From Quantum Physics to Quantum Biology in 100 years

How long to Quantum Medicine?

Jack TuszynskiUniversity of AlbertaEdmonton, Canada

Solvay ConferenceBrussels 1927

Basics of Quantum Mechanics

Classical mechanics (Newton's mechanics) and Maxwell's equations (electromagnetic theory) can explain MACROSCOPIC phenomena such as motion of billiard balls or rockets.

Quantum mechanics is used to explain MICROSCOPIC phenomena such as photon-atom scattering and flow of the electrons in a semiconductor. But there are macroscopic quantum effects in: superfluids, superconductors, lasers and crystal dynamics (phonons)

QUANTUM MECHANICS developed postulates based on a huge number of experimental observations. It has a precise mathematical formalism of Hermitian operators in Hilbert spaces

Basics of Quantum Mechanics

Microscopic physical systems can act as both particles and waves WAVE-PARTICLE DUALITY

Quantum state is a superposition of a number of possible outcomes of measurements of physical properties Quantum mechanics uses the language of PROBABILITY theory

An observer cannot observe a microscopic system without altering some of its properties (an observer problem)

QUANTIZATION of energy is yet another property of "microscopic" particles.

Heisenberg Uncertainty Principle

One cannot unambiguously specify the values of particle's position and its momentum for a microscopic particle, i.e.

Position and momentum are, therefore, considered as incompatible variables (same for angle and angular momentum; time and energy)

22

100 )()( h

x tptx

The Photoelectric Effect

A Photocell is Used to Study the Photoelectric Effect

Larger frequency, means smaller wavelength, and larger Energy=hf.

Additional experiments demonstrating quantum nature of the microscopic universe

The Compton effect (photon-electron scattering)

Atomic absorption/emission spectraDouble slit experiments (electrons and

photons)Stern-Gerlach experiment (magnetic spin)

The First Postulate of QM

States of microscopic systems are represented by wave functions STATE FUNCTIONS (square integrable).

First postulate of Quantum mechanics:Every physically-realizable state of the system is described in quantum mechanics by a state function that contains all accessible physical information about the system in that state.

State function function of position, momentum, energy that is spatially localized.

If 1 and 2 represent two physically-realizable states of the system, then so is their linear combination

The Second Postulate of Quantum Mechanics

If a system is in a quantum state represented by a wavefunction , then

is the probability that in a position measurement at time t the particle will be detected in the infinitesimal volume dV.

Note: position and time probability density

According to the second postulate of quantum mechanics, the integrated probability density can be interpreted as a probability that in a position measurement at time t, we will find the particle anywhere in space (i.e one= certainty)

dVPdV 2

2),( tx

The Third Postulate of Quantum Mechanics -

Every observable in quantum mechanics is represented by an operator which is used to obtain physical information about the observable from the state function. For an observable that is represented in classical physics by a function Q(x,p), the corresponding operator is ),( pxQ .

Observable Operator

Position x

Momentum xi

p

Energy )(

2)(

2 2

222xV

xmxV

mpE

Basics of Quantum Mechanics

- Fourth Postulate of Quantum Mechanics -1926 Erwin Schrödinger proposed an equation that describes the evolution of a quantum-

mechanical system SWE which represents quantum equations of motion, and is of the form:

titxxV

xmtxxV

xm

),()(2

),()(2 2

22

2

22

This work of Schrödinger was stimulated by a 1925 paper by Einstein on the quantum theory of ideal gas, and the de Broglie theory of matter waves. Note:

Examining the time-dependent SWE, one can also define the following operator for the total energy:

tiE

Fourth (Fundamental) postulate of Quantum mechanics:

The time development of the state functions of an isolated quantum system is governed by the time-dependent SWE , where is the Hamiltonian of the system. Note on isolated system:

The TDSWE describes the evolution of a state provided that no observations are made. An observation alters the state of the observed system, and as it is, the TDSWE can not describe such changes.

Describes well quantum vibrational modes of molecular gases

Describes well specific heats of solids

Macroscopic Quantum Effects

• Superconductivity• Superfluidity• Laser Action• Crystal Vibrations (Phonons)• Magnetism

Quantum Mechanics and Life Nature over 2B years of experimentation on

Earth must have taken advantage quantum mechanics

Quantum Mechanics and Life

• Where does quantum weirdness fit in?

• Coherence– superposition of states

• Entanglement– “spooky action at a

distance”:distant particles affecting

one another without energy transfer

Quantum Mechanics and Life

Five Gifts of Quantum Mechanics to Nature

StabilityCountabilityInformation

Information ProcessingRandomness

physicists think everything reduces to physics

But interactions matter:hierarchies of systems form

BiochemistryChemistry

Condensed matterPhysics

Elementary particlePhysics

nucleic acids proteins

ions molecules (valence is important)

quarks nucleons

electrons & protons solids

Combinatorial Barriers

Elsasser’s immense numberI = 10110

I = atomic weight of the Universe measured in proton’s mass (daltons) time the age of the Universe in picoseconds (10-12 s)

No conceivable computer could store a list of I objects, and even if it could, there would be no time to inspect it !

Dimensions Matter, tooOrganism

Cell

System

Biomolecule

Molecule

Atom

1020 Atoms

1010 Atoms

105 Atoms

103 Atoms

101 Atoms

1 Atom

Thermodynamics

Mesoscale:Quantum Biology?

QuantumChemistryQuantumPhysics

Energy/Affinity Scale

Covalent bond 90 kcal/mol at 1.5 Å Ion-Ion 60 kcal/mol at 5 Å Disulphide bond 40 kcal/mol at 2.2 Å Salt bridge 4-7 kcal/mol at 2.8 Å Ion-dipole 6 kcal/mol at 5 Å Hydrogen bond 0.5-12 kcal/mol at 3-5 Å VdW 1-4 kcal/mol at 3.5 Å kT at 310K is ~0.6 kcal/mol GTP/ATP hydrolysis (biological energy quanta): 3 kcal/mol-60 kcal/mol

Many discounted QM in biology because…• Life is big (cells) in comparison to photons/electrons where

QM is applicable• Life is hot (and active) in comparison to where QM works

best in cold isolated environments where it is currently studied [to keep QM coherence]

• Life is wet in comparison to controlled QM experimental environments where it is studied in a vacuum to avoid environmental influences which decoheres QM effects

• Life is slow in comparison to QM events where it is measured in milliseconds or less

• Life is complex, requiring billions of particle relationships/bonds in comparison to simple QM relationships/entanglements involving < 100 particles

• Life is not fuzzy (yes/no) and real in comparison to the QM random world which is probablistic multi value/states superpositions

• Life is real, local, and stable in comparison to Heisenberg QM uncertainty and non-local realism

• Life brings out discrete realism/information and QM always reverts to its fuzzy world

• … BUT Nature is the nanotech MASTER!!!!! … so it was soon found out that IT can!! since QM works in the nano-world of BIO

• Collective dynamics of many freedom degrees. • Life – a metastable state.• Various types of local and global order. • Structural and dynamic hierarchy, successive levels.• Biological complexity – order without repetition.• Short- and long-range correlations and interactions. • Living organisms are open, irreversible, disipative

systems. • They are self-organized, optimal systems (-

>homeostasis), with cooperative interactions. • Nonlinear interactions, highly integrated dynamics. • Such features – to some degree in various complex

non-living systems – but only organisms join them altogether.

Features of life unsolved by molecular biology

Quantum Mechanics and Life

Quantum computers use entanglement and coherence

These states are fragile environmental

decoherence keep cold &

isolated Biological

systems too “warm and

wet” Or are they?

Physiological Quantum Effects

• Light detection by the human eye• Resonant recognition of aromatic

molecules in olfaction (sense of smell)• Bird navigation• Photosynthesis• Mitochondrial Metabolism • Consciousness (?)

Wiki Definitions: Quantum biology refers to applications of quantum mechanics to

biological objects and problems. Usually, it is taken to refer to applications of the "non-trivial" quantum features such as…

superposition (no single value – fuzzy in that it exists partly in all its particular, theoretically possible states (or, configuration of its properties) simultaneously… multi-value or quantum combination property)

nonlocality (no local realism… reality is not solely determined by “local” spacetime values)

entanglement (shared functions/information for non-local realism consistency/correlation between sets of “ entangled particles”) and

tunneling (non particle single motion, multiple probability wave super positions due to Heisenberg uncertainty principle, and the wave–particle duality of matter, as opposed to the "trivial" applications such as chemical bonding which apply to biology only indirectly by dictating quantum chemistry.

Quantum biology• N.Bohr, W. Heisenberg, E. Schrodinger, J. von Neumann, C. von

Weizsacker, W. Elsasser, V. Weisskopf, E. Wigner, F. Dyson, A. Kastler, and others – QM essential for understanding life.

• Quantum biology (QB): “speculative interdisciplinary field that links quantum physics and the life sciences” (Wikipedia) –Some directions :– Quantum metabolism.– “Biophoton” (ultraweak emission) statistics.– Photosynthesis, light harvesting– Solitons (Davydov), phonons, conformons, plasmons, etc.– Decoherence, entanglement, quantum computation.– Long-range coherent excitations – Froehlich.– QED coherence in cellular water – Vitiello,Preparata, Del Giudice.

• Herbert Fröhlich postulated a dynamical order based on correlations in momentum space, the single coherently excited polar mode, as the basic living vs. non-living difference. Assumptions:

• (1) pumping of metabolic energy above a critical threshold; • (2) presence of thermal noise due to physiologic temperature; • (3) a non-linear interaction between the freedom degrees.

Physical image and biological implications:• A single collective dynamic mode excited far from equilibrium. • Collective excitations have features of a Bose-type condensate. • Coherent oscillations of 1011-1012 Hz of electric dipoles arise.• Intense electric fields allow long-range Coulomb interactions.• The living system reaches a metastable minimum of energy.• This is a terminal state for all initial conditions (e.g. Duffield 1985);

thus the genesis of life may be much more probable.

Fröhlich’s long-range coherence in living systems

Morphogenetic fields

• 1912:AlexanderGurwitsch introduced for the first time in biology the idea of a field as a supracellular ordering principle corresponding to spatial but immaterial factors of morphogenesis.

• Kraftfeld,a field in which a force is exerted.• Gurwitsch tried to solve the biological problem of morphogenesis: How living

tissues transform and transfer information about the size and shape of different organs.

• Chemical reactions do not contain spatial or temporal patterns a priori, and that is why Gurwitsch looked for a "morphogenetic field".

• Geschehensfeld,afield in which events, occur in an integrated, coordinated manner.Gurwitsch, A.G. (1912). Die Vererbung als Verwirklichungsvorgang, Biologisches Zentralblatt, vol. 32, no. 8, pp. 458-486.

Modern bioelectromagnetic field concepts

• 1970 Presman:Review on Soviet research in bioelectromagnetism stimulated the breakthrough and beginning of modern theories

• Non-equilibrium thermodynamics Organisms as open systems that exchange energy, matter and information –how they establish a stable state far from equilibrium A.Gurwitsch, E.Bauer, V.Vernadsky, and L.Bertalanffy.

• Contributions to modern concepts• Negative entropy Organisms preserve their high order by feeding on negentropy

(highly-organized energy) from the environment Erwin Schrodinger, Albert Szent Gyorgyi, Ilya Prigogine.

• Ilya Prigogine introduced his theory of dissipative structures, a discovery that won him the Nobel Prize in Chemistry in 1977

• •Herbert Frohlich introduced his concept of biological coherence.

Anatomy of the Intelligent CellGunther Albrecht-Buehler, NWUniv Chicago

Centriole-Mitochondria Connection (G. Albrecht-Buehler)

The control center detects objects and other cells objects by pulsating near infrared signals.

Cells have ‘eyes’ in the form of centrioles. They are able to detect infrared signals and steer the cell movements towards their source.

Percentage of cells that removed thelight scattering particle as a functionof wavelength. The near infraredwavelength, between 800 and 900 nm, is most attractive.

Extension of surfaceprojections towards thepulsating light source.

Centrioles

Basal bodies and centriolesconsist of a 9-fold arrangementof triplet microtubules. A molecularcartwheel fills the minus end of the cylinder; it is involved in initiating the assembly of the structure.The cylinders – now called cetrioles – are always found in pairs orientated at right angles. Dense clouds of sattelite material associated with the outer cylinder surfaces are responsible for the initiation of cytoplasmatic microtubules.

DNA

TF

MT

Free Tubulin Dimer

Nuclear Wall

Membrane

Cytoplasm

MT Bundle

Chromosome Pair

Centrosome

Mitotic Cell

. . . . .

Microtubule: function

Quantum MetabolismMetabolic activity is localized in the biomembranes

(1.) Plasma membrane Uni-cells(2.) Thylakoid membrane Chloroplasts in plants(3.) Inner membrane Mitochondria in animals

Evidence for quantum coherence• Engel 2007: Quantum Beating: direct evidence of quantum

coherence• Lee 2007: “correlated protein environments preserve

electronic coherence in photosynthetic complexes and allow the excitation to move coherently in space”

• Sarovar 2009: “a small amount of long-range and multipartite entanglement exists even at physiological temperatures.”

• What does this mean for other biological systems?

Photosynthesis

Photosynthesis Light energy absorbed by light harvesting

complexes (LHC) LHCs transfer energy to photosynthetic

reaction centers (RCs) RCs chemically store some energy (ie. ATP) Remaining energy removes electrons from

water or sulphates. Electrons used to turn CO2 into organic

compounds.

Photosynthesis LHCs are pigment-protein antennas, Densely packed chromophores efficient at

transporting excitation energy in disordered environments (~99%)

Chromophore number and spacing vary but separations on the scale of ∼ 15˚A

FMO Complex in C. Tepidum From a New Zealand

hot spring. Grow in dense mats

over hot springs that contain sufficient hydrogen sulfide

LHCs made of bacterio -chlorophylls (Bchls)

FMO Complex in C. Tepidum

FMO Complex in C. Tepidum

Quantum Search Algorithms

Mohseni et. al. investigated quantum search algorithms in FMO based on the Cho et. al. Hamiltonian

single-celled algae have a light-harvesting system where quantum

coherence is present.

A UNSW Australia-led team has discovered how cryptophytes that survive in very low levels of light are able to switch on and off a weird quantum phenomenon that occurs during photosynthesis.

Quantum Entanglement

Evidence for the existence of entanglement in the FMO complex for picosecond timescales

Prediction of entanglement is experimentally verifiable because of these timescales.

Evidence for the beneficial role of quantum coherence in LHC excitation transport.

Entanglement a by-product of quantum coherence.

Quantum Beating and Coherence

Superposition states formed during a fast excitation event allows the excitation to reversibly sample

relaxation rates from all component exciton states,

efficiently directs the energy transfer to find the most effective sink.

The system is essentially performing a single quantum computation

Analogous to Grover’s algorithm, Hamiltonian describing both relaxation to the

lowest energy state and coherence transfer

Extensions Penrose and Hameroff suggest quantum

computations in microtubules as playing a role in higher brain functions

“Aromatic" ring structures provide regions of delocalizable/ polarizable electrons and electronic excited states.

Tryptophan has an "indole ring" giving it a

high electron resonance and fluorescence

indole rings may take part in energy transfer (photon exchange).

Unexplained 8 MHz non-thermal radiation from microtubules.

Tryptophan path in tubulin and MTSpacing ~ 20 Ang

A lattice of seven tubulin dimers as found in the microtubule lattice. Red lines connect tryptophans, and rectangles show four possible winding patterns.(The work of Alexander Nip, Université de Montréal.)

• In photosynthesis coherent energy transferred between chromophoric chlorophyll molecules.

• Tubulin possesses a unique arrangement of chromophoric tryptophan amino acids.

• Spacing comparable to photosynthetic units.

Chromophore Network in Tubulin

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Dipole Interactions in Tubulin

• Chromophores transfer energy via transition dipole moments.

• Tryptophan may be excited by 260 - 305 nm light (UV range)• Possesses a transition dipole moment of ~ 5.5 - 6 Debye• Non-negligible dipole coupling strengths

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Tryptophan excitations in tubulin

In collaboration with Travis Craddock

Excitation Coherence in Tubulin

• Diagonalization of the Hamiltonian Matrix yields the excitation energies and distribution.

• Values indicate a significant delocalization of the excitation over several tryptophan residues.

• Quantum and local field corrections of protein environment taken into account.

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Dec

reas

ing

Ener

gy

Trp

1Tr

p 2

Trp

3Tr

p 4

Trp

5Tr

p 6

Trp

7Tr

p 8

<10%10-20%20-30%30-40%40-50%50-60%60-70%70-80%80-90%90-100%

Regulation of the Metabolic

Pathway

Regulated by several Mechanisms:• Product Inhibition • Feedback Inhibition • Reactant ActivationA lot of redundancy among pathways

Electron Transport Chain – Oxidative Phosphorylation

• Movement of electrons from NADH to terminal electron acceptor through Redox reactions

• Release of energy as electron moves from high to low Redox potential facilitates movement of H+ across the mitochondrial inner membrane

• Movement of H+ back across membrane through ATPase results in ATP synthesis from ADP

Energy consumption in organisms history

1. Laplace and Lavoisier (1780)Respiration is a form of combustionMetabolic rate could be measured by the amount of heatproduced by the organism

• Rubner (1904)i. Body size and metabolic rate of domesticated animals ii. Body size and life span

1. Kleiber (1940)Systematic study of the relation between basal

metabolic rate and body size

Body Size – Metabolism Allometric Relation

Y = α Wβ

W = body sizeThe Parameter Y

a) Measures of physiological time:I. Respiratory CycleII. Cardiac Cycle

b) Measures of metabolic activity:I. Basal metabolic RateII. Field metabolic RateIII. Maximal metabolic Rate

Y = Physiological time : β ~ 1/4

Y = Basal metabolic rate: uni-cells: β = 3/4

plants: 2/3 < β < 1animals: 2/3 < β < 3/4

ProblemsWhat is the mechanistic basis for these

scaling rules?

Issues to be addressed

1. Variation in proportionality constant α (Birds) > β (Mammals)

2. Variation in scaling exponentsβ (Plants) > β (Animals)

β (Large mammals) > β (Small birds)

Quantum Metabolism Metabolic activity has its origin in biochemicalprocesses which occur within biomembranes.

The theory integrates three classes ofphenomena: i. The chemiosmotic coupling between the electron

transfer process and ADP phosphorylationii. The storage of this metabolic energy in vibrational

modes among the molecular components of the membrane

iii. The quantization of the energy stored in the membrane

QM: molecular phenomena1. Chemiosmotic coupling: Mitchell (1970)

Process with ADP phosphorylationCoupling of electron transport

• Energy storage: Froehlich (1968) Storage of metabolic energy in the dipolar

oscillation modesamong the molecular components

• Energy quantization: After Debye (1912)Analogies between: coupled oscillations of

atoms incrystalline solids and coupled oscillations of

moleculesin biomembranes

Results – e vs. V0, T = 300 K

• Only Type IIB behaviour below e of 7.8.

• A narrow range of parameters are defined for MTs capable of information processing.

L. Demetrius (2003) Quantum statistics and allometric scaling of organisms. Physica A: Statistical Mechanics and its Applications 322:477-490.

Biological “Planck constant”: E=kf• Human energy production: 1021 ATP molecules per second• There are on the order of 3.5 × 1013 cells in the human body• each cell has on the order of 103 mitochondria, so there are approximately 3.5 x10 16

mitochondria in the human body• hence approximately 3 × 104 ATP production events per mitochondrion per second.• net effect: conversion of 1 molecule of glucose into 38 molecules ATP. • each ATP synthase operates at a rate of 600 ATP molecules/s, we estimate that each

mitochondrion has on average 50 ATP synthase enzymes.•  Consequently, the frequency of the oxidative phosphorylation reaction is

approximately 1,000 cycles per second for each complex. • Using: E0 = κf where E0  ~ 10 -20 J is the biological energy quantum we conclude that the

biological equivalent of Planck’s constant is κ = 10-24 J s which, when compared to the physical Planck’s constant h = 6.6 × 10−34 J/s, gives a ratio of κ/h = 1.8 × 1011.

• The physical Planck’s constant corresponds to a single atom, the biological constant corresponds to a mitochondrion. There are approximately 1.9 × 1014 atoms per cell and approximately 1000 mitochondria per cell, which gives 1.9 × 1011 atoms per mitochondrial “sphere of influence” within the cell.

The Microtubule Cytoskeleton

Hameroff et. al., In: Toward a Science of Consciousness pp. 507-540 (1996)

• Microtubules (MTs) form elaborate networks in neurons• Learning/memory involves reordering of the MT cytoskeleton.• Cognitive diseases (Alzheimer’s, Dementias, Bipolar Disorder,

Schizophrenia) show dysfunction in the neuronal MT cytoskeleton.

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Dendritic spine has microtubules interacting with membrane receptors.

Challenge: integration of various levels in a hierarchy

Building a bridge between the molecular level (cytoskeleton) the membrane level (synaptic activity, AP)

Microtubule: structure is made of a- and b- tubulins

a b

Source of UV Radiation• Tryptophan requires UV radiation to be excited.• Is there a UV source inside cells?• Rahnama et. al. 2010 (arxiv.org/pdf/1012.3371)

points out:– Absorption/emisison of tryptophan dependent on

tubulin conformation – Microtubule polymerization is sensitive to UV

(Staxén et al. 1993)– Mitochondria are sources of biophotons at this

wavelength (Vladimirov and Proskurnina 2009, Hideg et al. 1991, Batyanov 1984)

– Microtubules co-localize with mitochondria (Tuszynski, Microtubule Plenary, TSC 2011)

http://www.mitochondrion.info/

Quantum link to function• Mitochondria provide UV source.• TRP excitations influenced by:

– C-terminal tail positions– Microtubule associated

proteins (MAPs)– Post-translational

modifications• Resulting TRP dipole could affect:

– C-terminal tail position– MAP attachment– Ionic currents around MTs

• Quantum computation in TRPs could couple to MT-MAP computations

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Modes of Communication/Signaling

C-termini oscillationsElectron hoppingTryptophan excitationsConformational changes

Brain questions• What makes the brain special?

• What is consciousness?• Where is memory stored?• What is the computational power

of the brain?• Is information processing in the

brain classical, quantum, or fractal resonant (or something else)?

• How can the brain work with so low power compared to computers?

The Human Brain:a computer cluster of computers

• 1011 neurons in our brains• 1015 synapses operating at about 10 impulses/second

(CPUs have 108 transistors) • Approximately 1016 synapse operations per second i.e. at

least 10 PF ( Blue Gene performs at 1015 FLOPS=1 PETAFLOP)

• Total energy consumption of the brain is about 25 watts (Blue Gene requires 1.5 MW)

• Is there anything special inside each neuron?• YES, probably another computer that has both classical

and quantum processors

http://www.merkle.com/brainLimits.html

Potential for Memory Storage, Computation and Signaling in MTs

C-termini states (4 per dimer) Electron hopping (4 per dimer) Conformational changes/GTP states(2 per dimer)Phosphorylation states: 4 per dimerTotal: 128 states/ dimer100 kB/MT or 1 GB/neuron

100 billion neurons: 1020 bits/brainAt microsecond transitions: 1026 flops=100 yottaflops!!!BlueGene 1015 flops = 1 Petaflop

Energy limitations on information processing in the brain

• P = 25 W but 60% used by ribosomes on protein synthesis alone• Approximately 70% of the rest used to maintain temperature, so we assume that 3 W at most is

used for information processing• Cost of 1 bit is at least 3 10 -21 J, if ATP used, then 5 10 -20 J• The amount of information processed then depends on the clocking rate but ranges from 109 to to

10 10 bits/neuron/sec.• The clocking time ranges from 1 ns for a microtubule exciton to1 ms for protein conformational changes to 1 ms for action potentials to 1 s for brain’s Libet pre-

processing times.So: the number of bits per time step per neuron can vary between: 1-10 (ns), 1000-10,000 (ms), 1,000,000-10,000,000 (ms) to billions (s)

Hierarchical model of information processing: Few fast transitions but many processing units ( 1018 tubulins in brain)

Many slow transitions but few processing units (1011 neurons per brain)

Fractal organization on time andspatial scales

Ghosh S., et al. Information 2014, 5:28-100..

Hierarchical model of information processing: Few fast (ns) transitions but many processing units ( 1018 tubulins in brain)

Many slow (s) transitions but few processing units (1011 neurons per brain)

Brain has a bandwidth of 1030 Hz (from 10-15 to 1015 Hz)

Anirban Bandhopadhyay.

Microtubules in neurons

Focusing on the Dendrite

Previous and current study

future study

MTs and Neurodegenerative

diseases A common feature: a deteriorating cytoskeleton: Typical sequence of events: DNA Mutation or PTM ->misfolding->aggregation ->loss of

function->NeurodegenrationExamples: AD, PD, CJD, ALS, HD, TBI

Bioengineered cytoskeletal protein products or pharmacological agents can stabilize, or destabilize the existing cytoskeletal matrix, and prevent neuronal degeneration resulting from multiple causes.

Alzheimer’s disease Both the neuronal and cognitive consequences of

cytoskeletal protein disruption Cortical neurons in AD brain accumulate

hyperphosphorylated tau, a MAP, which triggers the formation of neurofibrillary tangles.

Neurons in AD demonstrate impaired axonal transport and compromised MT matrixes, even in the absence of neurofibrillary tangles.

Beta amyloid protein accumulates in the ECM

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Alzheimer’s Disease (AD)

• Alzheimer’s disease (AD) characterized by b-Amyloid plaques (bAPs) and neurofibrillary tangles (NFTs).

• NFTs formed from hyperphosphorylated MAP-tau. • bAPs correlate with cell death, NFTs with memory impairment.• Link between these unknown.

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MT’s in Parkinson’s and Huntington’s diseases

Mutations in genes for α-synuclein and parkin proteins lead to familial Parkinson’s, and contribute to sporadic cases

Altered α-synuclein and parkin proteins result in impaired axonal transport of dopamine-containing vesicles. Dopamine is released and degraded into toxic by-products that kill dopamine-containing neurons.

Huntington’s chorea: an autosomal dominant disorder caused by mutations in huntingtin protein, characterized by polyglutamine repeat expansion. Polyglutamine repeats in huntingtin protein disrupt its binding to microtubules resulting in impaired axonal transport.

Stroke and traumatic brain injury – The cytoskeleton is disrupted following ischemia due to blood hemorrhage, occlusion, or injury.

Epilepsy – Microtubule-associated protein, MAP2, shows decreased phosphorylation in parts of brain where epileptic seizure activity is prevalent. This is indicative of impaired cytoskeletal dynamics.

Amyotropic lateral sclerosis (ALS) – Axonal transport is compromised in this movement disorder as a result of cytoskeletal disruption.

Charcot-Marie-Tooth disease – A cause of impaired axonal transport may be stalled microtubules that assume a hyperstabilized state due to mutated dynamin2 protein.

Multiple sclerosis – This demyelinating disease also involves disruption of axonal cytoskeleton.

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What is Memory? Ability to encode, store and

recall information. Postulated to be represented by

vastly interconnected networks of synapses in the brain.

Memories formed by changing synaptic strengths (Hebbian Theory / Synaptic Plasticity)

Supported by the paradigm of Long-Term Potentiation (LTP)

How is this achieved on the molecular level?

What is the underlying substrate?

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Memory storageHolographic: Lashley, Pribram: mouse studiesFractal, resonant, tubulin: Anirban

Sheldrake: Memories not storedin the brain at all

caterpillar study, slime mold, antsPlants that learn.Bacteria that learn.Mice descendants that do mazes morequickly

• Is memory localized? Persistence of long-term memory after head regeneration

Memory Storage

Shomrat & Levin, Journal of Experimental Biology 216:3799-3810, 201398

• If we want to listen to our intuition or gut feeling, what information are we accessing?

• Is this information holographic or localized? Are microtubules involved to access it?

• Can we measure this ability?– Galvanic skin response (lie detector)– Heart rate variability– Noninvasive nanosensor biofeedback

Memory, Intuition, Gut feeling

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Capacity of Human Memory? Von Neumann (1950) – 3x1020 bits

Total life experience -we agree Anatomists (1970’s) – 1013-1015

synapses allowing 1016 syn-ops/sec Landauer (1986*) – 109 bits

assumed we retain 2 bits/sec of visual, verbal, tactile, musical memory!

Human lifetime ~ 2.5 billion secondsThomas K. Landauer "How Much Do People Remember? Some Estimates of the Quantity of Learned Information in Long-term Memory" Cognitive Science 10, 477-493, 1986

Historical Perspective 1 Human = 1019 bytes

# of Words ever written = about 1016 bytes # of Words ever spoken = about 1019 bytes Data on all Digital Media = 3x1019 bytes

http://www.lesk.com/mlesk/ksg97/ksg.html

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Cytoskeletal Involvement in Memory Synaptic plasticity:

neuronal differentiation, movement, synaptogenesis and regulation.

All involve cytoskeletal remodeling. Assembly/reorganization of Microtubules

(MTs) and MAP cross bridges Directing motor proteins transporting

molecular cargo along MTs MT-MAP alterations correlate with

memory formation. Dysfunction affects learning/memory. MT disrupting agents affect memory.

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Calmodulin kinase complex CaMKII as memory read/write device

104

Information Storage

• Phosphorylation conveys information.

• Each CaMKII – MT event conveys 64 - 5218 bits.

• Each kinase event releases ~20 kT

• Robust encoding

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Memory storageLong-term Potentiation (LTP): synaptic strength

Craddock:MT phosphorylation

“Cytoskeletal Signaling: Is Memory Encoded in Microtubule Lattices by CaMKII Phosphorylation?” by Craddock, Tuszynski, Hameroff (2012).

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Ca2+/Calmodulin Kinase II (CaMKII)

• Vital for memory (long term potentiation – LTP)• Single point mutations cause memory impairment.• Suggested as a molecular switch for memory.• Records synaptic activity, retaining a ‘memory’ of past Ca2+

influx events in terms of activated phosphorylation states.106

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CaMKII Phosphorylates MT

• CaMKII phosphorylates S/T residues in many protein substrates.• Tubulin one target of CaMKII.• a,b-tubulin phosphorylated on S/T beyond residue 306. • Phosphorylation alters MT interactions with MAPs.

107

Serine

Threonine

Positive

Negative

108

Geometric Matching

• Basic homology models of CaMKII and MT.

• Positional geometry aligned.

• Kinase regions found to closely match MT lattice geometry with multiple forms.

108

109

Electrostatic Matching

• Field lines convergent showing electrostatic attraction.

• ~10 kT/e (6 kcal/mol at 310 K) attraction for single kinase.

• Considerable binding energy.

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110

Information Storage

• Phosphorylation conveys information.

• Each CaMKII – MT event conveys 64 - 5218 bits.

• Each kinase event releases ~20 kT

• Robust encoding

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How does this affect neural function?

111

• PTMs may serve as tags for MAPs to bind.

• Control: • Neural structure• Transport• Synapse structure• TRP excitation

Potential base for Universal Logic

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AND XOR

Computational predictions and partial experimental conformation exists for the binding of psychoactive drugs to tubulin which suggests enhancement of cognitive functions by the action of these drugs

This is consistent with the Hameroff hypothesis of the quantum states of tubulin being involved (if not responsible) for mental processes.

Anesthetics quench quantum hoppingPsychoactive drugs enhance quantum transitions

Our hypothesis: these compounds interact with the quantum information processing in MTs

Mental Activity, Microtubules and Quantum Biology

Caffeine THC Marijuana LSD Adrenaline

Nicotine MDMA Ecstasy Chocolate Methamphetamine

Xanax Heroin Rohypnol (Date rape) Alcohol

What about Consciousness?• Much harder to define.• Related to brain function and memory.• Penrose-Hameroff “Orch OR” most

comprehensive extended thcory • Quantum computation in brain MTs.• Anesthetics inhibit quantum states.• But, isn’t biology too “warm and wet”

for quantum effects?• Recently, quantum coherent energy

transfer shown photosynthetic systems. • Can microtubules support similar

phenomena? • Could anesthetics inhibit this

phenomena?

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Anesthetic-Microtubule Interactions?

Hypothesis: The microtubule (MT) network in dendrites is related to memory, and interaction with anesthetics can influence consciousness and alter memory formation.

Anesthetics natural probe for functional sites of consciousness

Memory formation and learning rely on normal MT cytoskeleton functioning

Postoperative Cognitive Dysfunction (POCD)

Exacerbation of diseases (Alzheimer’s, FTD, Schizophrenia) following anesthesia http://www.brainleadersandlearners.com/wp-

content/uploads/2008/09/blog-brain-business2.jpg

GAs Possess Dissimilar Structure Inhaled Intravenous

Propofol

Ketamine

Etomidate

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What about anesthetics?

119

• Anesthetics provide analgesia, hypnosis, paralysis and amnesia.

• Volatile anesthetics reduce polymerized MTs• MT to macrotubule transformation by halothane.• Halothane modifies colchicine-tubulin binding.• Tubulin altered out to 3 days by desflurane.• Tubulin altered out to 28 days by sevoflurane in

rat.• Halothane binds specifically to tubulin in humans• Tubulin is changed by halothane and isoflurane in

rat.• Of ~500 detectable proteins, tubulin among the

~2% affected by halothane, and ~1% altered by isoflurane (1 of 3 affected by both)

• Location/ mechanism of interaction unknown

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• 47 Distinct Sites found• 9 sites found to persist for more than 70% of the 5 ns simulation.• Of these 9, key sites of interaction include:

– GTP binding site (responsible for dimer stability)– Colchicine binding site (a MT depolymerizing agent)– Vinca Alkaloid binding site (a MT depolymerizing agent)– Putative zinc binding sites (involved in MT polymerization)

• Findings indicate only longitudinal/intradimer interactions are affected.

Putative Anesthetic Binding Sites

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Anesthetics and Tryptophan Excitation

• Anesthetics possess a large dipole moment.• Putative anesthetic sites lie as close as 7 Å to tryptophan

residues.• Anesthetic dipole can influence tryptophan transition dipoles.• Plausible that anesthetics interfere with potential energy transfer.

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Quantum PsychologyThe Development of a New Formalism: Second Quantization:

Transitions between Normal States of Mind (Maslow’s hierarchy of needs)

Bosons and Fermions

Creation and annihilation operators

Commutator and anti-commutator algebras

Quantum energy states and the action of creators and annihilators on energy eigenstates (excitation and de-excitation processes)

In mental states, the processes that either spontaneously or by external intervention take the subject either to a higher level of mental excitation or towards depression

Excitation in affective or psychotic termsCoherent states and squeezed states

Psycho-Pathology• The Development of a New Formalism: Q-Deformed Algebras and the

Distorted States of Mind in Mental Diseases• q-bosons and q-fermions• q-statistics• the number of q deformations and the strength of deformation• examples: an extension to quaternion values of the deformation parameter • I= affective polarization (Fermi-Dirac statistics)• J=cognitive efficacy (Superpositional probability)• K=social integration (Bose-Einstein statistics)• defining mental state axes in stages, (1) psychotic-non psychotic; (2)

affective-euthymic: (3) impulsive-controlled, (4) anxious – not anxious: (5) autononous – enmeshed;

Connection to clinical psychiatry• multidimensional classification systems taking account of quantum

statistics• transitional states between normality and illness (even healthy people at

times can experience psychiatric problems• transitional states grading severity of illness and predicting clinical course• predictable and random effects determining clinical course and

catastrophic events

Future Goals• To use quantum models to create a more adequate explanatory framework

for psychopathological phenomenology.• To enlist quantum-formal actuarial tools for rigorous prospective

estimation of the impact of random and potentially predictable events on the evolution of illness states and catastrophic events

• To use quantum statistics in actual risks assessments in a prospective and hence more realistic context.

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The Problem with Embryology

Egon Schiele Kneeling Male Nude (Self-Portrait). 1910. http://www.moma.org/exhibitions/schiele/artistwork.html

Nikas, G., T. Paraschos, A. Psychoyos & A.H. Handyside (1994). The zona reaction in human oocytes as seen with scanning electron microscopy. Hum. Reprod. 9(11), 2135-2138.

?

How did your spherically symmetrical egg turn into such a highly asymmetrical shape?

1,000,000 µm = 1 meter

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Staging of Axolotl Development

Top views

Side views

Bottom views

Side view

L R

Bordzilovskaya, N.P., T.A. Dettlaff, S.T. Duhon & G.M. Malacinski (1989). Developmental-stage series of axolotl embryos. In: Armstrong, J.B. & G.M. Malacinski, Developmental Biology of the Axolotl, New York: Oxford University Press, p. 201-219.

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Staging of Axolotl Developmenthead

tail

right side

Timing, at 20oC:Stage Time

inhours

What’sstarting

2- 0 Synchronous cleavage

2 0.6 2 cells

3 2 4 cells

8 16 Blastulation, asynchronous cleavage

10 26 Gastrulation

14 36 Neurulation

19 69 Neural tube, eyes, somites

44 340 =14 days

Mouth opens, hatching

16

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Stages 23-35 of Axolotl Development

130

Stages 36-44 of Axolotl Development

No increase in dry weight since it was an egg!

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The Cell State Splitter

MF = microfilament ring

MT = annular apical microtubule mat

IF = intermediate filament ring

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The Unstable (Bistable) Mechanical Equilibrium between the Microfilament Ring and the Microtubule Mat in the Cell State Splitter

Gordon, R., N.K. Björklund & P.D. Nieuwkoop (1994). Dialogue on embryonic induction and differentiation waves. Int. Rev. Cytol. 150, 373-420.

MF ring is a torus of radius r and cross sectional area A,empirically of constant volume VForce F AV = 2πrA, soF 1/r, a hyperbola

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The Differentiation Tree

Embryogenesis may be modelled as a bifurcating sequence of tissues generated as each tissue is split into two new tissues by pairs of contraction and expansion waves.

Unsolved problems:

1. What launches these waves at specific times and locations?2. What confines their trajectories?3. What stops them?

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The Differentiation Tree is the Physical Embodiment of Conrad Waddington’s Epigenetic Landscape

Held Jr., L.I. (1992). Models for Embryonic Periodicity, Basel: Karger.

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Nouri, C., R. Luppes, A.E.P. Veldman, J.A. Tuszynski & R. Gordon (2008). Rayleigh instability of the inverted one-cell amphibian embryo [In: "Physical Aspects of Developmental Biology" special issue]. Physical Biology 5, 015006.

in collaboration with:Institute of Mathematics & Computing ScienceUniversity of Groningen

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Cortical Rotation

•Forced Cortical Rotation:

Direction of the last forced rotation determines the left-right symmetry. Gerhart et al (1989)

Many observers report the alignment of microtubules during and after the cortical rotation

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When an egg is inverted:

•1. The egg will not develop at all.

•2. It will develop but with colors of dorsal and vegetal . regions exchanged.

We suggest that it has to do with the way the heavy fluid on top sloshes down the inverted egg’s volume, Case 1 corresponds to symmetric fluid flow. Case 2 to asymmetric flow.

One of the following happens:

Wakahara, et al (1984), Neff, et al (1986), Malacinski and Neff (1989),

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Working Hypothesis

• Cortical rotation aligns microtubules attached to the inner surface of the cortex via global torque T

• Microtubules drive the cortical rotation by polymerization and/or motor molecules attached to them, each contributing torque Ti, with T = Σ Ti

• This can be represented as a mean field Ising model in which the mean field is precisely the same as the local field

139

ComFlo Computational Fluid Dynamics Simulation

Symmetric sloshing of the heavier liquid (yolk) in the inverted egg. This particular case has too low a viscosity.

140

Summary• Memory depends on the neuronal cytoskeleton.• This basis yields:

– A molecular mechanism of synaptic plasticity and memory encoding.

– A link between the hallmarks of Alzheimer’s Disease.– A mechanism for the amnesiac affect of anesthetics.

• Quantum phenomena in microtubules could serve as a basis for consciousness, and anesthetics could potentially inhibit this phenomena.

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Implications for Health and Disease

Quantum coherence= a healthy state Decoherence=transition to disease

Location of decoherence determines “disconnection” from the rest of the organism;

canonical example: cancer

141

• Already doing this with EKG, EEG for diagnostic purposes

Body: Bioelectric medicine

142

• Is this an avenue for non-invasive signals?– Yes

• Able to deliver quality information on the health of the body?– Yes

• Able to detect disease at an early stage?– That’s what we’re working on

Bioelectric medicine

143

• Bioelectric signals• Morphogenesis• Cell membrane (cancer depolarized)

Michael Levin

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Morphogenesis and cancer

Levin, BioSystems 109:243-261, 2012145

• Hypothesized by Dr. James Oschman• High-speed electric communication system

made up of biological wires in the body: networks of:– Microtubules– Actin– Collagen

The Living Matrix

Friesen et al. BioSystems 127:14-27, 2015146

Microtubule conductivity

Friesen et al. BioSystems 127:14-27, 2015

CoherentEnergyTransfer

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• Flexible, transient electronics

Nanotechnology advances

John A. Rogers GroupUniversity of Illinois

148

• NanoFET (Nano Field EffectTransistor)

• Intracellular electricalrecordings

• Charles M. Lieber group(Harvard)

Nanotechnology advances

Tian and Lieber, Annu. Reb. Anal. Chem 6:31-51, 2013 149

• Nanosensors to measure health of body, in terms of communication within cells and between cells and between organs and tissues (pictures of nanosensors)

• Possible explanation of acupuncture meridian system, and 24 hour monitoring of this system

• Further understanding of microtubule to understand possible quantum computation and access to holographic information

• Better models to understand why processes like NLP work

Bioelectronic future

150