ELF/LF - Electromagnetic Fields
Potentialities of ELF-EMF in regenerative medicine, cancer treatment and experimental issues
As in other electromagnetic field (EMF) frequency ranges, the medical or/and experimental application of extremely low frequency (ELF) electromagnetic fields are used to cause a great variety of outcomes; cellular differentiation, brain activity modulation, experimental cancer treatment, and others. ...
As all exposures revised in this site, all the intensities applied in all the experiments mentioned below are of low intensity, 1mT or less (except for very few exceptions), and being of low frequency the cause of any of the effects has nothing to do with heating, these radiations also are non-ionizing.
One of the most interesting outcomes for a future medical application, as regenerative therapy, is the promotion of cellular differentiation, in this ambit numerous positive results have been reached, that show that ELF-EMFs can promote osteogenesis, angiogenesis, or neurogenesis using cardiac stem cells, neural stem cells, and bone narrow mesenchymal cells among others.
In  is proposed that the differentiation of bone marrow mesenchymal stem cells (BMSCs) into neuronal phenotype is reached via reactive oxygen production that can cause the epidermal growth factor receptor (EGFR) activation via phosphorylation and clustering, which may, in turn, lead to the activation of the PI3K/Akt signaling pathway and an increase of the CREB phosphorylation. In  otherwise they found that early growth response protein 1 (Egr1) is one of the key transcription factors in ELF-EMF-induced neuronal differentiation.
One of the possible medical application of the neuronal differentiation promotion is to recover brain after ischemic damage, where some experiments have auspicious results. In an experiment  with neural progenitor cells (NPC data show that ELF-EMF promotes neurogenesis of ischemic NPCs and suggest that this effect may occur through the Akt pathway. On the other hand in an experimental thesis by Gao  in rat´s model with cerebral ischemia, it is showed that the provoked proliferation and differentiation of neural stem cells probably occur by the also detected upregulation of Hes1, Hes5 and Notch1.
Neurogenesis of hippocampal neural stem cells with upregulation of Hes1 has also found in , along with upregulation of Neurogenin 1 and NeuroD1 that are strongly associated with the pan-neuronal gene expression and the neuronal fate determination.
Also, in an experimental setup with embryonic neural stem cells  increased expression of NeuroD and Neurogenin 1 proneural genes has been found, and also that
" the expression of transient receptor potential canonical 1 (TRPC1) was significantly up-regulated accompanied by increased the peak amplitude of intracellular calcium level."
Some genes are found recursively affected along different experiments and targets, some others are detected to be affected in a novel way, in an experiment with human embryonic kidney cells they are identified 24 genes whose expression changed after ELF-EMF exposure , and their results points toward an important role of e histone lysine methyltransferase (Mll2), that is an enzyme that in humans is encoded by the KMT2D gene.
More interestingly, in this last study  they found that
" Remarkably, an EMF-free system that eliminates Earth's naturally occurring magnetic field abrogates these epigenetic changes, resulting in a failure to undergo reprogramming."
They point out that results support a model in which the environmental magnetic field promotes chromatin reorganization through the activation of Mll2, specifically, during the dynamic epigenetic changes initiated by expression of the 4 Yamanaka reprogramming factors. Anyway, it is interesting to note here that some special properties of water, as cluster formation, requires a geomagnetic natural-like EMF exposure (in particular its natural Schumann resonance frequency at 7.8Hz) to form , or as is argued in some experimental procedures  to develop its information storing properties, see sections [10,11].
Other use for regenerative medicine is the osteogenic differentiation to regenerate bone tissue. Findings in  suggests that the effects of electromagnetic fields on rat BMSCs’ proliferation differentiation and mineralization are time duration dependent and that the MEK/ERK signalling pathway plays important role. Meanwhile in  it is showed that although when combined the EMF exposure with osteogenic differentiation medium the stimulation is more effective, electromagnetic field stimulation alone also motivated the expression of osteogenic genes.
It is an interesting review on dependence of Stem cell fate on electromagnetic fields  where the electromagnetic (EM) nature of the cells is also discussed.
Last but not least, in an experimental procedure that uses very low intensity electromagnetic fields tuned to the Ca2+ ion cyclotron resonance (ICR) at 7 Hz  (see this text below for a section on ICR) it is show that exposure also induced neuronal differentiation.
There is a very interesting line of investigation by Persinger and co-workers [16,17,18,19] where they are using physiologically-patterned ELF-EMF of very low intensity to treat cancer, inhibiting cancer cell grow and dissolving them, although with some difficulties that are trying to resolve as expressed in :
" Exposure to a particular pattern of weak (~3 to 5 μT) magnetic fields produced by computer-generated point durations within three-dimensions completely dissolved malignant cancer cells but not healthy cells. Biomolecular analyses and confocal microscopy indicated excessive expansion followed by contraction contributed to the “explosion” of the cell. However, after months of replicable effects, the phenomenon slowly ceased."
A great advantage is that unlike chemical therapies and ionizing radiation, the ELF-EMF diminish the growth of only malignant cells but not normal cells. In their latest investigation  they confirm that the effects of electromagnetic fields on melanoma cells are dependent on their spatial and temporal character, with some configurations that provoke inhibition of cell proliferation and others with no effects, and all this using same intensities and frequencies (but differently activated over time).
The capacities of applied ELF-EMF to affect cancer specifically is very probably related to special endogenous electromagnetic fields of cancer cells, to which is a complete section  is dedicated here, where numerous facts and theories are presented. In  for example is proposed that disrupted respiration of cancer cells generate incoherent EM that in turn promote DNA strand break, and in  is proposed to use the enhanced electromagnetism from cancer’s centrosome clusters to attract therapeutic nanoparticles, in  is expressed that
" Disturbances in oxidative metabolism and coherence are a central issue in cancer development. Oxidative metabolism may be impaired by decreased pyruvate transfer to the mitochondrial matrix, either by parasitic consumption and/or mitochondrial dysfunction. This can in turn lead to disturbance in water molecules’ ordering, diminished power, and coherence of the electromagnetic field. In tumours with the Warburg (reverse Warburg) effect, mitochondrial dysfunction affects cancer cells (fibroblasts associated with cancer cells), and the electromagnetic field generated by microtubules in cancer cells has low power (high power due to transport of energy-rich metabolites from fibroblasts), disturbed coherence, and a shifted frequency spectrum according to changed power."
Some Experimental Findings
In  it has found a similar down regulatory effect of EMF on cyclic adenosine monophosphate (cAMP) as would be seen in morphine treatment so ELF-EMF of very low intensities have potential to be used also as complementary or alternative treatment to morphine, reducing both pain and enhance patient quality.
In an experimental thesis  were physiologically patterned low frequency electromagnetic fields are used, it is show that exposure provoke the aggregation of bacteria in solutions, with changes in the structures of water that surround them, this effect is also seen around proteins were water is irradiated with infrared light  and the effect is related to the existence of Exclusion Zone waters, see section .
In  an ELF-EMF of 9 Hz was shown to exert the greatest effect on aqueous solutions of the hepatitis virus DNA amplicons, with changes in their hydration sell that suggest, again, that the aqueous milieu plays a key role as a primary target for weak effects. In this sense is very interesting the possible electromagnetic mediated DNA-Water interaction that is supported in this robust theoretical work , you can see this  section for more.
In  it’s
" believed that if we are in an environment with bio-inspired electromagnetic signals generated by mimicking natural earth and body cells frequencies (ELF's), then our cells will be more energetic and active, providing greater health … This innovative bio-inspired system has been applied for the health enhancement of humans, equines and pets etc. … It has been proven that this bio-inspired system can be effectively applied to many areas such as (1) human health enhancement and illness treatment, (2) pet health enhancement, (3) equine health treatment and (4) reduction or elimination of 'jet lag'."
Returning to the detected outcomes, in  it has found that exposure to a 50-Hz magnetic field induced mitochondrial permeability transition (that can lead to mitochondrial swelling and cell death through apoptosis or necrosis depending on the particular biological setting), presumably through the ROS/GSK-3β signaling pathway. Evidences in  results conﬁrm that the ELF-EMF affects not only the ROS product but also the enzymatic activity with the modulation of catalase, cytochrome P450 and inducible nitric oxid protein expression.
In , after exposed human embryonic kidney cells grown in culture increased both arachidonic acid (AA) and leukotriene E4 (LTE4) levels in HEK293 cells, is concluded that 50Hz ELF-EMF inhibits T-type calcium channels (widely expressed and that play key roles in various physiological functions like neuronal burst firing, cardiac pacemaking or secretion of hormones) through AA/LTE4 signaling pathway. The effect on those channels is also found in  where the promoted Ca2+ influx could be blocked by inhibitors of voltage-gated T-type Ca2+ channels. The results of  in cultured entorhinal cortex neurons, on the contrary, has found that exposure have to influences the intracellular calcium dynamics via a calcium channel-independent mechanism.
Various studies studies have been focused in neuronal or cerebellar cells.
In  Increased Na+ Currents in Rat Cerebellar Granule Cells as a result of cAMP/PKA Pathway modulation was detected after 50 Hz 1mT exposure, in  is show that ELF-MF and ischemia separately increase oxidative stress on brains, but when applied together they have capability to decrease values it.
More generally in the brain function, relative low intensity (maximum 0.3 mT) ELF-EMFs, in the frequency range used by the brain, have show to change brain´s intrinsic EEG, with for example, decreased alpha band of frontal and central areas in closed-eyes state . In  the results have led the authors to conclude that exposure to ELF-EMF facilitates vesicle endocytosis and synaptic plasticity in a calcium-dependent manner by increasing calcium channel expression at the nerve terminal.
Exposure to 5Hz 0.1mT  increased the numbers of rearing, sniffing, and locomotor activity of Wistar rats, with alterations in plasma stress hormones and glucose levels bot in 1Hz and 5Hz exposure frequencies used.
In a somewhat extended line of research, very low intensity ELF-EMF in the order of the geomagnetic field intensity or less are used at frequencies that correspond to in cyclotron frequencies of specific molecules, for example in case of ca2+ :
" Ca2+ ions within the specific centers of Ca2+binding proteins are the primary target of the magnetic field. Bound Ca2+ is regarded as an isotropic charged oscillator, and the MF causes precession of the axis of the Ca2+ oscillator vibration. Significant changes in the character of precession, as well as in the time average value of the degree of polarization of the oscillations of Ca2+ in a plane perpendicular to MF direction, can be induced if an alternating low frequency MF with specific resonance parameters is applied … A low frequency MF with Ca2+ ion resonance parameters (Ca2+MF) causes a change in the Ca2+ binding constant of the protein, that is, a change in the duration of Ca2+ association with the Ca2+ binding center of the molecule, by approximately one order of magnitude."
In the mentioned experimental paper using the calculated frequency of 18.5 HZ (third harmonic of the main or “cyclotron” frequency) a considerable effect on the level of activity of Ca2+ dependent proteinases is achieved, which is further confirmed in . Use of the Ca2+ main cyclotron frequency at 7 Hz is decided in  where an important change in shape and morphology with the outgrowth of neuritic-like structures together with a lower proliferation rate and metabolic activity is achieved for human pluripotent embryonal carcinoma cells.
In the review , in the first table, is visible the calculated ion cyclotron frequencies, those are for 0.001 mT “environmental” static MF intensity, for other intensities simply it must be multiply, for example the ICR for Ca2+ at 0.01 mT will be 7.6 Hz. In table 2 are listed various experiments with different outcomes where Ca2+ ICR was used with intensities ranging from 0.010 mT to 0.060 mT (as comparison, earth geomagnetic fields range proximately from 0.025 mT to 0.065 mT). As mentioned, It must be said that ICR experiments also involve a static magnetic field with a strength that is in the same order of magnitude, to emulate in a controlled way a geomagnetic static MF.
In another experiment where is used the hydronium (H3O+) ion cyclotron frequency  it is found that:
" under ICR stimulation water undergoes a transition to a form that is hydroxonium-like, with the subsequent emission of a transient 48.5 Hz magnetic signal, in the absence of any other measurable field. Our results indicate that hydronium resonance stimulation alters the structure of water, enhancing the concentration of EZ-water. These results are not only consistent with Del Giudice’s model of electromagnetically coherent domains, but they can also be interpreted to show that these domains exist in quantized spin states."
For more on Exclusion Zone (EZ) water you can visit the section .
Further confirmation of this effects come in  where weak magnetic field (50 nT) hydronium ICE at the field combination of 7.84 Hz,7.5 µT, markedly changes water structure, as evidenced by the finding of an altered index of refraction exactly at this combined field.
Ion cyclotron frequencies of higher harmonics are used in a recent Nature publication  where ICR related frequency components significantly increased bone formation activity and it slightly increased bone resorption activity indirectly on mice. The frequencies used in this experiment are based on the following premises:
" According to ICR model, the resonant frequencies of many biologically important ions, such as Na + , K + and Ca 2+ , are intermittent frequency points and fall within 1–100 Hz 23, 25 . Aparting from the fundamental frequency of resonant frequencies, when the frequency of EMF is equal to higher harmonics of the cyclotron frequencies, the biological resonant effectiveness might also be attained 26, 27 . Moreover, these higher harmonics of the cyclotron frequencies of the biologically relevant ions is blow 3,000 Hz 24 . In addition, high frequency EMF is also capable of inducing osteogenic differentiation of osteoprogenitor cells 28 . Therefore, we designed four kinds of EMF with different frequency spectrum bands (1–100 Hz, 100–3,000 Hz, 3,000–50,000 Hz and 1–50,000 Hz), among which 1–100 Hz and 100–3,000 Hz are designated as ICR frequency bands."
Ion cyclotron resonance is also was used to suppress atrial fibrillation  in an experiment that use very low intensity fields (4 orders of magnitude less than geomagnetic fields) applied over different levels of the cardiac autonomic nervous system of dogs, and the authors believe that the effect is due to some form of subtle resonance related to neurotransmitters, they calculated ICR for vasostatin-1 a critical element in suppressing the activity of the intrinsic cardiac autonomic nervous system.
A review on ICR can be found in .
Very related and complementary are the studies that pay more attention to the possible pernicious effects of the indiscriminate artificial ELF-EMF generated in this technological and industrial age and that are widely employed in electrical appliances and different equipment such as television sets, mobile phones, computers and microwaves. There is a section dedicated to that , where it can be found, as example, a study that speak about radiation effect on secondary structure of proteins  among others.
1. Park, Jeong-Eun, et al. "Electromagnetic fields induce neural differentiation of human bone marrow derived mesenchymal stem cells via ROS mediated EGFR activation." Neurochemistry international 62.4 (2013): 418-424.
3. Cheng, Yannan, et al. "Extremely low-frequency electromagnetic fields enhance the proliferation and differentiation of neural progenitor cells cultured from ischemic brains." NeuroReport 26.15 (2015): 896-902.
4. Gao, Qiang. “The effect of extremely low frequency electromagnetic fields on the proliferation and differentiation of endogenous neural stem cells in rats with cerebral ischemia.” The Hong Kong Polytechnic University (2016).
6. Ma, Qinlong, et al. "Extremely low-frequency electromagnetic fields promote in vitro neuronal differentiation and neurite outgrowth of embryonic neural stem cells via up-regulating TRPC1." PloS one 11.3 (2016): e0150923.
8. Konovalov, D. A., et al. "Effect of weak electromagnetic fields on self-organization of highly diluted solutions of alkylated p-sulfonatocalix  arene." Doklady Physical Chemistry. Vol. 463. No. 1. Pleiades Publishing, 2015.
12. Song, Ming-Yu, et al. "The time-dependent manner of sinusoidal electromagnetic fields on rat bone marrow mesenchymal stem cells proliferation, differentiation, and mineralization." Cell biochemistry and biophysics 69.1 (2014): 47-54.
15. Ledda, Mario, et al. "Non Ionising Radiation as a Non Chemical Strategy in Regenerative Medicine: Ca 2+-ICR “In Vitro” Effect on Neuronal Differentiation and Tumorigenicity Modulation in NT2 Cells." PloS one 8.4 (2013): e61535.
17. Karbowski, Lukasz M., et al. "Seeking the source of transience for a unique magnetic field pattern that completely dissolves cancer cells in vitro." Journal of Biomedical Science and Engineering 8.8 (2015): 531.
18. Murugan, N. J., L. M. Karbowski, and M. A. Persinger. "Elimination of Frequency Modulated Magnetic Field Suppression of Melanoma Cell Proliferation by Simultaneous Exposure to a Pattern Associated With Memory in Mammals." Arch Can Res 4 (2016): 2.
24. Ross, Christina L., Thaleia Teli, and Benjamin S. Harrison. "Effect of electromagnetic field on cyclic adenosine monophosphate (cAMP) in a human mu-opioid receptor cell model." Electromagnetic biology and medicine 35.3 (2016): 206-213.
31. Feng, Baihuan, et al. "Exposure to a 50-Hz magnetic field induced mitochondrial permeability transition through the ROS/GSK-3β signaling pathway." International journal of radiation biology 92.3 (2016): 148-155.
32. Patruno, Antonia, et al. "Effects of extremely low frequency electromagnetic field (ELF-EMF) on catalase, cytochrome P450 and nitric oxide synthase in erythro-leukemic cells." Life sciences 121 (2015): 117-123.
35. He, Yan-Lin, et al. "Exposure to Extremely Low-Frequency Electromagnetic Fields Modulates Na+ Currents in Rat Cerebellar Granule Cells through Increase of AA/PGE 2 and EP Receptor-Mediated cAMP/PKA Pathway." PloS one 8.1 (2013): e54376.
36. Balind, Snežana Rauš, et al. "Extremely low frequency magnetic field (50 Hz, 0.5 mT) reduces oxidative stress in the brain of gerbils submitted to global cerebral ischemia." PloS one 9.2 (2014): e88921.
38. Sun, Zhi-cheng, et al. "Extremely low frequency electromagnetic fields facilitate vesicle endocytosis by increasing presynaptic calcium channel expression at a central synapse." Scientific reports 6 (2016).
40. Kantserova, N. P., et al. "Modulation of Ca2+ dependent protease activity in fish and invertebrates by weak low-frequency magnetic fields." Russian Journal of Bioorganic Chemistry 39.4 (2013): 373-377.
Very related sections:
↑ text updated: 10/05/2017
↓ tables updated: 13/12/2017