Our work is currently supported by the Czech Science Foundation, Project No. 16-12757S, Ferroelectric properties of biological structures.
Jiri Pokorny, Jan Pokorny
Life exists in a great variety of forms. The simplest living systems are very likely viruses. Mammals may be regarded as the most advanced living systems. The great family of living creatures differs in many aspects especially in the complexity and hierarchical organization. Neural activity connected with the highest form of life is one of the most striking features. Research of biochemistry and molecular biology has disclosed a great amount of fundamental data about biological systems. Nevertheless, science has to formulate the general law governing the life — the coherent electrodynamic state.
Coherent electrodynamic state excited and maintained by energy supply far from thermodynamics equilibrium is a nature of life. Fröhlich (1968a, b; 1969; 1973; 1980) formulated a hypothesis that the coherent electrodynamic state is formed by coherent electric polar vibrations. In eukaryotic cells microtubules form the generating structure (Pokorný et al. 1997; Pokorný and Wu 1998). Pelling et al. (2004; 2005) measured coherent vibrations of yeast cells by atomic force microscope in the acoustic frequency range. Kasas et al. (2015) investigated vibration of different types of cells with a conclusion, that vibrations are a signature of life. Jelínek et al. (2009) found that frequencies of vibrations and electric oscillations coincide. Using dielectrophoretic effect Pohl (1981) experimentally proved that the highest power level of oscillations is in the M phase of the cell cycle. Direct measurement of the electromagnetic field in the frequency range 8—9 MHz of the synchronized yeast cell S. cerevisiae in the M phase disclosed the increased power in the period of mitotic spindle formation, metaphase, and anaphase A and B (Pokorný et al. 2001). Electromagnetic field may mediate interactions between living cells. Interaction forces between red blood cells acting up to a distance of about 1 μm were measured by Rowlands (1988). Sahu et al. (2013a, 2014) measured resonance frequencies of separated microtubules in the bandwidths 100 kHz—20 GHz, far infrared, and UV region.
Typical representative of molecules with a filamentous structure are proteins. Amino acids are joined together by a rigid planar peptide bond. The structure of a protein is not stable and unique. A protein can assume a large amount of different conformational substates which can be described by the energy landscape (Frauenfelder, 2005). Transition between different conformational substates can result in different dynamics and function of the protein. Deformability of macromolecules provides sensitivity to the surrounding medium. Conformational substates can be used as a memory for storing data. Preliminary measurement of microtubules disclosed capability of storing data into microtubules. Sahu et al. (13b) measured about 500 bits with 2 pA resolution and current between 1 nA and 1 pA. But the real memory should be much higher. A tubulin monomer has about N = 7500 atoms and about M = 460 peptide bonds. Assuming that each atom may occupy two different positions the number of states is 2N. If the configurations differ in energy then each of them forms a bit of memory. The total capacity corresponds to about 1030 TB. If each peptide bond link may have about 10 positions due to rotation changes of dihedral angles then the capacity of the memory may be about the same. This represents an elementary rough assessment of possible capacity of a cell memory in a microtubule component.
Electric polarity depends on distribution of charge in the macromolecular structure. The peptide bond is an electric dipole whose inner electric field is oriented from nitrogen to oxygen. Two types of charges were analyzes in amino acids. One type is formed by ionized side chains, the other type by partial atomic charges - each atom has some fraction of a positive or a negative charge, which depends on electronegativity of the atom. The positively charged amino acids side chains are in Lys, Arg, His, and negatively charged in Asp and Glu. The polarity with partial atomic charges is formed in the side chains of Asn, Gln, Ser, Thr, Tyr. The most important protein structure in eukaryotic cells is formed by microtubules built from heterodimers consisting from two monomers called α and β tubulin. Each heterodimer represents an electric dipole originating from 18 calcium ions bound within each β monomer (Satarić et al. 1993; Tuszyński et al. 1995). An equal number of negative charges (electrons) is localized in the neighboring α monomer. After polymerization the main component of the dipole vector is oriented along the axis of microtubule from its — to + end. Hydrolysis of GTP to GDP in the β tubulin changes its conformation and position of the β tubulin is tilted with respect to α tubulin and the main component of the dipole moment reverses orientation. Frequencies of electric resonant oscillations in microtubules were measured in the classical frequency bands 100 kHz—20 GHz, far infrared region around 500—700 cm−1, and UV band around 300 nm by Sahu et al. (13a; 14).
Energy supply to living systems excites and maintains the coherent electrodynamic state far from the thermodynamic equilibrium. Energy may be supplied from water, sunlight, radiation in the far infrared, infrared, visible, and UV bands, by conduction of heat, from energy rich molecules, etc. Life exists at the bottom of the sea around active volcanic sources. In mammalian cells conversion of energy of glucose and fatty acids into energy bonds of ATP and GTP is a dominant process. Glucose is cleaved into two pyruvates with a net gain of two ATP molecules by glycolysis (fermentation). Pyruvates and fatty acids are processed by oxidative metabolism in mitochondria.
Energy is supplied to microtubules by several mechanisms and processes (Pokorný et al. 2013). Energy supplied by hydrolysis of GTP to GDP in the β tubulin after polymerization is a basic process. Energy supply by treadmilling in the M phase is more than one order of magnitude greater than that in the interphase by growth and shrinking of microtubules. Energy is supplied by motor proteins moving along microtubules. Non utilized energy liberated from mitochondria may be also used. Photons released from chemical reactions in the UV and visible part of the wavelength spectrum are a source of energy too. Excess thermal energy which was not utilized for building of coherent domains may also excite vibrations.
Energy supply to microtubules is a crucial point of the whole cell’s metabolic turnover. Lamprecht (1980) disclosed by calorimetric investigations that under optimal conditions a yeast cell of S. cerevisiae obtains power of 10−13 W. Mammalian cell may obtain higher power but on average not exceeding 10−12 W. Microtubule excitation in a mammalian cell is assessed to be of the order of magnitude of 10−13 W.
Water constitutes 70 % of the total mass of a cell and its function is essential for life. The liquid phase of water was generally assumed to be preserved in living cells. But water has extraordinary properties which were not known and are undoubtedly necessary for the living state. The physical analysis of water is based on quantum electrodynamics (Del Giudice et al. 1988; Voeikov 2007; Arani et al. 1995; Del Giudice et al. 2009a, b). Coherent interaction of water molecules with quantized radiation of electromagnetic field results in a macroscopic permanent polarization. Random thermal fluctuations are transformed into coherent dynamic state of interacting electrons in water molecules and formation of coherent domains (CD) which are able to interact mutually. Experimental research performs measurement of the water layers at charged surfaces (Voeikov 2007; Zheng and Pollack 2003; Zheng et al. 2006; Pollack et al. 2006; Chai et al. 2009). Electric field at the charged surfaces provides arrangement of CDs into ordered layer. The layer is called exclusion zone — the solvent particles are excluded from the ordered layer. Strong static electric field of about 600—700 kV/m organizes water and forms a floating water bridge about 1—3 cm long between two glass beakers (Fuchs et al. 2007, 2008; Giuliani et al. 2009).
CD’s with linear dimension about 100 nm are formed at the physiological temperature. Energy with high entropy from the environment is transformed into energy with low entropy. The energy of a molecule in the CD is lower than in the bulk water. CD is formed when superfluous energy is transferred to the outside. CD of water is able to transform the whole amount of collected energy without thermal losses in chemical reactions.
CD is formed when thermal energy is transferred into coherent oscillation of electrons in single molecules between two different configurations, i.e. between a fundamental state (with energy 12.60 eV to release an electron) and a coherent state excited by energy 12.06 eV (and energy 0.54 eV to free an electron). The coherent state displays tendency to yield electrons and the fundamental state (incoherent state) to produce H2O− ions. Ordered water has a gel-like structure, high viscosity, lowered thermal motion, pH and spectroscopic properties different from bulk water, and separation of charge.
Infrared radiation from ordered water is reduced. Measurement was performed by an infrared-camera with the spectral window of 3.8—4.6 μm and at 200 frames/s sampling rate. Temperature noise equivalent 0.015 K was limited by camera noise (Zheng et al. 2006). Averaging of 100—200 frames reduced temperature noise equivalent to 0.001 K which corresponds to noise energy k*T = 1.38*10−26 Ws. In living cells extremely low power could be distinguished from noise.
Water ordering affects cell function by separation of charge, low damping of electric polar vibrations and generated electromagnetic field, low noise (the temperature noise equivalent is less than 1 K), and by release of energy.
The coherent electrodynamic state far from thermodynamic equilibrium is a necessary condition of life and represents a unique property of each living entity. The state is excited and maintained by continuous energy supply. The living systems are different and the basic attributes, i.e. the sources of energy, filamentous and oscillating structures, electric polarity, and water ordering correspond to the life entity.
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Oncogene is mutated as a byproduct of mass somatic mutation of the genome which may be caused by increased probability of random reactions resulting from parasitic energy consumption in the cell. Oncogene mutation results in mitochondrial dysfunction causing disturbed ordering of water. Due to disturbed layer of the ordered water electric polar vibration in cancer cells (the Warburg effect) or in fibroblasts associated with cancer cell (the reverse Warburg effect) are damped. Power of electric oscillations in a cancer cell of the Warburg effect is lowered due to damping and in a cancer cell of the reverse Warburg effect increased due to transport of energy rich metabolites from the associated fibroblasts. Due to nonlinear properties of oscillating structures (microtubules) frequencies of electric oscillations are changed with respect to the tissue frequency and the cells lose interaction with the tissue.
Cancers are initiated by oncogene mutation which may be produced as an event of mass non-localized somatic genome mutation. Tomasetti and Vogelstein claim that the majority of variations in cancer risk are due to “bad luck”, that is to random events. Mechanism controlling storing information into DNA seems to be an important cellular function. The experimental results (Jandová et al., 2001, 2009) indicate a causal mechanism of the genome mutations by lactate dehydrogenase elevating (LDH) virus infection or an infection agent eliciting similar cell-mediated immunity (CMI) response. Measurements of the CMI of T lymphocytes in healthy humans, precancerous, and cancer patients using cancer and LDH virus antigens elicit very similar responses. RNA of the LDH virus is a parasite on the energy of the cell producing lactate from pyruvate which may affect oxidative metabolism. After decrease of pyruvate oxidative metabolism power of coherent polar vibrations and of the cellular electromagnetic field may be reduced. Biochemical reactions depend on high intensity of the electric field (Fried et al. 2014; Hildebrand et al. 2014). For a low intensity of the electric field generated in cells probability of random biochemical reactions is enhanced.
After oncogene mutation abrogation of oncogene-induced senescence leads to induction of pyruvate dehydrogenase kinases PDK1—4 and inhibition of pyruvate dehydrogenase phosphatases PDP1—2. Three sites of pyruvate dehydrogenase in mammals are utilized for inhibition of pyruvate transfer into mitochondria (Kolobova et al. 2001).
However, oncogene mutation need not be a necessary condition for cancer initiation. Cancer might be initiated by parasitic lowering of energy supply to mitochondria under a critical level necessary for the change of the ordered water layer around mitochondria. Conducting nanofibers may also initiate cancer by short-circuiting the electrodynamic field in a cell.
Mitochondria have a central function in the oxidative metabolism. They transform energy for cell utilization and make possible excitation and maintaining of coherent electric polar state. O. Warburg disclosed defects of oxidative energy transformation in cancer tissues. Experimental evidence demonstrated that cancer tissues can obtain approximately the same amount of energy from fermentation as from respiration, whereas cells in healthy tissues obtain the majority of energy from oxidation (Warburg et al. 1924; Warburg 1956). He also proved that in cancer, the impairment of oxidative metabolism, which displays disturbance of pyruvate transfer, is conditioned by mitochondrial dysfunction, and intuitively described the consequences as a structure type defect which is now explained as disturbance of water ordering. He wrote that “…it is immaterial to the cells whether they obtain their energy from respiration or from fermentation…” and that “The adenosine triphosphate synthesized by respiration therefore involves more structure than adenosine triphosphate synthesized by fermentation.” Mitochondrial dysfunction is called the Warburg effect. Research in the recent time disclosed that mitochondrial dysfunction may be caused not only in cancer cells but also in fibroblasts associated with cancer cell. Energy rich metabolites are transported to cancer cell with functional mitochondria. This type of dysfunction is called the reverse Warburg effect (Pavlides et al. 2009).
Electric polarization of the mitochondrial inner membrane depends mostly on the production of reactive oxygen species, proton transfer across the inner membrane, and the distribution of ions in the cell. Inhibition of pyruvate transfer into mitochondrial matrix causes a step decrease of proton transfer and potential barrier across the inner membrane. Dimension of layer of ordered water depends on pH (Zheng and Pollack, 2003). The layer thickness increases as a function of the distance from a point of zero thickness. For smaller pH than that of zero thickness the ordered water excludes positively charged particles and for higher pH values the negatively charged entities, mainly electrons. In dysfunctional mitochondria the arrangement of the ordered water is shifted from the point of a normal pH value smaller than the value in the point of zero thickness to a pH value higher than that in the point of zero thickness, i.e., exclusion of the positively and negatively charged entities is exchanged (Pokorný et al. 2015). The shift is confirmed by measurement of mitochondrial inner membrane potential by uptake and retention of positively charged fluorescent dyes and their high accumulation around dysfunctional mitochondria, which is overviewed and analysed in (Pokorný et al. 2014). Damping of the electrodynamic oscillations might be caused by the mobile electrons.
Disturbance of the coherent electric polar vibrations and change of frequency of oscillation in cancer process were predicted by Fröhlich (1978). Mitochondrial dysfunction causes disturbed ordered water layer around mitochondria which affect coherent polar vibration in the cancer cells of the Warburg effect and in the fibroblasts associated with cancer cells of the reverse Warburg effect. In the cancer cells of the Warburg effect coherent polar vibration are damped and power of the coherent polar vibrations diminished. In the cancers of the reverse Warburg effect mitochondrial dysfunction is in fibroblasts associated with the cancer cell and they supply energy rich metabolites to the cancer cell which increase power of the cancer cell. The frequency of the microtubule oscillations depends on the nonlinear characteristic of the microtubule oscillators. If the force constant in the potential valley increases with decreasing power than decreased vibration power of the cancer cells of the Warburg effect results in increase of frequency. In cancer cells of the reverse Warburg effect the frequency shift is in opposite direction, towards lower frequencies.
Vedruccio and Meessen (2004) measured frequency of glycolytic phenotype cancers at 465 MHz. The measured value corresponds to the shifted spectral lines of healthy cells in the frequency bandwidth below 200 MHz.
Changes of the electrodynamic state exclude the possibility of a cancer cell to interact with other cells in the tissue. Cancer cells develop individual existence, begin local invasion and metastasis. Tissue and body regulation is switched off.
Cancer treatment might use novel knowledge on cancer development mechanism. Two principal strategies may be used for cancer treatment: Killing of cancer cell or restoring a normal, heathy state. The strategy of cancer cell killing has to be highly selective. Targeting of cancer cells should be based on differences of biochemical and/or biophysical parameter of healthy and cancer cells. A wide spectrum of biochemical treatment method is based on high metabolic activity of cancer cells but this targeting need not be selective enough. One of the chemical killing tools may be based on the oxidation potential which may be greater for killing a cancer cell but smaller for causing damage to a heathy cell. However, the difference between oxidation potential of healthy and cancer cell should be analysed. The killing strategy based on physical parameters may be based on differences of coherent electric polar vibrations, their coherence and frequency. Macromolecules resonating with cancer cells may transport killing drug and target cancer cell. Hyperthermia based on resonant heating may selectively kill cancer cells. But in nonlinear systems the resonant frequency depends on energy stored in the oscillating systems and, therefore, the frequency of the emitted signal for the heating should be continually adjusted to the highest absorption of the near electromagnetic field in the cancer cells similarly as in cancer diagnostics. However, the killing strategy has a big disadvantage: the treatment may fail if the rate of proliferation exceeds the rate of killing. The waste products of killing may exceed the body capability to manage with or get rid of them.
Restoring normal healthy state of cancer cells is another strategy for cancer treatment. A dream for this type of treatment is a restoration of mutated oncogenes. A promising therapeutic strategy could be based on targeting mitochondrial dysfunction. Dephosphorylation of the serine residues of the pyruvate dehydrogenase enzyme opens the way for pyruvate transfer to the matrix and normal mitochondrial function. However, this method by itself only temporarily removes a mitochondrial dysfunction. As oncogene-induced senescence is abrogated, the cancer phenotype may be restored. But even in this case the repeated temporary restoration of PDH function in mitochondria might very likely lead to positive results by triggering apoptosis of severely damaged cells. Establishment of normal oncogene-induced senescence could enable steady restoration of a normal state and apoptotic function of the cell.
Cancer is one of the deseases of disturbed coherent electrodynamic state which endangers life. Not only the biochemical but also the biophysical links of energy processes may be targeted for treatment.
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Professor H. Fröhlich participated at the first meeting in 1987