Congenital anomalies from a physics perspective. The key role of “manufacturing” volatility

Abstract

Genetic and environmental factors are traditionally seen as the sole causes of congenital anomalies. In this paper we introduce a third possible cause, namely random “manufacturing” discrepancies with respect to “design” values. A clear way to demonstrate the existence of this component is to “turn off” the two others and to see whether or not there is still remaining variability. Perfect clones raised under well controlled laboratory conditions fulfill the conditions for such a test. Carried out for four different species, the test reveals a variability remainder of the order of 15% in terms of coefficient of variation (i.e. ratio of standard deviation to average, subsequently denoted by CV). As an example, the CV of the volume of E. coli (Escherichia Coli) bacteria immediately after binary fission is of that order.In short, “manufacturing” discrepancies occur randomly, even when no harmful mutation or environmental factors are involved. If the pathway is particularly long or requires exceptional accuracy, output dispersion will be high and may lead to malformations. This effect will be referred to as the random dispersion effect. We conjecture that it will be particularly significant when major changes occur; this includes the early phase of embryogenesis or the first steps leading from stem cells to differentiated (organ-specific) cells.The dispersion effect not only causes malformations but also innocuous variability. For instance monozygotic (MZ) twins resemble each other but are not strictly identical. It is not uncommon to see only one of the twins of a MZ pair showing a congenital defect (see Appendix A).Not surprisingly, there is a strong connection between congenital defects and infant mortality. In the wake of birth there is a gradual elimination of defective units and this screening accounts for the decline of postnatal infant mortality. In humans, for reasons which are not yet understood, this decline continues until the age of about 10 years. Neither do we understand why, as a function of age, the downward trend of human infant mortality follows a power law with an exponent around 1 (whereas for fish it is about 3, see Bois et al. 2019a). Apart from this trend, post-natal death rates also have humps and peaks associated with various inabilities and defects.In short, infant mortality rates convert the case-by-case and mostly qualitative problem of congenital malformations into a global quantitative effect which, so to say, summarizes what goes wrong in the embryonic phase.Based on the natural assumption that for simple organisms (e.g. rotifers) the manufacturing processes are shorter than for more complex organisms (e.g. mammals), fewer congenital anomalies are expected and therefore also lower infant mortality. How this conjecture can be tested is outlined in our conclusion.