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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
non-commercial purposes only, provided this information and the
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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