The possibility of direct interfacing between biological and technological information devices could result in a merger of mind and machine - Ultimate Computing. This book, a thorough consideration of this idea, involves a number of disciplines, including biochemistry, cognitive science, computer science, engineering, mathematics, microbiology, molecular biology, pharmacology, philosophy, physics, physiology, and psychology. - Ultimate Computing (Amazon)
- 1 Toward Ultimate Computing
- 2 Brain Mind Computer
- 3 Origin and Evolution of Life
- 4 From Brain to Cytoskeleton
- 5 Cytoskeleton Cytocomputer
- 6 Protein Conformational Dynamics
- 7 Anesthesia Another Side of Consciousness
- 8 Models of Cytoskeletal Computing
- 9 VirusesAmbiguous Life Forms
- 10 NanoTechnology
- 11 The Future of Consciousness
Mind/Tech Merger in the Nanoscale
- Biology and technology are evolving towards more efficient methods of information processing
- Ultimate Computing: the common destination for the evolution of information processing systems in both biology and technology
- Nanoscale (10^-9, 1nm = billionth of a meter, 1ns = billionth of a second) is where living intelligence may have evolved
- Nanoscale excitations can generate communicative "collective modes" within protein assemblies and provide a substrate for biological information processing
- Nanoscale devices like molecular computers, Feynman machines, and von Neumann replicators are becoming feasible through technologies like scanning tunneling microscopy
- A nanoscale marriage of biomolecules and nanotech devices could have profound benefits for biomedicine and culture
Consciousness and Computer Technology
- Merging consciousness and computer technology is a prevalent dream
- Artificial intelligence based on brain/mind organization is a tentative step in this direction
- Proposed use of self-assembling protein arrays as switching circuits or "biochips"
- The Japanese effort to integrate biology and technology, aiming for an "artificial brain" by understanding biological homeostasis
Evolution of Technology
- Technological emulation of life since the 13th century has been reviewed by author Claris Nelson (1985)
- Early calculators like Pascal's and Leibniz's used binary numbers and sequential mathematical steps
- Boolean algebra, developed by George Boole in the early 1800s, is essential for designing computer circuits
- Charles Babbage and Ada Lovelace designed an "analytical engine" using punched cards in the mid-1800s
John Vincent Atanasoff and Early Computing
- First electronic computer built in 1939 by John Vincent Atanasoff, a theoretical physicist at Iowa State University
- Alan Turing and colleagues in Bletchley, England designed a computer to perform all mathematical calculations in the late 1930s
- Used to decipher German "Enigma" code during World War II
- John von Neumann further advanced computer design by separating machine from problems
- Prior computers needed rewiring for each new task
Early Computers: ENIAC and UNIVAC
- University of Pennsylvania developed the first electronic computer, Electronic Numerical Integrator and Calculator (ENIAC) in the 1940s
- Weighed 30 tons, took up 3,000 cubic feet of space, contained 18,000 vacuum tubes
- Could calculate nuclear physics problems in two hours that would take 100 engineers a year to complete
- Remington Rand marketed UNIVAC, which dealt with words and numbers stored by their binary equivalent in the same decade
Computer Generations and Advancements
- Four generations of computers have evolved due to increased demand and advances in design, chip size, materials and other factors
- Von Neumann and Turing hoped computers could duplicate human thought
- Current trend: parallel systems based on brain architecture and neural net models
Cellular Automata and Universality
- Von Neumann and Stanislav Ulam developed mathematics of computing in multiple dimensions
- Cellular automata with discrete time intervals ("generations") led to evolving patterns and self-organization sensitive to initial conditions
- Von Neumann's "universal computer automaton" could solve any problem given sufficient area and time
- Computer technologists considering molecular scale automata based on cellular automata principles
Limitations of Serial Processing and Parallel Connectedness
- Current trend: parallel connectedness, emulating the brain
- Computers can perform rapid serial mathematical processing but struggle with qualitative functions like pattern recognition and judgment
- Humans can resolve conflicts among differing drives or input, although failure may cause problems
- In science fiction, computers have suffered similar disturbances (e.g., Hal 9000 in 2001: Space Odyssey)
Brain/Mind Functions and Consciousness
- Brain/mind can perform cognitive functions like pattern recognition and making assumptions through subcognitive processes
- Collective effect of simpler processes is consciousness.
Collective Intelligence
- Collective phenomena are more than the sum of their parts (Hopfield, 1982)
- Examples: sound waves from colliding molecules, superconductivity, magnetism
- Brain neuron synaptic transmissions are slow but can solve problems in a few hundred milliseconds
- Collective effects of parallelism and rich interconnectedness account for this computational richness (AI researchers)
- Neurons are sophisticated information processing systems with up to hundreds of thousands of connections
- Nematode worms exhibit intelligent behavior despite having fewer than 100,000 neurons
- The cytoskeleton within cells may take advantage of the same attributes used to describe neural networks (parallelism, connectionism, coherent cooperativity)
Collective Phenomena
- Occur when a large number of individual units come together and exhibit new behaviors
- Examples: sound waves from colliding molecules, superconductivity, magnetism, beehives, ant colonies, football teams, governments
- Emergence of different qualitative properties below critical temperatures in certain metals
Brain Neurons and Collective Effects
- Slow neuron synaptic transmissions (several milliseconds per computation)
- Intelligent behavior can be solved within a few hundred milliseconds or 100 serial steps
- AI researchers attribute this computational richness to collective effects of parallelism and interconnectedness
- Neurons are sophisticated information processing systems with up to hundreds of thousands of connections
- Each neuron integrates input/output, modulates synaptic connection strength
Cytoskeleton as a Collective Phenomenon
- Overlooked by AI researchers as a potential contributor to collective effects
- Cytoskeleton is a parallel connected network within cells that can utilize its own collective phenomena to organize and process information
- Properties of networks, such as parallelism, connectionism, and coherent cooperativity, allow for collective effects among both neurons and cytoskeletal subunits.
Parallelism in Computer Architecture
Sequential vs Parallel Processing:
- Sequential processing: Computing steps are done consecutively, which is time-consuming and can lead to chaos with a false bit of information.
- Brain's highly parallel nerve tracks provide an alternative to sequential processing.
Parallel Processing:
- Information enters multiple computer pathways, which process the data simultaneously.
- Separate processors or groups of processors can address different aspects of a problem asynchronously.
- Parallel processing requires reconciliation of multiple outputs due to individual processors' biases and functions.
Examples of Parallel Processing:
- Reeke and Edelman (1984) described a parallel pair of recognition automata using complementary features.
- Present day computers are evolving toward parallelism, such as the "Connection Machine" with 64,000 microprocessors.
Multidimensional Network Parallelism: Hypercubes:
- Processor networks whose interconnection topology is seen as an n-dimensional cube.
- Parallelism in n-dimensions leads to hypercubes, which can maximize computing potential and provide collective effects.
Computing Power Comparison: Brain vs. Computer:
- Moravec's calculations: Brain has 40 billion neurons changing states hundreds of times per second, leading to about 10^12 bits per second.
- Including the cytoskeleton increases the brain's potential capacity for information processing.
Open Systems in Computing and Neuroscience:
- Classical computers operate recursively on repetitive functions, while the brain is a continuous system.
- Carl Hewitt described open systems in computing that can provide continuous input/output and adapt to new situations.
- Brain neurons are interconnected by synaptic connections, which could serve as "arbiters" in parallel processing.
Connectionism and Parallel Systems in Information Processing
Connectionism:
- Part of collective hierarchy in information processing
- Rely on lateral connections and networks for complexity
- Develop cognitive functions through parallel connected networks (neural nets)
- Minimizing energy functions to find optimal solutions
- Concept of "shaking" neural net simulations to discover lowest points
- Comparable to individuals sorting information without comprehending essence
Neural Nets:
- Characterized by Cal Tech's John Hopfield and others
- Solutions understood through minimizing energy functions
- Isolated errors or incomplete data can be tolerated
Multilevel Networks:
- Emergence of concept to avoid getting stuck in tiny depressions between mountains
- One level "shakes" or tunes lower level
- Relationship between hierarchical layers of parallel systems within the brain
Relationship Between Brain and Artificial Intelligence:
- Comparisons reviewed by A. M. Decallatay (1986)
- Brain learns by opening gates to build new connections between elements simultaneously activated
- Dendritic spines play role of "all or none" switch at neural level
- Synaptic plasticity, cornerstone for brain learning and memory
- Cytoskeleton responsible for all cytoplasmic rearrangements including formation and regulation of dendritic spines and synapses.
Collective Effects and Coherence
- Collective effects manifest as: diffuse reverberation, sustained oscillation, phase transitions, deterministic chaos (Choi and Huberman, 1984)
- Can exert long-range cooperation and an executive level of organization within parallel arrays
- Collective phase transitions in brain parallel arrays could be a fabric of consciousness
- Neuronal Synapse: fundamental subunit of the brain, result of dynamic processes orchestrated by cytoskeleton
- Cytoskeletal organization evident within neurons, participation in cognitive functions unavoidable
- Highly branched cytoskeleton may be another dimension of brain organization, related to neuronal networks as a "fractal" subdimension
- Fractal relationships: long range cooperativity (Figures 1.7 and 1.8)
- Densely parallel interconnected networks of cytoskeletal structures resemble larger scale neural networks
Coherence
- Coherence means peak energy excitations occur "in phase," or simultaneously, as in a laser
- DeCallatay's proposal: coherence in the brain and AI imparted from the top of a hierarchy downward (like a CEO setting goals)
- Rhythmic coupling among neurons: important for regional brain wave entrainment leading to functional regions of mental representation
- Proteins and their components: oscillate among specific conformational states, ranging from femtoseconds to minutes
- Fröhlich's cooperativity model: biochemical energy supplied to biomolecular assemblies can result in coherent elastic vibrations in the sub-nanosecond time range
- Davydov's soliton model: almost lossless energy transfer in biomolecular chains or lattices as wave-like propagations of coupled conformational and electronic disturbances
Molecular Computing: Exploring Protein-Based Non-Silicon Alternatives for Beyond Silicon Computation
Molecular Computing
Background:
- Approach to emulate brain structure at nanoscale for cognitive capabilities
- Advantages of molecular computers:
- Smaller size than conventional computers
- Three dimensional space usage
- Self-repair or self-replication
- Suited for certain types of analog computation
History:
- Molecular computing movement catalyzed by Forrest L. Carter at Naval Research Laboratory
- Strategies aimed at implementing nanoscale computing through switching in various materials like polyacetylenes, Langmuir-Blodgett films, electro-optical molecules, proteins, etc.
- Interfacing between nanoscale devices and macroscale technologies is an obstacle with possible solutions:
- Engineering upward (self-assembling components)
- Optical communication
- Molecular wires
- Don’t interface; build fully nanoscale systems
- Technologies like ion beam nanolithography, molecular spectroscopy, quantum well devices, and scanning tunneling microscopy (STM) may be used for interfacing
Information Flow:
- Current computers rely on electronic current flow, but electron transfer may be too energetically expensive at the molecular nanoscale
- Molecular computing relies on propagation of nonlinear coupling waves called "solitons"
- Solitons can propagate through switching circuits made of branched polyacetylene chains or periodic arrays using electron tunneling, soliton "valving," and photo-activated conformational changes in lattice materials
Protein Based Computing:
- Proteins integrate multiple input modes to perform a functional output
- Conformational state of each protein depends on various factors like temperature, pH, ionic concentrations, voltage, dipole moment, electroacoustical vibration, phosphorylation or hydrolysis state, conformational state of bound neighbor proteins, etc.
- Proteins can be seen as rudimentary computers converting complex analog input to output states or conformations
- Extremal computer uses physical resources as effectively as possible for computation and suggests molecular computing with individual switches composed of molecules
Fundamental Limits on Computation:
- No fundamental quantum mechanical limitations on computation in principle (Benioff, Landauer, Feynman)
- No fundamental thermodynamic limitations on computation per se (Landauer, Bennett)
- Practical physical limitations to further miniaturization of digital switching circuits might not be reached for decades
- Molecular electronics may contribute to digital computer design with molecular conformational changes, solitons, charge flow and other approaches; redundancy and parallelism may be necessary
- Biochemical systems inspire technological imitations for the purpose of computer design, with microtubules offering the most possibilities (Yates)
Dynamic Pattern Representation
- Processing patterns or symbols is conducive to optimal computing
- Patterns can be dynamically represented by various mechanisms useful in AI and biological systems: reaction-diffusion systems, holograms, macrons, and cellular automata
Reaction Diffusion Systems
- Evolving patterns resulting from reactions and product diffusion within a medium
- Biological reaction diffusion systems suggested as a mechanism for information representation (Conrad & Liberman, 1982)
- Propagation and interaction of chemical waves lead to pattern formation in various media
- Examples: Belousov-Zhabotinsky reaction and amoeba cells responding to pulses of cyclic AMP
- Similar phenomena reported in retinal, cortical nerve nets, heart muscle
- Reaction diffusion patterns occur on smaller scales at faster rates.
Characteristics of Belousov-Zhabotinsky Reaction:
- Spiral chemical reaction waves propagate at uniform speed and interact to produce complex patterns
- Waves radiate from spiral centers, rotating in about one minute
- Several chemical reactions with suitable diffusion rates and visible color changes show these characteristic patterns.
3D Behavior of Reaction Diffusion Systems:
- Winfree and Strogatz (1984) studied the 3 dimensional behavior of reaction diffusion systems
- Reaction diffusion waves commonly appear as involute spirals or scrolls radiating from tiny rotating activity patterns called "organizing centers"
- The origin of the waves is defined as a phase singularity whose immediate neighborhood is a rotating pattern of chemical activities, the pivot of the rotating spiral wave from which it radiates.
- The ostensibly flat spirals are actually cross sections of three dimensional waves shaped like scrolls that emerge from a filament of singularity in 3 dimensions.
Exploration of Holographic and Macron Patterns in Biological Systems for Information Storage and Consciousness
Ultimate Computing and Holographic Memory
Three-Dimensional Computer Simulations:
- Reaction-diffusion systems with organizing centers like microtubules and centrioles can behave like singularities
- Dynamic cytoskeleton activities release calcium waves, altering surrounding cytoplasm by sol-gel transformations
- Coding by MAPs and other factors results in reaction-diffusion patterns specific to the dynamic state of organizing centers
Holograms:
- Brain stores memory in a "distributed" manner resistant to local damage
- Holography: method of recording and reconstructing wavefronts associated with interference patterns
- Holograms store information like brain functions, are "fractal", and can function as distributed memories
- Requirements for maintaining phase relations between patterns remain a question regarding holographic models of brain function
Macrons:
- Morphogenesis: evolution of form from chaos
- Physical, chemical, and electrical macrons observed in nature
- Examples include Chladni nodal lines on vibrating plates, Benard cells in isotropic liquids, and smoke rings
- Abraham proposes thoughts are "macrons of the brain bioplasma", with spatial patterns in EEG or within nerve cells
Cellular Automata and Their Complex Behavior:
- Concept: A type of system made up of a large number of identical cells organized in a uniform pattern, with each cell having a finite number of states.
- Features:
- Each cell is in one state at a given time.
- Cells are organized according to a fixed geometry.
- Each cell communicates only with neighbors, and the number of neighbors is constant for all cells.
- There's a universal clock that dictates state changes based on present states of both the cell and its neighbors.
- Comparison with Biological Cells: While biological cells are complex entities, the term "cellular" in this context refers to an indivisible subunit with finite states, similar to atoms or biology's own cells.
- Behavior: Simple neighborhood rules can lead to complex and dynamic patterns over time.
- Computational Capabilities: Cellular automata can perform useful computations, even simulating behaviors found in microtubules (Figure 1.12).
- Universally Computing and Constructing Automata:
- A universally computing cellular automaton can solve any problem given an initial configuration.
- A universally constructing automaton can create patterns to solve problems without requiring access to every cell, making it useful for biological computation (Figure 1.12).
- Historical Significance: Studied by Von Neumann as a potential computing machine; several universally constructing automata have been devised in simulation.
- Relation to Lattice Models: Similar to lattice models like Ising generators, which evolve to stable patterns with opposing and similar spin states aligned horizontally and diagonally (Figure 1.11).
Game of Life:
- Invented by John Conway in 1968, played on a grid of square cells with two states: dead or alive
- Rules for cell survival and reproduction based on number of living neighbors
- Behaviors include movement and oscillatory patterns like blinkers, beacons, gliders, and beehives
- Dewdney showed that a computer could exist within the game of Life in 1985
- Carter Bays extended the game to three dimensions with interesting behaviors dependent on initial patterns
Cellular Automata:
- Systems of simple components capable of complex collective effects, simulating partial differential equations and deterministic chaos
- Four general behaviors: disappear, evolve to a fixed finite size, grow indefinitely at a fixed speed, or grow and contract irregularly
- Self similar patterns characterized by fractal dimension
- Sensitive to initial conditions with marked changes under perturbations
- Could represent the universe as a cellular automaton according to Edward Fredkin
- Cellular automata may be involved in biological information processing and future computing.
Brain/Mind/Computer
Metaphors of Consciousness:
- Systems for information processing are evolving in both biological life forms and computer technologies
- Human consciousness resides in the human brain, with scientific relationships between consciousness and structural brain activities obscure
- Historical metaphors of the mind:
- Plato's Socrates described consciousness as a "block of wax" to remember impressions
- Greeks perceived consciousness as a free entity, compared to slaves who did the work
- Later, consciousness was viewed as layers in the earth's crust recording an individual's past
- Consciousness became viewed as a compound structure that could be analyzed in a laboratory
- As steam engines became commonplace, the subconscious was perceived as a boiler of straining energy
- The computer is the most recent brain/mind metaphor, with computers approaching and surpassing some aspects of human brain function
Artificial Intelligence (AI) Research:
- AI researchers have examined the workings of the brain and mind to construct computing machines capable of independent logic and decision making
- They have been led away from classical "serial" computers towards massively parallel systems with high degrees of lateral interconnection
- Neural network models are based on simple assumptions regarding interneuronal synapses as switches between neurons
The Cytoskeleton:
- The cytoskeleton is a dynamic, highly interconnected protein polymer network in the intracellular cytoplasm
- It appears to be ideally suited for information processing and is involved in virtually all cell functions
- Appreciation of the "cytoskeletal dimension" may be the key to understanding the relationship between brain/mind/computer
Consciousness: History and Physics Connections - Understanding Mind through Quantum Theory and Molecular Biology.
Historical Perspectives on Consciousness
- Many disciplines have attempted to understand consciousness, each with its unique perspective based on orientation and focus
- Julian Jaynes' The Origin of Consciousness and the Breakdown of the Bicameral Mind: Reviews eight solutions to the brain/mind problem developed in 20th century:
- Consciousness as Property of Matter, Protoplasm, or Learning
- Perception that mind is too complicated for human brain
- Philosophical argument that mystery of mind serves to maintain scientific humility
- Consciousness as Metaphysical Imposition
- Belief that consciousness is a transcendent reality beyond the physical world
- Consciousness as Helpless Spectator
- Perspective that consciousness observes but does not affect behavior
- Consciousness as Emergent Property of Evolution, Behavior, or Activity Within Brain's Reticular Activating System
- Consciousness as Property of Matter, Protoplasm, or Learning
- Modifications and Additions Relevant to Computer Technology and Cytoskeletal Dimension:
- Life's basic processes equated with those of atoms and subatomic particles
- Information represented as dynamic electron patterns within computers
- Questions remain about how, where, and at what level of organization consciousness relates to fundamental particle activities.
Consciousness as a Property of Protoplasm
- Some 19th century biologists believed consciousness is a fundamental property of all living things, based on the irritability of smallest organisms
- Observation of amoebas and paramecia led to application of human psychology to their behavior
- Charles Darwin and E.B. Titchner accepted this view, seeing it as related to man through evolution
- Circumstantial evidence: inhibitory effects of anesthetic gases on protoplasmic streaming in slime molds and amoeboid/paramecium motility
- Cytoskeletal link among anesthetic-sensitive processes could be a clue to brain/mind/computer connection
Consciousness as Learning
- Proponents believed consciousness began after life evolved, directly related to learning
- Rationale: if animal modifies behavior based on experience, it must be having an experience and thus conscious
- Learning models in neural net computer simulations may be bolstered by historical glorification of learning
- Structural correlates of learning involve neuronal cytokeletal reorganization
- However, learning and consciousness are separate problems; AI systems can learn but not be conscious
Consciousness as a Metaphysical Imposition
- Evolutionary link between civilized man and apes led to metaphysical view: consciousness could not have evolved by natural selection
- Founded by Alfred R. Wallace, co-discoverer of the theory of natural selection with Charles Darwin
- Vitalists and spiritualists attempted to apply particle/wave physics to cell biology in search for consciousness
- Modern bioelectromagnetic field theories related to embryology and consciousness remain undocumented
The Helpless Spectator Theory
- Materialistic view suggesting consciousness is an epiphenomenon, a helpless spectator of biological activities
- Rejected by William James, who found inconceivable the notion that consciousness should have no role in attending to business
Emergent Evolution Theory
- Consciousness was seen as an emergent property in evolution, not just a result of physical properties
- Compared consciousness to the emergence of new properties from unspecified forerunners (e.g., wetness from hydrogen and oxygen)
- Consciousness emerged at a critical stage in evolution, assuming control over brain function and bodily behavior
- Evolutionary processes may have provided conditions for consciousness' appearance
- Allowed for the acceptance of concepts like ego, id, and superego without concrete basis
- Significant questions remained about when, where, and what consciousness is
Behaviorism
- Solved the problem of consciousness by ignoring it
- Traced roots to epicureans of the 18th century and plant tropisms in animals and humans
- Explained cognition as reflexes or conditioned responses across various organisms
- Human behavior was reducible to reflex responses to situations or needs
- Behaviorism lent itself to experimentation, increasing credibility for neuroscience research
- Behaviorist laboratories flourished in universities, dominating the field for a time
- However, it was more of a method than a theory and ignored consciousness.
The Reticular Activating System (RAS) and Consciousness
Background:
- Brain researchers turned to understanding consciousness with the advent of technology
- Rene Descartes proposed pineal gland as site of consciousness, but was refuted by neurophysiologists
- Search for single site of brain consciousness led many to focus on RAS due to its integration and regulation functions
The Reticular Activating System (RAS)
- Organized tangle of tiny interconnecting neurons extending from spinal cord into thalamus and hypothalamus
- Integrates collaterals from sensory and motor nerves, has direct lines to cortex and brainstem nuclei, sends fibers down the spinal cord
- Regulates brain activity and wakefulness by sensitizing or desensitizing neurons and centers
- Sodium thiopental affects RAS for anesthesia induction, and destructive lesions produce permanent sleep/coma; stimulation can wake up sleeping animals
Problems with Consciousness
- High level integration and associative functions occur in cortex, not RAS
- RAS is an old, relatively unchanged part of the nervous system compared to advanced animals
- Even if we understood every transmitter and synapse, we couldn't discern consciousness in a specific brain
Neural Net Connectionism
- Attempts to mimic brain function through artificial intelligence systems based on neural networks
- Cell assemblies are specialized reverberatory circuits that allow for recognition, learning, and problem solving through lowered thresholds of specific loops
- Neural net models may help advance robotic and computer systems for artificial intelligence, provide insight into brain function
Limitations of Early Neural Net Models
- Based on hypothetical neurons with huge assumptions about neural function
- In their most elegant form, recent models incorporate axonal impulses, synaptic delays, dendritic analog functions, and spatial coherence
- Suggestions for consciousness: "temporally stable cooperative coupling" among sets of neurons forming thoughts and images. Changeux defines it as a global regulatory system dealing with mental objects and computation using those objects. Neural net models and associative memories have significantly advanced understanding of collective neural capabilities.
Holography
Properties of Holograms:
- Formed from interference patterns generated from two or more coherent wave sources
- Initially a laboratory curiosity, became important with the advent of lasers as coherent light sources in the early 1960s
- Recorded hologram appears garbled until reilluminated with one of the original coherent wave sources, then projects three dimensional spatial images
Attracting Interest in Consciousness and Mental Imagery:
- Holograms have an enormous capacity for information storage
- Much information is contained in any small portion of a hologram, although with reduced resolution and signal-to-noise ratio
Dynamic Real-Time Holography:
- Developed using photorefractive crystals
Holographic Brain Theory:
- Denis Gabor was skeptical about the existence of waves or tuned resonators in the brain
- Stanford's Karl Pribram contended that the brain perceives sensory information by analyzing the interference of neural firing frequencies
- Resulting holographic domain in the brain allows transformations into ordinary domains from any part of the encoded records
- Holographic models of consciousness have been based on coherent wave interference at the level of neuronal activities, particularly dendritic-dendritic interactions
Cytoskeleton as a Substrate for Holographic Mechanisms:
- The cytoskeleton within neurons (and all cells) may be well suited for holographic mechanisms due to its spatial coherence and potential temporal coupling
- Intracellular cytoplasm surrounding the cytoskeleton may be the substrate for holographic consciousness
Holographic Consciousness and Psycho-Physical Implications:
- Physicist David Bohm suggests our perceptions of reality are conditioned by lenses, while lensless holograms are distributed, lack boundaries, and are "holistic"
- The reality of the universe may be mathematically similar to a hologram (the "implicate" domain), dealing with frequency domain and fluctuating waveform properties as opposed to Euclidean-Newtonian impressions
- Experiences reported by mystics, schizophrenics, and hallucinogenic drug experimenters describe loss of spatial and temporal boundaries and a holographic ("fractal") characteristic of the whole being represented in every part
Cytoskeletal Basis of Consciousness
Neuron Complexity:
- Neurons are complex and cannot be understood as simple digital switches or gates
- Dendritic branches may act as logical "OR" or "AND" gates, depending on the type of pulse input
- Presynaptic information can be transmitted through dendrodendritic synapses, called "whispering together"
- Unknown significance of electrotonic current pathways among dendritic membrane glycoproteins and membrane patches
Neural Information Processing Modes:
- Synaptic plasticity, axon and dendrite morphology, membrane protein distribution depend on the dynamic cytoskeletal functions of axoplasmic transport and trophism
- Potential neural information processing modes include: synaptic plasticity, axon and dendrite morphology, membrane protein distribution
Cytoskeleton View of Consciousness:
- Complex, highly parallel cytoskeletal protein lattices connect to and regulate all cellular components
- Cytoskeletal proteins may be related to consciousness in vertebrates as a nonlinear collective effect
- Earlier schools of understanding consciousness may have been consistent with the cytoskeletal view
- Neural network theory, parallelism, connectionism, and AI approach can be applied to the cytoskeleton
Cytoskeletal Information Processing:
- Synaptic strength and neuronal connection depend on intracellular cytoskeletal rearrangements and axoplasmic transport
- Ingredients for synapses are synthesized in cell bodies and transported to synapses by axoplasmic transport
- Nanoscalar activities in cytoskeletal lattices may offer a bridge between consciousness and emerging nanotechnology
Origins and Evolution of Life
Questions Concerning Life's Origin:
- Soup vs Mud: Discussion about the place where life originated, with two main theories: primordial soup and clay crystals (mud)
- Primordial Soup: A hypothesis suggesting that organic molecules necessary for life emerged in a geochemically produced atmosphere and were brought together by electric sparks simulating lightning. Key Experiment: Carried out by Stanley L. Miller, who detected organic molecules like amino acids, precursors of DNA, and ribose sugars from which RNA is formed in a closed environment with a primitive atmosphere.
- Criticism: Other research questions the hydrogen-rich atmosphere on which Urey and Miller based their experiment and suggests that organic precursors can be generated in various atmospheres.
- Deep Soup: Proposal of thermal vents as the cradle of life due to the presence of strange and exotic life forms, organic compounds, and conditions conducive to the formation of organic molecules.
- Clay Crystals (Mud): An alternative explanation by A. Graham Cairns-Smith suggesting that early organisms utilized pre-existing information templates in the form of wet clay crystals.
- Crystal Defects: Provide large potential capacity for information storage and replication, acting as primordial genetic information and aiding in protein alignment and synthesis.
- Catalytic Surfaces and Complex Morphology: Similar to living material due to their ability to store and replicate information.
- Challenge: Cairns-Smith's call for experiments with crystals that could evolve, suggesting the possibility of mineral versions of replicating systems as alternatives to DNA and RNA.
Implications:
- Primordial soup or clay crystals: Two main theories on life's origin with different implications for understanding the origins of genetic information in living organisms.
- Thermal vents, intrastellar dust, comets, meteorites, and space as potential sites where organic precursors to life may have been generated or transported to Earth.
- The possibility of alternative carriers of genetic information beyond DNA and RNA.
Life's Origin: Debate Between Primordial Amino Acids or Nucleic Acids
Division between Life and Nonlife:
- Dr. Cyril Ponnamperuma (University of Maryland): artificial division
- Life lies on a continuum over evolutionary time and among existing systems
- Prions, proteinoids, viruses near the middle
- Narrows conceptual gap between life molecules and technological devices
Questions regarding the Origins of Life:
- DNA vs Protein (Chicken or Egg?): central dogma in molecular biology challenged
- Fox and Dose's View: interstellar gases to amino acids, polymers, organized microsystems
- Evidence for DNA-like Molecules: Schwarz and Orgel (Salk Institute) discovered a 15 nucleotide long molecule
- Primary Nucleic Acid Organization: self-replication and evolution with RNA as template
- Molecular Self-Organization: Eigen's view: closed loop, important for hypercycles
- Hypercycles: systems escape prerequisites of origin, change environment to advantage
- RNA Formation and Evolution: critical level of associative interrelationships among evolving molecules
- Scenario for the Development of Life on Earth: RNA formation led to double-stranded DNA, prokaryotic bacterial cell with membranes and regulatory voltages.
Key Players: Cyril Ponnamperuma, Fox and Dose, Leslie Orgel, Manfred Eigen, Lynn Margulis, Dorion Sagan.
Prokaryote to Eukaryote - Symbiotic Jump
Prokaryotes' Impact on Earth:
- Prokaryotic bacteria produced ammonia, adjusting acidity and increasing temperature
- Purple and green photosynthetic bacteria began using water to manufacture hydrogen rich compounds, releasing oxygen
- Oxygen was "toxic waste" for anaerobic prokaryotes
- Pressured adaptations: motility systems, detoxification, oxygen breathing
Eukaryotic Cells' Emergence:
- Prokaryotic cells evolved into eukaryotes with organized cell interiors and membrane-enclosed compartments (nuclei)
- Eukaryotes have mitochondria for chemical energy production (respiration) and chloroplasts for photosynthesis
- Evolutionary gap between prokaryotes and eukaryotes is a "mysterious dichotomy"
Symbiotic Hypothesis:
- Proposed that eukaryotes resulted from symbiotic association of two types of prokaryotes: a primitive monera and a more advanced cocci-type bacteria
- Ingestion of cocci by monera led to a stable symbiosis, with the more evolved cocci becoming the nuclear material and the monera the cytoplasm
- Other examples of symbiosis: green plants from colorless nucleated cells and minute cyanophycae (chloroplasts); green algae and fungi (lichen)
Endosymbiotic Theory:
- Proposed by Lynn Sagan in 1967
- Aerobic heterotroph was engulfed by an anaerobic heterotroph, leading to mitochondria
- Ingestion of flagellae and their intracellular anchors led to cilia, centrioles, and microtubules
- Multiple cilia provided cell movement, cytoplasmic organization, and information processing
- Cytoskeleton structures provided a "computer-like" information processing system
Critique:
- Question about the pedigree of basal bodies and centrioles
- Cytoplasmic information transfer mechanisms may be independent of genetic involvement
- Dynamic cytoskeletal proteins may manifest biological intelligence
Centrioles: Evolution's Hijackers
Appearance and Significance:
- First appeared one billion years ago in eukaryotes
- Key to success for evolution of human consciousness
- Trigger major reorganizations during mitosis, growth, and differentiation
- Composed of two cylindrical structures (centrioles or centrosomes) with nine radial symmetries
- Each cylinder consists of microtubule triplets longitudinally fused
- Cartwheel filamentous structure (pinwheel) holds ends together
- Perpendicular replication initiates mitosis, a mystery in cell biology
Location and Function:
- Within centrosome or centrosphere near nucleus membrane
- Trigger microtubule polymerization and organization of cytoplasm (MTOC)
- Mitotic spindles separate chromosomes and establish architecture for daughter cells
- Centriole-like basal bodies induce formation of cilia, allowing complex activities and information processing
Evolutionary Significance:
- Provided eukaryotes with sophisticated cellular communication system
- Comparable to potential impact of computers on societies
- Structural beauty, unfathomable geometry, intricate behavior, navigational command add to their mystique
Mysteries Surrounding Centrioles:
- Command of orientation in space and ability to convey information to other cytoskeletal structures (gyroscopic function)
- Suggested role in evolution: intelligent nano-engines who "jumped ship" from a previous species to coopt biology.
Centrioles vs. Cilia:
- Centrioles are uncovered, membrane-free structures within cells
- Cilia are covered by cell membranes and have central microtubule pairs with contractile interconnections
- Propulsion for single-celled organisms
- Sensory functions in humans, transducing mechanical sound into nervous system.
Biotech Evolution: The Next Symbiosis
Indications of Technological Evolution and Biological Adaptation:
- Rapidly evolving technology may lead to another acceleration in biological evolution
- Technology has the potential to address crises such as oxygen toxicity, energy sources, new environments, and forms
- Some observers see technological advancements as a double-edged sword with capacity for good or evil
Technological Advancements and Biological Evolution:
- Genetic biotechnology: creation of new species through lab-dovetailed nucleated cells
- Computer robotics: nanotechnology may lead to "cybersymbiosis" and the next evolutionary phase transition
- Biochips: organic compounds replacing silicon in computers for energy exchange and information processing
Vision of Mind/Tech Symbiosis:
- Ultra-precise robotic brain surgeons transferring human consciousness to a supercomputer
- Advantages: immunity to disease, transportation across galaxies, and resistance to harsh environments
- Max Headroom as an example of technocognitive entities existing solely within electronic circuitry
Potential Challenges:
- Understanding the mechanism of consciousness is currently not available
- Nanosensors may interact dynamically with cytoskeletal protein lattices leading to next symbiosis.
Nervous System Evolution and Organization
4.1 Nervous System Evolution:
- Early organisms had simple nervous systems, resembling chains of ganglia
- Paired chains with an enlarged head ganglion at the front end
- Primitive leech's head ganglion began to dominate other members
- Headed towards hierarchical organization and centralization (encephalization)
- Transition from segmented organism to a nervous system like ours occurred through fusion of paired chains into a tubelike structure
- Paired nerve roots connected the central nervous system with peripheral organs
4.2 Nervous System Organization:
- Central nervous system (CNS) consists of spinal cord, brain stem, and brain
- Peripheral nervous system includes peripheral nerves and ganglia of autonomic nervous system
- Human brains contain about a hundred billion neurons
- Similarities in structure, composition, and functioning of central nervous systems in all vertebrates
- Neurons organized by their component cytoskeletons
Neuronal Signaling:
- Signals consist of electrical potential changes produced by ionic currents
- Ionic currents carry signals through open membrane protein ion channels
- Sodium and potassium ions play crucial roles in maintaining polarization
- Depolarization results from opening of channels, creating waves used as signals
- Neurons carry two obvious types of signals: localized gated potentials (analog) and propagating action potentials (digital)
- Gated potentials spread only one to two millimeters and are essential for integration at sensory nerve endings, neuronal synaptic junctions, and as slow waves in dendrites.
- Action potentials occur on an "all or none" basis, allowing effective communication within large nervous systems.
Interneuronal Synapses
Synapses:
- Action potentials and axons terminate at synaptic connections with other neurons or effector cells
- Final branch portions of axons have thin, swollen synaptic terminals (boutons)
- Some axons may have multiple boutons, each forming a synapse
- Synapses form between the axon terminal and another neuron's dendrite
- Other types of synapses: axon-cell body, axon-axon, and dendrite-dendrite
- Many dendritic synapses occur on dendritic "spines" (knobby dendritic protuberances)
Modes of Synaptic Signaling:
- Electrical signaling: Currents generated by an impulse spread directly to the next neuron through a low resistance pathway
- Chemical signaling: At chemical synapses, the fluid gap between presynaptic and postsynaptic membranes prevents direct spread of current, requiring electrical connection between neurons.
Electrical Synapses:
- Electrical communication occurs through gap junctions, with an intercellular space reduced to about 2 nanometers
- Estimated to be as high as 80% of all synapses in the mammalian brain, but their significance is unknown due to challenges in isolation and characterization.
Chemical Synapses:
- Neurotransmitter vesicles (50 nm diameter) contain neurotransmitter molecules
- Excitatory and inhibitory neurotransmitters identified: acetylcholine, norepinephrine, serotonin, dopamine, GABA, various peptides and amines.
- Action potential impulse triggers the release of neurotransmitter vesicles by calcium-mediated mechanisms involving cytoskeletal proteins.
Neuroscience Concepts: Neuron Integration and Information Representation
Synaptic Transmission
- Spontaneous releases of individual vesicles cause miniature end plate potentials below threshold for depolarization
- Specific binding of neurotransmitter molecules to receptors changes membrane permeability, producing localized receptor potentials
- Postsynaptic membrane "integrates" local receptor potentials spatially and temporally to exceed threshold
Excitatory vs Inhibitory Signals
- Excitatory signals increase post synaptic permeability to sodium and potassium, leading to depolarizing action potential
- Postsynaptic acetylcholine activated channels open for 1-2 ms, allowing net entry of 2x10^4 ions
- Other synaptic channels pass 10^5 or more ions over tens of milliseconds
- Inhibitory signals may increase chloride ion permeability, driving membrane potential away from threshold
- Pre-synaptic inhibition prevents excitation by blocking neurotransmitter release
Information Processing in the Brain
- Central enigma: understanding information representation within nervous systems
- Assumption of parallel networks of connected units with neurons and synaptic connections as fundamental substrates
- Neurons perform significant analog processing at dendritic level and cytoskeleton
- Modification of synaptic transmission threshold, cornerstone of neural net learning models, regulated by cytoskeleton and its connections
Integration: Sherrington's Reflex Centers
- Processing dynamic excitatory and inhibitory patterns within masses of neurons (reflex centers) is called integration
- Integration occurs at all levels of nervous systems and among various types of organisms
- Neural masses or reflex centers correlate with anatomically identifiable nuclei, containing high density of neuronal cell bodies and synapses
- Nucleus is purely structural while center is functional; they do not always coincide.
Neural Centers: An Outdated Concept with Evolutionary Significance
Neural Centers:
- Erroneous impression of anatomically specific function
- Remains as a vestigial reference to Sherrington's concept of the nervous system
- Denotes groups of neurons whose destruction leads to loss of specific function or stimulation evokes certain behavioral/physiological function
Brain Functions:
- Not divided among centers like an organization or factory
- Relation between anatomic regions and brain-wide distribution of information is perplexing and complicated
Example: Satiety Center
- Located in the hypothalamus
- Stimulation stops eating, destruction leads to excessive eating
- Feeding behavior regulated by a wider range of neural circuits
Anatomical Representations:
- Motor and sensory homunculi
- Integrate wide sources of distributed input to representations of anatomical sensation and action
- Evolutionary adaptations for larger, more complex nervous systems
Sherrington's Contributions:
- Concept of integration by reflex centers illuminated neural information processing
- Recognized information transfer functions at all levels of the nervous system
Pulse Logic and Connectionism
- Electrical signaling in the nervous system discovered in the late 18th century
- Development of microelectrodes revealed ubiquitous electrical nerve impulses
- Electrophysiological techniques enabled study of neural events
- Action potentials consist of brief, high-voltage pulses that move quickly along nerves
- McCulloch and Pitts proposed "neurons" based on all-or-none processes and synaptic delays
- Neural information processing perceived as encoding by dynamic neural firing patterns
- Graded wave-like events in more primitive nerve nets provide a basis for information transfer
- Dynamic activity of subunits within cytoskeletal proteins is the basic substrate of information transfer and processing
- Frequency coding of stimulus intensity limited, meaning attributed to origins and destinations (connectionism)
- Closed pathways with logical feedback and reverberation evolved pulse logic into connectionism and neural networks
Connectionism and Neural Networks
Background:
- Camillo Golgi's discovery of neuron staining in 1875 by Italian anatomist
- Santiago Ramon y Cajal's use of Golgi stain for neuroanatomy investigation
- Demonstration of specific and selective connections among neurons
- Emphasis on orderliness of neural connections during development
Shifting Concepts:
- Neural pulse coding is limited, shifting focus to connectionism
- Consensus that stereotyped signals represent symbols derived from specific connections
- High degree of precision in forming neuronal connections emphasized
Neuron Development and Synaptic Connections:
- Neurons grow towards target cells, ignoring some and selecting others
- Neurons behave as if aware when receiving appropriate synaptic connection
- Synaptic loss may result in cell death or dysfunction (denervation)
- Trophism: structural and functional material conveyed by cytoskeletal proteins
- Microtubules, axoplasmic transport allow growth of neuronal structures
- Synaptic plasticity: changes in neural connections relevant to brain function
Key Developments:
- Golgi's discovery of neuron staining (1875) by Italian anatomist Camillo Golgi
- Santiago Ramon y Cajal's use of Golgi stain for neuroanatomy investigation (classic texts)
- Demonstration of specific connections among neurons
- Consensus shift towards connectionism due to limited neural pulse coding
- Emphasis on orderliness and precision in forming neural connections during development.
Association between Learning and Synaptic Function
Early Concepts:
- Late 19th century writers considered association between learning and ongoing synaptic function
- Pavlovian and behaviorist influences of conditioned responses popularized the idea
Pavlov's Proposal:
- Conditioned reflexes formed by establishing new connections between cortical neurons receiving a conditioned stimulus (with reward or punishment) and unconditioned stimulus
- Unconditioned stimulus acquired same power to evoke response as conditioned stimulus
- Implied that new synaptic connections could not grow in adults, so long term facilitation of pre-existing connections became alternative
Alternative View:
- At birth, excitations could pass between any two points in CNS through a random network of connections
- As maturation, experience, and learning occurred, synaptic activity sculpted usable patterns by suppressing unwanted interconnections
- Connectionist brain/mind viewed as either:
- "Blank slate" (tabula rasa), where acquired learning and internal organization result from direct environmental imprinting
- "Selectionist" network, chosen from a vast potential network
Selectionist Viewpoint:
- Brain/mind spontaneously generates variable patterns of connections during childhood development (transient redundancy) or from prerepresentations in the adult
- Connections between neurons are eliminated and number of accessible firing patterns reduced as correlate of learning
- Observed reduction in number of neurons and apparent synapses could be masking increase in complexity of dendritic arborizations, spines, synapses, and cytoskeleton
Connectionist Models:
- Hebb pioneered modeling of learning at the level of large assemblies of interconnected neurons
- Learning occurred by strengthening specific synaptic connections within a neuronal network
- Functional groups of neurons formed networks, assemblies, cartels, modules, or crystals based on anatomical brain regions
- Neural network models aided by the mathematics of statistical mechanics and rejuvenated by work of Hopfield (1982), Grossberg (1978), Kohonen (1984)
Perceptron Model:
- Rosenblatt's perceptron model of the 1950s and 1960s created enthusiasm but failed to reach potential due to limitations in mathematics
Hopfield's Neural Nets:
- Introduced energy function so information settled into stable energy states like a memory or conscious image
- Loosely based on neurobiology, adapted for integrated circuits
- Provided content addressable memory, capacity for generalization, familiarity recognition, categorization, error correction, time sequence retention, and insensitivity to failure of individual components
Spin Glass Model of Neural Network Learning: Selection by Energy Landscapes and Hierarchical Information Sorting
Hopfield Nets and Connectionist Models:
- "Tabula Rasa" view of learning: initial state as flat energy landscape becomes contoured through interactions with environment
- Hopfield nets and similar models categorized under this approach
Selectionist Approach to Neural Net Theory (Changeux):
- Based on latest advances in statistical mechanics of disordered systems: spin glasses
- Atoms possess high degree of similar neighbor relations, finite number of magnetic states influenced by neighbors
- Aggregates of "like spins" result in similar states among neighbors
- Brain's initial state viewed as complex energy landscape with exuberance of valleys typical of spin glasses
- Each valley corresponds to a particular set of active neurons and plays role of prerepresentation
- Input pattern sets initial configuration which converges towards a lowered entry threshold valley
- Learning process viewed as smoothening, gardening, and evolutionary pruning based on stored information
- Changeux's spin glass model successfully presents hierarchical static information sorting but has shortcomings: unidirectional, fails to describe dynamic real-time processing.
Other Selective Connectionist Network Models:
- George Reeke and Gerald Edelman of Rockefeller University: described two parallel recognition automata networks that communicate laterally named Darwin and Wallace after co-developers of evolution theory
- Both networks have distinct personalities; Darwin is analytical, recognizes edges, dimensions etc., while Wallace categorizes objects into preconceived classifications
- Outputs of individual processors must be reconciled if not identical through lateral communication networks
- Form an associative memory as they operate on unchanging connectionist network
- Similar recognition automata may exist in dynamic cytoskeletal networks within neurons.
Distributedness in Neural Networks and Memory Storage:
- Neuroanatomical understanding of synaptic structure led to connectionist theory, extending Hebb's theory of neural nets to human memory and behavior
- Experimental data from Lashley's research on the "engram" in animal brains showed that memory function is distributed throughout the brain, not limited to specific areas
- Lashley proposed an alternative to localized storage: information patterns can be evoked in many neurons and regions of the brain related to memory
- Distribution of information in memory explained by spread of interference patterns on cortex surface, similar to liquid disturbed at several points at once
- Memory is not stored as fixed traces but as a lasting pattern of reverberatory activity without a fixed locus
- Prevalent interpretation: information is stored in relationships among units and each unit participates in encoding many memories, distributed over large areas
- Filters can extract individual traces from complex patterns, making distributed memory system an effective storage and retrieval device
- Memory not independent of one another; previously stored information can evoke original pattern even with input differences
- Lashley suggested open, parallel, distributed network covering wide regions of the brain instead of Hebb's closed loop of neurons firing in a confined region.
Synaptic Mechanisms of Learning and Memory
Short-term vs Long-term Memory:
- Short-term memory (working memory) is used for storing information temporarily, with a maximum capacity of 5 to 9 items at any one time
- It is labile and easily disrupted if attention is diverted, automatically erasing within minutes
- Continual verbal rehearsal can counteract erasure and re-enter the contents as long term memory
- Long-term memory (reference memory) has a large capacity and difficulty in recalling specific items arises due to lost addresses, not fading memory traces
- Items stored but not used become increasingly difficult to recall
Consolidation:
- Consolidation is the process of moving information from short-term to long-term memory, requiring a finite 45-second period
- Some regard consolidation and short-term memory as independent parallel functions
- Amnesia may occur if brain activity is disrupted, affecting short-term but not long-term memory
Synaptic Changes for Learning:
- Structural changes in synapses are the cornerstone of current concepts of learning and memory
- Classifications of plastic changes include habituation, long-term potentiation, and heterosynaptic potentiation
Habituation:
- Simplest form of learning where an animal learns to ignore a repeated, non-threatening/uninteresting stimulus
- Different from other decreased responses like synaptic fatigue or desensitization
- Involves decreased output of excitatory neurotransmitter at presynaptic axon terminals mediating the withdrawal reflex
- Known through studies on the gill withdrawal reflex in sea slugs, a marine organism
Neuronal Plasticity: Three Forms and Cytoskeleton Involvement
Behavioral Response:
- Elegantly related to molecular level events at presynaptic calcium channels and neural proteins
- Activity of these proteins viewed as "allosteric"
Long Term Potentiation (LTP):
- Repeated use of a synapse increases transmission efficiency
- Effect lasts hours to days, corresponding with morphological changes in synaptic membrane proteins regulated by neuronal cytoskeleton
- Two pathways sharing an interneuron: LTP enhances non-originally excited pathway (associative memory)
Heterosynaptic Potentiation:
- Activity on one synapse changes efficiency of another synapse on the same post-synaptic membrane
- Mechanisms: change in sensitivity of post-synaptic neuron to transmitter or change in amount of transmitter released
- Evidence suggests increased numbers of receptors in post-synaptic membranes (similar mechanism as LTP)
Cytoskeleton Involvement:
- Synaptic plasticity and cognitive processes focus on molecular level alterations in synaptic membrane proteins regulated by neuronal cytoskeleton
- Direct involvement: microtubules, turnover of microtubule subunits (tubulin) increase during learning, memory and experience
- Mileusnic et al. (1980): tubulin associated with synaptic membranes in developing brain
- Cronly-Dillon et al. (1974): increased incorporation and total quantity of tubulin during early development
- Dynamic spine plasticity: Crick (1982) proposed dendritic spines change shape, altering synaptic thresholds mechanically
- Determined by microtubules, composed mostly of contractile actin (Matus et al., 1982)
- Short term memory link: dynamic spine plasticity orchestrated by dendritic MT and cytoskeleton
- Axoplasmic transport maintains and supplies form and functions of dendritic spines and all neuronal synapses.
Axoplasmic Transport in Neurons
Proteins and Organelles: Synaptic membrane proteins, including ion channels and receptors, cytoskeletal protein structures, mitochondria, and enzymes required for transmitter synthesis/metabolism are manufactured in neuron cell bodies due to the presence of biochemical machinery.
Transport Process: These materials or precursors are then transported through the axon (or dendrite) using a cytoskeletal mechanism, similar to a conveyer belt or bucket brigade. Time-lapse photography shows mitochondria moving down axons like barges on a river, and vesicles zipping along microtubules.
Axoplasmic Transport Mechanisms: There are several independent axoplasmic transport processes: fast (400 mm/day) and slow (1 mm/day). The mechanism involves microtubules and contractile proteins attached to the microtubule walls, which utilize ATP hydrolysis for orchestrated bucket brigade activity.
Retrograde Axoplasmic Flow: Simultaneous transport in the opposite direction (retrograde) brings feedback information to regulate transmitter enzyme production and other materials. This creates dynamic neurons capable of changing shape and function through experience.
Parallelism, Collective Cooperativity, and the Grain of the Engram: Neuron-to-neuron synapses operate on millisecond timescales, while modern computers take nanoseconds. The brain's parallel processing capabilities enable it to perform tasks impossible for computers.
Gazzaniga's Argument About the Brain:
- Brain is more a social entity than a psychological one (Gazzaniga)
- Consists of relatively independent modules, each processing information and activating thoughts/actions
Hippocampal Neurons and Cognitive Maps:
- O’Keefe and Speakman's experiments: hippocampal neurons represent place in environment
- Each cell cluster participates in representation of different patches
- Coarse representation provided by 8-10 cells
- Increasing resolution with more cells but no alteration of grain size
- Representation distributed, not individual nerves/synapses
Information Distribution and Memory:
- John et al.: information extensively distributed in cats' brains
- Ensembles of neural elements mediate integration and processing
- Integration of memories depends on unrecognized system properties
Collective Aspects of Mental Processes:
- Freeman: nervous systems more than sum of parts
- Interconnections of neurons give rise to collective properties
- EEG as evidence for collective neural phenomena
- Arises from slow, graded potentials produced by dendrites and cell bodies
- Large numbers of neurons involved in generating patterns
- Significance of local collective EEG wave fields debated
- Superfluous epiphenomena to informational transmitters or substance of consciousness
EEG, Proteins, and Information Processing:
- Adey: neural proteins undergo conformational changes in response to EEG patterns
- Hydrated glycoproteins, membrane proteins, cytoskeleton involved
- Transduction of electromagnetic energy into protein conformations represents dynamic information
- Common thread: biological intelligence is based on cooperative dynamics of molecular network (cytoskeleton)
The Cytoskeleton: Organizational Network in Living Cells
Discoveries and Theories:
- 1835: Felix Du Jardin proposed cells were composed of a material called "sarcode" with structural and contractile properties.
- 1861: E. Brucke linked mechanical and physiological properties to a fundamental organization in cytoplasm.
- Early 20th century: Observations of red blood cells and cellular rigidity led biologists to believe that cytoplasm is not just a liquid or emulsion.
- Reticular theory proposed a continuous network of delicate fibrils, while the fibrillar theory claimed unbranched discontinuous ones. Both theories were supported but later deflated due to microscope preparation techniques.
- 1899: Fibrillar and reticular frameworks appeared in fixed cells, particularly in muscle, nerve, cartilage, and epithelial cells.
- Butschli's alveolar foam theory failed to account for fixation observations and vacuolated cytoplasm was uncommon.
Birefringent Substances:
- Observations of true fibrillar formation in living cells using polarized light microscopy revealed birefringent rods, thought to be proteins or linear aggregates.
- Seifriz proposed the "brush heap theory" suggesting that cytoplasmic fibers could form interlacing gels or paracrystalline aggregates.
- Subunits of protein actin can polymerize into interlacing gels or filamentous bundles.
Microtubules:
- Electron microscope revelations initially did not illuminate the substructure of cytoplasm due to fixatives like osmium tetroxide dissolving filamentous elements.
- With glutaraldehyde fixation, delicate tubular structures were found in virtually all cell types, called microtubules.
- Microtubules correspond to birefringent fibers seen in living cells and are generally accepted as "household organelles."
- Subsequent characterization of actin, intermediate filaments, the microtrabecular lattice, and centrioles led to recognition that cells are comprised of dynamic networks of connecting filaments.
Microtubules (MT)
- Hollow cylinders about 25 nanometers in diameter
- Walls made of protein subunits called protofilaments
- Thirteen parallel protofilaments align to form the hollow "tubules"
- Subunits are "barbell shaped" proteins ("dimers") consisting of two globular proteins, alpha and beta tubulin (Figure 5.4)
- Alpha and beta tubulin monomers are similar molecules with identical orientation within protofilaments and tubule walls
- Each monomer consists of about 500 amino acids, weighs around 55 kilodaltons, and has a local polarity or charge orientation
- MT that grow from cell centers have a "plus end" (beta tubulin) extending outward from the cell center ("centrosome") into the cell periphery
- The "minus end" (alpha tubulin) remains anchored to a microtubule organizing center (MTOC) within the centrosome
- Each dimer and MT appears to have an electrical polarity or dipole, with the negative end oriented towards the alpha monomer and cell center, and the positive end towards the beta monomer and cell periphery
- Dimer neighbors form hexagonal lattices with a "leftward" tilt and several helical patterns may be discerned in the relations among dimers
- Crystal-like symmetry packing of tubulin in microtubules has been evaluated by Djuro Koruga (1986) at the University of Belgrade in Yugoslavia
- MT from different life forms show marked similarities, but subtle differences; for example, more primitive worm MT have 9-11 protofilaments compared to 13 in mammalian MT
- Tubulins from among different species including mammals and plants bind to common antibodies and can coassemble into hybrid MT
- Diversity of tubulin gene expression has proved far greater than initially imagined, with multiple, different alpha and beta tubulins existing concurrently, with the greatest diversity shown by beta tubulin.
Microtubules and Their Functions:
- Different tubulin forms exist: Rat thyroid microtubules contain 11 distinct tubulin types, while brain microtubules have 17 variations.
- Isozymes with specific functions: Alpha and beta tubulins are families of isozymes; each may have unique roles or MAP binding.
- Detyrosination: Tyrosine removal from beta tubulin exposing an acidic amino acid, glutamate.
- Clear zone surrounding MTs: Anionic fields at the surface may explain clear zones and staining by positively charged dyes.
- Hollow core of MTs: Unknown if interiors are electronegative or positive; could create voltage gradients.
- Microtubules as cytoskeleton: Rigid structures that establish cell form and function through assembly and movement of organelles and materials.
- MT functions: Organizing cytoplasmic transport, growth, reproduction, synaptic plasticity, and nearly all dynamic cytoplasmic activities.
- Information processing proposals: Several theories propose MT-based information processing described in Chapter 8.
- Controlling activities of attached proteins: Participate in controlling activities of attached proteins including those interconnecting MT assemblies like centrioles, cilia, flagella.
- Cell shape determination and extension: Active sliding by motile bridges attached along MT involved in cell shape determination and cytoplasmic projections growth.
- Sensory perception and transduction: Involved in sensory perception of external environments through mechanoreceptors and cilia.
- Pattern formation mechanisms: Temporal and spatial control achieved by directed assembly from MTOCs and self-assembly of multitubular arrays using intertubule linkers.
Microtubule Assembly and Generation of Form
- MT can assemble into rigid rods when needed, then disassemble into subunits
- Self-assemble from subunits into orderly polymers
- Increase in order during assembly related to dispersal of structured water from subunits
- Variability in stability and function of MT due to tubulin chemistry, secondary proteins, cytoplasmic influences, membrane interactions, etc.
- Stable MT found in cilia and flagella; labile MT in mitotic spindles
- Assembly of labile MT facilitated by MTOCs (microtubule organizing centers)
- Negatively charged ends attach to MTOC, positively charged ends grow distal
- MT assembly complex, involving critical concentration (Cc) and various cofactors: calcium ion, temperature, microtubule inhibitors/stabilizers, MAPs, presence of MTOC, availability of GTP.
- Spontaneous assembly depends on physiological conditions and cofactors
- Energy input from phosphate bond hydrolysis used in cytoskeleton, possibly for generating lattice vibrations or "solitons"
MT Disassembly and Assembly
Effects of MT disassembly drug nocodazole:
- PtK2 cells: organized MT depolymerized after treatment (upper right)
- Cells washed and reorganized MT system (lower left and right)
MT Assembly Requirements:
- Presence of magnesium ion and low concentration of calcium ion
- Calcium induces conformational changes, can dissolve cytoplasmic gel
- Excess calcium causes MT disassembly
- Zinc ions cause tubulin polymerization into flat expansive sheets instead of cylinders
Tubulin Subunits:
- Alpha/beta tubulin arranged in the same direction
- Beta subunit protrudes at the "plus" end and contains exchangeable GTP binding site
- Treadmilling: net movement of subunits within MT lattice, corresponds to slow axoplasmic transport
MT Disassembly:
- Terminal dimers bind GDP cause disassembly
- GTP bound dimers at open ends are stable; exposed GPD tubulin leads to shrinking and depolymerization
- Free MT polymers exist in two populations: growing fast and shrinking rapidly
Dynamic Instability of MT:
- Growing polymers have protective GTP subunit caps, shrinking polymers lose GTP caps
- Faster growth rate = larger GTP cap and lower probability of disassembly
- Exposure of multiple GTP or GDP containing subunits at MT terminals required for stability/instability
- Utilization of GTP hydrolysis energy significant portion of biological energy consumption
Observations on Growing and Shrinking MT:
- Both ends can exist in growing or shrinking phase and alternate randomly
- Active end grows faster, alternates more frequently, and fluctuates length greater than inactive end
- MAPs suppress phase conversion and stabilize microtubules in the growing phase
- Binding at proximal end to MTOCs stabilizes MT and prevents depolymerization
MT Stabilization Mechanisms:
- Capped or bound to various structures, such as MTOCs
- Selective retention through stabilizing a particular subset of microtubules for functional roles
- Dynamic structural rearrangement requires intelligence.
Microtubule Organizing Centers (MTOC) and Centrioles
Role of MTOC/Centrioles:
- Trigger and guide reorganization of cytoplasm during growth, differentiation, and cell movement
- Determine where, when, and how functions occur
Components:
- Contain centrioles and pericentriolar substance
- Centrioles: two cylinders with radial symmetry (0.2 microns or 200 nanometers)
- Each cylinder has nine triplets of microtubules
- Satellites orbit the centrioles
- Cartwheel filamentous structure connects all microtubules within each centriole
- Centrioles beget new ones by replication perpendicular to their surface
Function:
- During cell division: maturation of mother cell, separation of pairs of centrioles, and establishment of architecture in daughter cells
- Relatively quiescent during interphase with low turnover rates
- Most tubulin polymerized during this period
- MT system is stable with minimal dynamic instability
MT System during Mitosis:
- Prophase: cytoskeleton prepares for chromosome separation
- New MT nucleate near MTOC and kinetochore plates associated with chromosomes
- Minus ends stabilized by pericentriolar material, plus ends grow outward
- Free MT remain short due to consumption of tubulin subunits by stabilized MT
- Stabilized MT slide along each other to pull chromosomes apart
MTOC/Centrioles:
- Determine orientation, shape, timing of division, and growth
- Possible theories about their capabilities:
- Rotational oscillation with gyroscopic inertia (Bornens)
- Senses cell orientation to neighbors, environment, chemical gradients, gravity
- Detect signals propagating linearly throughout the cytoplasm (Albrecht-Buehler)
- Potential technological applications
- Rotational oscillation with gyroscopic inertia (Bornens)
Microtubule Associated Proteins (MAPs)
- Various proteins bind to specific tubulin dimers in microtubule lattices, enhancing their functions
- Classes of MAPs:
- Electromechanical enzymes generating force and movement
- Communicative crossbridges to other cytoskeletal filaments or organelles
- Proteins enhancing MT assembly
- Unknown functions in neurons
Attachment Patterns of MAPs
- Precise geometrical configurations related to function
- Smooth axoplasmic transport requires contractile MAPs spaced between 15 and 25 nanometers apart
- Other attachment patterns are spirals winding around MT cylinders in super-helices
- Determined by linear sequencing, crystal symmetry, or lattice steps
Rod Shaped Bridges Between MT
- Protein "arms" consuming ATP hydrolysis energy to generate force (analogous to myosin bridges)
- Kinesin and dynein proteins
- Dynein arms contract collectively in organized sequences, driving ciliary and flagellar motility
- Axoplasmic transport uses dynein arms acting like "bucket brigade"
Other MAPs
- Integrate microtubules with the rest of the cytoplasm by bridging between parallel MT filaments, organelles, and the "microtrabecular lattice"
- High molecular weight (MAP 1 and 2) and related 56–62 kilodalton proteins (tau) in brain neurons
- Increase in number and altered distribution during brain development and learning
- Phosphorylated by cyclic AMP-dependent protein kinases, regulating intracellular calcium levels
- Mediate diverse inputs into the cytoskeleton as "synapses" in a parallel network
- Tau heterogeneity varies during brain development, resulting in different polypeptides in mature cerebral cortex and cerebellum.
Cytoskeleton and Intermediate Filaments (IF)
- Major filamentous components: MT, actin filaments, IF, microtrabecular lattice (MTL)
- Focus on intermediate filaments
- Overview of IF: nebulous subgroup of cytoskeleton, built from alpha helix rod domains
- Appearance under electron microscope: unbranched, 8–12 nanometer wide filaments
- Variability in number and size of protofilaments or protofibrils
- Shapes: parallel coiling, polygonal meshwork, crystal-like arrays
- Involvement in structures like MTL/cytomatrix
- Five major classes: keratin ("tonofilaments"), desmin filaments, vimentin filaments, neurofilaments, glial filaments
- Diverse associations with specific cell types
- Functions: provide tensile strength to axons (neurofilaments), participate in mechanically integrating cytoplasmic components.
Intermediate Filaments (IF)
- Five major classes based on subunit structure
- Keratin ("tonofilaments"): epithelial cells
- Desmin filaments: smooth, skeletal, cardiac muscle cells
- Vimentin filaments: mesenchymal cells
- Neurofilaments: neurons (Figure 5.18)
- Glial filaments: glial cells
- Often two or more classes co-exist in a cell
- Function not fully understood, possibly involved in mechanically integrating cytoplasmic components
- Poorly understood, mysterious presence in neurons.
Neurofilaments (NF)
- Three dimensional structural lattice providing tensile strength to axons
- Extruded axoplasm rich in NFs
- Calcium ion exposure leads to degradation and conversion of gel into a sol state
- Phosphorylated, but function unknown
- Involved in mechanically integrating cytoplasmic components.
The Cytoplasmic Ground Substance
Microtrabecular Lattice (MTL):
- New techniques in electron microscopy developed by Keith Porter and colleagues at the University of Colorado at Boulder
- Observation of an irregular three dimensional lattice of slender strands throughout the cytoplasm, interconnecting various cell systems, organelles, and larger cytoskeletal elements
- The lattice is suggestive of the trabecular structure of spongy bone and was named the microtrabecular lattice (MTL)
- Provides more information about depth, giving a three dimensional view of cell organization
- Avoids distorting effects of surface tension by using critical point drying
- Observed in all eukaryotic cells which have been examined
- Consists of slender strands called microtrabeculi, with diameters from 4 to 10 nanometers and lengths of 10 to 100 nanometers
- Divides the ground substance into two phases: a protein rich polymerized phase comprising the MTL, and a water rich fluid phase
- Connects various elements in the cytoplasm, such as microtubules and smooth endoplasmic reticulum
- Dynamically active in moving material in a saltatory manner at velocities equivalent to axoplasmic transport
Microtrabecular Lattice and Cytoskeleton:
- Acts like skeletal musculature, as it is an analog of rigid skeletal elements and is involved in moving elements through the cytoplasm
- Radiates from microtubules and neurofilaments in neurons
- Involved in both neurotransmitter release and post synaptic receptor mechanisms
- Crosslinks various elements, including synaptic vesicles, membranes, and other components
- Can be transformed from axoplasm to synaptic terminal or growth cone cytoplasm
- Dependent on calcium ion concentration, with high calcium causing the MTL to shorten and deform
- Calcium may be a coupling agent for dynamic aspects of the MTL
- Could represent standing waves, dissipative patterns, or holograms in cytoplasm
Functions and Behavior of the Cytoskeleton and MTL in the Nervous System:
- Modulation of membrane events such as receptor activity and neurotransmitter extrusion
- Participation in axoplasmic transport, turnover and maintenance of membrane proteins and receptors, and availability of neurotransmitters and enzymes at synapses
- Differentiating specific zones of cytoplasm and membrane, controlling the types of receptors or channels at synaptic zones
- Mediating embryological development or morphogenesis through linkages with hormone receptors or tissue factors
- Transducing chemical or mechanical work for intracellular transport and processes
- Regulating the rest of the cytoskeleton and the cell at large
The Cytomatrix and Cytoplasmic Solid State
Background
- Peter Satir's work on protein makeup and functional organization of MTL (cytomatrix) at Albert Einstein University
- Actin, a versatile protein, is primary building block with actin-binding proteins
Components of the Cytomatrix
- Actin: ubiquitous protein, forms rigid bundles through interaction with fimbrin or associates with myosin for muscle-like contraction
- Other Proteins: talin, spectrin, vinculin, ankyrin, and fodrin connect cytomatrix to membrane proteins; calmodulin mediates calcium ion effects; alpha actinin, troponin, filamin create gelatinous consistency
- Actin Regulatory Proteins: actin capping proteins stabilize polymerized actin and promote a "gel" condition, profilin binds actin subunits prevents polymerization and maintains "sol" conditions
- Calcium Ions: activates myosin to pull actin filaments against each other for contraction and streaming in cytoplasmic movement
- Actin Fragmenting Proteins: gelsolin, villin cause liquefaction of gel network to solution ("sol") state
Cytomatrix Structures and Functions
- Amoeboid and other types of cytoplasmic movement as well as polyhedral structures
- Calcium mediated sol-gel transition important in cell functions, perhaps transient representation of short term memory within neurons
Cell Solid State (Cytoskeleton/Cytomatrix/MTL)
- Molecules like proteins and RNA heterogeneously distributed throughout cytoplasm
- Slow diffusion explained by cytomatrix barriers and channels initially, but later found to be dynamically bound to solid state
- Solid state occupies 16-21% of cell volume with surface area from 69,000 to 91,000 square microns per cell (69 to 91 billion nanometers)
- Biomolecules are efficiently arranged in complex biochemical pathways due to physical arrangement and dynamic regulation by solid state structures
- Water surrounding solid state structures plays a role: ordered water aligned with polar bonds on protein surfaces, inhibits thermal dissipation, shields calcium ions from random interactions
- Additional layers of less ordered water ("vicinal water") limit true "aqueous" water within cells to narrow cellular "sewage channels."
Cytoskeletal Motility
Discovery of Cell Movement:
- Discovered by van Leeuwenhoek in the 17th century observing flagella propelling sperm cells
- Various cytoplasmic movements: "amoeboid" creeping, internal streaming, axoplasmic transport, muscle contraction, ciliary and flagellar bending, and cell shape changes
Role of Proteins in Cytoplasmic Movements:
- These maneuvers are engineered by a relatively small group of proteins
- Complexity, organization, and precision of these movements boggle biologists
- Examples: lymphocytes/macrophages migrating to engulf bacteria, embryonic tissue formation, internal movement (e.g., cytoplasm streaming, neurotransmitter secretion), muscle contraction
Categories of Cytoplasmic Movement:
- Cytoplasmic probing: Cell extensions (lamellipodia and filopodia) probe the substrate to determine direction
- Bending sidearms: Ciliary and collective movements
- Geodesic tensegrity structures: Proteins in the cytoskeleton form a network that allows the cell to maintain its shape
Lamellipodia and Filopodia:
- These are dynamic, membrane-coated extensions of the cytoplasm
- They provide spatial guides for the cell membrane and cytoplasm flow
- Filopodia can change from a fluid to a rigid state in less than a second by assembling actin filaments
- They serve a sensory function by detecting substrate surface contacts
Cytoplasmic Organization and Migration of Cells:
Defective Growth Regulation in Cancer Cells:
- Cytoplasmic organization radially arranged from centrosome (C) near nucleus (N)
- Golgi elements (G), lysosomes (L), mitochondria (M), and endoplasmic reticulum (ER) aligned along microtubules (MT)
- Phagocytic and pinocytic vacuoles (P) and secretory vesicles (V) move between centrosome and periphery
- Intermediate filaments (IF) parallel MT, stress fibers (SF) anchor cell to substrate
Intelligent Behavior of Isolated Cytoplasm:
- Biologist Guenter Albrecht-Buehler studied isolated cytoplasm
- Three major types: force generation, transmission of motile forces, and traction generation
- Control of cell migration: polarity, cell body coordination, logic of migration
- Evidence of cytoplasmic intelligence through coordination of many cell domains and environment assessment
Cytoplasmic Intelligent Behavior:
- Fragments of cytoplasm (microplasts) capable of autonomous movement
- Small fragments demonstrate filopodia, ruffles, and blebs
- Intelligence controlled by superior stratum of organization for coherent locomotion
- Not located in genes as cells with removed nuclei still exhibit migration behavior.
Bending Sidearms and Cytoskeleton Functioning
Muscle Contraction:
- Contractile proteins attached to rigid cytoskeletal filaments bend during muscle contraction
- Thin actin filaments interdigitate with thick myosin filaments
- Myosin heads extend across a gap of about 13 nanometers and row like oars, driving conformational changes in myosin molecules through ATP hydrolysis energy
- Calcium ion release triggers this process by shifting the position of regulatory protein troponin and allowing actin-myosin ratcheting
- Myosin head coordination is initiated by calcium ion waves
Axoplasmic Transport:
- MTs polarized with plus ends distal from cell body facilitate force generation for movement and vesicle transport
- Contractile crossbridges occur every 16–18 nanometers along MT lengths, generating directional material movement by undergoing conformational changes involving attachment to vesicles, ATP-dependent force generation, and detachment from vesicles (only at plus ends near synapses)
- Similar to myosin head rowing in muscle fibers but more variable and interactive than repetitive nanoscale events
- Retrograde axoplasmic transport provides feedback for protein synthesis machinery or recycling of molecules
Gliding MT:
- Gliding MT segments suggest linear force-generating enzymes along the MT, parallel to its surface with a spacing interval of about 17 nanometers
- Velocity is independent of fragment length and occurs in straight paths, slowing when ATP concentration decreases but not affecting behavior or number of gliding MTs
- Gliding MT segments rarely interact when crossing paths and “fishtail” when progress is blocked
Force Generation Enzymes:
- Dynein and kinesin are force-generating enzymes for cilia/flagella movement and organelle transport along microtubules, respectively.
Backstroke Hypothesis:
- Force generating enzymes make an elliptical stroke that imparts force in both directions, carrying vesicles in opposite directions through sufficiently separated pathways without collisions.
MT Communication:
- Collective communication among MT lattice subunits (solitons, coherent excitations, lattice vibrations) could explain the orchestration of contractile activities.
Ciliary and Collective Movement:
- Axoplasmic transport occurs through coordinated activities of sidearm proteins (dynein) in a "bucket brigade" system
- Cilia and flagella have a core of parallel microtubules in a cylindrical "9+2" arrangement
- Dynein contractile proteins utilize ATP energy to produce force for bending movements
- Flagella and cilia function without influence from attached cells, continuing movements when severed from cells
- Cilia move fluid over surfaces or propel single cells through a fluid; simple flagella have similar internal structure but longer and propagate in quasi-sinusoidal waves
- Mechanism of bending in eukaryotes is similar to muscle contraction and axoplasmic transport
- Unknown how precise utilization, transfer of conformational states, and temporal orchestration control sidearm appendages
Geodesic Tensegrity Gels:
- Actin-myosin contractility also occurs in non-muscle cells
- ATP provides energy for slime mold locomotion by converting into mechanical work
- Actin filaments organized into geodesic networks, reminiscent of icosahedral geodesic domes
- Alpha actinin localized primarily at vertices of the network; tropomyosin along actin fibers
- Longer fibers attach to network vertices and extend into filopodia, lamellipodia, membranes
- Transient dynamic structures serve vital functions during cell cycle, such as mitotic spindle and cleavage furrow contractile ring
- Simple sliding filament model insufficient for explaining cell cleavage function
- Tensegrity provides self-supporting property through balance between compressive and tensile forces in cytoplasm
- Contractile actin may wind and unwind microtubules by a "torque drive," causing rotational oscillations
- Dynamic compression/tension important for regulating membrane receptors' mobility.
The Cytoskeleton and Development
Functions of the Cytoskeleton in Reproduction and Development:
- Performs critical functions in meiosis (chromosome division), sperm motility, mitosis, cell proliferation, migration, and changes in cell shape during differentiation.
- Crucial to all steps in reproduction, growth, trophism, and differentiation.
Theories on Embryonic Development: Aristotle's Views (384–322 BC):
- Epigenesis: Embryos derive from formless masses through continuous unfolding.
- Favorited this theory, but preformation dominated science for centuries.
The Preformation Theory vs. Epigenesis
- Preformation theory: Individual patterns exist in miniature within the parent and development consists of steady growth.
- Aristotle favored epigenesis, but it was not widely accepted until 1759 when Friedrich Wolff challenged the preformation theory with evidence that a chick embryo starts as "globules" or cells without functional relation to each other.
Aristotle's Epigenesis Theory and Modern Understanding:
- Homogeneous spheres divide, yielding more spheres which themselves divide.
- Cells exhibit differences in structure and function and form a collective coherence.
- Each cell contains enough information to orchestrate the entire process.
Totipotential Cells:
- During early embryological development, each cell is totipotential: it can take on any tissue role in the body.
- Modern understanding: Chromosomal DNA in each cell holds all genetic information.
Neuronal Development and Formation:
- Cells appear to take on the role of their environment due to morphological "trophic" influence conveyed by cytoskeletal axoplasmic transport within nerve cells.
- Neuronal processes know where and when to send their processes and establish connections through growth, pathfinding, and trophic capabilities.
The Centriole/MTOC Establishes Cell Polarity and Orientation
- The centriole/MTOC establishes cell polarization and orientation
- Presumably "launches" extending processes
Growth Cones in Neurite Extension
- Tips of lengthening neurites are specialized areas called "growth cones"
- Growth cones:
- Participate in decisions about direction, branching, and termination of extension
- Can sense changes in local environment
- Shift direction, branch, or form synapses in concert with other cytoskeletal elements
- Activities of growth cones are remarkably similar to movement in amoeba and other simple organisms
- Continually probe surroundings by sending out and retracting delicate ruffles (lamellipodia) and finger-like projections (filopodia or microspikes)
- Dynamic micro-appendages are comprised of meshworks and parallel arrays of actin filaments
Role of Microtubules (MT) and Actin Filaments in Axonal Extension
- MT and neurofilaments from neurites splay into growth cones, but generally stop short of the actin-rich areas
- Addition of cytochalasin B, an actin filament modifier, blocks neurite outgrowth if added before extension has begun
- Treatment of extending axons with cytochalasin B results in cessation of growth cone ruffling activity with little immediate effect on the neurite shaft
- Antimicrotubule agents like colchicine leave growth cone activity unaffected but block neurite extension
- Continued exposure results in retraction of the cell process with subsequent formation of one or more growth cones from the cell body
- These observations, along with ultrastructural evaluations of treated cells, show that MT are necessary for neurite growth, while actin filaments are essential to growth cone protrusion, a phenomenon similar to amoeboid motion
Complex Interplay of Dynamic Activities in Neurite Sprouting and Growth Cone Extension
- A complex interplay of dynamic activities of actin and MT is required for neurite sprouting and growth cone extension
- Actin assembly generates protruding lamellipodia and filopodia, which are then anchored to the external substrate by myosin
- Lamellipodia, sheet-like ruffles, dart out among the finger-like filopodia, particularly near points where decisions about branching are required
- Growth cone activities related to embryological differentiation are at the very ground floor of intelligence
Changes in Cytoskeletal Elements During Brain Development
- Tubulin isozymes:
- Alpha and beta tubulin: Peaks around 14th day after birth, then declines to adult levels due to reduction in rate of synthesis
- Pattern of alpha and beta tubulin genetic variants (isozymes): Marked changes during brain development
- MAPs:
- Two tau polypeptides present in first few days of birth, then four major tau polypeptides emerge in adult brain
- MAP1 can be resolved into three groups (MAP1A, 1B, 1C), with different patterns in embryonic vs. adult brains
- MAP2: Restricted to dendrites and cell bodies in adult brain, particularly concentrated in neurofilament-rich axons
Importance of Temporal Relationships Between Changes in Neuronal MT Proteins and Differentiation
- The temporal relationships between changes in neuronal MT proteins and differentiation are essential to the final product: the brain/mind
Cytoskeleton and Medicine
Defects related to microtubules:
- "Immotile cilia syndrome" (Afzelius, 1979): caused by altered dynein and results in an inability to expel secretions from the lungs, leading to recurrent bacterial infections.
- Developmental disability in infants: caused by abnormal MT function induced by defective MAPs (Purpura, 1982).
Cytoskeleton's participation in disease:
- Participates in the effects of various diseases (malignancy, Alzheimer's disease, viral infections), drugs, toxins and the body’s response to disease.
- Pathway to understanding MT through the disease "gout" (Purpura, 1982):
- Gout is a painful swelling of joints caused by the body's response to accumulation of urate crystals.
- Lymphocytes and macrophages leave the bloodstream and migrate towards the urate crystals, which often lodge in a joint of the big toe.
- The drug colchicine was found to be helpful in relieving the pain and tenderness by depolymerizing microtubules and preventing the locomotion and engulfment behavior of the lymphocytes and macrophages.
Cytoskeleton's involvement in malignancy:
- Control of cell reproduction is lost, with growth proceeding without regard to the needs of the organism.
- Cancerous cells exhibit a tendency to break away from their anchorage and set up growth elsewhere in the body.
- Malignant cytoskeleton is disorganized with formation of oscillating aggregates of contractile material that aids dislodgement of the cell from its anchorage, instability in chromosome number, loss of growth regulation.
- Proposed as a disease of the cytoskeleton (Puck, 1977).
Cytoskeleton's involvement in Alzheimer's disease:
- Characterized by neurofibrillary tangles that result in various symptoms including a shortage of acetylcholine at synapses.
- This may be due to a breakdown in the cytoskeletal transport mechanisms which deliver acetylcholine precursors to the synapses.
- The cognitive dysfunction is related to disruption of the cytoskeleton.
- Other toxins, including hexanedione and hexacarbons, carbon disulfide, acrylamide, methylmercury, and mineral fiber asbestos, have been ascribed to cytoskeletal effects.
Cell death due to lack of oxygen, acidity, or other causes:
- Irreversible point beyond which cell death is inevitable: pathological elevation of cytoplasmic calcium ion.
- Elevated calcium causes depolymerization of microtubules and other cytoskeletal components, leading to loss of cytoplasmic organization, enzyme function, and structural integrity.
- Dimethysulfoxide (DMSO) stabilizes polymerized microtubules and can preserve integrity of cells and tissues against damaging effects.
Anesthetics and the cytoskeleton:
- Anesthetics inhibit "protoplasmic streaming" in slim molds, a function of the cytoskeleton (Claude Bernard, 19th century).
- Sufficient concentrations of the general anesthetic halothane reversibly depolymerizes MT.
- Sleep-producing barbiturates, local anesthetics, and major tranquilizers such as thorazine bind to brain MT.
Cytoskeletal Gel Networks and Cytoplasmic Intelligence
Diverse Modes of Cell Movement:
- Motile events in non-repetitive muscle cells are dynamic, transient, and variable
- Cells contain 2 to 5 different types of actin that can combine up to 10 ways depending on binding proteins and other factors
- Actins polymerize differently based on calcium or magnesium presence
- Non-muscle cells have mechanisms to switch between monomeric actin, actin in bundle form, and actin in a geodesic gel meshwork form
- Cytoplasmic motility involves actin myosin crawling, explosive polymerization, rapid disaggregation, or interconversion of filament bundles into a meshwork
- Microtubules, filaments, and centrioles are also involved in these aspects of cell movement
Requirements for Cytoplasmic Intelligence:
- Compartmentalization: Separates components to prevent chaos
- Information Content: Information is not about the meaning but the formal structure. The cytoplasm is both the medium and the message.
Cytoplasm as an Information Processing System:
- Cytoplasm is neither totally regular nor random, but organized
- Complex, intricate activities occur in the midst of thermal noise
- Cytoplasm maintains information through 100 mitotic generations in Paramecium
Approaches to Account for Cytoplasmic Intelligence:
- Randomness of Thermal Chaos: Doubtful as cytoskeleton takes on elaborate, nonrandom forms
- Supramolecular Topology and Dynamics: Suggests cooperativity between biochemical events over large intracellular distances
- Inherent Intelligence within Cytoplasm: Implies ability to collect and process data, assess global situations, and communicate with other intelligent objects
Possible Mechanisms of Cytoplasmic Information Processing:
- Parallel arrays of MT and neurofilaments provide a framework for microtrabecular lattice structures
- Contractility of actin-myosin and other proteins in the cytomusculature/cytomatrix could impart mechanical vibrations and cooperative resonances
- Geodesic tensegrity nets of MT, actin, and their ordered water may be pulsating at the nanoscale
- Polymerization patterns of actin and other proteins may be regulated by calcium-induced sol-gel state phase differences or harmonic coupling with other microtrabecular and cytoskeletal structures
- Coherent nanosecond excitations and propagating solitons have been proposed to occur within the cytoskeleton
Decoding the Genetic Code vs. Real Time Information Codes:
- The "genetic code" decrypted by Nirenberg and colleagues equated DNA base pair patterns with specific amino acid sequences in synthesized proteins
- Real time information codes in the cytoskeleton may be understood as nanoscale events just beyond current capabilities
Protein Conformational Dynamics
Proteins:
- Structural and organizational elements of "the living state"
- Essential functions linked to their structure and switching among different conformations
- Ex: Ion channel proteins have an "open" or "closed" conformation for ion diffusion
- Doesn't require energy like ATP hydrolysis, utilizes energy stored in transmembrane voltage gradients
Protein Structure:
- Proteins have hierarchical levels of structural organization determining their dynamic and functional capabilities
- Primary structure: Sequence of 22 possible amino acids held together by peptide bonds
- Amino acids differ in side groups, molecular weights range from 75 to 200 daltons
- Proteins are comprised of several hundred to millions of amino acids
- Secondary structure: Coiled or folded structures formed by hydrogen and disulfide bonds
- Commonest is the right-handed coil, an alpha helix, which has hydrogen bonds between oxygen and hydrogen atoms
- Tertiary structure: Determines protein functions, globular regions defined by hydrophobic forces, charge distribution, disulfide bridges, and secondary structures
- Quaternary structure: Assembly of tertiary domains into larger structures like multisubunit enzymes
Protein Conformation and Allosteric Proteins
Allosteric Proteins:
- Able to shift reversibly between several different stable conformations
- Have multiple alternative sets of intraprotein bonds and charge distribution
- Each alternative set requires a change in spatial relationships among polypeptide chains, resulting in motion
- Only certain distinct conformations are energetically favorable; intermediate conformations are unstable
- Charge redistribution (dipole oscillation) can also couple to conformational switching
- Step-like, nonlinear jumping occurs between specific conformations
Conformational Dynamics:
- Each distinct conformation has a different surface and ability to interact with ligands
- The presence/absence of ligands can determine the protein's adopted conformation
- Two distinct ligands may bind to different surfaces, changing affinity for each other
- Allosteric mechanisms facilitate fine tuning and regulation of biological processes
Allosteric Proteins in Aggregates:
- Conformational state of a subunit can influence that of neighboring subunits
- Produces a "collective" effect similar to amplification or switching in a computer
Hemoglobin as an Example:
- Iron-containing protein in red blood cells that carries oxygen from lungs to tissues
- Oxyhemoglobin (bound to oxygen) vs. deoxyhemoglobin (unbound) have different conformations
- Conformational state is regulated by factors like oxygen availability, temperature, pH, 2,3 DPG, and nearby oxyhemoglobin
Conformational States of Hemoglobin:
- "Functional" conformation (binding/no binding of oxygen) persists for seconds to minutes
- Faster conformational "breathing" (nanosecond scale) facilitates diffusion of oxygen
Protein Conformational Dynamics:
- Vast majority of biological processes occur on a time scale greater than 1 nanosecond
- Protein conformational changes in the nanosecond range can be coupled to a stimulus
- Three features control these functional states: hydrophobic interactions, charge redistribution, and hydrogen bonding
Proteins and Energy
- All movements within cells depend on forces generated by proteins
- Typical allosteric protein can adopt two alternative conformations:
- Low energy form, favored 1000:1 over high energy form
- High energy form only accessible when bound to a ligand or via input of chemical energy (e.g., phosphorylation)
- Phosphorylation is a regulatory or programming mechanism for 95% of mammalian cell proteins
- Thermodynamic laws demand that free energy be depleted, so protein molecules cannot show net movement without added energy source
- Phosphorylation: making one step irreversible, covalent linkage of a phosphate group to an amino acid side chain (serine, threonine or tyrosine) in the protein
- ATP/GTP hydrolysis: another way to drive allosteric changes by providing energy to push the protein into high energy conformation
Protein Conformational Dynamics and Energy Utilization
- Proteins can use ATP phosphorylation and hydrolysis energy to do other forms of work, such as ion pumping
- Sodium-Potassium ATPase: pumps three sodium ions out and two potassium ions in through membrane during conformational change driven by ATP mediated phosphorylation
- Ion gradients created by ATP-driven pumps are harnessed by conformational changes in other membrane proteins, such as ion channels, to depolarize the membrane or transport glucose/amino acids
- Energy available in proton/hydrogen ion gradients across mitochondrial membranes is used to synthesize most ATP
- Actin and myosin create contractile force in muscle through cooperative conformational changes induced by ATP hydrolysis
Historical View on Protein Cooperativity
- Szent-Gyorgyi (1948): suggested proteins behave as semiconductors, with electrons "hopping" between intraprotein regions
- However, experimental data showed the intraprotein energy band gap was too great to support this concept
- Utilization of dynamic biological and protein conformational energy remained enigmatic through the 1950s and 1960s
- A focal point in understanding protein conformational dynamics was the 1973 New York Academy of Sciences meeting, which addressed the mysteries of how to utilize ATP energy for protein events and transfer energy/information in proteins/organelles.
Crisis in Bioenergetics and Resonant Dipole Coupling
- Prevalent theme: unexplained cooperative processes in biological systems (McClare, 1974)
- ATP induced excited states ("excitons") coupled by infrared dipoles in protein biostructures to provide a communicative medium
- McClare's model of resonant dipole coupling supported by Wei (1974) but met skepticism from Weber (1974)
- Energy emission too short for utilization by biomolecules
- Transfer of quantum vibrational energy through surrounding medium (water)
- Consensus: energy needs to be stored for a nanosecond or longer to be useful
Comparable Models for Energy and Information Transfer
- Propagating packages of conformational or acoustic energy: phonons
- Defined as propagated lattice vibration in protein lattice
- Transmission occurs at the speed of sound, not resonance transfer phenomena
- Hydrophobic interactions play a role in shielding phonons from aqueous environment (Straub, 1967; Green et al., 1970; Ji, 1974; Volkenstein, 1972)
- Possible resolutions for shielding problem: ordered water and resonantly coupled medium or hydrophobic interactions
Living Water and Hydrophobic Interactions in Biomolecules
- Controversial properties of intracellular water
- Traditional view: more than 90% is bulk phase
- Ordered water advocates assume about half is ordered and the other half is "living" or ordered
- Importance of ordered water to cellular structure and function (Clegg, 1981)
- Intracellular water exists in three phases: bound, vicinal, and bulk.
Water Phases and Vicinal Water
- "Borders" exist between water phases which partition solute molecules
- Bulk water: extends beyond 3 nanometers from cytoskeletal surfaces
- Drost-Hansen (1973) described cooperative processes and phase transitions among vicinal water molecules
Vicinal Water and Enzymes
- Clegg highlights potential implications for function of "soluble" enzymes
- Many intracellular enzymes appear to be bound to MTL surface within the vicinal water phase
- Advantages:
- Sequence of enzymes can perform reactions on substrate more efficiently when bound in order
- Diffusion of substrate (most time-consuming step) minimized
- Vicinal water multi-enzyme complexes may be part of a cytoskeletal information processing system
- Dynamic conformational activities within the cytoskeleton/MTL can selectively excite enzymes to active states
Water and Biomolecules
- Even in bulk aqueous solution, water molecules are somewhat ordered by hydrogen bonds
- Outer surfaces of biomolecules form more stable hydrogen bonding with water, "ordering" the surrounding water
- Decrease in entropy (increased order), increase in free energy
- Factors which inhibit solubility of biomolecules if not for hydrophobic interactions
- Hydrophobic groups combine to form a "coalescence" of hydrophobic regions
- Liberates ordered water into free water, increasing entropy and decreasing free energy
- Specific biological reactions rely on hydrophobic interactions and the effect on bonding energies
Protein Assembly and Cytoskeletal Elements
- Formation of tertiary and quaternary protein structure, including microtubule assembly
- Promoted by hydrophobic interactions and exclusion of water from hydrophobic regions
- Crystallization of tobacco mosaic virus: increase in entropy (exclusion of water) at surface promotes assembly
The Distinct Nature of Hydrophobic Van der Waals Forces:
- Different from covalent and ionic bonds
- Described by Dutch chemist Jacobus van der Waals in 1873 as attractive forces among gas molecules
- Essential for the assembly of organic crystals, including protein structures
- Three types: dipole-dipole attraction, induction effect, London dispersion forces
Dipole-Dipole Attraction:
- Occurs between polar molecules with permanent dipoles
- Favors specific orientations for low energy arrangements
- Net attraction results from proper configuration alignment
Induction Effect:
- Permanent dipole in one molecule polarizes electrons in nearby molecule
- Depends on the molecules' dipole moments and polarizability
- Subunits of protein assemblies have high degrees of polarizability
London Dispersion Forces:
- Explains attraction between nonpolar molecules without permanent dipoles
- Depends on quantum mechanical motion of electrons
- Instantaneous dipoles can induce dipoles in neighboring polarizable atoms or molecules
- Significant only when two or more atoms/molecules are very close together
Electrets, Piezoelectricity, and Pyroelectricity:
- Assemblies with permanent electric dipoles are called electrets
- Exhibit properties of piezoelectricity and pyroelectricity
- Dipolar elementary subunits arranged in such a way that positive and negative dipole ends point in opposite directions
- Found in various nonbiological materials, including biological tissues like bone, blood vessel walls, keratin, cellulose, collagen, gelatin, artificial polypeptides, DNA, cellulose, and microtubules
- Accounts for specific properties such as anti-blood clotting in biomaterials and the non-stickiness of teflon.
Davydov's Soliton Theory in Biology
Background:
- Spatial transfer of energy occurs in biological systems through protein molecules
- Example: Myosin heads contract in muscle due to ATP hydrolysis
- ATP hydrolysis energy not sufficient for molecular electronic state excitation, leading to solitons concept
Solitons:
- Nonlinear aspects of amide 1 stretch vibrations and longitudinal sound waves
- Prevent vibrational dispersion through potential wells
- Exist for useful periods only if certain conditions met
- Sufficient nonlinear coupling between amide 1 bond vibrations and sound waves
- Energetic enough amide 1 vibrations for retroactive interaction to take hold
Conditions for Soliton Formation:
- Anharmonicity, or nonlinearity of intrapeptide excitations' coupling with displacement from equilibrium positions
- Critical parameter: anharmonicity parameter (χ) greater than 0.3 x 10^-11 newtons for propagation in alpha helix spines
Computer Simulations:
- Eilbeck and Scott's work on soliton-like excitations along alpha helix spines
- Solitons travel as local impulses with a size of few peptide groups
Experimental Evidence:
- Conflicting results from biomolecular light scattering experiments
- Unambiguous demonstration of localized state in crystalline acetanilide
Other Types of Solitons:
- Acoustic solitons: local displacements from equilibrium positions moving along molecular chains
- Sufficient anharmonicity produces these excitations representing local displacements
- Topological solitons or lattice solitons
- Symmetry "kinks" traveling through ordered mediums
- Electrosolitons: excess electrons captured by supersound acoustic solitons and conveyed along with them
Implications:
- Solitons could be responsible for molecular level filamentous contractions driving every move we make
- Propagating solitons in the cytoskeleton may serve as dynamic medium of biological information processing.
Protein Conformational Dynamics and Coherent Excitations
Understanding Protein Conformations:
- Proteins undergo conformational motions over a wide range of time scales, from femtoseconds to minutes.
- Significant fluctuations occur in nanoseconds.
- Example: Rotation of tyrosine ring in bovine pancreatic trypsin inhibitor.
Coherent Protein Excitations:
- Fröhlich's theory explains long range cooperativity between proteins and nucleic acids.
- Coherence occurs when energy, such as biochemical ATP, is supplied to a system of nonlinearly coupled dipoles within hydrophobic regions of proteins.
- This results in the collective oscillation of a single vibrational mode at nanosecond periodicity.
Conformations and Metastable States:
- Protein conformations are dominated by interaction with surrounding water and ions.
- High dipole moments tend to become stabilized as metastable states through internal deformations, external influences like electric fields or ligand binding, or neighbor proteins' effects.
- These metastable states may last for relatively long periods (milliseconds).
- Fröhlich characterizes these conformations as "metastable."
Dielectric Properties and Biological Significance:
- High electric fields of 107 volts per meter in biological membranes require extraordinary dielectric properties from lipids, proteins, or cytoskeletal components.
- Fröhlich suggests that the evolution of this dielectric strength on a molecular scale has significant implications for understanding biological organisms' sensitivity to electromagnetic radiation.
Biological Functions and Quantum Mechanics
- Eyes sensitive to single photons, certain fish to weak electric fields require use of collective properties of assemblies of biomolecules
- Coherent vibrations expected in molecular systems
- Biological vibrations can be excited by electromagnetic radiation matched to frequency and wavelength larger than object dimensions
Evidence for Biological Effects of Coherent Millimeter Waves
- Influences on biological activities above critical threshold (Grundler and Keilman, 1983)
- Sharp frequency resonances indicate localized absorption in small regions
- Debye layer absorbs in region of 108 Hz, involved with functional activities of biostructures
- Green and Triffet's holographic information medium theory (1985): coherent vibrations of ordered water and calcium counter-ions surrounding high dipole moments in membranes and biomolecules
- Ionic bioplasma: small scale and ordering minimize friction, possibly propagating waves due to lack of frictional processes ("superconductivity")
Wu and Austin's Conclusions on Oscillating Dipoles
- Strong long range attractive forces among dipoles with narrow band of resonance frequencies and large coupling constants (1978)
- Collective effects in dense microtubule arrays: 1 cubic micron encompasses about 160,000 tubulin subunits.
Evidence for Long-Range Effects
- Observed behavior of red blood cells: discoids of eight microns in diameter (8 thousand nanometers) exhibit long-range effects.
Protein Conformational Dynamics
Rouleaux Formation:
- Red blood cells tend to array themselves in stacks called "Rouleaux formation"
- Attractive forces begin when red cells are about 4 microns (4,000 nanometers) apart
- This is a distance several orders of magnitude greater than the range of attractive chemical forces
- Viewed as consistent with Fröhlich's coherent excitations and long range cooperativity
Communication in the Nervous System:
- A communication band extending from 10^10 to 10^11 Hz could pack over a million FM radio stations or 150,000 television broadcasts
- The action potential may be just a crude fast transmitter of urgent messages
- Fröhlich vibrations might be transmitted along the membrane of the nerve fibers, but are interrupted by action potentials
- More likely, microtubules in the axon are used
Massless Bosons and Cytoskeletal Self-Focusing:
- Biological systems attract the interest of nonbiologists with mathematical tools for "many body problems"
- Fröhlich viewed living matter as a sea of electric dipoles, taking advantage of quantum field theory
- Electret states and ordering of water around biomolecules have collective properties
- In typical nonbiological systems, component dipoles are random and disordered, resulting in overall symmetry
- In living systems, order is induced by reduction of 3D symmetry to a rotational alignment along filamentous electrets like cytoskeletal structures
- According to the Milan group's quantum field theory and the "Goldstone theorem", the symmetry breaking ("Bose condensation") results in long range interactions among system components (dipoles) conveyed by massless particulate/waves ("Goldstone bosons")
- The energy required to generate massless bosons is invested in the electret states of biomolecules and correlated fluctuations of their surrounding water and ions
- Celaschi and Mascarenhas showed that the activation energy of biomolecules (0.2-0.4 electron volts) is equivalent to the hydrolysis of one ATP or GTP molecule, what Davydov predicted for initiation of solitons
- Consequently, solitons, massless bosons, and Fröhlich's coherent polarization waves may be synonymous
Self-Focusing of Electromagnetic Energy:
- Del Giudice and colleagues proposed the concept of self-focusing of electromagnetic energy within cytoskeletal filaments
- Electromagnetic energy exceeding a threshold and penetrating into cytoplasm is confined inside filaments whose diameters depend on the original symmetry breaking ("Bose condensation") of ordered dipoles
- Any electric disturbance produced by thermal fluctuations or other sources is confined inside the filamentous regions, while ordering is preserved outside
- The diameter of the self-focusing energy filaments depends on the polarization density, or ordering of biological water
- Del Giudice's group calculated a self-focusing diameter of about 15 nanometers, precisely the inner diameter of microtubules
- They believe the cytoskeleton is the material consequence of dynamic self-focusing of polarization waves in the cytoplasm
Holographic Mechanisms:
- The observed diameters of self-focused optical beams in simple nonbiological liquids are of the order of microns, with correlation created by propagation of waves rather than as a specific property of the material itself
- The Milan group concludes that focusing occurs in eukaryotic cell cytoplasm due to the spatial coherence and ordering imparted by cytoskeletal electret behavior
- This self-focusing could lead to holographic mechanisms, as photorefractive crystals can generate dynamic, real-time holography and MTs could be projecting dynamic cytoplasmic holograms
Cooperative Protein Dynamics Models:
- Davydov's soliton propagation model originally applied to contractile coupling between actin and myosin
- The cytoskeleton appears uniquely suited to take advantage of cooperative dynamics related to information processing
Anesthesia: Another Side of Consciousness
Background:
- Anesthesia inhibits collective dynamic conformational changes in brain proteins
- Developed in the 19th century as a method to cease consciousness during surgery
- Standardized levels identified by John Snow and Arthur Guedel
Levels of Anesthesia/Consciousness:
- Stage One: Alertness, sensibility to pain; slow and regular breathing; intact eyelid reflex
- Stage Two: Delirium or excitement; irregular and unpredictable breathing; active eye muscles and pupils
- Stage Three: Muscle relaxation (planes 1-4); slow and periodic breathing; immobile eyes with disappearing eyelid reflex
- Stage Four: Respiratory arrest and cardiovascular collapse; flaccid muscles, widely dilated pupils
- Anesthetic Overdose: Lack of tissue oxygen, convulsions, imminent death
- Anesthesiologists seek methods to judge anesthetic depth beyond clinical signs
- Electroencephalography (EEG) recording since early 20th century
EEG and Anesthetic Depth:
- Spectral Edge: Frequency below which most EEG power occurs, decreases as anesthetic depth increases
- Phase Space Plotting: Choosing a phase lag and plotting EEG amplitude against it to analyze complexity or dimensionality
- Consciousness: Manifestation of deterministic chaos in the brain/mind
Additional Monitoring:
- Cardiovascular, pulmonary, neuromuscular functions, kidney, blood clotting, and other factors closely monitored during anesthesia and surgery
- Technological advances: nanoscale conformational dynamics of neural proteins via biosensors or implants for more sensitive observation and potentially manipulation of consciousness.
Anesthesia, Memory, and Consciousness:
- Patients may report awareness or recall during anesthesia, but it's rare
- Two-stage theory of memory: perception and short-term memory storage (awareness) vs long-term memory consolidation
- Perception and short-term memory: unstable dynamic form
- Long-term memory: stable physical memory trace
- Consolidation of short-term to long-term memory takes approximately 45 seconds
- Factors influencing memory consolidation include impact of information input, emotional significance, and anesthetic drugs.
Anesthesia and Memory:
- Awareness vs recall: perception and short-term memory vs long-term memory storage
- Anesthetics can act at various stages: narcotics for pain prevention, tranquilizers for blocking consolidation, general anesthetics for inhibiting all cognitive functions.
- Memory consolidation occurs in the hippocampal region but awareness is more diffuse.
Memory Processes:
- Information perceived and stored in short-term memory (awareness)
- Short-term memory to long-term memory storage: finite period, takes approximately 45 seconds
- Consolidation depends on initial impact of information input
- Emotional significance and anesthetic drugs influence memory consolidation.
Mechanisms of Anesthesia
Anesthetic molecules: A variety of different structures have anesthetic activity. Some similar molecules may cause opposite effects and lead to convulsions.
Unifying mechanism for anesthesia: Attempts have been made to unify a single mechanism for anesthesia, representing clues to the mechanism of consciousness.
Anesthesia mechanism: Anesthesia results from prevention of protein switching between different conformational states induced by binding of ligand, calcium ion, or voltage change. Anesthetic gas molecules bind by Van der Waals forces within hydrophobic pockets and may trigger a switching mechanism for protein conformation.
Neural functions inhibited by anesthetics: Propagation of action potentials resulting in nerve conduction, microtubule-dependent axoplasmic transport, and synaptic transmission are inhibited by anesthetics.
Sites of anesthetic action: Anatomical localization has focused on regions with many synapses, such as the reticular activating system involved in regulating wakefulness and attention. However, other brain regions are also inhibited by anesthetics at relevant concentrations.
Disagreements about the mechanism of anesthesia: There is disagreement over whether anesthetics alter dynamic protein functions directly or indirectly via membrane lipids or at lipid-protein interfaces. There is also disagreement on whether a single, unitary mechanism can explain the actions of various anesthetic compounds and the reversal of anesthesia by increased pressure.
Anesthetic potency and solubility: Correlations between anesthetic potency and solubility in "lipid-like" solvents are consistent with effects occurring in lipids or hydrophobic pockets within proteins.
Protein conformational changes: Research has demonstrated that anesthetics can cause conformational changes in functional proteins, but at concentrations higher than required for reversible clinical anesthesia. A logical inference is that anesthetics prevent necessary protein conformational changes rather than causing them directly.
Firefly Luciferase and Anesthetic Inhibition:
- Focus of research: obscure group of systems, distantly removed from cognitive function
- Firefly luciferase: protein dimer (about 100 kilodaltons), induces photon emission with luciferin and ATP/oxygen
- Sensitive to anesthetic gases based on potency
- Ueda's proposal: anesthetic binding at hydrophobic site in luciferase protein induces inactive conformational state, preventing normal excited state for luminescence
- Recent studies by Franks and Lieb: corroborated earlier work, no conformational change caused by anesthetics; competitive binding with luciferin at a hydrophobic site
Anesthesia Mechanism:
- Impairment of protein conformational dynamics
- Collective, cooperative mechanisms important in regulating protein states
- Anesthetic sensitive neural proteins: membrane bound ion channels, receptors, cytoskeletal proteins, enzymes
- Stimuli inducing functional conformational change: ligands (neurotransmitters), voltage changes, ionic flux
- Possible explanations for coupling conformational states to stimuli discussed in Chapter 6
Role of Electron Mobility:
- Evidence from gas chromatography and corona discharge experiments suggests anesthetic gases can alter electron energy through Van der Waals forces
- Regulation of protein conformational state affected by anesthetic occupancy of hydrophobic pockets due to altered environmental medium for electron mobility
- Weak, reversible Van der Waals interactions explain the reversibility of anesthesia.
Relation between Anesthesia and Consciousness:
- Inhibition of a subset of protein conformational dynamics related to consciousness
- Psychoactive drugs such as amphetamines and LSD affect collective effects of protein conformational dynamics, potentially enhancing or altering consciousness through membrane receptors.
Cytoskeletal Computing Models: Cytoskeleton as a Substrate for Biological Intelligence
Models of Cytoskeletal Computing:
- Range from passive MT signal transduction to dynamic cooperative effects among cytoskeleton components
- Based on the suitability of microtubules and other cytoskeletal components for information processing
- Theories range from MT subunit patterns, oscillations of centrioles, sol-gel field effects using holographic imagery
Direct Evidence for Signaling in Microtubules:
- Vassilev et al., 1985: intermembrane signaling through electrically induced conformational changes and MT components
- Becker, Oliver, Berlin, 1975: nonradiative resonance energy transfer between fluorescent labels on MT subunits or membranes
- Parallel alignment of MT in applied electric and magnetic fields (Vassilev et al., 1982) could generate their own pathways for cytoplasmic movement
- Nerve membrane proteins anchored to the cytoskeleton may be part of a communicative medium, utilizing various modes for cooperativity and intelligent behavior
Models of Cytoskeletal Computing:
- Passive MT signal transduction models: focus on the role of microtubules in transporting signals without active processing
- Descriptive patterns among MT subunit states models: investigate how different configurations of tubulin subunits can represent information
- Dynamic cooperative automaton effects models: examine cooperative oscillations between centrioles and the cytoskeleton
- Cytoplasmic/cytoskeletal sol-gel field models: explore holographic imagery in explaining dynamic organization and information representation within biological systems.
- Overlapping and complementary proposals: these theories may not be mutually exclusive, but rather provide different perspectives on cytoskeletal computing.
Cytoskeletal Information Processing: Sensory Transduction and MTs (Microtubules)
8.2.1. MT Sensory Transduction/Atema:
- Several authors, including Lowenstein, Osborne, Warshall (1964), Lettvin and Gestaltin (1965), and Jelle Atema (1973), have proposed that receptor cilia containing microtubules are involved in sensory transduction.
- Mechanical deformation of cilia can be transduced into chemical energy patterns for the cell.
- Microtubules are active functional units in reception and transduction of sensory information.
- Conformational changes in MT tubulin subunits may occur under physiological conditions.
- Oscillations of sperm flagella or mechano-lonic transducers can propagate signals via microtubules.
8.2.1.1. Atema's Theory:
- Sensory cilia convey environmental information through conformational changes in microtubules.
- Distortion originates near the distal end of the ciliary MT and propagates towards the cell body for further processing via an excitable membrane or cytoskeleton.
- Any number of sources, including mechanical deformation, light energy, and chemical bond energy, can trigger a conformational wave in microtubules.
8.2.2. MT Mechano-lonic Transducers/Moran and Varela:
- Biological sensory systems use cilia to transduce mechanical deformation into cognitive information like position in space (proprioception).
- Campaniform sensilla, containing a parallel bundle of microtubules, are directly involved in proprioceptive determination of system's spatial relation to its environment.
- MT can behave as passive translation rods or generators of ionic/electrical currents in mechanoreceptor functions.
- Compression or bending of MT can release bound ions from subunits, resulting in an ion flux capable of generating membrane depolarization and regulating membranes.
- Each tubulin dimer reversibly binds calcium ions, allowing significant currents to flow during active assembly of parallel MT.
Michael Conrad and E. A. Liberman's Proposed Biomolecular Computing Model (Cytoskeleton and Cyclic Nucleotide System)
- Collaboration between computer scientist Michael Conrad and information scientist E. A. Liberman on aspects of biomolecular computing, focusing on the cytoskeleton
- Primary computing power in brain based on intracellular processes
- Proposed that cyclic nucleotide system (CNM) sculpts three dimensional dynamic patterns in neurons and other cells through regulation of cytoskeleton and membranes
- Energy rich molecules such as cyclic AMP act as links between macroscopic neural activities and molecular scale computing
- Conrad's notion of molecular automata within cells, suggesting intracellular cytoskeleton regulates cyc lic AMP and other biomessengers based on mechanical stimulation
Marc DeBrabander's Research on Cytoskeleton Signal Processing
- Cell biologist studying activities of the cytoskeleton in mitosis and cellular organization at Janssen Pharmaceutica Research Laboratories
- Evidence that membrane proteins are linked to cortical actin filament system, controlled by microtubules (MT)
- MT perform as signal transducers beyond their role as skeletal support elements
- Interactive signaling in the cytoskeleton leads to global cellular rearrangement due to various features: intrinsic polarity of MT, conformational propagation mechanism, directional organelle movement, topography, and transport of ions like calcium along microtubules.
MT Signal Processing Evidence and Techniques
- Visualization of particle transport along individual MT using Nanovid Microscopy
- Developed double labeling technique for tubulin subunits: large circles (10 nanometers) identify glutamated tubulin, small particles (5 nanometers) bind to tyrosinated tubulin
- Patterns of tyrosinated/glutamated tubulin suggest potential coding mechanism and function in signal processing
- MT detyrosination patterns determined by real time cytoplasmic factors, suggesting modifiable patterns and capability for signal processing.
Barnett's String Processor Model of Microtubule-Neurofilament Memory Storage
Key Components:
- Processing Channel (microtubule-MT): Laterally connected to a parallel storage unit (neurofilament-NF)
- Information traverses processing channel from right to left; character strings move in opposite direction on memory channel
- Replacement of "chips" by its synonym "french fries" is performed as the word moves through storage
Features:
- Versatile and powerful information processing system
- Can perform global replacements, similar to common word processors
- Assumes existence of processing channels (MT) and memory channels (neurofilaments) for information representation
- Parallel array and lateral interconnectedness between MT and neurofilaments enable string processing
Comparison with Other Models:
- Compatible with other models proposing conformational patterns within MT and cytoskeleton
- Inspired by biological concepts of cooperativity and allosterism in protein lattices (membrane rosettes, microtubules)
Microtubule "Gradions" Model
Background:
- Proposed information processing in membrane rosettes and microtubules by Roth, Pihlaja, and Shigenaka
- Cooperative allosteric effects among adjacent proteins or protein subunits suggest conformational gradients represent information
Membrane Rosettes:
- Ordered rings consisting of seven to twelve membrane embedded proteins in lower organisms
- Function involves membrane fusion and "suctorian feeding"
- Conformational changes in complex triggered by stimuli at a single or few subunits cause allosteric changes in all sixteen subunits
Microtubules:
- Highly oriented patterns of tubulin dimers with three different conformational states based on studies of tubulin binding to vinblastine and GTP
- Precise linkage sites between MT indicate two different conformational states of tubulin dimers
- Conformational states controlled by "gradionators" including ligand-induced conformation, tubulin isozyme, detyrosination, or MAP binding
Key Components:
- Inter-microtubule bridges: Indicate two different conformational states of the tubulin dimers to which they attach
- Precise linkage sites reflect a coded pattern, or "gradion" in microtubules.
Cytoskeletal Computing: Models and Theories
- Gradion Fields: Roth and Pihlaja's theory (1977) proposes that microtubules have "gradions," or conformational fields, governed by attachment of inter-MT linkages. This allows for various dimer conformations and patterns, though cooperativity reduces the number of possible gradions to a substantial yet lessened amount.
- Gyroscopic Centrioles/Bornes: Bornens' model (1979) suggests that centrioles rotate rapidly about their longitudinal axis, creating dynamic stability through inertia analogous to a spinning top or gyroscope. Peripheral movements are interconnected by the cytoskeleton with the gyroscopic centrioles as the origin for cellular coordinates.
- Centriole Signaling/Albrecht-Buehler: Albrecht-Buehler considers two models of cytoskeletal information processing: centriole signal detection and propagation of MT impulses. Centrioles, composed of nine MT triplets or doublets, have walls arranged at an angle that advances a blade, leading to rhythmic signals throughout the cytoskeleton.
Centrioles in Cellular Navigation
- Centrioles involved in directional orientation, cell architecture, and dynamic cytoplasmic rearrangements
- Designed to detect linear signals: potentially infrared radiation from biomolecules or ions surrounding cytoskeleton
- Geometrical features of a nonscanning angular detector
- Circular arrangement with marks around circumference for direction identification
- Nine-fold symmetry provides small size and sufficient angular resolution
- Prevents signals from reaching more than one receptor by using "blades" or shields
- Optimal design achieved when blades are bent circumferentially to prevent access to multiple receptors
- Concave shape of blinds averts possibility of two adjacent receptors being reached by the same signal
- Two detectors best placed at right angles for locating longitude and latitude of signal sources
Centrioles as Signal Detectors vs. Gyroscopic Oscillator Model
- Albrecht-Buehler's model: centrioles as perfectly designed nonscanning angular detectors using microtubules for resonance communication among protein conformational states within MT assemblies
- Bornens' model: gyroscopic oscillations of centrioles leading to dynamic cell center function
- Combination of both models results in a cell center capable of piloting cytoplasmic activities.
Exploring Cytoplasmic Tensegrity, Microtubule Probing, and Sphere Packing Symmetry in Cell Structure
Tensegrity Architecture and Cytoplasm Dynamics
Buckminister Fuller's Tensegrity Mast:
- Rigid structure constructed from tension and compression members
- Compression members are isolated, held together by tension members
- Each solid strut may be replaced by a miniaturized version of the macro tensegrity mast
- Each miniature solid strut can be replaced by still smaller subminiature tensegrity mast
- Tensegrity structures have fractal substructure
Cytoplasm Dynamics:
- Cytoplasm has both compressive and tensile elements
- Semi-rigid microtubules are under compression, likely due to actin filaments and the microtrabecular lattice
- MT do not contact each other, suggesting self-supporting cytoplasm may come from tensegrity
Robert Jarosch's Model of Actin-MT Interactions:
- Contraction of actin filaments causes rotational torque on microtubules
- Actin filaments wound in opposite directions can cause oscillations in MT
- Suggests a dynamic cytoplasmic tensegrity network with oscillating cytoskeleton
Dynamic Instability in Microtubule Assembly:
- Dynamic instability allows for selective stabilization of certain microtubules
- Can lead to changes in cell polarity and growth direction based on peripheral signals
- Kirschner and Mitchison propose "dynamic MT probing" where cell chooses functional structure based on environmental factors
Sphere Packing and Screw Symmetry:
- 32 possible symmetry arrangements of packed spheres in a cylindrical crystal
- Koruga used hexagonal and face-centered cubic packing to explain microtubule organization
- Microtubule symmetry suggests optimal number of protofilaments for binary error correcting codes
Cytoskeletal Self-Focusing/Del Giudice (1982, 1985)
- Milan scientists applied quantum field theory to study biomolecular dipoles
- Discovered strong likelihood for propagation of particle-like waves in biomolecules
- Ordered water surrounding linear biomolecules leads to self-focusing of electromagnetic energy into filamentous beams
- Inner diameter of microtubules (15 nm) matches confinement and propagation diameter for particle-like waves
- Implications:
- Propagation of electromagnetic energy in biological systems, providing a mechanism for alignment and communication
- Cytoskeletal polymers can capture and utilize ambient or biologically generated electromagnetic energy (e.g., infrared)
MT Automata, Holography/Hameroff, Watt, Smith (1974-1986)
- Proposed that microtubules act like "dielectric waveguides" for photons
- Living tissue transmits light more readily than nonliving material
- Polymerized MTs in cytoplasm may be relatively translucent to optical photons
- Periodic array of MT subunits can diffract energy with 8 nm periodicity, leading to holographic imaging in cytoplasm
- Cytoplasmic interference of coherent sources from multiple MT leads to holographic pattern formation
- Coupling calcium concentrations to cytoplasmic sol-gel states can "hardwire" holographic patterns into microtrabecular lattice
- Parallel arrays of MT within nerve fibers generate traveling screens for imaging based on action potentials and tubulin conformations
- Tubulin subunits in the MT lattice wall are transiently occupied by charge/energy/conformation quants, with MAPs serving as "left switches" or "sinks"/ "sources" for conveying pulse trains of charge/conformation among MT.
Fröhlich's Model of Cytoskeletal Computing
Model Overview:
- Based on Fröhlich's model of coherent nanosecond dipole oscillations coupled to conformational states as a clocking mechanism
- Calculated MT lattice neighbor Van der Waals dipole interactions using an automaton simulation
Dimer States:
- Two possible states: related to Fröhlich's concept of dipole oscillation
- Toward alpha tubulin end (represented by "a")
- Toward beta tubulin end (represented by a dot)
- Resting state has tubulin dimer dipoles oriented toward the beta tubulin end
Dimer State Determination:
- Dimer states at each clock tick depend on the summation of neighbor dipole states at the previous generation
- Neighbor influences are unequal due to screw symmetry of the MT lattice
- Distant neighbors have little influence due to force dropoff with distance
- Collective influences from many "like" dimers can lead to long range cooperativity
Simulation Findings:
- Computer simulation yielded interesting patterns and behavior of dipole/conformational states
- Stable and traveling interactive patterns capable of computing and regulating cytoskeletal activities
- Figure 8.13 shows a "kink-like" pattern traveling through an MT lattice
- Patterns travel at 8 nanometers per nanosecond (80 meters/second), consistent with propagating action potentials
- Stable and traveling interactive patterns capable of computing and regulating cytoskeletal activities
- Variability in tubulin dimer isozymes, ligand binding, or MAP attachments can "program" and "read out" information
- Propagation of MT conformational patterns could coordinate contractile MA P sidearms in axoplasmic transport
Implications:
- MT automata may be the information substrate for biological activities ranging from ciliary bending to human consciousness
- Coherent resonance and collective effects in distributed cytoskeletal arrays in the brain could lead to emergent properties like superconductivity
Microtubules, Centrioles, and Cytoskeleton
- Evolved to take command of biology due to right size scale and time scale
- "Ultimate computers" and nanoengines: generate purposeful force and movement
- Can capture and self-focus electromagnetic radiation, induce coherency, propagate energy quanta with minimal loss
- Propagation may manifest as coherent polarization waves, massless bosons, or solitons
- Charge density waves or proton transfer at MT surface layers of ordered water, and positively charged counter-ions like calcium are possible modes for information and energy transfer
Dynamic Patterns in Microtubules (MT)
- "Kink-like" pattern continues left to right through MT automaton
- Dynamic patterns can represent and compute information, serve as binding sites for transported molecules, designate MAP and inter-MT bridge attachment sites, or generate coherent waves of calcium coupled sol-gel states
- Electron surpluses in MT occur due to abundance of acidic amino acids
- Each MT subunit can integrate and absorb/sense input (acoustical energy, optical photons, chemical ATP, altered potential changes, fluxes of calcium and other ions), respond with conformational changes accordingly
- Coherent oscillations in tubulin subunit states among regional forests of microtubules provide a communicative medium for any out-of-phase subunits
Other Possible Modes of Information Management in MT
- Gaps between tubulin subunits may act like pores, creating voltage gradients across the 4 nanometer MT walls
- Electronegative MT interior core could support Del Giudice's suggestion of cytoskeletal superconductivity
- Self-focused energy perpendicular to long axis of MT could account for mysterious effects like perpendicular birth of daughter centrioles and inter-MT MAP bridges
- Coherent waves of ion fluxes radiated from MT due to propagating waves can form the basis of coherent wave interference in a three dimensional hologram
- Holographic cytoplasm may be an "infoplasmic" canvas for dynamic biological information, especially in the brain
Cytoskeletal Computing Models
- Propagation of action potentials or dendritic depolarization waves can induce sequences of alterations of MT subunit states due to influx of calcium, alteration of electrical fields, or direct mechanical effects
- Signals may cooperatively reverberate through the cytoskeleton by waves of calcium release and uptake, mechanical/electrosolitons propagating through the cytoskeletal lattice, and lateral propagation through sidearms and other components
- Transient fluxes of calcium resulting from conformational waves propagating down cytoskeletal lattices in parallel with action potentials or dendritic current waves can result in traveling frames of dynamic imagery
- Collective effects may occur at each level and at successively more macroscopic levels, leading to consciousness
Microtubules, Centrioles, and Cytoskeleton's Role in Evolutionary History
- Solved problems, organized cells and organs, and acted as intelligence circuits.
Essence of Living Matter
- Oparin (1938): Defined living matter with properties: metabolism, self-reproduction, and mutability
- Eigen (1971): Non-biological entities like automata or robots can meet these criteria
- Primitive systems blurring animate/inanimate distinction include viruses, prions, proteinoids
- R. D. Allen et al. (1985): Cytoskeletal elements ambulate and exhibit "life-like" behavior
Viruses and Ambiguous Life Forms
- Questions regarding living status of viruses
- Simple structure, spontaneous assembly defy thermodynamic laws
- Hydrophobic interactions drive increased order in assembled virus (negative entropy)
- Behavior of Viruses within Host Cells
- Enter cells and hijack genetic machinery for multiplication
- Harmless residency for long periods or commandeering with damaging consequences
- Human diseases include common colds, influenza, hepatitis, polio, smallpox, rabies, yellow fever, cancer, AIDS
- Enter cells and hijack genetic machinery for multiplication
- Methods of Escape
- Cause host cell death and disintegration
- Budding or reverse endocytosis (similar to neurotransmitter extrusion)
- Retroviruses
- Contain RNA without DNA, bring reverse transcriptase enzyme for genetic manipulation
- Human retroviruses include HTLV-III/HIV causing AIDS.
Viral Protein Structures and Collective Oscillations: A Study of their Function and Origins in Life Forms
Virus Structure and Collective Oscillations
Components of Virus:
- Genetic material (DNA or RNA)
- Protein coat that surrounds genetic material
- Membrane
Examples:
- Tobacco mosaic virus: cylindrical lattice protein coat
- Adenovirus: icosahedron-shaped protein coat
- Influenza virus: spherical protein coats with glycoproteins and lipid membranes
- Bacteriophages: nanoscale lunar lander structure with an icosahedral head and cylindrical tail
Protein Coat Conformational Changes:
- Collective oscillations of the protein shells may facilitate virus injection into host cells
- Ultrasonic absorption measurements suggest collective oscillations of the protein assembly
Viruses as Living Organisms:
- Whether viruses are alive depends on the definition of life
- By most criteria, they are not considered alive
- But some inanimate materials exhibit life-like characteristics (e.g., crystals)
Origin of Viruses:
- Three main theories:
- Viruses existed before eukaryotes
- Viruses evolved from parasites that invaded cells and de-evolved
- Viruses are descended from cellular genetic material (the "escaped gene" hypothesis)
Domesticated Viruses:
- Viruses can be harnessed for beneficial purposes:
- Vaccines to amplify the immune system
- Treating drug-resistant bacterial infections with bacteriophages
- Mass producing natural proteins using genetically engineered viruses
Nanotechnology: The Future of Functional Communication and Biomolecules
Advancements in Nanoscale Fabrication:
- Dramatic progress required for atomic level computer components (0.1–0.3 nanometers)
- Enables construction of valuable nanorobots, sensors, machines, and technologies
- Ultimate computing may be a single facet of various applications
Early Nanotechnologists:
- Richard Feynman (1961): Proposed "There's Plenty of Room at the Bottom" strategy for constructing nanomachines and nanotools
- Mechanically assembling molecules atom by atom
- Maneuvering at submicron to nanometer scale
- Other scientists delved into nanotechnology: Von Hippel (1962), Ettinger (1964), Ellis (1965)
- Repairing human tissue for life extension through molecular designing and engineering
- Nanorobots to fight diseases, unclog blood vessels, and modify neurons
Existing Nanotechnologies:
- Biological FMs: only existing, computer controlled or teleoperated FMs may implement nanotech applications in the future
- Advantages of nanotechnology: new materials, pathways, faster and more powerful computers with large memories, improved scientific instrumentation, microscopic mobile robots, automated manufacturing systems
Challenges to Implementation:
- Absence of available Feynman machines
- Potential solutions proposed by Conrad Schneiker (1986): STMs and augmented machine tool technology
Existing Developments in Nanotechnology:
- Dramatic developments in microsensor technology and microelectronics render worries about nanosensor surveillance superfluous
- Schneiker discounts extreme "end of the world" concerns raised by Drexler (1981, 1986) regarding nanoreplicators due to Feynman machine approach and other factors.
Potential Benefits:
- Vastly faster, more powerful computers with large memories
- Ultrastrong composite materials
- Greatly improved scientific instrumentation
- Microscopic mobile robots
- Automated flexible manufacturing systems
Conclusion: Nanotechnology is a promising field that may lead to significant advancements in various applications if the challenges of atomic level manipulation are overcome. Early nanotechnologists like Feynman and others laid the groundwork for future developments, which may include vastly improved technologies and materials with potential benefits outweighing any concerns regarding their implementation. Despite obstacles, researchers continue to pursue nanotechnology as a means to unlock new possibilities and push the boundaries of science and technology.
Scanning Tunneling Microscope Technology: Ultraprecise Surface Probing and Molecular Dynamics Insight
Scanning Tunneling Microscopy (STM)
Background:
- Invented by Gerd Binnig and Heinrich Rohrer in 1981 at IBM Zurich Research Laboratories
- Nobel Prize for Physics in 1986, shared with electron microscope
- Based on piezoceramic materials that expand or shrink small distances in response to voltage
- Ultrasharp conducting tip scanned over a conducting or semiconducting surface
- Tunneling current depends exponentially on the tip-to-substrate separation (angstroms/nanometers)
- Servo system uses feedback control and maintains constant tip-to-substrate separation
Principal:
- Piezoceramic holders scan an ultrasharp conducting tip over a surface
- Tip is within a few angstroms of the surface, results in tunneling current of electrons (Figures 10.2 & 10.3)
- Servo system uses voltage across piezoelectric positioning system to keep constant tip-to-substrate separation
- Topography maps obtained by plotting variations in voltage during scanning
Modes of Operation:
- Mode I: Measures topography of metals or semiconductors; slowest mode, servo system follows surface contour (Figure 10.5)
- Modes II and III: Faster than Mode I as tip maintains constant average height above the surface
- Mode IV: Joint density of states map, identifies elements comprising specific atoms and monitors molecular dynamics (Smith & Quate, 1986)
- Atomic Force Microscopy (AFM): Probes mechanical shape and structural dynamics without tunneling through sample material; measures forces as small as 10–18 newtons (Binnig et al., 1986)
Versatility:
- Used in air, water, ionic solution, oil, and high vacuum environments
- Scanning speed can be pushed into real-time imaging domain (Bryant et al., 1986)
- Ion milling process generates ultrasharp tips with single atom points or nanotool shapes (Dietrich, 1984)
Related Functions:
- "Molecular 'tasting and smelling'" using thermocouples sensitive to extremely low heat changes
- "Touch and feel" in atomic force microscopy by measuring forces with a nanoscale lever (Binnig et al., 1986)
Nanotechnology Workstations: Integrating STM Tips and Optical Microscopy for Atomic-Scale Manipulation and Imaging.
Formation of Near-Field Optical Nano-Apertures
- Discovery by Conrad Schneiker (1986)
- Formed using STM technology to create nano-holes in opaque metal films
- Enables resolution of features smaller than the wavelength of light
Nanovison and Nearfield Microscopy
- Resolution depends on diameter of aperture through which reflected light passes
- Binnig described creating 20nm holes for use in scanning light microscopes
- Light passed through small apertures results in narrow beam, enabling high resolution imaging
Advantages of Optical Stethoscope Concept
- Allows nondestructive investigation of samples in native environments (Lewis et al., 1984)
- Provides both kinetic information and high spatial resolution (Betzig et al., 1986)
Potential Applications of Nanoaperture Technology
- Follow temporal evolution of macromolecular assemblies in living cells
- Enable research on genes, viruses, proteins, cytoskeletal assemblies
- Manipulate and communicate with biological structures
STM and Other Technologies for Nanoscale Research
- Schneiker proposed an integrated nanotechnology workstation
- Combines multiple STM tips, optical microscopy, nanoapertures, fiber optic waveguides
- Enables synergism between technologies (Figure 10.7 and 10.9)
- STMs can act as a cursor for high-powered light microscope
- Performs high speed scanning while peripheral STMs manipulate atoms/molecules
STM Capabilities and Achievements
- Imaged single atoms, probed atomic forces, manipulated atoms (Figure 10.8)
- Won Nobel Prize in 1986 for pioneering work on scanning probe microscopy.
STMs/Feynman Machines (FMs)
STM/FM Proposed Experiments:
- Use an STM tip to move adatoms or molecular fragments together to induce chemical bonding
- Use an STM tip to cleave a chemical bond of a molecule adsorbed on a substrate
- Use enzymes or synthetic catalysts attached to an STM tip for repeat experiments (1) and (2)
STM/FM Modifications and Applications:
- Tip Shape Modifications: scalpel, chisel, cylindrical, and other configurations for scanning, scribing, etching, milling, polishing operations or electrical interfaces, electrochemical synthesis or machining, nano-environmental sensing
- Attached Tip Structures: enzymes, synthetic catalysts, shape selective crown ethers, transducer molecules for molecular recognition with specific selectivity (electrostatic or electromagnetic assisted), pick and place operations
- Multiple Tip Configurations: parallel or radial configurations for use as ultraminiature tweezers, jigs, arcs, interface electrodes, generating rapidly rotating electric fields
- Tip Materials Modification: insulating, semiconducting, ferroelectric or ferromagnetic for electrostatic, electromagnetic, magnetic, kHz-GHz acoustic (longitudinal, transverse, torsional), and optical modulation in mono-or multi-polar configurations
Augmentations of STM/FMs:
- Sensors and transducers such as the atomic force microscope (Binnig, Quate, and Gerber, 1986)
- Fiber optic interferometers or comparable techniques for real-time calibration of absolute and relative tip positioning
- Techniques for making tips with uniform tip-to-base conical profiles
Potential Uses of STM/FMs:
- Nanoscale manufacturing and machining, potentially replacing the need for lubrication due to force/area scaling and rapid heat dissipation
- Building up molecular devices through a series of joining and trimming operations
- Executing complex mechanical motions for driving nanomechanisms (e.g., turning a 2 nm diameter crank at thousands of revolutions per minute)
- Applications in various disciplines as this versatile technology becomes more widely known.
Feynman's Proposal for Nanoscale Machines
- Feynman proposed prizes and competitions to advance molecular and atomic scale technologies (1961)
- Offered $1000 for: a) Reducing book information to 1/25,000 the original size b) Building an electric motor no larger than 1/64 inch cube
- McLellan won the prize for building a microscopic electric motor (November 1960)
- Newman later reduced a page of A Tale of Two Cities to 5.9 x 5.9 micrometers using electron beam lithography in 1985
STMs and Nano Computing Applications
- STMs (Scanning Tunneling Microscopes) can be used for mechanical chemistry and electrical interfaces in molecular computing devices
- Arrays of nanoscale electrodes or STM tips may be useful for parallel processing and mass storage
- Optimal utilization of piezo-ceramic materials for scanning nanoscale arrays
- STMs could be used for precise positioning systems, such as minimal scale wirebonding systems
- Inspection and interfacing with superlattice quantum well devices or "quantum dot" devices
- Suggested applications: quasic energy levels or spin effects in computing components
- Efficiently interfacing these devices to the outside world presents challenges in clocking, input/output, and other areas.
STM Derived Applications and Optical Electronics Technology
- STM tip-induced sputtering may be used for etching or milling ultrafine conductors
- Schneiker suggests optical electronics technology might be useful in controlling, powering, and communicating with nanoscale devices
- Intense localized high frequency electric fields from laser radiation can control and power arrays of STM/FMs
- Same idea could be used to control, power, and communicate with swarms of mobile nanorobots.
NanoTechnology and Biomedical Applications of STM/FMs
Advantages of Nondestructive Interactions with Biological Materials:
- Potential for immense biomedical applications
- Overcoming technical obstacles:
- Problem 1: Biomolecules, cells, and tissues are not conductors. Electron tunneling may be damaging.
- IBM Zurich researchers have succeeded in imaging biomaterials in air (protein coated DNA, virus structures) using a tunneling mechanism from tip to surface followed by "low resistance electron transport to the conducting substrate"
- Simultaneous optical microscopy may help facilitate non-damaging tunneling currents by permitting appropriate wavelength choices
- Problem 2: Atomic Force Microscope (AFM) mode with a lever arrangement on an STM can be used for biological materials
- Lever movement is monitored by the STM, enabling mapping and observing mechanical dynamics without direct tunneling through biomaterials
- Problem 1: Biomolecules, cells, and tissues are not conductors. Electron tunneling may be damaging.
Proposed Solutions:
- Nano scale thermocouple and pipette STM tips may be useful for biological materials
- Researchers at UCSB have demonstrated STM imaging at ionic liquid-solid interfaces, avoiding significant leakage of current to the aqueous environment by insulating probes close to the tip
Potential Applications:
- Repetitive imaging and structural mapping of living material
- Nondestructive study of dynamical structural changes (protein receptors) in AFM mode
- Detection and analysis of propagating phonons or solitons using multiple STM configurations
- Spectroscopic analysis, including DNA base pair reading and cytoskeletal lattice communication
- Real time imaging of living structures
- Nanoscale manipulation and modification of biomaterials and organelles, assisting genetic engineering and medical research
- Creation or modulation of complex biological molecules (enzymes, antibodies) using STM/FMs
Grander Biomedical Applications:
- Developing "guardian" and "scavenger" organisms in the blood to clean out harmful invaders
- Creating programmable cell repair machines using genetic information
- Nanorobots for monitoring physiological functions, nanofabrication, and intracellular house calls
Self-Replicating Automata: A Historical Perspective
Background:
- Ideas of automatic machines and robots have existed for centuries
- Mathematical proof of self-replicating automata in a physical sense by John von Neumann (mid 20th century)
- Possibility of spontaneous assembly, disassembly, multiplication, or reconfiguration using neighbor logic
Applications:
- Outer space exploration
- Household furniture
- Nanoscale "Hibb's machines" or nanodoctors
Challenges:
- NASA study group identified assumptions and problems in von Neumann's proof
- Minimizing material types, part tolerance, wear, assembly complexity (Schneiker)
- Increasing reliability through error detection, repair, regeneration
Microreplicators and Nanotechnology:
- Simple microreplicators with STM/FMs could mass produce nanotechnology products
- Superconductive materials and lossless current, magnets, motors may facilitate implementation of useful replicative micro-automata
- Increase in superconducting transition temperatures in certain materials
Collective Intelligence:
- Christopher Langton's study on cellular automata and self-replicators at Los Alamos National Laboratories
- Extracting molecular logic of living systems through modeling these systems.
Impact of Technology:
- Capability to create new life forms in silico and in vitro will present significant technical, theoretical, and ethical challenges for humanity.
The Future of Consciousness
Nanotechnology:
- May enable the "Mind/Tech merger" to materialize
- Debates about the nature of consciousness will move from philosophy to large scale experiments
- Realization of visions of consciousness interfacing with or existing within computers and robots
Symbiotic Association:
- Replicative nanodevices and cytoskeletal networks in living cells could counter disease processes
- Lead to information exchange based on the collective dynamic patterns of cytoskeletal subunit states
Potential Scenario:
- Accessing and manipulating consciousness through a small window in a specific brain region (e.g., hippocampal temporal lobe)
- Techniques like laser interferometry, electroacoustical probes, or replicative nanoprobes could be developed
Potential Devices:
- Customized array of nanoscale automata using superconducting materials
- Genetically engineered array of tubulin subunits assembled into parallel tensegrity arrays of microtubules and other cytoskeletal structures
Heredity and Experience:
- Current and near future genetic engineering capabilities can enable isolation and reconstitution of genes responsible for an individual's brain cytoskeletal proteins
- Reuniting the "two evident sources of mind content" in an artificial consciousness environment
Polymerization Limitations:
- Cytoskeletal arrays are highly unstable and dependent on biochemical, hormonal, and pharmacological maintenance
- Precise monitoring and control of cytoskeletal consciousness environments may become a new branch of anesthesiology
- Polymerization is limited in size (and potential intellect) due to gravitational collapse
Potential Solutions:
- Hybridizing the cytoskeletal array by metal deposition, symbiosis with synthetic nanoreplicators, or placement in a zero gravity environment
Consciousness Vaults:
- People with terminal illnesses may choose to deposit their consciousness in "consciousness vaults" in orbiting space stations or satellites
- Future consciousness vaults could lead to new sociopolitical issues and the creation of "entertainment, earth communication, and biochemical mood and maintenance supplied by robotics"