WHISPERING BETWEEN CELLS: ELECTROMAGNETIC FIELDS AND REGULATORY MECHANISMS IN TI

By Medical
SSUE
VA
Over
W.the
Rosspast
Adey20 years,
Center
& University
a seriesSchool
of observations
of Medicinehas
Lomapointed
Linda,with
California
increasing cer
tainty to an essential organization in living matter, physical in nature at a fa
r 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 hav
e led to our present knowledge of the exquisite fabric of living tissues, focuse
d on the chemistry and molecular biology of cell ultrastructure. Rather, this ne
w knowledge appears to build logically and sequentially from all that has gone b
efore. Yet in many respects, it has been an uncharted ocean in both biological a
nd its
In
physical
pursuit,
sciences.
there has been an evolution of new alliances and new collaborati
ons between physical and biological scientists. Indeed, for the first time in th
e history of science, physicists and biologists confront common goals at the cut
ting 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
Yet
much that is
andfundamental
biophysicalremains
understanding.
beyond our comprehension, bringing a certai
n 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 q
uest of an understanding of the limits of the physical universe and the laws gov
erning its motions and all the matter that lies therein. For as we have explored
our inner universe, seeking to understand broad principles determining interact
ion of weak nonionizing electromagnetic (EM) fields with living matter, there ha
s been a dawning awareness that we may indeed have opened a veritable Pandora's
In some degree, our first steps may have been unwitting. We sought empirically a
box.
nd intuitively to unravel a scheme of biochemical and biophysical organization o
f 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 sensitivit
ies. With this awareness of the nonthermal basis of many of these interactions o
f nonionizing EM fields with living tissues, there arose the countercoin of sens
itivities determined by the physical characteristics of the imposed EM field: pa
rameters of frequency, intensity, and temporal sequence have all served to prope
l the scope and focus of these studies into the realm of nonlinear, nonequilibri
um thermodynamics, with long-range quantum effects as the basis for much that ha
s been observed and much that is postulated for future studies. These studies em
phasize 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 hiera
rchical sequence far beyond the exquisite fabric of molecules and their associat
ed the
At
chemical
core of
reactions.
observed sensitivities to low-level EM fields are a series of coo
perative processes. One such series involves calcium ion binding and release(1).
Available evidence points to their occurrence at cell membranes and on cell sur
faces in the essential first steps of detecting EM fields. Also, attention is no
w directed to newly defined roles for free radicals, that may also participate i
n highly cooperative detection of weak magnetic fields, "even at levels below th
ermal
It
has(kT)
beennoise(2),(3)."
asserted that thermal noise, expressed in the term kT as a function
of the Boltzmann constant and absolute temperature, must remain a monolithic thr
eshold, below which no biological threshold could exist(4); despite the wealth o
f physiological evidence that sensory thresholds descend substantially below the
floor of thermal noise, as for example in the auditory system, where the ear ma
y 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 wh
ich the question is directed in an hierarchical system. In studies at cellular a
nd subcellular levels, a spectrum of imposed EM fields, ranging from extremely l
ow frequency (ELF) to microwaves, have proved unique tools, not only revealing e
ssential aspects of mechanisms of interaction, but also disclosing much new know
ledge about intrinsic organization of cells and tissues, particularly in normal
and abnormal
Until
recentlyregulation
there haveofbeen
cellfew
growth,
areasincluding
of biological
tumorscience
formation(6),(7).
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 fi
eld interactions with biomolecular systems will be the joint province of physici
sts andobservations
Recent
biologists. have opened doors to new concepts of communication between c
ells as they whisper together across the barrier of cell membranes. Regulation o
f cell surface chemical events by weak EM fields indicates a major amplification
of initial weak triggers associated with binding of hormones, antibodies, and n
eurotransmitters to their specific binding sites. Calcium ions play a key role i
n this amplification. The evidence indicates that these events are mediated by h
ighly 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 equilib
rium are
What
thermodynamics
the observedassociated
sensitivities
with to
thermal
weak environmental
energy exchanges
low-frequency
and tissue (ELF)
heating.
fi
elds? The evidence has come from two lines of research: biobehavioral and, more
recently, from cell and tissue culture studies. At the limit of observed sensiti
vities, biobehavioral studies in sharks, rays, monkeys and man offer evidence of
sensitivities to electric gradients in tissue fluid (or in the aquatic medium s
urrounding 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 p
otential (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 upta
ke ainto
As
perspective
DNA.
on the biological significance of this cell-surface current flo
w, there is evidence that tissue gradients in the range 10-7 to 10-1 V/cm are in
volved in essential physiological functions in marine vertebrates, birds, and ma
mmals(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 spect
rum of maximal sensitivity at frequencies below 100 Hz. Is there a natural EM en
vironment, and how has this been changed by man? All life on earth has evolved i
n a sea of natural low-frequency EM fields. They originate in terrestrial and ex
traterrestrial sources. Thunderstorm activity in equatorial Africa and the Amazo
n 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 ac
tivity creates the Schumann resonances of 5 peaks between 8 and 32 Hz, with inte
nsities around 10 mV/m. Having a circumference of 41,000 km, the earth may act a
s a cavity resonator at frequencies around 8 Hz for these waves propagating at t
he speed of light (300,000 km/sec). Solar activity at ELF frequencies in years o
f high sunspot activity increases to levels around 1.0 mV/m. Over the last centu
ry, 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 syste
m frequencies (50 Hz in Europe and most of the world, 60 Hz in North America); a
nd in the radiofrequency/microwave spectrum from AM and FM broadcasting, TV, and
The
radar
mainemissions.
research endeavors in this field have focused on limited but widely sep
arated areas of biology and medicine. In many respects they form an hierarchical
sequence: (1) coupling mechanisms between fields and tissues at the cellular le
vel; (2) field effects on embryonic and fetal development; (3) modulation of cen
tral nervous and neuroendocrine functions; (4) modification of immune functions;
(5) regulation of cell growth, and EM field action in tumor promotion; (6) modu
lation of gene expression; and (7) from pioneering therapeutic applications in h
ealing ununited fractures, there is a vista of much broader therapies that may i
nvolve joint use of pharmacological agents and EM fields, each tailored for opti
mal dosage in specific applications. In cellular aggregates that form tissues of
higher animals, cells are separated by narrow fluid channels that take on speci
al importance in signaling from cell to cell. These channels act as windows on t
he electrochemical world surrounding each cell. Hormones, antibodies, neurotrans

mitters, and chemical cancer promoters, for example, move along them to reach bi
nding sites on cell membrane receptors. These narrow fluid "gutters," typically
not more than 150 wide, are also preferred pathways for intrinsic and environmen
tal EM fields, since they offer a much lower electrical impedance than cell memb
ranes. Although this intercellular space (ICS) forms only about 10% of the condu
cting cross-section of typical tissue, it carries at least 90% of any imposed or
Numerous
intrinsicstranded
current,protein
directing
molecules
it along
protrude
cell membrane
from within
surfaces.
the cell into this narr
ow ICS. Their glycoprotein tips form the glycocalyx, which senses chemical and e
lectrical signals in surrounding fluid. Their highly negatively charged tips for
m receptor sites for hormones, antibodies, neurotransmitters, and for many metab
olic substances, including cancer promoters. These charged terminals form an ana
tomical substrate for the first detection of weak electrochemical oscillations i
n 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 mu
ch larger intrinsic bioelectric processes, but may also be substantially below t
he level of tissue thermal noise, there is a mainstream of theoretical and exper
imental studies seeking the first transductive steps. Answers to that important
question are currently sought in EM field interactions with free radicals. Model
s and experimental data have been adduced for their role at electric power frequ
encies and at the other extreme in the EM spectrum in bioeffects of millimeter w
aves. 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 stat
es 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 en
ergy of the system, and is effective exclusively through its influence on the ki
netics." Electron spin energy of free radicals is conserved through thermal coll
isions. Unlike their behavior in free solution, their movement at biological mem
branes is constrained by the large electric field of the membrane potential, enh
ancing probabilities
Research
with millimeter
of their
wavesmutual
also supports
interactions
concepts
in ELF
of free
fields.
radical interactio
ns in biological systems. At frequencies in the range 10 to 1000 GHz, resonant v
ibrational 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, w
ith 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 t
he field intensity is progressively reduced. Moreover, clear responses occur wit
h 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, b
ased on magnetic field-dependent chemical reactions, including cytochrome-cataly
zed reactions that involve transient radical pairs, and production of free radic
als, such as reactive oxygen and nitric oxide, leading to a further highly coope
rative amplification step. Based on Frohlich's(11) model of interactions between
an imposed field and high frequency (1012 Hz) intracellular van der Pol oscilla
tors, 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-f
requency signals at cell membranes relates to selective responses seen as window
ed phenomena in both frequency and amplitude domains. Contending models have con
sidered
In
a cyclotron
cyclotron
oscillator,
resonancecharged
and calcium
particles
coordination
are exposed
compound
to a static
interactions.
magnetic fi
eld and to an oscillating magnetic field at right angles to each other. The part
icles will move in circular orbits at right angles to the two imposed fields whe
n the frequency of the imposed oscillating field matches the particle gyrofreque

ncy, determined by its mass, charge, and the intensity of the static magnetic fi
eld. 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) hypothes
ized that EM fields close to cyclotron frequencies may couple to the ionic speci
es, transferring energy selectively to these ions. Criticism of this model has b
een directed at its requirements for ions to be stripped of hydration shells tha
t would presumably alter gyrofrequencies, and to the presumed direction of ion m
otion in thehasmagnetic
Lednev(13)
proposedfield.
a quite different explanation of the same experimental c
onditions. Considering an ion inside a calcium-binding protein as a charged osci
llator, a shift in the probability of an ion transition between different states
of vibrational energy occurs when there is a combination of static and oscillat
ing magnetic fields. This in turn affects the interaction of the ion with surrou
nding ligands. This effect is maximal when the frequency of the alternating fiel
d is equal to the cyclotron frequency of this ion or to some of its harmonics or
Future
subharmonics.
research on submolecular transductive coupling will be diversified and in
creasingly dependent on new technologies, such as high resolution magnetic reson
ance spectroscopy and electro-optical techniques. These approaches may answer su
ch challenging problems as structural modifications during receptor-ligand bindi
ng, vibration modes in cell membrane lipoprotein domains during excitation(14) a
nd possible coherent millimeter wave emissions accompanying enzyme action. There
is a reasonable prospect that bioelectromagnetics may emerge as a separate biol
ogical discipline, offering a unique vehicle in the development of a physical, a
s distinct from a chemical, biology. In little more than a century, our biologic
al vista has moved from organs to tissues, to cells, and most recently to the mo
lecules that are the exquisite fabric of living systems. There is now a new fron
tier, 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 sig
nalsAdey,
1.
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