Current concepts of the interaction of weak electromagnetic fields with cells *

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255
Bioelectrochemistty and Bioenergetics, 210992) 255-268
A section of J. Electroanal. Chem., and constituting Vol. 342 (19921
Elsevier Sequoia S.A., Lausanne
JEC BB 01482
Current concepts of the interaction of weak electromagnetic
fields with cells *
Roland Glaser
Institute of Biophysics, Department of Biology, Humboldt Uniuersity, Berlin (Germany)
(Received 9 October 19911
Abstract
The interaction of electromagnetic fields with biological systems must be considered not as a result
of the influence of a foreign energy (as in the case of ionizing radiations), but as a modification of the
proper electric in-vivo structure of the biological system. This structure indicates the same structural
hierarchy (atomic, molecular, cellular, organismic1 as that known from the morphological point of view.
According to this, effects are possible on the basis of quantum mechanics as well as on the basis of the
dipolar orientation of molecules, double-layer structures and modifications of systems of ionic equilib-
ria. Considering the time constants of these effects, the frequencies used for medical treatments today
are in no way the best possible, but just predicted by technical conditions. It is recommended that the
frequency region of 103-10 Hz be used. The frequently observed effects of pulsed for modulated)
electromagnetic fields (PEMF) are understandable if one considers that the carrier frequency will
produce the primary physical reactions and that the low-frequency oscillations of these reactions which
are produced by the low-frequency modulation will come into resonance with biological reactions.
(I) INTRODUCTION
It may be the fate of bioelectricity, biomagnetism or bioelectromagnetism that
from the beginning of their discovery this area was burdened with the omen of
mystery and charlatanism. Really, this area was and still is a playground for
impostors and quack doctors. An example of an early paper is Franz Anton
Mesmers Sentschreiben an einen auswlrtigen Arzt iiber die Magnetkur (Letter
to a non-resident doctor concerning magnet treatment) dated 1775. This omen was
not even removed by the most serious and epoch-making work of Luigi Galvani on
Paper presented at the symposium High-Frequency Electromagnetic ac Fields and their ,Effects on
Biological Systems, Braunschweig, 9-10 July 1991.
0302-4598/92/$05.00 0 1992 - Elsevier Sequoia S.A. AI1 rights reserved
256
animal electricity, done at the same time. Unfortunately, this scientific effort was
overshadowed at that time by Galvanis most serious controversy with his colleague
Alessandro Volta.
Neither the enormous progress of physics in the following centuries, i.e. the
creation of scientific electrodynamics and electrical engineering, nor the develop-
ment of electrochemistry and electrophysiology was able to change this situation
basically. It was always promoted by the attractiveness of all mysterious things in
general as well as by the trend of all patients to look for every kind of help.
From time to time, various special topics and fields stand out from this realm of
mystery, indicating a clear scientific character. This, for example, is true for:
(a) the phenomenon of electrical excitability of cells, i.e. the whole area of
electrophysiology;
(b) the phenomenon of electroreception in fish and other animals;
(c) the phenomenon of magnetoreception in bacteria and birds;
(d) the phenomenon of passive movement of cells in artificially applied fields,
such as electrophoresis, dielectrophoresis and electrorotation; and
(e) the electrical breakdown of membranes induced by short pulses of electric
fields, leading to cell perforation and cell fusion.
This process is continuing. Scientifically accepted directions always appear if the
observed phenomena are verified significantly and if they seem to be comprehensi-
ble biophysically.
At present, problems connected with the influence of weak electromagnetic and
magnetic fields have been shifted to the centre of interest. The word weak
means field strengths with energies close to thermic noise (k7). This is the area of
electric fields which are mostly used for therapeutic treatments. Currently the
problem of environmental electropollution is being discussed very controver-
sially [ 1,21.
This paper concentrates on the following question: How can electromagnetic
fields influence cellular processes? A large number of experiments seem to have
documented reliably that such effects exist, that they mostly occur preferentially at
windows of particular frequencies and intensities, and that they are connected in
many cases with Ca2+ transport [3-121. In many cases, it seems that high frequency
fields are more effective if they are modulated by low frequencies (16-60 Hz)
[12-181. We will formulate a hypothesis for this later and discuss the problem of
possible optimization of field applications.
First, it must be underlined that the conditions for all these effects are
extremely heterogeneous with regard to field strength and frequency (Fig. 1).
Besides this divergence of the frequency scale, ranging from extremely low fre-
quencies up to the GHz region, the use of pulsed or modulated fields yields an
additional problem (Fig. 2).
The effects in strong fields, like electrical breakdown, electrophoresis, dielec-
trophoresis, electrorotation, electric shocks, etc., are understandable, even if the
real molecular mechanisms have not yet been fully clarified. In contrast to this, the
phenomena of weaker fields, even if they are experimentally verified, are not at all
257
Fig. 1. Schematic illustration of the variety of magnetic, electrical and electromagnetic influences on
biological systems.
clear from the biophysical point of view. Mostly, they even seem to contradict the
basic principles of statistical thermodynamics. A theoretical explanation for these
phenomena, however, is necessary in order to avoid harmful influences, on the one
hand, and to optimize methods of electrotherapy, on the other.
Fig. 2. Various kinds of pulsed and modulated fields.
258
ELECTRO-
DYNAMICS
(Haxrol, mY.LI"nd
PHENOMENOLOG.
THERMODYNAMICS
wornst-Pla"ck c""allo")
WAVE
MECHANICS
~Schrddlwier eLl"al,o",
Fig. 3. Schematic illustration of the hierarchy of biological structure levels from the morphological and
from the electrical point of view.
In discussing the mechanisms of the observed phenomena, the following three
questions have to be answered:
(1) How does the applied field enter the body?
(2) How does the introduced field interact with the biological system, with
molecules and cells?
(3) What are the biological consequences of the primary effects produced?
The first problem is a purely physical one. It can be solved using the Maxwell
equations, knowing the impedance of the body and the corresponding tissue. The
second question leads to a true biophysical problem. In answering this question,
one must accept the electrical structure of the biological system in vivo (Fig. 3). It
must be underlined that it indicates the same hierarchical structure which is
already well known for conventional morphology. The levels defined from the
structural point of view correspond to the physical laws of various theoretical
approaches. The first problem mentioned above relates to the organismic level.
The second problem must be solved on the basis of the molecular level, mostly as a
consequence of the Boltzmann equation.
(II) THE ELECTRICAL PROPERTIES OF THE MEMBRANE IN VIEW OF POSSIBLE MECHA-
NISMS .OF FIELD INTERACTIONS
The biological membrane is a diffusion barrier for ions and an interface, i.e. a
matrix for functional proteins. The first of these properties means, electrically, a
259
layer of extremely decreased electrical conductivity (in relation to the surrounding
plasma) and a lowered dielectric constant. As a result, the membrane behaves as a
capacitor with a relative capacity of 1 I.LF cm -2. Additionally, the specific transport
systems for ions through the membrane are responsible for its non-linear conduc-
tivity. In some respects, the membrane even indicates rectifying properties.
The electrical field E in the membrane is a gradient of electrical potential Wx,
y, z), where x is the direction perpendicular to the membrane surface and y, z
span the plane parallel to it. The function q(x) determines the transmembrane
potential A* over the membrane thickness Ax. This is generated by the electro-
chemical gradient, chiefly of Na+ and K+, and usually amounts to lo-100 mV. It
leads to an internal field strength of theorder of 10 V m-l. This field will be
modified additionally by the double layers on both surfaces of the membrane
[19,89]. The dynamics of this field, especially the possibility of its fast depolariza-
tion, are important not only for nerve and muscle cells, but also for a large number
of other biological functions in other cells [20,21]. Externally applied electrostatic
fields or low-frequency electromagnetic fields will superimpose this membrane
field.
Before discussing the possibilities of modifying this field, one must underline a
general aspect which is trivial for electrochemists, but inconvenient for electronic
engineers and partly for physicists: in contrast to electronic conditions, an electric
field is possible in electrochemical systems, indicating ionic conductance but not
necessarily requiring an ionic current. Actually, the force driving an ionic current is
determined not simply by the electric field, but also by the gradient of the
electrochemical potential, containing an electrical as well as a concentration
gradient. An electrical double layer, for example, is completely in equilibrium,
even forming a strong electric field. The same happens for a number of ions,
distributed between cells and the external medium by a Donnan equilibrium. If,
however, an external field is super-imposed on such a system, an ionic current will
be induced, even if this field is much smaller than the one already existing, because
this additional field disturbs the equilibrium state. One must always differentiate
between field effects and current effects induced by external fields. This is
especially important for the case of time-varying magnetic fields.
The relation between an externally applied electrostatic field E and the
resulting modification of the transmembrane potential (A*) in a spherical cell of
radius r can be calculated to a good approximation by the following relation
(where (Y is the angle between the vectors of the membrane field and those of the
applied field):
AP = 1 SrE cos a
In order to influence the already existing transmembrane potential significantly,
strong external fields must be applied. To avoid a significant temperature increase,
this can only be done by using single short pulses of the order of magnitude of ,us
[22-241.
The field Wy, z> in the plane parallel to the membrane surface depends on the
mosaic of proteins and lipids in the membrane. The membrane mosaic of electro-
260
genie pumps and leaks additionally generates non-equilibrium fields and ionic
currents [25-271.
As clearly shown in electrorotation experiments [28-301 at frequencies Y > 1
MHz, the membrane is short-circuited capacitively. This corresponds to the so-
called /3- and y-dispersion regions of the impedance curves [31]. High-frequency
fields (HF and higher), therefore, will not contribute to modifications of the
membrane potential. On the other hand, in contrast to static and low-frequency
electromagnetic fields, they can penetrate the membrane easily and even influence
intracellular molecules. (In this respect, there is no difference whether these HF
fields are modulated by low frequencies or not.)
This situation means that neither the membrane nor the transmembrane poten-
tial can be neglected in high-frequency field interactions. In any case, the mem-
brane acts as a matrix for the orientation of proteins. The existing in-vivo
transmembrane potential may orientate dipolar parts of the molecules in the
membrane electrostatically. This is important if cooperative effects of proteins
which strongly depend on their mutual orientation are to be considered.
(III) CURRENT CONCEPTS OF POSSIBLE PRIMARY BIOPHYSICAL MECHANISMS OF
INTERACTION
In this section, various concepts will be demonstrated which explain the primary
step of absorption of electromagnetic fields by cellular structures. In fact, none of
these concepts has been verified. With regard to the situation demonstrated in Fig.
1, it seems clear that no single mechanism can be expected to work in the entire
spectrum of frequencies. Schwan and Piersol [32] attributed the effects of electro-
magnetic fields on biological material in general to three categories: thermal,
specific thermal and non-thermal. Thermal effects are not the subject of this paper.
Specific thermal, according to Schwan and Piersol [321, is a sort of structural
heating or the generation of internal temperature gradients. Considering the paper
by Schafer and Schwan [33], however, they came to the conclusion that the
selective temperature rise which a particle may experience by developing internal
heating due to absorption of electrical energy is inversely proportional to the
square of the particle size. Even under favorable conditions for selective heating in
particles of microscopic size and colloidal dimensions, the temperature rise is less
than l/lOOOC (See also refs. 33-35.) Although this decision seems to prohibit
the occurrence of this effect in real biological systems, it cannot be completely
ruled out that it could occur under special conditions [36]. In 1943, Schafer and
Schwan were only able to calculate a stationary solution of the corresponding
differential equations. It cannot be ruled out that an effect occurs under specific
non-stationary conditions, taking into account the specific parameters for heat
conductivity of biological membranes. In a number of papers, the possibility is
discussed that a living cell could possibly generate a stationary temperature pattern
in vivo by biochemical reactions. Even if the transmembranal temperature differ-
ences were only about 0.01 K, this could result in significant functional conse-
261
quences [37,38]. If this were true, small perturbations of this pattern would possibly
lead to significant effects.
In investigating non-thermic effects of electromagnetic fields on cells, one must
take into account the electrical and electrochemical structure as demonstrated in
Fig. 3. In this respect, the membrane, as an electrically heterogeneous structure in
relation to the surrounding plasma, is of special interest. At present, models are
being discussed based on the following general phenomena:
(a) influences on processes of phase transitions of membrane lipid domains
[8,39-411;
(b) direct influence of the functional properties of membrane proteins, espe-
cially on transport processes and enzymatic activities [42-591;
(c) influence on the lateral organization of the membrane as well as inductions
of lateral ionic currents [27,50,60-631; and
(d) influence on surface charges, local concentrations and properties of electri-
cal double layers on the membrane-plasma interfaces [40,53,64,65].
All of these hypotheses have to tackle two problems:
(1) How can the artificially applied field overcome the strong fields existing in
vivo?
(2) How can the weak energies introduced by the external fields compete with
the thermal noise?
The above-mentioned theories usually overcome these two problems by three
types of phenomena: by cooperativity, by resonance effects and by triggering the
transition between multistationary states.
At frequencies v < 1 MHz, not only can the transmembrane field E(x) be
modified, but possibly also the lateral field component, i.e. the electric field E(y,
z) in the plane of the membrane. This field is usually much weaker than the
transmembrane field E(x), but even the fields applied artificially are smaller
because of the high conductivity [20]. An electrophoretic movement of membrane
constituents was obtained only by the long-lasting actions of dc fields
[27,50,60,62,63].
We have already mentioned the possibility that even externally applied weak
fields are able to shift the equilibrium distributions of ions slightly. This is the basis
of Blanks surface compartment model (SCM). It is postulated that small
deviations of the local concentrations near membrane-bound enzymes may trigger
their function.
A significant increase in the electrochemical potential of ions which are pumped
by metabolic energy (Na+,
K+ Ca*+, for example) by application of weak electric
fields in a direct way is not poseible. This would require energies which are so large
that they would lead to a temperature increase. On the other hand, externally
applied fields in resonance with the pumping processes of these ions can possibly
shift this energy level successively over a longer time. In contrast to Blanks SCM,
the transport proteins could be directly affected by the field, and the shift of the
ion concentrations is a subsequent secondary effect. In addition, it seems possible
262
that in this way enzymes can capture free energy from oscillating electric fields not
only for transport processes, but also for other reactions [49,56-59,661.
Processes of passive ion transport, including permeabilities, can be stimulated
or even triggered by fields, just modifying slightly the dipolar structure of the
functional proteins. The general optimization of biological structures, however,
seems to exclude a direct influence of weak external fields on excitation. Other-
wise, the processing of biological information in the body would become unstable
even in the course of daily life.
For the influence of a weak electromagnetic field on functional proteins in
general, two processes are discussed: (i) the resonance with periodic oscillations of
dipolar protein structures or periodically oscillating charges [43,49,56-59,661 and
(ii) the coherent excitation of these molecules. This hypothesis of coherent excita-
tion means a quantum-biochemical effect occurring in molecules which are strongly
oriented in the electrostatic field of the membrane and are deviated far from
equilibrium by metabolic processes 144,451. (The cyclotron-resonance hypotheses of
Liboff [46,47] do not seem to be very realistic.) It must be stressed that the dipole
oscillations occur between lo3 and lo6 Hz, whereas the process of coherent
excitation occurs at frequencies close to lOlo Hz.
(IV) FREQUENCY BANDS USED FOR EMF TREATMENTS
As already mentioned in the Introduction, the application of magnetic, electric
and electromagnetic fields (EMF) for medical treatment is as old as the investiga-
tions of these fields and their generation by technical devices. Recently, these
fields have been applied not only for cell manipulations in biotechnology [22-241,
but more and more for medical treatments. These applications range from bone
fracture healing to cancer treatments via a long list of various diseases [67-721. A
third area of interest in the possible hazards .of electric fields produced by
technically used frequencies of 50-60 Hz [l].
Research on the molecular and cellular mechanisms of field effects therefore
concentrates more or less on selective frequency bands. (To illustrate this, some
examples are given in Table 1.) This is the ELF and SLF region between 16 and
60 Hz; the ISDN regions for mobile communication networks of the HF, VHF and
UHF bands (13-40 MHz, 120-150 MHz, 420-440 MHz); and two regions in the
SHF and EHF bands (2.45 GHz, 42 GHz) (nomenclature of the bands according to
ref. 86).
This is quite understandable from a technical point of view. Considering,
however, the possible mechanisms of biophysical field interactions, as discussed in
Section (III), these frequencies are in no way the best possible. Blank [64]
calculated for his surface compartment model (SCM) resonance effects for the
influence of ionic fluxes by an imposed sinusoidal voltage between lo2 and lo3 Hz.
Markin et al. 149,661, Tsong and Astumian 156-581 and Westerhoff et al. [59]
predicted resonance frequencies for transport proteins between lo3 and lo6 Hz.
One really could find an influence of the Na+ transport at 1 kHz and an influence
263
of the Rb+ transport at 1 MHz [48,56]. Donath et al. [43] calculated a transfer rate
of 50000 Cl- ions transported per second by a band-3 protein of human erythro-
cytes. Even for probably occurring phase transitions, low frequencies should be
preferable. Only the Frijhlich theory of coherent excitations predicts sensitive
frequencies of the order of 10 Hz.
In contrast to Frohlichs coherent excitation phenomenon, which is a process
predictable by wave mechanics (see Fig. 31, all the other phenomena are in the
region of molecular fluctuations or as Blanks SCM hypothesis in the kinetics of
TABLE 1
Frequency bands used for investigations of weak electric field interactions and biological systems
Frequency First
log WI
author
Ref.
Field
intensity
Effect
o-
l-
* 16 Hz
.- 45-60 Hz
2-
3--tlkHz
4-
5-
6--clMHz
7-
+ 27,12 MHz
8-
+ 140-150
MHz
+ 4.50 MHz
9-
+ 2.45 GHz
+ 2.8 GHz
Gandhi
lo-
+ 42 GHz
McLeod 73
20.9 mT
Mobility of diatoms
+ Rodemann 74
6mT
Fibroblasts, differentiation
+ Wei 75
0.2-2 mT
HL-60 cells, transcriptions
Brayman
76
200 V/m Zeu mais roots, growth inhib.
Seegal
77
lo-30 fiT Primates, neurochem. effects
+ Tsong 56
20 V/cm Erythrocytes, Rb transport
+ Tsong 56
20 V/cm Erythrocytes, Na transport
+- Accini 78
Rabbits, Kidney necroses
* Bawin
Wittekindt
+ Byus
Liu
Lyle
Baker-
Kubiczek
+ Grundler 85
IO-25 mW Saccharomyces, growth
4,79,80
l-2 mW/
2
81
14
48
82
3;:
all
about
1 mW/cm2
83
5-15 yw/
84
10CmmW,
cm2
Modulation lo-20 Hz
Chicken brain, Ca flux
Mycotypha, growth
Lymphocytes, protein kinase
Synaptosomes, Ca flux
T-lymphocytes, cytotoxicity
Mouse fibroblasts, transform.
Brain synaptosomes,
ionsit metabolism
264
TABLE 2
Characteristics of the action of LF-modulated (or LF-pulsed) HF fields (PEMF)
Steps of action Consequences
Penetration into the Generation of a local field
biological system
Primary biophysical Modification of a molecule,
reaction
modification of a local
concentration modification
of the in-vivo electrical
potential, phase transition,
etc.
Secondary biological Modification of transport
Possible mechanisms of
amplification
Focusing of the field
in non-homogeneous
dielectrics
Cooperative phenomena
triggering of multistationary
states, spatial orientation
of molecules
Biochemical cascades LF modulation
effects
processes, modification
of reaction kinetics,
excitation of cells, etc.
physiological triggers,
neuronal triggers
Effective
compound
of the field
HF carrier
frequency
HF carrier
frequency
electrical double layers. All these processes proceed with much larger time
constants. To optimize the field effects in therapeutic applications, therefore, from
a biophysical point of view, a shift into the ULF, VLF, LF and MF frequency
bands would be recommended.
Many investigators and therapists use fields of 150 or 450 MHz, modulated or
pulsed with frequencies of lo-20 Hz [2,4,8,12,14,79-821. This treatment is usually
motivated by the idea that a high frequency helps the field to penetrate into the
biological material, where the low-frequency modulation is the compound which in
fact acts. This idea seems to be supported by the findings that apparently
frequency windows exist for the modulation frequency, but not for the carrier
frequency. Strictly speaking, however, only the low-frequency modulation was
modified in most experiments.
In Table 2, the steps of realization of the field effects, already mentioned in
Section (I), are explained for the case of low-frequency modulated fields. This
indicates that only the carrier frequency of the field is responsible for the primary
biophysical reaction. Energy can only be absorbed and an effect can only be
established in this frequency if the frequency is in resonance with atomic or
molecular processes. The low-frequency modulation of the field just acts as a
periodic (or pulsed) increase or decrease of the level of effects which are produced
by the carrier frequency.
(V) THE SECONDARY BIOLOGICAL EFFECTS
As already mentioned, biological effects of electromagnetic fields, as well as
many other physical influences on biological systems too, are possible only by
26.5
means of amplification processes. As indicated in Table 2, such amplifications are
possible in each of the three steps of action. It seems clear that in no case can only
a single mechanism be responsible for the final effect. So, the field, for example,
could influence a transport protein in the membrane, leading to modification of
the flwr and subsequently to changes of the cellular ionic concentrations. As we
know, calcium is a secondary messenger and, in this respect, a sensible trigger for a
number of biochemical cascades, regulating, for example, protein synthesis. A
number of other examples are imaginable.
In the same way as in the primary physical processes, resonance effects would
be important for the secondary biological effects, too. This requires a correspon-
dence of field frequencies with biological time constants.
As we know, the biological systems indicate a strong time hierarchy [87,88],
which is essential for the stabilization of these complex non-linear systems. A large
class of biochemical processes indicates characteristic time constants of the order
of 0.1-0.01 s. Additionally, a number of other processes in living organisms (ciliary
movement, membrane vibrations, nerve pulses, etc.> show similar constants. This
INDIRECT INFLUENCE ON
EIESSSENGER TRANSPORT
BY PEUF
DIRECT INFL UENCS ON
MESSENGER TRANSPORT
BY LF+FX.LD
BIOLOGICAL EFFECTS
Fig. 4. The indirect way by PEMFs and the direct way by low-frequency fields of exciting biological
mechanisms.
266
leads to the conclusion that such effects could get in resonance with the applied
field, or with its periodic pulse (in the case of PEMF).
As illustrated in Fig. 4 in principle two ways are possible for the same effect: an
indirect influence of the messenger concentration by PEMFs, via the influence of
functional proteins, or a direct influence on these concentrations by low-frequency
fields. This would explain the similarity of the effects which is observed in both
sorts of experiments,
(VI) CONCLUSION
As a result, one can conclude that the number of reliably indicated effects of
electromagnetic fields on biological systems is now so convincing that there can be
no doubt as to whether even fields not exceeding the energy of thermic noise can
become effective. We are, however, still far from having clear knowledge of the
biophysical mechanisms governing these effects. Nevertheless, model experiments
with a higher field strength allow us to formulate some hypotheses. These hypothe-
ses should be checked by practical field applications, even in medical treatment.
The development of the methods of medical treatment with electromagnetic fields,
however, was guided by technical conditions, not by these proposed mechanisms.
The frequencies used in these treatments, therefore, do not correlate with those
promising the optimal effect (103-lo7 Hz).
ACKNOWLEDGEMENT
The author is grateful to MEDI-LINE Ltd. for their technical help in preparing
this paper by the generous gift of a computer as a word processing system.
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