Electronic Energy Migration in Microtubules.

The repeating arrangement of tubulin dimers confers great mechanical strength to microtubules, which are used as scaffolds for intracellular macromolecular transport in cells and exploited in biohybrid devices. The crystalline order in a microtubule, with lattice constants short enough to allow energy transfer between amino acid chromophores, is similar to synthetic structures designed for light harvesting. After photoexcitation, can these amino acid chromophores transfer excitation energy along the microtubule like a natural or artificial light-harvesting system? Here, we use tryptophan autofluorescence lifetimes to probe energy hopping between aromatic residues in tubulin and microtubules. By studying how the quencher concentration alters tryptophan autofluorescence lifetimes, we demonstrate that electronic energy can diffuse over 6.6 nm in microtubules. We discover that while diffusion lengths are influenced by tubulin polymerization state (free tubulin versus tubulin in the microtubule lattice), they are not significantly altered by the average number of protofilaments (13 versus 14). We also demonstrate that the presence of the anesthetics etomidate and isoflurane reduce exciton diffusion. Energy transport as explained by conventional Förster theory (accommodating for interactions between tryptophan and tyrosine residues) does not sufficiently explain our observations. Our studies indicate that microtubules are, unexpectedly, effective light harvesters.

Anesthetic Alterations of Collective Terahertz Oscillations in Tubulin Correlate with Clinical Potency: Implications for Anesthetic Action and Post-Operative Cognitive Dysfunction.

Anesthesia blocks consciousness and memory while sparing non-conscious brain activities. While the exact mechanisms of anesthetic action are unknown, the Meyer-Overton correlation provides a link between anesthetic potency and solubility in a lipid-like, non-polar medium. Anesthetic action is also related to an anesthetic's hydrophobicity, permanent dipole, and polarizability, and is accepted to occur in lipid-like, non-polar regions within brain proteins. Generally the protein target for anesthetics is assumed to be neuronal membrane receptors and ion channels, however new evidence points to critical effects on intra-neuronal microtubules, a target of interest due to their potential role in post-operative cognitive dysfunction (POCD). Here we use binding site predictions on tubulin, the protein subunit of microtubules, with molecular docking simulations, quantum chemistry calculations, and theoretical modeling of collective dipole interactions in tubulin to investigate the effect of a group of gases including anesthetics, non-anesthetics, and anesthetic/convulsants on tubulin dynamics. We found that these gases alter collective terahertz dipole oscillations in a manner that is correlated with their anesthetic potency. Understanding anesthetic action may help reveal brain mechanisms underlying consciousness, and minimize POCD in the choice and development of anesthetics used during surgeries for patients suffering from neurodegenerative conditions with compromised cytoskeletal microtubules.

Anesthetics act in quantum channels in brain microtubules to prevent consciousness.

The mechanism by which anesthetic gases selectively prevent consciousness and memory (sparing non-conscious brain functions) remains unknown. At the turn of the 20(th) century Meyer and Overton showed that potency of structurally dissimilar anesthetic gas molecules correlated precisely over many orders of magnitude with one factor, solubility in a non-polar, 'hydrophobic' medium akin to olive oil. In the 1980s Franks and Lieb showed anesthetics acted in such a medium within proteins, suggesting post-synaptic membrane receptors. But anesthetic studies on such proteins yielded only confusing results. In recent years Eckenhoff and colleagues have found anesthetic action in microtubules, cytoskeletal polymers of the protein tubulin inside brain neurons. 'Quantum mobility' in microtubules has been proposed to mediate consciousness. Through molecular modeling we have previously shown: (1) olive oil-like non-polar, hydrophobic quantum mobility pathways ('quantum channels') of tryptophan rings in tubulin, (2) binding of anesthetic gas molecules in these channels, and (3) capabilities for π-electron resonant energy transfer, or exciton hopping, among tryptophan aromatic rings in quantum channels, similar to photosynthesis protein quantum coherence. Here, we show anesthetic molecules can impair π-resonance energy transfer and exciton hopping in tubulin quantum channels, and thus account for selective action of anesthetics on consciousness and memory.

Quantum effects in the understanding of consciousness.

This paper presents a historical perspective on the development and application of quantum physics methodology beyond physics, especially in biology and in the area of consciousness studies. Quantum physics provides a conceptual framework for the structural aspects of biological systems and processes via quantum chemistry. In recent years individual biological phenomena such as photosynthesis and bird navigation have been experimentally and theoretically analyzed using quantum methods building conceptual foundations for quantum biology. Since consciousness is attributed to human (and possibly animal) mind, quantum underpinnings of cognitive processes are a logical extension. Several proposals, especially the Orch OR hypothesis, have been put forth in an effort to introduce a scientific basis to the theory of consciousness. At the center of these approaches are microtubules as the substrate on which conscious processes in terms of quantum coherence and entanglement can be built. Additionally, Quantum Metabolism, quantum processes in ion channels and quantum effects in sensory stimulation are discussed in this connection. We discuss the challenges and merits related to quantum consciousness approaches as well as their potential extensions.

Quantum mathematical cognition requires quantum brain biology: the "Orch OR" theory.

The "Orch OR" theory suggests that quantum computations in brain neuronal dendritic-somatic microtubules regulate axonal firings to control conscious behavior. Within microtubule subunit proteins, collective dipoles in arrays of contiguous amino acid electron clouds enable "quantum channels" suitable for topological dipole "qubits" able to physically represent cognitive values, for example, those portrayed by Pothos & Busemeyer (P&B) as projections in abstract Hilbert space.

The zinc dyshomeostasis hypothesis of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia in the elderly. Hallmark AD neuropathology includes extracellular amyloid plaques composed largely of the amyloid-ß protein (Aß), intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated microtubule-associated protein tau (MAP-tau), and microtubule destabilization. Early-onset autosomal dominant AD genes are associated with excessive Aß accumulation, however cognitive impairment best correlates with NFTs and disrupted microtubules. The mechanisms linking Aß and NFT pathologies in AD are unknown. Here, we propose that sequestration of zinc by Aß-amyloid deposits (Aß oligomers and plaques) not only drives Aß aggregation, but also disrupts zinc homeostasis in zinc-enriched brain regions important for memory and vulnerable to AD pathology, resulting in intra-neuronal zinc levels, which are either too low, or excessively high. To evaluate this hypothesis, we 1) used molecular modeling of zinc binding to the microtubule component protein tubulin, identifying specific, high-affinity zinc binding sites that influence side-to-side tubulin interaction, the sensitive link in microtubule polymerization and stability. We also 2) performed kinetic modeling showing zinc distribution in extra-neuronal Aß deposits can reduce intra-neuronal zinc binding to microtubules, destabilizing microtubules. Finally, we 3) used metallomic imaging mass spectrometry (MIMS) to show anatomically-localized and age-dependent zinc dyshomeostasis in specific brain regions of Tg2576 transgenic, mice, a model for AD. We found excess zinc in brain regions associated with memory processing and NFT pathology. Overall, we present a theoretical framework and support for a new theory of AD linking extra-neuronal Aß amyloid to intra-neuronal NFTs and cognitive dysfunction. The connection, we propose, is based on ß-amyloid-induced alterations in zinc ion concentration inside neurons affecting stability of polymerized microtubules, their binding to MAP-tau, and molecular dynamics involved in cognition. Further, our theory supports novel AD therapeutic strategies targeting intra-neuronal zinc homeostasis and microtubule dynamics to prevent neurodegeneration and cognitive decline.

"Memory bytes" - molecular match for CaMKII phosphorylation encoding of microtubule lattices.

Learning, memory and long-term potentiation (LTP) are supported by factors including post-synaptic calcium ion flux activating and transforming the hexagonal calcium-calmodulin kinase II (CaMKII) holoenzyme. Upon calcium-induced activation, up to six kinase domains extend upward, and up to six kinase domains extend downward from the CaMKII association domain, the fully activated holoenzyme resembling a robotic insect 20 nanometers in length. Each extended kinase domain can be phosphorylated, and able to phosphorylate other proteins, thus potentially further encoding synaptic information at intraneuronal molecular sites for memory storage, processing and distribution. Candidate sites for phosphorylation-encoded molecular memory include microtubules, cylindrical lattice polymers of the protein tubulin. Using molecular modeling, we find spatial dimensions and geometry of the six extended CaMKII kinase domains can precisely match those of microtubule hexagonal lattice neighborhoods (both A- and B-lattices), and show two feasible phosphorylation mechanisms. In one, phosphorylation sites (e.g., valine 208) on a CaMKII extended kinase domain interact with serine 444 on a C-terminal "tail" of tubulin. In the second, the CaMKII kinase domain unfurls, enabling phosphorylation sites to contact threonine and serine sites on the tubulin surface. We suggest sets of six CaMKII kinase domains phosphorylate hexagonal microtubule lattice neighborhoods collectively, e.g., conveying synaptic information as ordered arrays of six "bits", and thus a "byte", with (minimally) 26 (64) possible bit states per CaMKII-microtubule interaction. We model two levels of interaction between CaMKII and microtubules, suggesting a testable framework for molecular memory encoding.

The brain is both neurocomputer and quantum computer.

In their article, Is the Brain a Quantum Computer,? Litt, Eliasmith, Kroon, Weinstein, and Thagard (2006) criticize the Penrose-Hameroff "Orch OR" quantum computational model of consciousness, arguing instead for neurocomputation as an explanation for mental phenomena. Here I clarify and defend Orch OR, show how Orch OR and neurocomputation are compatible, and question whether neurocomputation alone can physiologically account for coherent gamma synchrony EEG, a candidate for the neural correlate of consciousness. Orch OR is based on quantum computation in microtubules within dendrites in cortex and other regions linked by dendritic-dendritic gap junctions ("dendritic webs") acting as laterally connected input layers of the brain's neurocomputational architecture. Within dendritic webs, consciousness is proposed to occur as gamma EEG-synchronized sequences of discrete quantum computational events acting in integration phases of neurocomputational "integrate-and-fire" cycles. Orch OR is a viable approach toward understanding how the brain produces consciousness.

A new theory of the origin of cancer: quantum coherent entanglement, centrioles, mitosis, and differentiation.

Malignant cells are characterized by abnormal segregation of chromosomes during mitosis ("aneuploidy"), generally considered a result of malignancy originating in genetic mutations. However, recent evidence supports a century-old concept that maldistribution of chromosomes (and resultant genomic instability) due to abnormalities in mitosis itself is the primary cause of malignancy rather than a mere byproduct. In normal mitosis chromosomes replicate into sister chromatids which are then precisely separated and transported into mirror-like sets by structural protein assemblies called mitotic spindles and centrioles, both composed of microtubules. The elegant yet poorly understood ballet-like movements and geometric organization occurring in mitosis have suggested guidance by some type of organizing field, however neither electromagnetic nor chemical gradient fields have been demonstrated or shown to be sufficient. It is proposed here that normal mirror-like mitosis is organized by quantum coherence and quantum entanglement among microtubule-based centrioles and mitotic spindles which ensure precise, complementary duplication of daughter cell genomes and recognition of daughter cell boundaries. Evidence and theory supporting organized quantum states in cytoplasm/nucleoplasm (and quantum optical properties of centrioles in particular) at physiological temperature are presented. Impairment of quantum coherence and/or entanglement among microtubule-based mitotic spindles and centrioles can result in abnormal distribution of chromosomes, abnormal differentiation and uncontrolled growth, and account for all aspects of malignancy. New approaches to cancer therapy and stem cell production are suggested via non-thermal laser-mediated effects aimed at quantum optical states of centrioles.

A quantum approach to visual consciousness.

A theoretical approach relying on quantum computation in microtubules within neurons can potentially resolve the enigmatic features of visual consciousness, but raises other questions. For example, how can delicate quantum states, which in the technological realm demand extreme cold and isolation to avoid environmental 'decoherence', manage to survive in the warm, wet brain? And if such states could survive within neuronal cell interiors, how could quantum states grow to encompass the whole brain? We present a physiological model for visual consciousness that can accommodate brain-wide quantum computation according to the Penrose-Hameroff 'Orch OR' model. In this view, visual consciousness occurs as a series of several-hundred-millisecond epochs, each comprising 'crescendo sequences' of quantum computations occurring at approximately 40 Hz.