Oxygen, evolution and redox signalling in the human brain; quantum in the quotidian.

Rising atmospheric oxygen (O2 ) levels provided a selective pressure for the evolution of O2 -dependent micro-organisms that began with the autotrophic eukaryotes. Since these primordial times, the respiring mammalian cell has become entirely dependent on the constancy of electron flow, with molecular O2 serving as the terminal electron acceptor in mitochondrial oxidative phosphorylation. Indeed, the ability to 'sense' O2 and maintain homeostasis is considered one of the most important roles of the central nervous system (CNS) and probably represented a major driving force in the evolution of the human brain. Today, modern humans have evolved with an oversized brain committed to a continually active state and, as a consequence, paradoxically vulnerable to failure if the O2 supply is interrupted. However, our pre-occupation with O2 , the elixir of life, obscures the fact that it is a gas with a Janus face, capable of sustaining life in physiologically controlled amounts yet paradoxically deadly to the CNS when in excess. A closer look at its quantum structure reveals precisely why; the triplet ground state diatomic O2 molecule is paramagnetic and exists in air as a free radical, constrained from reacting aggressively with the brain's organic molecules due to its 'spin restriction', a thermodynamic quirk of evolutionary fate. By further exploring O2 's free radical 'quantum quirkiness', including emergent (quantum) physiological phenomena, our understanding of precisely how the human brain senses O2 deprivation (hypoxia) and the elaborate redox-signalling defence mechanisms that defend O2 homeostasis has the potential to offer unique insights into the pathophysiology and treatment of human brain disease.