and trunk: possible dependency on sympathetic nervous system and hormones with implications for medical therapy

Anthropometric data from three groups of adolescent girls - preoperative adolescent idiopathic scoliosis (AIS), screened for scoliosis and normals were analysed by comparing skeletal data between higher and lower body mass index subsets. Unexpected findings for each of skeletal maturation, asymmetries and overgrowth are not explained by prevailing theories of AIS pathogenesis. A speculative pathogenetic theory for girls is formulated after surveying evidence including: (1) the thoracospinal concept for right thoracic AIS in girls; (2) the new neuroskeletal biology relating the sympathetic nervous system to bone formation/resorption and bone growth; (3) white adipose tissue storing triglycerides and the adiposity hormone leptin which functions as satiety hormone and sentinel of energy balance to the hypothalamus for long-term adiposity; and (4) central leptin resistance in obesity and possibly in healthy females. The new theory states that AIS in girls results from developmental disharmony expressed in spine and trunk between autonomic and somatic nervous systems. The autonomic component of this double neuro-osseous theory for AIS pathogenesis in girls involves selectively increased sensitivity of the hypothalamus to circulating leptin (genetically-determined up-regulation possibly involving inhibitory or sensitizing intracellular molecules, such as SOC3, PTP-1B and SH2B1 respectively), with asymmetry as an adverse response (hormesis); this asymmetry is routed bilaterally via the sympathetic nervous system to the growing axial skeleton where it may initiate the scoliosis deformity (leptin-hypothalamic-sympathetic nervous system concept = LHS concept). In some younger preoperative AIS girls, the hypothalamic up-regulation to circulating leptin also involves the somatotropic (growth hormone/IGF) axis which exaggerates the sympathetically-induced asymmetric skeletal effects and contributes to curve progression, a concept with therapeutic implications. In the somatic nervous system, dysfunction of a postural mechanism involving the CNS body schema fails to control, or may induce, the spinal deformity of AIS in girls (escalator concept). Biomechanical factors affecting ribs and/or vertebrae and spinal cord during growth may localize AIS to the thoracic spine and contribute to sagittal spinal shape alterations. The developmental disharmony in spine and trunk is compounded by any osteopenia, biomechanical spinal growth modulation, disc degeneration and platelet calmodulin dysfunction. Methods for testing the theory are outlined. Implications are discussed for neuroendocrine dysfunctions, osteopontin, sympathoactivation, medical therapy, Rett and Prader-Willi syndromes, infantile idiopathic scoliosis, and human evolution. AIS pathogenesis in girls is predicated on two putative normal mechanisms involved in trunk growth, each acquired in evolution and unique to humans

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

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 mother's 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

Epigenetic mechanisms that underpin metabolic and cardiovascular diseases

Cellular commitment to a specific lineage is controlled by differential silencing of genes, which in turn depends on epigenetic processes such as DNA methylation and histone modification. During early embryogenesis, the mammalian genome is 'wiped clean' of most epigenetic modifications, which are progressively re-established during embryonic development. Thus, the epigenome of each mature cellular lineage carries the record of its developmental history. The subsequent trajectory and pattern of development are also responsive to environmental influences, and such plasticity is likely to have an epigenetic basis. Epigenetic marks may be transmitted across generations, either directly by persisting through meiosis or indirectly through replication in the next generation of the conditions in which the epigenetic change occurred. Developmental plasticity evolved to match an organism to its environment, and a mismatch between the phenotypic outcome of adaptive plasticity and the current environment increases the risk of metabolic and cardiovascular disease. These considerations point to epigenetic processes as a key mechanism that underpins the developmental origins of chronic noncommunicable disease. Here, we review the evidence that environmental influences during mammalian development lead to stable changes in the epigenome that alter the individual's susceptibility to chronic metabolic and cardiovascular disease, and discuss the clinical implication

Low birthweight and subsequent obesity in Japan

The Lancet's 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 Japan's obesity epidemic and a further point for intervention. Japan's next 10-year public-health plans might have to include nutritional recommendations for pregnant women.<br/

Birth weights of survivors of severe acute malnutrition.

<p>Key: M = marasmus; K = kwashiorkor; MK = marasmic kwashiorkor. The horizontal bars are mean values.</p

Clinical, anthropometric, survival and birth weight data of 1336 patients who had been admitted to the Tropical Metabolism Research Unit with severe acute malnutrition between 1963 and 1992.

<p>Clinical, anthropometric, survival and birth weight data of 1336 patients who had been admitted to the Tropical Metabolism Research Unit with severe acute malnutrition between 1963 and 1992.</p