The First International Conference on Radiation and Dosimetry in Various Fields of Research Niš, Serbia, April 25 - 27th, 2012 Odessa National Medical University The First International Conference on Radiation and Dosimetry in Various Fields of Research Niš, Serbia, April 25 - 27th, 2012 Field nature of Life Valeriy Zaporozhan and Andriy Ponomarenko Odessa National Medical University, Ukraine Realization of the correct hierarchy of life-keeping and life-regulatory structures and forces is very important for scientific progress. Evolution of our conceptualization in the field has been intimately coupled with the progress in our general scientific knowledge and accessible methodology Conditional gradation of our understanding of the main life-keeping and liferegulating entity: 1) Spiritual: Temple of spirit by White Citrus, from Digital Art Gallery Online 2) Morphological: Picture from Wikipedia 3) Biochemical: knowledge about different chemicals and their biological effects accumulated. Chemical and Biochemical aspects of Life and disease treatment attracted most scientific interest. Pharmacists elaborated remedies for treatment of various diseases; Doctor and Pharmacist from: Brunschwig, Hieronymus 4) Genomic: Author: Madprime Accumulated data suggests that the genome is mostly an instrument than independent player, and that the melody it produces depends significantly on the “musician” who plays music (“musician” means: posttranslational modifications, DNA methylation, histone acetilation and other epigenetic effects influencing gene expression). 5) Proteomic: Understanding that the final protein structure and protein assembly is the thing which really matters and determines biological effects, brought to life the Proteom Era. Examples for subcellular localisation of different proteins Is there a need to develop any other conceptual model of Life organization ? If yes, what the next concept will be? We believe it’ll be worthy to consider the Electromagnetic Fields produced by cells and biomolecules (the “Electromagnetic Life Matrix”) and corresponding interactions in living objects as the most basic level of Life organization and regulation. Fundamental interactions Interaction Mediators Relative Strength Range(m) Strong gluons 1038 10-15 Electromagnetic photons 1036 infinite Weak W and Z bosons 1025 10-18 Gravitation gravitons (not 1 infinite yet discovered) Table from Wikipedia, the free encyclopedia Can we find any life-specific interactions on this table ? …enzime-substrate interactions ? …hormone-receptor interactions ? …promoter-target gene interactions ?.... The only known force that implements all specific biological interactions is the Electromagnetic Force. An example of protein interaction scheme (from Kurt W. Kohn, Molecular Biology of the Cell Vol. 10, 2703–2734, August 1999) There is a famous statement: “Final manifestation of each emotion is a muscle contraction” We would say that “Final manifestation of each emotion is ion redistribution in specific neurons and a chain of electromagnetic interactions which elicit muscle contraction” Electromagnetic force in Immunity Evidences of the regulatory function of electric charges in immune recognition and immune response: The most immunogenic are regions of a protein that have negative electrostatic potential [Geysen et al.]. Purposeful change of surface electric charge of antigens cause alteration of their immunogenic properties [Muckerheide et al.]. A straightforward correlation has been shown between the net electrical charge on a variety of natural and synthetic antigens and the type of antibody they elicited [Sela et al.]. DIFFERENCES IN ELECTROPHORETIC MOBILITY BETWEEN DIFFERENT CELL TYPES: between T and B cells; between mature T-cells and – thymocytes --lymphocytes isolated from bone marrow; between normal and malignant cells; between “young” erythrocytes and “old” ones. Glycocalix Glycocalyx is formed from free fragments of plasmalemma’s glycoproteins interconnected whith anionic-cationic movable bridges. Glycocalyx is an “executive apparatus, which mediates interaction of a cell with intercellular medium and neighbouring cells”. Glycocalyx is needed for perception, recognition, transmission, and modulation of incoming and outgoing cell signals in the form of substance, energy, and information. Many functions of glycocalyx are mediated via electric charge of its components and by changes of this charge. Electric charge of antibodies and possible significance of this parameter The index of Circulation and index of Epidemic danger for different influenza strains in Odessa population at studied period according to average concentration of positively and negatively charged specific antibodies in human sera. Dynamics of the Index of epidemic danger for different influenza strains in Odessa region (Ukraine). Correlation between Electrokinetic potential of virions and biological features of virus strains Model of Influenza virus surface glycoprotein – HA (model of Wilson et al.). Arrow indicates localization of the receptor-binding pocket An intimate feature of life is rhythmicity. Life on the Earth since its very beginning experienced continuous influences of Electromagnetic Radiation in form of Sun light and Geomagnetic field. It is natural that bio-cycles became correlated with these natural EM-signals: • Day-night cycles cause circadian biorhythms; • Annual rhythms are also well known; • Bio-rhythms of much more longer period exists, some of them correlate with cycles of Solar activity. An intimate feature of life is rhythmicity. The cause and pacemaker of rhythmicity in numerous life processes are Electromagnetic signals: Circadian rhythm (picture from the Wikipedia) Biological clock (file from the Wikimedia Commons) Periodicities in solar and geomagnetic activity (from Pulkkinen, T. "Space Weather: Terrestrial Perspective", Living Rev. Solar Phys. 2007). Correlation between level of solar activity and influenza pandemics in 20-th century (Tapping et al.) Correlation of Solar and Geomagnetic activity with Human morbidity and mortality Stoupel E. Atherothrombosis: environmental links. J Basic Clin Physiol Pharmacol. 2008; 19 (1):37-47. Stoupel E, Petrauskiene J, Abramson E, Kalediene R, Sulkes J. Distribution of monthly deaths, solar (SA) and geomagnetic (GMA) activity: their interrelationship in the last decade of the second millennium: the Lithuanian study 1990-1999. Biomed Pharmacother. 2002; 56 Suppl 2:301s-308s. Mikulecky M, Moravcikova C, Czanner S. Lunisolar tidal waves, geomagnetic activity and epilepsy in the light of multivariate coherence. Braz J Med Biol Res. 1996 Aug; 29 (8):1069-72. Neronov VV, Malkhazova SM, Ponirovskii EN, Charyev BCh. [The multiyear changes in the epidemic activity of the foci of zoonotic cutaneous leishmaniasis at the Murgab oasis. I. An analysis of the relations of morbidity to heliogeophysical factors]. Med Parazitol (Mosk). 1996 Jul-Sep; (3):3-7. Cornélissen G, Halberg F, Kovac M, Mikulecky M, Otsuka K, Bakken E. Geographic and extraterrestrial aspects of morbidity and/or mortality patterns from myocardial infarction and stroke. Biomed Pharmacother. 2005 Oct; 59 Suppl 1:S68-75. What is the reason of the correlation between solar cycles and human health ? Schematic picture of “Sun wind” consisting of plasma fluxes erupted from the Sun’s surface and their interaction with Earth’s magnetic field. Magnetic fields can interact with magnetic dipoles of electron spins, whose carriers are paramagnetic molecules, metal ions and ion-radicals “Electrons and nuclei, which possess magnetic moment, are the “magnetic antennae” in any biosystem, including human beings. They are able to receive and radiate electromagnetic energy selectively depending of the field’s frequency (ν) and gyromagnetic ratio (γ)” (Fursa EY) Proposed mechanisms of the biological effects of extremely weak magnetic fields: (1) “Plasma membrane hypothesis”: cell membrane is a primary biological receiver of magnetic signals, it responds by changes of its potential, and distribution and activity of integral membrane proteins and ion channels (e.g., Ca2+ channels). (2) Free radical mechanisms: magnetic fields can increase the lifetime of free radicals. This results in an increase in free radical concentration in cell compartments, and biological changes, including activation of signaling cascades (reviewed by M.Simko). (3) The ion resonance model, which implicates the combined action of the ELF MF and a weak static magnetic field (for example - geomagnetic field). Radical Pair mechanism of Magnetoreception by Schulten and coauthors, 1978 The radical pair is generated by an electron transfer from a donor molecule D to an acceptor molecule A. An external magnetic field affects interconversion between singlet and triplet states of the radical pair. (Reproduced from [Schulten et al., 2000] ) Cryptochromes: Ancient Regulatory Proteins Sensitive to Electromagnetic Radiation and Magnetic Fields Cryptochrome is a signaling protein found in bacteria and a wide variety of plants and animals. Cryptochromes are ubiquitously expressed in the organs and tissues, and have a predominantly nuclear localization. Among known functions of CRY are the regulation of growth and development (in plants) and entrainment of circadian clocks. Localization of CRY in nuclei of cells (from Chaves I. еt al., 2006). Scheme of the magnetic field effect on the radical pairs between FADH and tryptophan in cryptochrome active site. (From Solov'yov IA et al., 2007, reproduced by the kind permission of the authors and the publisher) Genome-regulatory effects of CRY Co-operation of CRY with the major circadian clock regulatortranscription factor CLOCK/BMAL1, transcriptional corepressors and PER proteins. (From Chaves et al., 2006) Scheme representing possible mechanisms of CRY bio-regulating activity. (a) CLOCK/BMAL1-heterodimer function as transcriptional activator. (b) interaction between CRY1 and CLOCK/BMAL1 causes CLOCK/BMAL1 to adopt a transcriptional repression function. (c) modification of CRY activity by weak external magnetic field and subsequent restoration of CLOCK/BMAL1 transcriptional activation function Probable mechanisms of the magnetic field influence on gene expression and virus-host interactions: MAGNETIC FIELD Cryptochromes membrane potential CLOCK/BMAL1 + CBP Ion resonance effects ion channels function Circadian genes expressio n Circadian control of stress and other “noncircadian” responses by active transcriptional repression mechanism Ca2+ signaling Ca2+-Operated Transcriptional Networks Expression and function of proteins of NF-kB signaling pathway Immunity regulation Regulation flu RNA synthesis Regulation of virus-host interactions and other biological processes To summarize, CRY are unique bio-compounds, which combines sensory and bioregulatory functions. They act as mediators between living beings and their physical environment, providing a mechanism for both the reception of electromagnetic signals and the triggering (or entraining) of biological responses. It appears that biological effects of the Electromagnetic field can be compared with human speech: loudness has small effect, but meaning is very important: several words can ignite a conflict or, alternatively, to stop a war. Signaling pathways probably affected by the geomagnetic storms NF-κB is a protein complex that acts as a transcription factor. It is widely expressed and regulates the expression of genes involved in immune responses, inflammation, proliferation, apoptosis and other cellular activities. It plays a key role in immune reactions, including response to infection. Genes encoding proteins of Rel/NF-κB/IκB pathway are exposed to transcriptional regulation by the CRY/CLOCK/BMAL1 complex… CRY/CLOCK/BMAL1 transcription complex also regulates the transcriptional activity of the glucocorticoid receptor. Signaling pathways probably affected by the geomagnetic storms Several viruses, including HIV, have binding sites for NF-κB that control the expression of viral genes, which in turn contribute to viral replication and/or pathogenicity. In the case of HIV-1, activation of NFκB may, at least in part, be involved in activation of the virus from a latent, inactive state [Hiscott, 2001]. This indicates the theoretical possibility of magnetic field effects on the processes of HIV activation and replication. NF-κB is chronically overexpressed in inflammatory diseases (arthritis, sepsis, asthma, among others). There is evidence for a critical role of NF-κB in carcinogenesis, and NF-κB is a key mediator of chemotherapy resistance, as well as having a major role in tumor development, particularly in its early phases [Pikarsky, 2006]. “Electric fields are present in all developing and regenerating animal tissues, yet their existence and potential impact on tissue repair and development are largely ignored. This is primarily due to ignorance of the phenomenon by most researchers, some technically poor early studies of the effects of applied fields on cells, and widespread misunderstanding of the fundamental concepts that underlie bioelectricity”. (McCaig et al., 2005). Consequences of the magnetic field influence on gene expression and virus-host interactions: Dynamics of our knowledge in the field confirms ideas of Alexander Chizhevsky about the electromagnetic nature of communications between spatially distant components of the single whole (integrated) system comprising our Biosphere and the Sun. Has God separated heavens from the earth… by geomagnetic field ? Use of biophysical approaches and electronics for disease diagnostics, prophylaxis and treatment Spiritual Morphological Biochemical Genomic Electromagnetic Matrix Proteomic Conclusions: 1. Biological reactions in living beings, including responses to stress and infection, are probably sensitive to the functional activity of Cryptochromes, which in turn may be regulated by weak magnetic field, like geomagnetic field, thanks to the radical pair mechanism of magnetoreception; 2. Presented data suggest the potential use of magnetic fields for temporary modification of the gene expression pattern in different cell types, without the aid of gene transfer technologies; 3. Dynamics of the biological processes could be evaluated, predicted or changed by way of study of corresponding EM-interactions and their biological effects; 4. Elaboration of new efficient treatment methods can be achieved by utilizing EMF. Examples: a) Stimulation of Cell differentiation and regeneration by Magnetic field; b) Transcranial Magnetic Stimulation (TMS) for treatment of various neurological and psychiatric disorders; c) New Cancer treatment methods based on cancer cell membrane permeabilization using High frequency EMF. Thank you for your attention ! Millimeter-range electromagnetic waves therapy (UHF therapy) apparatus «EHF-ND» Main technical parameters Weight, full set, kg Consumed energy EHF-radiation in wave length ( sweep width 100 mHz) Power flux density of one emitter, mW/cm2 Exposure period, min 1.2 200V/50Hz- 12 W 7.1; 5.6; 4.9 4-12 1-99 Conclusions: The correlation between EKP of virions and biological features of influenza viruses has been shown. These results can be used for prognosis of biological features of recently isolated and experimentally obtained influenza viruses, that necessary both: for perfection of epidemiological surveillance and creation of efficient vaccines; Correlation between average contents of definite subtypes of specific influenza antibodies and serum inhibitors of agglutination correlates with level of epidemiological danger of given flu strain for studied human population; Use of biophysical methods of treatment in clinics increases efficacy of conventional treatment and decreases percentage of complications. Further exploration of direct and indirect mechanisms for participation of electromagnetic interactions in various biological activities is feasible and may yield many interesting results both: of theoretical and clinical significance.