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Making sense of oxygen; quantum leaps with ‘physics‐iology’

2019; Wiley; Volume: 104; Issue: 4 Linguagem: Inglês

10.1113/ep087546

1469-445X

Damian M. Bailey,

Hemoglobin structure and function

In the first Guest Editorial, published in the July issue of Experimental Physiology, Dr van Tulleken spoke to the powers of physiology, stating that, ‘…it is only physiology that has created an understanding of the body that can usefully guide an individual's approach to their own life’ (van Tulleken, 2018). True words indeed, and since the landmark publication of Harvey's Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus in 1628 (Harvey, 1976), the journey of physiology to prominence has been a colourful one. Originally rooted to anatomy and medicine through an organ–system approach, it has since matured into a distinct discipline that has made huge strides by taking an integrated molecular approach to provide ever more refined explanations of macroscopic phenomena and thereby illuminate the cellular and organismal ‘workings’ of the human body. Indeed, we have much to thank Ivan Pavlov, the first physiologist to win the Nobel Prize, for this hypothetica motus, because it was Pavlov, in 1897, who originally proposed that its future lay in understanding the ‘physiology of life molecules’ (Pavlov, 1955). Yet despite more than a century of research, our understanding of the complexities underlying physiological processes and systems is often incomplete and lacks explanatory power, suggesting that we need to move beyond the ‘classical’ approaches to explore deeper meanings and unravel how we, as humans, really work. Quantum ‘physics-iology’ (the ‘-ics’ being all important!) might well signal the breaking of a new dawn. Physiologists have taken up the quantum baton, becoming increasingly interested in the fusion of ‘quantum physics’ with the ‘physiology’ of life molecules to provide answers where traditional classical approaches have consistently failed (Natochin Iu, 2010; Wolynes, 2009). On the face of it, this makes intuitive sense because, after all, every object in this universe, including you and I, is made up of atoms, in fact a whopping 7 × 1027 (7 billion billion billion) of them in a 70 kg human (Freitas, 1999), arranged in a fortuitously obliging manner, complemented by an array of subatomic particles that are ultimately governed by the laws of quantum physics. Could the molecular mechanisms of life exploit some of these notoriously counterintuitive behaviours for physiological gain and could all its complexity be reduced to some unifying differential equation? Why not? After all, physics is considered the most fundamental of all sciences. But first, a brief word on those counterintuitive behaviours; mind-numbing paradoxes, puzzles and mathematical complexity that breathe fear into anyone with more than merely a fleeting interest in what the quantum world has to offer the jobbing physiologist. Since Max Planck first suggested that electromagnetic waves were emitted in discrete packets of energy or quanta (Planck, 1901), quantum mechanics (QM) has evolved into the fundamentally non-deterministic revolution that has overthrown classical (common-sense) physics. It has since matured into the best theory there is to describe the world around us at the nuts-and-bolts level of atoms and subatomic particles, whose behaviour cannot be understood within a classical context. In theory, and to some extent in practice, its tenets demand that particles can penetrate through solid barriers (tunnelling), be in two places at once [both as particle and wave (superposition)] and instantly exchange information despite being spatially separated, violating our intuition about locality (entanglement), so that even Albert Einstein referred to it as ‘spooky action at a distance’, and it led Niels Bohr, the father of the orthodox ‘Copenhagen interpretation’ of quantum physics, to remark, ‘If quantum mechanics hasn't profoundly shocked you, you haven't understood it yet’ (Griffiths, 2017). Yet it was Erwin Schrödinger, famous for his wave equation for non-relativistic QM, popularized by his alive and dead cat conundrum, who was the first to venture across disciplines and ask whether humans can harness non-trivial quantum effects to perform a task more efficiently than even the best classical equivalent for selective advantage. In his landmark book, What is Life?, he argued that life somehow opposes the entropic tendency towards dissolution, feeding on negative entropy (second law of thermodynamics), and further anticipated a quantum molecular basis for human heredity, with genetic information transmitted by an arrangement of atoms in an ‘aperiodic crystal’, which was confirmed 9 years later to be the DNA molecule (Schrödinger, 1944); remarkable! However, the notion that the macroscopic order of life is somehow based on order at its quantum level was met with justifiable scepticism, given that quantum phenomena are typically observed on the smallest of subatomic scales under vacuum at ultra-low cryogenic temperatures (avoiding the detrimental effects of decoherence and dephasing) and should simply fade away in the warm, wet mess of the macroscopic (Ball, 2011). Yet emerging evidence now suggests that quantum coherence can survive in vivo as life hovers in a posed realm between the pure quantum and incoherent classical world to improve our physiological lot. Many of these revelations have stemmed from our understanding of the behaviour of electrons, the first subatomic particles to be discovered by Joseph Thompson (originally given the physiological term, corpuscle, meaning ‘small body’; Thomson, 1897), weighing in at an infinitesimal 9.10939 × 10−31 kg (to be precise!), whose position and momentum cannot be determined simultaneously with perfect accuracy thanks to the Heisenberg uncertainty principle (Heisenberg, 1927). Their quantum weirdness has helped explain to explain the following: the mysteries of avian navigation, exploiting properties of electronic spin in birds’ retinas (Ritz, Adem, & Schulten, 2000); olfaction, whereby an electron within a smell receptor in our nose can ‘jump’ or tunnel across it and dump a quantum of energy into one of the molecule's bonds, causing the molecular ‘spring’ to vibrate and resulting in smell (Turin, 1996); genes that may be ‘written in quantum letters’, with quantum effects underlying the hydrogen bonds that keep the DNA double helix glued together (McFadden & Al-Khalili, 1999); general anaesthesia, which is accompanied by changes in electron spin, implicating a role for neuronal electron current in its effects (Turin, Skoulakis, & Horsfield, 2014); and, arguably the best described of all, light harvesting in photosynthesis, whereby excitons, generated by ancient green, sulphur-breathing bacteria, travel as a coordinated quantum wave in superposition rather than (classically) as a simple straight line, ‘feeling out’ the most efficient pathway to transport energy to the plant's reaction centre within a staggeringly short 10−9 s, achieving close to 100% efficiency (Thyrhaug et al., 2018), considered until now to be thermodynamically inconceivable. These new ideas have since led to the concept of directed ‘quantum evolution’, whereby quantum effects might have been selected for at the very beginning of life owing to their ability to improve the efficiency of energy transduction, providing a tantalizing alternative to how the first ‘self-replicator’ molecules arose and gave life the edge it needed to survive (McFadden, 2000). Even oxygen (O2), the ancient gas that our mitochondrion has evolved to be so irreversibly reliant upon since it first appeared in the atmosphere during the Proterozoic aeon of the Precambrian period ∼2500–540 million years ago, is defined by a quantum weirdness that simply beggars belief (Bailey, 2019a). Its quantum structure reveals that in its most stable ground state, O2 exists in air as a potentially toxic, mutagenic free radical gas, because it has two unpaired electrons with parallel spins in opposing orbitals (Figure 1a). Thankfully for us, this configuration means that O2 is ‘spin restricted’, forcing it to accept electrons one at a time, with the sequential formation of free radicals and reactive oxygen species (ROS) during its reduction to water in the mitochondria. This means that, despite its powerful oxidizing nature (it is highly explosive rocket fuel, after all!), O2 reacts sluggishly with our body's organic biomolecules; indeed, if it was not for this thermodynamic quirk of fate, we would combust spontaneously in room air (Figure 1a). The fact that the Michaelis constant of the terminal reductant, cytochrome c oxidase, for O2 is so extraordinarily low (0.03–0.3 mmHg; Vanderkooi, Erecinska, & Silver, 1991) stands as further testament to how important it is to harness this molecule within ‘safe’ physiological limits. Thus, with the Janus face of O2, you would be excused for assuming that the human brain would be especially prone to the ravages of free radical attack, given that its evolutionary ‘drive for size’ means that it now consumes a disproportionate 10 times more O2 than that expected from its mass alone, coupled with limited regenerative capacity and histological susceptibility to oxidative damage (Bailey et al., 2018; Herculano-Houzel, 2012). Not surprising when you consider that the brain has been estimated to hold up to a staggering 580 terabytes of information, equivalent to 5 years-worth of high-definition film (Nunn, Guy, & Bell, 2016)! Yet rather than simply misbehaving as random, destructive ‘accidents’ of in vivo chemistry constrained to cellular oxidative damage and pathophysiology, free radicals, defined by their unpaired electron(s) and all their quantum weirdness, are rapidly emerging as purposeful intra/extracellular signal transductants capable of titrating exactly the right amount of explosive rocket fuel to the brain (Bailey, 2019b). Given that its O2 supply is indeed so delicate, walking the tightrope between too much or too little, the ability to ‘sense’ changes in and mount a defence against metabolic compromise and/or structural damage was probably one of the first roles of the CNS and probably represented a major driving force in the evolution of the human brain, providing a selective advantage (Costa, Accorsi-Mendonca, Moraes, & Machado, 2014). Even the last universal common ancestor, a genetically and metabolically diverse community containing the molecular origins of all present life forms, estimated to have appeared ∼3.8 billion years ago, took advantage of the univalent reductant of O2, the superoxide anion (O2•−; Briehl, 2015), which is not terribly super in terms of its thermodynamic reactivity (one electron reduction potential of +940 mV; Figure 1a), yet nonetheless heralded as arguably the first signal transductant. This ancient species has certainly stood the test of time, and it has become increasingly clear that the brain, as indeed all other organ systems, relies on controlled mitochondrial formation of O2•− and hydrogen peroxide (yet another rocket fuel!) in times of O2 lack (hypoxia) as a ‘quantum trigger’ that provides superfast upstream control of blood flow and, importantly, stabilization of the ‘mother gene’, hypoxia-inducible factor-1 alpha, resulting in transcription of genes that collectively preserve cerebral O2 homeostasis (Figure 1b; Chandel et al., 1998). Importantly, it appears that this mechanism might well exploit QM to optimize energy transduction, because the speed at which many of these reactions proceed cannot be explained adequately by traditional (classical) ‘strait-jacketed’ methods of thinking. Mitochondrial formation of ‘spin-correlated radical pairs’, generated through activation of molecular O2 by reduced flavins (Usselman et al., 2016), superposition, tunnelling, entanglement and altered coherence triggered by changing mitochondrial membrane potential, have since emerged as quantum contributors implicated in the coordinated regulation of cellular bioenergetics, coupling electron flow and protonation through a process known as redox tuning at a quantum coherence ‘sweet spot’ (de Vries, Dorner, Strampraad, & Friedrich, 2015; Nunn, Guy, & Bell, 2017). The nuclear spin properties of phosphorous allow for quantum processing in the brain via transfer of information (qubits) via quantum-entangled pairs protected by so-called Posner clusters, affecting neurotransmitter release and neuronal firing rates, notwithstanding enhanced chemical reactivity of ROS (Fisher & Radzihovsky, 2018). Furthermore, proton (not only electron!) tunnelling has been shown to play a key role in enzymatic reactions with calcium, sodium and potassium, whose particle–wave duality accounts for ion channel selectivity, helping to explain differences between those classically predicted by the Hodgkin–Huxley equation and experimental observations in neural circuits (Moradi, Scholkmann, & Salari, 2015). These emergent findings force a reappraisal of currently (i.e. classically) accepted concepts, revealing more complex redox-regulated signalling mechanisms than previously thought (Bailey, 2019a). Whether energy/information transfer in the human brain takes advantage of nature's other, more recently identified, quantum tricks, such as quantum beating (thermal vibrations used to pump coherence and facilitate QM effects; Weber, Ohmes, Thurnauer, Norris, & Kothe, 1995), vibronic coupling (stimulation of vibrational modes in proteins to create a sweet spot for coherence and electron tunnelling, recently speculated to occur between mitochondria behaving like fused ‘power cables’ and microtubules, with the latter contributing to resonant energy transfer and consciousness; Srobar, 2012), or quantum criticality (proteins acting as charge carriers, exhibiting properties between an insulator and conductor; Craddock, Friesen, Mane, Hameroff, & Tuszynski, 2014), remains to be explored, although designing studies to test these hypotheses remains a major experimental challenge. Nonetheless, it is a challenge worth taking, given our current ignorance; take one of the world's most powerful supercomputers (Japan's Fujitsu-built ‘K’), the first to break the 10 petaflop barrier, or 10 quadrillion operations per second, which boasts computing power equivalent to 250,000 personal computers, programmed to simulate 1.73 billion virtual neurons and 10.4 trillion virtual synapses, each holding 24 bytes of memory. While requiring >9 MW of power (equivalent to a small power station), ∼450–750 × 103 more than that required to run the human brain (12–20 W), it still took 40 min to crunch the data and replicate a meagre 1 s worth of 1% of human brain activity (Sparkes, 2014)! Current computing power, even at the exascale level (one quintillion ‘floating point’ operations per second), fails to adequately simulate the brain's level of ‘interconnectedness’ (Bradler, 2018). Perhaps the collaborative union of physics-iology, by transcending traditional disciplinary boundaries and bridging the gap between the atomic and the cellular, could be a winning formula that can reveal buried treasures and provide unique insight into the pathophysiology and treatment of neurodegenerative diseases that remain impervious to classical treatments. It is fitting to look into the past to predict the future, reminding ourselves of one of Richard Feynman's (many) prescient quotations after winning the 1965 Nobel prize in Physics for fundamental work in quantum electrodynamics, ‘…there is nothing that living things do that cannot be understood from the point of view that they are made of atoms acting according to the laws of physics’ (Feynman, 1963). None declared.