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         MindNet Journal - Vol. 1, No. 50
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         V E R I C O M M / MindNet         "Quid veritas est?"
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    The views and opinions expressed below are not necessarily the
    views and opinions of VERICOMM, MindNet, or the editors unless
    otherwise noted.

    The following is reproduced here with the express permission of
    the publisher, Frontier Sciences, Temple University.

    Permission is given to reproduce and redistribute, for
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    copy remain intact and unedited.

    Editor: Mike Coyle

    Contributing Editors: Walter Bowart
    		      Alex Constantine
    		      Martin Cannon

    Assistant Editor: Rick Lawler

    Research: Darrell Bross

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    WHISPERING BETWEEN CELLS: ELECTROMAGNETIC FIELDS AND REGULATORY
    MECHANISMS IN TISSUE

    By W. Ross Adey

    VA Medical Center & University School of Medicine Loma Linda,
    California

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       Over the past 20 years, a series of observations has
    pointed with increasing certainty to an essential organization in
    living matter, physical in nature at a far finer level than the
    structural and functional image defined in the chemistry of
    molecules. This is indeed a new frontier. It neither ignores nor
    neglects the great accomplishments across centuries of
    biological research, studies that have led to our present
    knowledge of the exquisite fabric of living tissues, focused on
    the chemistry and molecular biology of cell ultrastructure.
    Rather, this new knowledge appears to build logically and
    sequentially from all that has gone before. Yet in many respects,
    it has been an uncharted ocean in both biological and physical
    sciences.
       In its pursuit, there has been an evolution of new
    alliances and new collaborations between physical and biological
    scientists. Indeed, for the first time in the history of science,
    physicists and biologists confront common goals at the cutting
    edge of their respective fields. We have glimpsed a new and
    splendid vista, for much has been accomplished in recent years
    to achieve our present platform of biological and biophysical
    understanding.
       Yet much that is fundamental remains beyond our
    comprehension, bringing a certain malaise not unlike the
    philosophic uncertainty that has beset astronomers over the past
    century as they have moved from one physical horizon to the
    next, in quest of an understanding of the limits of the physical
    universe and the laws governing its motions and all the matter
    that lies therein. For as we have explored our inner universe,
    seeking to understand broad principles determining interaction of
    weak nonionizing electromagnetic (EM) fields with living matter,
    there has been a dawning awareness that we may indeed have opened
    a veritable Pandora's box.
       In some degree, our first steps may have been
    unwitting. We sought empirically and intuitively to unravel a
    scheme of biochemical and biophysical organization of
    unparalleled complexity. Gone from the outset were the isotropy,
    the linearity of equilibrium systems, and comfortable notions of
    thermal interactions as sole and sufficient models for an
    understanding of essential biomolecular sensitivities.
       With this awareness of the nonthermal basis of many of
    these interactions of nonionizing EM fields with living tissues,
    there arose the countercoin of sensitivities determined by the
    physical characteristics of the imposed EM field: parameters of
    frequency, intensity, and temporal sequence have all served to
    propel the scope and focus of these studies into the realm of
    nonlinear, nonequilibrium thermodynamics, with long-range quantum
    effects as the basis for much that has been observed and much
    that is postulated for future studies. These studies emphasize
    how close we are, and yet so far, from an understanding of an
    essence of living matter, to be defined in physical terms at the
    atomic level, in an hierarchical sequence far beyond the
    exquisite fabric of molecules and their associated chemical
    reactions.
       At the core of observed sensitivities to low-level EM
    fields are a series of cooperative processes. One such series
    involves calcium ion binding and release(1). Available evidence
    points to their occurrence at cell membranes and on cell surfaces
    in the essential first steps of detecting EM fields. Also,
    attention is now directed to newly defined roles for free
    radicals, that may also participate in highly cooperative
    detection of weak magnetic fields, "even at levels below thermal
    (kT) noise(2),(3)."
       It has been asserted that thermal noise, expressed in
    the term kT as a function of the Boltzmann constant and absolute
    temperature, must remain a monolithic threshold, below which no
    biological threshold could exist(4); despite the wealth of
    physiological evidence that sensory thresholds descend
    substantially below the floor of thermal noise, as for example in
    the auditory system, where the ear may appear to function as
    though close to a temperature of absolute zero(5).
       What has been learned about mechanisms of EM field
    interactions with living organisms and biomolecular systems? The
    answer depends on the level of organization at which the question
    is directed in an hierarchical system. In studies at cellular and
    subcellular levels, a spectrum of imposed EM fields, ranging from
    extremely low frequency (ELF) to microwaves, have proved unique
    tools, not only revealing essential aspects of mechanisms of
    interaction, but also disclosing much new knowledge about
    intrinsic organization of cells and tissues, particularly in
    normal and abnormal regulation of cell growth, including tumor
    formation(6),(7).
       Until recently there have been few areas of biological
    science so closely linked to research at the cutting edge of a
    key area of the physical sciences, in this case to research in
    the physics of matter. Indeed, biological observations may well
    become benchmarks and pacesetters in the future of this field of
    physics(8). Observations on biological coherence and cooperativity
    now challenge physical scientists to seek models and to design
    experiments in the realm of biology. For the future, progress in
    elucidating these sensitivities and subtleties of EM field
    interactions with biomolecular systems will be the joint province
    of physicists and biologists.
       Recent observations have opened doors to new concepts
    of communication between cells as they whisper together across
    the barrier of cell membranes. Regulation of cell surface
    chemical events by weak EM fields indicates a major amplification
    of initial weak triggers associated with binding of hormones,
    antibodies, and neurotransmitters to their specific binding
    sites. Calcium ions play a key role in this amplification. The
    evidence indicates that these events are mediated by highly
    nonlinear, non-equilibrium processes at critical steps in signal
    coupling across cell membranes. In other words, these events
    appear to depend on quantum states and resonant responses in
    biomolecular systems, and not on simple equilibrium
    thermodynamics associated with thermal energy exchanges and
    tissue heating.
       What are the observed sensitivities to weak
    environmental low-frequency (ELF) fields? The evidence has come
    from two lines of research: biobehavioral and, more recently,
    from cell and tissue culture studies. At the limit of observed
    sensitivities, biobehavioral studies in sharks, rays, monkeys and
    man offer evidence of sensitivities to electric gradients in
    tissue fluid (or in the aquatic medium surrounding marine
    vertebrates) in the range 10-7 to 10-8V/cm. These pericellular
    gradients are thus much weaker than the electric barrier of the
    cell membrane potential (105V/cm). Sensitivities to electric
    fields at the same intensities in cell culture media have also
    been observed in bone cells, with an ELF frequency "window" for
    extracellular matrix formation, mitogen release, and thymidine
    uptake into DNA.
       As a perspective on the biological significance of
    this cell-surface current flow, there is evidence that tissue
    gradients in the range 10-7 to 10-1 V/cm are involved in
    essential physiological functions in marine vertebrates, birds,
    and mammals(9). There are three emergent conclusions from these
    studies: (1) these are not responses to single transients; (2)
    they occur only in response to coherent ELF stimuli integrated
    over time; and (3) there is a biological frequency spectrum of
    maximal sensitivity at frequencies below 100 Hz.
       Is there a natural EM environment, and how has this
    been changed by man? All life on earth has evolved in a sea of
    natural low-frequency EM fields. They originate in terrestrial
    and extraterrestrial sources. Thunderstorm activity in equatorial
    Africa and the Amazon basin contribute huge amounts of ELF energy
    that is ducted world-wide between the ionosphere (at an altitude
    of about 200 km) and the earth's surface. This activity creates
    the Schumann resonances of 5 peaks between 8 and 32 Hz, with
    intensities around 10 mV/m. Having a circumference of 41,000 km,
    the earth may act as a cavity resonator at frequencies around 8
    Hz for these waves propagating at the speed of light (300,000
    km/sec). Solar activity at ELF frequencies in years of high
    sunspot activity increases to levels around 1.0 mV/m.
       Over the last century, this natural background has
    changed sharply with the introduction of a vast range of man-made
    devices and systems. These artificial EM fields expose humans in
    the home, workplace, and environment to spectral peaks typically
    many orders of magnitude above natural background levels. There
    are ELF peaks at power system frequencies (50 Hz in Europe and
    most of the world, 60 Hz in North America); and in the
    radiofrequency/microwave spectrum from AM and FM broadcasting,
    TV, and radar emissions.
       The main research endeavors in this field have focused
    on limited but widely separated areas of biology and medicine. In
    many respects they form an hierarchical sequence: (1) coupling
    mechanisms between fields and tissues at the cellular level; (2)
    field effects on embryonic and fetal development; (3) modulation
    of central nervous and neuroendocrine functions; (4) modification
    of immune functions; (5) regulation of cell growth, and EM field
    action in tumor promotion; (6) modulation of gene expression; and
    (7) from pioneering therapeutic applications in healing ununited
    fractures, there is a vista of much broader therapies that may
    involve joint use of pharmacological agents and EM fields, each
    tailored for optimal dosage in specific applications.
       In cellular aggregates that form tissues of higher
    animals, cells are separated by narrow fluid channels that take
    on special importance in signaling from cell to cell. These
    channels act as windows on the electrochemical world surrounding
    each cell. Hormones, antibodies, neurotransmitters, and chemical
    cancer promoters, for example, move along them to reach binding
    sites on cell membrane receptors. These narrow fluid "gutters,"
    typically not more than 150 wide, are also preferred pathways for
    intrinsic and environmental EM fields, since they offer a much
    lower electrical impedance than cell membranes. Although this
    intercellular space (ICS) forms only about 10% of the conducting
    cross-section of typical tissue, it carries at least 90% of any
    imposed or intrinsic current, directing it along cell membrane
    surfaces.
       Numerous stranded protein molecules protrude from
    within the cell into this narrow ICS. Their glycoprotein tips
    form the glycocalyx, which senses chemical and electrical signals
    in surrounding fluid. Their highly negatively charged tips form
    receptor sites for hormones, antibodies, neurotransmitters, and
    for many metabolic substances, including cancer promoters. These
    charged terminals form an anatomical substrate for the first
    detection of weak electrochemical oscillations in pericellular
    fluid, including field potentials arising in activity of adjacent
    cells or as tissue components of environmental fields.
       As evidence has mounted confirming occurrence of
    bioeffects of EM fields that are not only dwarfed by much larger
    intrinsic bioelectric processes, but may also be substantially
    below the level of tissue thermal noise, there is a mainstream of
    theoretical and experimental studies seeking the first
    transductive steps. Answers to that important question are
    currently sought in EM field interactions with free radicals.
    Models and experimental data have been adduced for their role at
    electric power frequencies and at the other extreme in the EM
    spectrum in bioeffects of millimeter waves.
       In essence, in models proposed by McLauchlan (2) for 50
    and 60 Hz fields, very low static or oscillating magnetic fields
    cause triplet pairs to break and form singlets. At higher field
    levels around 8 mT, two of the three triplet states are entirely
    decoupled from the singlet state. Thus, at this field level,
    two-thirds of the radical pairs may not react as they would in a
    weaker field, "an enormous effect of a small magnetic field on a
    chemical reaction, and the effect begins at the lowest applied
    field strength, even at levels below thermal (kT) noise. ...The
    all-important reaction has an energy much less than the thermal
    energy of the system, and is effective exclusively through its
    influence on the kinetics." Electron spin energy of free
    radicals is conserved through thermal collisions. Unlike their
    behavior in free solution, their movement at biological membranes
    is constrained by the large electric field of the membrane
    potential, enhancing probabilities of their mutual interactions
    in ELF fields.
       Research with millimeter waves also supports concepts
    of free radical interactions in biological systems. At
    frequencies in the range 10 to 1000 GHz, resonant vibrational or
    rotational interactions, not seen at lower frequencies, may occur
    with molecules or portions of molecules. Studies in yeast cells
    over the past 15 years in athermal millimeter wave fields by
    Grundler and Kaiser(10) have shown that growth appears finely
    "tuned" to applied field frequencies around 42 GHz, with
    successive peaks and troughs at intervals of about 10 MHz.
       In recent studies, they noted that the sharpness of
    the tuning increases as the intensity of the imposed field
    decreases; but the tuning peak occurs at the same frequency when
    the field intensity is progressively reduced. Moreover, clear
    responses occur with incident fields as weak as 5 picowatts/cm2.
       In a recent synthesis emphasizing nonthermal
    interactions of EM fields with cellular systems, Grundler et
    al. (3) present models of the transductive sequence of EM field
    transductive coupling, based on magnetic field-dependent chemical
    reactions, including cytochrome-catalyzed reactions that involve
    transient radical pairs, and production of free radicals, such as
    reactive oxygen and nitric oxide, leading to a further highly
    cooperative amplification step. Based on Frohlich's(11) model of
    interactions between an imposed field and high frequency (1012
    Hz) intracellular van der Pol oscillators, they conclude that
    "imposed fields can be active even at intensities near zero."
    In other words, a threshold might not exist in such a system.
       Beyond the low energies of EM fields in the first
    transductive step, amplification of low-frequency signals at cell
    membranes relates to selective responses seen as windowed
    phenomena in both frequency and amplitude domains. Contending
    models have considered cyclotron resonance and calcium
    coordination compound interactions.
       In a cyclotron oscillator, charged particles are
    exposed to a static magnetic field and to an oscillating magnetic
    field at right angles to each other. The particles will move in
    circular orbits at right angles to the two imposed fields when
    the frequency of the imposed oscillating field matches the
    particle gyrofrequency, determined by its mass, charge, and the
    intensity of the static magnetic field. Free (unhydrated) calcium
    ions in the earth's magnetic field would exhibit cyclotron
    resonance frequencies around 10 Hz, with cyclotron currents as
    much as five orders of magnitude greater than the Faraday
    currents. Liboff(12) hypothesized that EM fields close to
    cyclotron frequencies may couple to the ionic species,
    transferring energy selectively to these ions. Criticism of this
    model has been directed at its requirements for ions to be
    stripped of hydration shells that would presumably alter
    gyrofrequencies, and to the presumed direction of ion motion in
    the magnetic field.
       Lednev(13) has proposed a quite different explanation of
    the same experimental conditions. Considering an ion inside a
    calcium-binding protein as a charged oscillator, a shift in the
    probability of an ion transition between different states of
    vibrational energy occurs when there is a combination of static
    and oscillating magnetic fields. This in turn affects the
    interaction of the ion with surrounding ligands. This effect is
    maximal when the frequency of the alternating field is equal to
    the cyclotron frequency of this ion or to some of its harmonics
    or subharmonics.
       Future research on submolecular transductive coupling
    will be diversified and increasingly dependent on new
    technologies, such as high resolution magnetic resonance
    spectroscopy and electro-optical techniques. These approaches may
    answer such challenging problems as structural modifications
    during receptor-ligand binding, vibration modes in cell membrane
    lipoprotein domains during excitation(14) and possible coherent
    millimeter wave emissions accompanying enzyme action.
       There is a reasonable prospect that bioelectromagnetics
    may emerge as a separate biological discipline, offering a unique
    vehicle in the development of a physical, as distinct from a
    chemical, biology. In little more than a century, our biological
    vista has moved from organs to tissues, to cells, and most
    recently to the molecules that are the exquisite fabric of living
    systems. There is now a new frontier, more difficult to
    understand, but of vastly greater significance. It is at the
    atomic level that physical processes, rather than chemical
    reactions in the fabric of molecules, appear to shape the
    transfer of energy and the flow of signals in living systems(15).

    References

    1. Adey, W. R., 1988. Physiological signalling across cell
    membranes and cooperative influences of extremely low frequency
    electromagnetic fields. In: Biological Coherence and Response to
    External Stimuli, H. Frohlich, ed., Heidelberg, Springer-Verlag.
    pp. 148-170.

    2. McLauchlan, K., 1992. Are environmental magnetic fields
    dangerous? Physics World, January, 1992, 41-45.

    3. Grundler, W., Kaiser, F., et al., 1992. Mechanics of
    electromagnetic interaction with cellular systems.
    Naturwissenschaften 79, 551-559.

    4. Adair, R. K., 1991. Constraints on biological effects of
    extremely-low-frequency electromagnetic fields. Phys. Rev. A.
    43(2), 1039-1048.

    5. Bialek, W., 1983. Macroscopic quantum effects in biology.
    Ph.D. Thesis, Department of Chemistry, University of California,
    Berkeley. 250 pp.

    6. Adey, W. R., 1992a. Collective properties of cell membranes.
    In: Interaction Mechanisms of Low-Level Electromagnetic Fields in
    Living Systems, B. Norden, C. Ramel, eds. Royal Swedish Academy
    of Sciences, 1989. Oxford University Press. pp. 47-77.

    7. Adey, W. R., 1992b. ELF magnetic fields and promotion of
    cancer: experimental studies. In Interaction Mechanisms of
    Low-Level Electromagnetic Fields in Living Systems, B. Norden, C.
    Ramel, eds. Royal Swedish Academy of Sciences, 1989. Oxford
    University Press. pp. 23-46.

    8. Frohlich, H., 1986. Coherent excitation in active biological
    systems. In: Modern Bioelectrochemistry, F. Gutmann, H. Keyzer,
    eds. New York: Plenum. pp. 241-261.

    9. Adey, W. R., 1981. Tissue interactions with nonionizing
    electromagnetic fields. Physiol. Rev. 61, 435-514.

    10. Grundler, W., Kaiser, F., 1992. Experimental evidence for
    coherent excitations correlated with cell growth. Nanobiology 1,
    163-176.

    11. Frohlich, H., 1986. Coherence and the action of enzymes. In:
    The Fluctuating Enzyme, G. R. Welch, ed. New York: Wiley. pp.
    421-449.

    12. Liboff, A. R., 1985. Cyclotron resonance in membrane
    transport. In: Interactions Between Electromagnetic Fields and
    Cells. New York: Plenum Press. pp. 281-296.

    13. Lednev, V. V., 1991. Possible mechanisms for the influence of
    weak magnetic fields on biological systems. Bioelectromagnetics
    12, 71-76.

    14. Christiansen, P. L., Eilbeck, J. C., et al., 1992. On
    ultrasonic Davydov solitons and the Henon-Heiles system. Phys.
    Lett. A 166, 129-134.

    15. Trullinger, S. E., 1978. Where do we go from here? In:
    Solitons and Condensed Matter Physics, A. R. Bishop, T.
    Schneider, eds. Berlin, Springer-Verlag. pp. 338-340.

    If you wish to receive a copy of the Vol.3, No.2 issue of our
    journal, please e-mail me your street address and I will forward
    you a copy. I trust that you will find the above paper
    interesting and I look forward to any comments. Dr. Adey is to
    be commended for the fine work that he has done in this field.

    My best wishes to all, Nancy Kolenda, Coordinator Center for
    Frontier Sciences, Temple University,

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