A Puzzling Question: How Can Different Phenotypes Possibly Have Indistinguishable Disease Symptoms?

Abstract

Homeostasis is a cardinal feature of our body’s response to changes in the environment. However, there are circumstances under which seemingly small changes may have much greater impact through emergent phenomena affecting the development of life as well as disease. Revisiting Peter Macklem’s paper “Emergent phenomena and the secrets of life” inspired a review of our current understanding of key concepts of emergent behavior at the “edge of chaos” between liquids and crystals where the spontaneous development of self-organized order occurs that is essential for both the development of life and the control of homeostasis. These phenomena occur at all length scales from the molecular to the whole-body level. During asthma attacks for example, bronchoconstriction within the airway tree results in the emergence of self-organized clustering of severe airway constriction causing large ventilation defects, while other areas of the lungs remain well-ventilated. This transition from stable open airways (homeostasis) to the regional clustering of severe airway constriction occurs at a critical point in the interactions among airways. The critical point itself can be shifted by several factors including increase in airway wall thickness, which is linked to airway inflammation and remodeling in asthma. However, injury of the airways may be caused by severe airway constriction within ventilation defects. That means that different asthma phenotypes causing increased airway wall thickness would shift the critical point of airway stability and promote the emergence of ventilation defects leading to symptoms independent of the phenotype. In summary, the example shows how different underlying processes (phenotypes) may affect or trigger disease-specific emergent phenomena that cause symptoms without phenotype-specific characteristics.