Stress Responses across the Scales of Life: Toward a Universal Theory of Biological Stress.

Although biological systems are more complex and can actively respond to their environment, an effective entry point to the development of a universal theory of biological stress is the physical concepts of stress and strain. If you apply stress to the end of a beam of steel, the strain will accumulate within that steel beam. If the stress is weak then the strain will disappear when the force is removed and the beam will return to its original state of form and functionality. If the stress is more severe, then the strain becomes permanent and the beam will be deformed, potentially losing some degree of functionality. In extremely stressful situations, the beam will break and lose most or all of its original functional capabilities. Although this stress-strain theory applies to the abiotic, stress and strain are also rules of life and directly relate to the form and function of living organisms. The main difference is that life can react and adjust to stress and strain to maintain homeostasis within a range of limits. Here, we summarize the rules of stress and strain in living systems ranging from microbes to multicellular organisms to ecosystems with the goal to identify common features that may underlie a universal biological theory of stress. We then propose to establish a range of experimental, observational, and analytical approaches to study stress across scales, including synthetic microbial communities that mimic many of the essential characteristics of living systems, thereby enabling a universal theory of biological stress to be experimentally validated without the constraints of timescales, ethics, or cost found when studying other species or scales of life. Although the range of terminology, theory, and methodology used to study stress and strain across the scales of life presents a formidable challenge to creating a universal theory of biological stress, working toward such a theory that informs our understanding of the simultaneous and interconnected unicellular, multicellular, organismal, and ecosystem stress responses is critical as it will improve our ability to predict how living systems respond to change, thus informing solutions to current and future environmental and human health challenges.

Differential sensitivity of oligodendrocytes and motor neurons to reactive nitrogen species: implications for multiple sclerosis.

Depending on its concentration, nitric oxide (NO) has beneficial or toxic effects. In pathological conditions, NO reacts with superoxide to form peroxynitrite, which nitrates proteins forming nitrotyrosine residues (3NY), leading to loss of protein function, perturbation of signal transduction, and cell death. 3NY immunoreactivity is present in many CNS diseases, particularly multiple sclerosis. Here, using the high flux NO donor, spermine-NONOate, we report that oligodendrocytes are resistant to NO, while motor neurons are NO sensitive. Motor neuron sensitivity correlates with the NO-dependent formation of 3NY, which is significantly more pronounced in motor neurons when compared with oligodendrocytes, suggesting peroxynitrite as the toxic molecule. The heme-metabolizing enzyme, heme-oxygenase-1 (HO1), is necessary for oligodendrocyte NO resistance, as demonstrated by loss of resistance after HO1 inhibition. Resistance is reinstated by peroxynitrite scavenging with uric acid further implicating peroxynitrite as responsible for NO sensitivity. Most importantly, differential sensitivity to NO is also present in cultures of primary oligodendrocytes and motor neurons. Finally, motor neurons cocultured with oligodendrocytes, or oligodendrocyte-conditioned media, become resistant to NO toxicity. Preliminary studies suggest oligodendrocytes release a soluble factor that protects motor neurons. Our findings challenge the current paradigm that oligodendrocytes are the exclusive target of multiple sclerosis pathology.