Considering the Pandemia of COVID-19 virus, the Advisory Board of UNESCO/UNITWIN Interregional Network on “Biophysics, Biotechnology and Environmental Health Control” organizeD weekly skype meetings with the leading scientists of participant universities of the NETWORK on the subject “The mechanism of COVID-19 virus protein spikes interaction with host cell membrane and its age-dependency”.
The first online meeting was held 20.03.2020.
The names of the participants are listed below.
Prof. Sinerik Ayrapetyan - Coordinator of UNESCO/UNITWIN Network and UNESCO Chair in Life Sciences (Armenia, Yerevan)
Dr. Vahagn Poghosyan - Union of Advanced Technology Enterprises (Armenia, Yerevan)
Prof. Andrey Rubin - Head of Biophysics Department of Lomonosov Moscow State University (Russia, Moscow)
Prof. Oleg Krishtal - Director of Bogomoletz Institute of Physiology (Ukraine, Kiev)
Prof. Anatoly Goltsev - Coordinator of UNESCO Chair– Institute for Problems of Cryobiology and Cryomedicine of NAS of Ukraine (Ukraine, Kharkov)
Prof. David Nadareishvili - Director of Ivane Beritashvili Center of Experimental Biomedicine (Georgia, Tbilisi)
Ali A. Moosavi-Movahedi - Coordinator of UNESCO Chair on Interdisciplinary Research in Diabets – University of Tehran (Iran, Tehran)
Prof. Hamod Mobasheri - Head of Laboratory of Membrane Biophysics and Macromolecules (LMBM), Institute of Biochemistry and Biophysics (IBB) University of Tehran (Iran, Tehran)
Prof. Majid Ghayour-Mobarhan - Mashhad University of Medical Sciences (Iran, Mashhad)
Prof. Suleyman Dasdag - Department of Biophysics, Istanbul Medeniyet University (Turkey, Istanbul)
Prof. Ehsan A. Khan - Jamia Hamdard University (India, Delhi)
Prof. Kusal Das - Head of Laboratory of Vascular Physiology and Medicine, Department of Physiology, Shri B.M.Patil Medical College BLDE SHRI B M Patil Medical College Hospital & Research Center (India, Karnataka)
Prof. Rob Ewing - Head of Biological Sciences, University of Southampton (UK, Southampton)
Prof. Robert Walker - Professor Emeritus at University of Southampton (UK, Southampton)
Prof. David Carpenter - Director of Institute for Health and the Environment, University at Albany (USA, Albany)
Prof. Gagik Bazikyan - Deputy Director of the National Center of Oncology of the Ministry of Health of the Republic of Armenia
Below are the short summaries of the possible perspectives to face COVID-19 challenges suggested by the participant scientists (the outcome of the first skype meeting dated 20.03.2020)
Dr. Alberto Foletti - “Some biophysical perspectives on the COVID-19 health challenge.”
Clinical Biophysics International Research Group, Lugano, Switzerland.
Institute of Translational Pharmacology, National Research Council-C.N.R., Rome, Italy.
Prof. Kusal K.Das - "Mechanism of action of SARS-COV2 in host cell"
Laboratory of Vascular Physiology and Medicine, Department of Physiology, Shri
B.M.Patil Medical College, Hospital and Research Centre, BLDE (Deemed to be University), Vijayapur, Karnataka, India
Vice President - The Physiological Society of India
Prof. Reza Yousefi - "The exogenous human recombinant ACE2 has therapeutic potential against covid-19"
Protein Chemistry Laboratory, Department of Biology, Shiraz University, Shiraz, Iran
Based on the discussions, the meeting participants outlined the main discussion outcome and the platform for the Second Meeting
The Second Meeting was held 27.03.2020, 2pm Armenian time
Based on the effective outcome of the first meeting, UNESCO General Office thanked UNESCO/UNITWIN Network in Biophysics in Armenia for starting this chain of discussion as a very valuable step for the product of scientific know-how on virological research in particular and in life science research in general.
Dr. Fahmi Ahmed - the Cheif of Section, from Division of Science Policy and Capacity Building, Natural Science Sector of UNESCO emphasized the importance to introduce other UNESCO chairs, Directors of UNESCO centres in Life sciences, and UNESCO network of scientits involved in the UNESCO Carlos Finlay Prize in Microbiology as well as members from the International Basic Science Programme, and partners.
Following his recommendations the NETWORK has engaged more scientists in the skype meeting from the above-mentioned institutions.
The idea was also to strengthen or increase University research and education (MSc, PhD programmes etc), around the world, so we can have better trained virologist, bacteriologists, or microbiologists, in general. Or creating or strengthening links between scientists and medics, whether this is between the basic scientists working on structure biology for example, or those involved in drug discovery and the health research system etc.
As UNESCO also has an MoU with the WHO, the skype meeting would help to develop a comprehensive picture of not only the public health side but buildng capacities in scientific research and know-how.
Thus, more scientists joined the second meeting discussion, namely:
Dr. Fahmi, Ahmed - the Cheif of Section, from Division of Science Policy and Capacity Building, Natural Science Sector of UNESCO
Prof. AHJ Wang - President, IUBMB, Distinguished Visiting Chair Institute of Biological Chemistry, Vice President (Emeritus), Academia Sinica, Taipei, Taiwan
Prof. Francesco Castelli - Director, University Department of Infectious and Tropical Diseases, University of Brescia and Brescia Spedali Civili General Hospital, Brescia, Italy
UNESCO Chair "Training and empowering human resources for health development in resource-limited countries"
Dr.Sumanta GOSWAMI - Albert Einsten Medical College, New York, USA
Prof. Gustavo Zubieta-Calleja - Director of IPPA - President of Zubieta University, Bolivia
Prof. Mehran Habibi-Rezaei - Professor of Biochemistry at University of Tehran
Dr. Reza Yousefi -Associate Professor of Biochemistry at Shiraz University
The Main Platform for Discussion for the Second Skype Meeting “Fighting against COVID-19" initiated by "UNESCO/UNITWIN Interregional Research and Postgraduate Educational Network in Biophysics, Biotechnology and Environmental Health is as follows:
Currently, the detailed intracellular mechanism of COVID-19 virus infection is not evaluated yet. Therefore, the real way to stop the infection is to inhibit virus penetration through the membrane into cell.
Traditionally, it is suggested that Coronavirus attaches to specific cellular receptors via the spike protein, triggers a conformational change in spike which then mediates fusion between the viral and cell membranes which results in the release of the nucleo-capsid into the cell. This statement is not in agreement with modern membranological approaches based on the following reasons:
a) the virus in cell membrane cannot have a specific receptor because of existence of a great number of viruses.
b) the explanation that the virus enters into cell by spike protein-induced receptor is also not real, as such a confirmation predicts the change of cell membrane conductance, which can be stopped by ionic gradient changes on the membrane.
The 2012 Nobel Prize for chemistry was awarded to Robert Lefkowitz and Brian Kobilka for their work on G protein-coupled receptors, the activation of which leads to modulation of intracellular messenger systems. By our study it has been shown that intracellular cyclic nucleotides-dependent Na/Ca exchange has quantum-mechanical sensitivity and by generation of water efflux from the cells controls low permeability for Na ions i.e. by these mechanisms the cell contacts to any foreign substances which could depress the semipermeable properties of cell membrane, which is a common consequences of any cell pathology. We have shown that cGMP-dependent F Na/Ca exchange is the primary mechanism through which cell protects its low permeability for Na ions, pushes Ca ions from the cells, activates Na/K pump and by water efflux from the cell inhibits Na inward current, brings to cell shrinkage by surface-dependent decrease of ionic channels and receptors and decreases membrane fluidity. Therefore, the virus could penetrate only by depressing cGMP-dependent FNa/Ca exchange. Although the Na/Ca exchange functions in stoichiometry of 3Na:1Ca, its activation in forward mode has dehydration effect on cell hydration, by activating Na/K pump in young animals, while in old animals, because of high [Ca]i, it has hydration effect because of water influx and increase of membrane fluidity promot virus penetration into cells. Therefore, the factors having stimulation effect on cGMP-dependent activation F Na/Ca exchange from the cells could increase cell resistance to virus infection.
The Third Meeting was held 03.04.2020, 2pm (Armenian time)
Coronavirus is spreading around the World but specific effective tools to stop it are still absent and only the antimalarial drugs - chloroquine and relative compounds are one of the effective and
promising drugs which are used around the world against coronavirus. Therefore, the subject for discussion of the coming Friday Skype Meeting was “The cellular and molecular mechanism of antivirus effect of chloroquine” on the basis of which it will be able to increase the therapeutic effects of these drugs as well as increase the resistance of public to coronavirus attack.
The outcome of the 3rd meeting in brief is presented below:
⇒ Be careful for treating patients with hydroxychloroquine on G6PDH metabolic disorders
⇒ Be careful on proper viral load while testing COVID-19 diagnosis
⇒ Blood Lactate may be used as prognosis for COVID-19 patients
⇒ Quantum mechanics is applicable to understand virus attack on host cell membrane. Na +K+ ATPase inhibitor may play some role on virus-induced cell signaling.
⇒ 4 Hz EMF treatment may be beneficial to treat COVID-19
⇒ High altitude adaptation with low PaO2 saturation possibly reducse SARS-COV2 efficacy
⇒ Turmeric with clove is good for COVID-19 (IRAN doctors observed)
⇒ Special attention on diabetic and NSAID-treated arthritic patients especially with Hydroxychloroquine
⇒ ACE2 receptors on alveolar Type I and II pneumocytes need to be protected by appropriate pH and microenvironment.
⇒ Avoid mobile during Covid-19 patients care as low frequency radiation may increase viral activities and counteract with beneficial UV radiation support.
⇒ Each country must follow its National Therapeutic Management directed by its Government.
⇒ Sharing data and collaborative research
The 4th online meeting was held 10.04.2020.
The subject for the 4th meeting was “The Age-dependent increase of COVID-19 risk"
In this respect, Prof. Sinerik Ayrapetyan suggested his hypothesis stating that "The Net Water Efflux from the Cells Serves as a Barrier for Coronavirus Absorption with Host Cell Membrane” as a platform for discussion of the 4th Skype meeting.
At present, the oxidative phosphorylation pathway is considered as one of the most promising targets through which the organism defends the hazardous effects of environmental factors, including virus infection. The 50-year-study of Prof. Ayrapetyan on the metabolic regulation of biophysical properties of cell membrane allows to suggest that “The age-dependent weakening of metabolic driving water efflux from the cells, controlling cell volume, membrane permeability, fluidity, enzymatic, chemoreceptive and excitable properties is a key cell protective mechanism to hazardous effects of environmental factors, including Coronavirus infection"
The generation of water efflux from the cells takes place by the increase of water formation during intracellular oxidative phosphorylation, and the function of electrogenic ion-transporting mechanisms in cell membrane, such as Na/K pump and Na/Ca exchange. The more detailed description of the quantum –mechanical nature of metabolic generation of water efflux from the cells and its physiological meaning are described in his reviews:
1. Ayrapetyan SN (1981), On the physiological Significance of the Na/K pump- induced cell volume changes, Adv. Physiol. Sci. vol.23, 67-82.
2. Ayrapetyan SN, (2015),The role of cell hydration in realization of biological effects of non-ionizing radiation (NIR). Electromagn Biol Med, 2015; 34(3): 197-210
3. Ayrapetyan SN,(2020), The Quantum-Mechanical Sensitive Na/K Pump Is a Key Mechanism for the Metabolic Control of Neuronal Membrane Function, Open Journal of Biophysics, 2020, 10, 59-83.
♦ During the 4th Skype meeting the partcicipants discussed the possibility of Organizing an International Project on "The use of Folk Medicine for potentiating the therapeutic properties of chloroquine, its relatives and depressing the effects of their side effects” as the participant countries of the meeting have rich history in Folk Medicine. Thus, it was thoughts to be helpful to invite the doctors and pharmacologists that use Folk medicine to join the discussions.
The 5th online meeting was held 17.04.2020.
The subject of discussion: The Stimulation of Intracellular Messenger System Controlling Cell Hydration as a Tool for Inhibition of Coronavirus Infection
Although the clinical use of antimalarial drugs, such as hydroxychloroquine and chloroquine for fighting against coronavirus infection is widely spread, the mechanism of action of these drugs is still emerging as the precise mechanism through which their antivirus effects are realized remain unexplored. Such vagueness of the nature of target mechanism through which its antivirus effect is realized causes difficulties to detect the dose–dependent effects of these drugs, which is important to find the minimum dose of clinical efficacy and the doses that are toxic challenges to clinical practice. The main barrier for solving the problem of choosing adequate methods for fighting against coronavirus is the unknown extremely sensitive and universal biomarker reflecting the functional state of cells which could serve as a diagnostic tool and therapeutic target for the increase of the resistance to the impact of foreign substances, such as viruses on the cell.
On the basis of literature and research data of Prof. Ayrapetyan it has been suggested that the metabolic control of cell hydration can serve as a quantum-mechanical sensitive cell parameter controlling cell functional activity, which is realized by surface-dependent changes activity of the number of functionally active membrane proteins, having enzymes, receptors and ionic channels-forming properties as well as by hydration-induced changes of intracellular macromolecules’ activity (including DNA activity) (see rev. Arapetyan 1981, 2006, 2015, 2020). The theoretical background and experimental evidence that cell hydration is a universal quantum-mechanical sensitive cell parameter through which living cell uses metabolic energy controlling its non-equilibrium (low entropy) state are shortly presented below.
From the thermodynamic point of view, the living cell is an open system, capable of exchanging both energy and matter with its surroundings and is in non-equilibrium state with the environmental medium because of the cell metabolism (having quantum-mechanical character) as a result of anti-gradient process generating osmotic gradients on mitochondria and cell membrane. According to the Nobel Prize Laureate Peter Mitchell's “chemo-osmotic” theory the proton pumps transfer the metabolic energy into electrochemical proton gradients on the membrane, which then is transferred into ATP. During this process, the oxidation of one molecule of glucose leads to formation of 42 H2O molecules, 36 molecules out of which during mitochondrial oxidation. The formation of water efflux from the mitochondrial membrane having inhibitory effect on inward proton current, determines the efficiency of oxidative phosphorylation process. In eukaryotic cell membrane the Na/K pump by utilizing ATP transfers the energy back to osmotic gradients on membrane which serves as energy sources for a number of exchange systems, including Na/H and Na/Ca exchangers. The efficiency of such ATP energy transformation into osmotic gradient energy is determined by the activity of metabolic driving water efflux from the cells, having inhibitory effects on inward going ionic membrane currents (Ayrapetyan et al.1988). As cell membrane is more permeable for water than for ions (in epithelial cells more than 13 times Hoffman et al. 2019) it makes cell hydration an extremely sensitive metabolic signaling cell parameter in response to the impact of environmental factors (Ayrapetyan 2006). As the dysfunction of Na/K pump leading to the loss of the aforementioned protective functions is a common consequence of any cell pathology it is suggested that more sensitive home-keeping mechanisms able to respond to the impact of environmental factors precede Na/K pump dysfunction. To evaluate the nature of these mechanisms we have studied the dose-dependent effect of different chemical and physical factors on membrane, which allows us to discover that intracellular cyclic nucleotides-dependent Na/Ca exchange which has a quantum-mechanical sensitivity, is a universal sensor through which, by modulation of Na/K pump activity, the resistance of cells to different environmental factors, including viruses is increased. The 50-year study assumes that the dose-dependent effects of biological active substances identify minimum three groups of metabolic mechanisms with different sensitivities, involved in realization of protective function of cells. More detailed information on this result is available from Research Gate (https://www.researchgate.net/profile/Sinerik_Ayrapetyan). Based on this result it can be suggested that the common platform for the discover of new drugs and physio-therapeutic factors to inhibit virus penetration through cell membrane could serve the use of their dose-dependent effects on metabolic controlling cell hydration to detect the minimal doses of factors having beneficial effects on organism. In case of Coronavirus infection it is important to study dose-dependent drugs, including chloroquine, or physical factors on lung tissue hydration. It is believed that by using this method, we will be able to find the optimal combination of drugs with minimal concentrations of folk medical drugs, having inhibitory effects on Coronavirus penetration into cells of respiratory tract. At present by using the mentioned methods, UNESCO Chair in Life Sciences has preliminary promising preclinical data on antitumor effects of 4Hz EMF exposure on experimental animals (Mikaelyan et al. 2019) which can be used as one of the tools for fighting against Coronavirus infection. All citations are available here
The 6th online meeting was held 24.04.2020.
Subject of discussion: “The impairment of metabolic driving water efflux from the cells is a key mechanism for aging-induced increase of Coronavirus infection risk”
As a subject of discussion Prof. Ayrapetyan suggested his hypothesis stating that “The dysfunction of intracellular signaling system controlling cell hydration is a main reason for increasing the risk for Coronavirus infection of unhealthy (aging) people”.
It is obvious that one of the important methods in fighting against coronavirus pandemic is to study the entry mechanism of the virus into the cells. It is known that any foreign substances (including Coronavirus) before entering the cell must be recognized by cell membrane signaling systems controlling the affinity of membrane proteins and lipid fluidity. Therefore, it is predicted that the S protein of viral membrane, could be the first to come close to the host cell membrane, bind to the membrane receptor and by the fusion between the viral and the cellular membranes penetrate into host cell.
As suggested in the 5th meeting, the main barrier for penetration of CoVs into the host epithelial cells is the mechanism of metabolic control of cell hydration which generates net water efflux from the cells. The water efflux inhibits CoVs infection of host cells by the following mechanisms: 1) inhibits the driving of the virus close to the membrane of host cell, 2) by leading to cell shrinkage it decreases membrane lipid fluidity and depresses the water influx through the membrane 3) brings to cell shrinkage-induced decrease of the number of functionally active receptors and their affinity to S protein in membrane, 4) controls the Na gradient on membrane serving as energy sources for controlling [H]i and [Ca]i and 5) controls membrane low permeability for Na, the increase of which is a primary step (marker) for virus intervention into the cells .
Based on the data elaborated by Prof. Ayrapetyan and other literature data it is assumed that the impairment of metabolic driving net water efflux from the host epithelial cells of unhealthy persons, including aged people, is due to the dysfunction of intracellular signaling systems controlling cell hydration which brings to the decrease of host cell resistance to virus penetration into host cells (i.e increases the risk of infection) by the decontrol of the aforementioned membrane biophysical properties.
The 7th online meeting was held 01.05.2020.
Subject of discussion: “The methods of detection of minimal therapeutic doses of drugs for individual patients”.
Most importantly the participants presented information on the methods of finding out the minimal doses of therapeutic drugs which have the lowest side effects on individual patients".
The 8th online meeting was held 08.05.2020.
Subject of Discussion: Joint Research and Postgraduate Project on “Finding out the biomarker reflecting the functional state of cells and organisms for fighting against COVID-19"
The present situation with Covid-19 pandemic urges the UNESCO/ UNITWIN Network on Research and Postgraduate Education in Biophysics, Biotechnology and Environmental Health Control to focus on using the modern knowledge in Biophysics to improve Public Health Protection. In this aspect, the subject of the previous Skype meetings was the use of biophysical methods to inhibit the virus intervention into cells, which is one of the promising strategies in fighting against virus infection of organism. As a starting point of these initiatives will be the elaboration of Joint Research and Postgraduate Project on “Finding out the biomarker reflecting the functional state of cells and organisms, which will serve as a universal sensor for different environmental factors, including viruses".
During previous 5th and 6th Skype meetings it was suggested that the intracellular messengers controlling cell hydration can be such a biomarker through which the metabolic generation of water efflux form the cell becomes a primary defense mechanism to the impact of environmental factors, including coronavirus.
After the 8th meeting Dr. Fahmi Ahmed - the Cheif of Section, from Division of Science Policy and Capacity Building, Natural Science Sector of UNESCO, apart from expressing his hearfelt thanks for the organization of the skype meetind, kindly suggested to solicit all the scientists of the meeting to share their scientific papers related to viruses research that can be put onto the portal of the UNTWIN network and think of creating an international coalition of professionals under the auspices of UNESCO to ensure scientists work collaboratively and remain funded in the fight against future pandemics.
Thus, following his suggestion the next 9th Skype meeting was dedicated to propose some concrete projects or programmes in microbiology or inter-disciplinary science that UNESCO can help in implementing and in sensitizing member states (countries) to work on, bearing in mind that our mandate is that to build capacities in the basic and applied sciences and to bridge the gap between those who can do research and those who can't.
The 9th online meeting was held 22.05.2020.
Following the suggestion of Dr. Ahmed Fahmi (the Chief of Section, Division of Science Policy and Capacity Building, Natural Science Sector of UNESCO) the 9th meeting was organized with wider team of scientists to take stock of what had been done in the other 8 skype meetings, to open discussion on other initiatives and propose some concrete projects or programmes.
The meeting participants welcomed:
♦ The colleagues from UNESCO Chair in Biotech at the University of Rome - Prof. Colizzi (Dr Antonella, Prof Zamparelli, Prof Colao and Prof Cappelli).
♦ The colleagues from the International Institute of Molecular and Cell Biology, under the auspices of UNESCO (Professors Urszula, Magdalena and Nowothny).
♦ Prof Oliva from Brazil, member of UNESCO IBSP board and the chair of the board,
♦ Prof. Moreau and colleagues from the World Federation of Culture collection (Doctors Depauw, Groenewald, Ma)
♦ Past and current presidents of the International Union of Pure and Applied Chemistry (Profs Tarasova and Brett)
♦ President of International Union of Biochemistry and Molecular Biology (Prof Wang).
During the meeting the participants discussed projects suggestions. The projects were according to the common platform for performing General Multidisciplinary Project based on a universal diagnostic biomarker, which would allow by dose-dependent effect study of chemical substances or physical factors to find out their minimum doses having therapeutic effects and less side effects.
Prof. Ayrapetyan suggested that the metabolic control of cell hydration could serve as such a diagnostic biomarker to find out adequate antivirus factors
The 10th online meeting was held 29.05.2020.
As discussed during the 9th meeting, according to the demands of the present situation connected with Coronavirus Pandemic and the problems of environmental health control generally, we need to improve our research and postgraduate education in biophysics and use it as a tool for counteracting a number of environmental problems having increasing character. The joint project directed to this purpose and aimed at integrating our research potential to find out a universal and extremely sensitive diagnostic biomarker and elaborating a method for its measurement, could open a possibility for earlier detection of possible hazardous effects of environmental factors (including virus) to protect the organism. It is obvious that without fundamental knowledge in biophysical mechanisms of environmental factor effects, it would be impossible to solve the problems of environmental health control. Therefore, the present project regarding cell hydration as a universal and extremely sensitive biomarker for detection of the effects of environmental factors, including the impact of the virus on the organism from the point of Public health would be a step forward. The discussions during the previous 9 webinars revealed the multidisciplinary team of the meeting is able to have essential contribution in solving a number of problems in environmental health control. Therefore, as a starting point, at the 10th meeting it was decided to integrate the efforts to perform a General Project.
!!! Currently the skype meetings are stopped for the purpose of investing the efforts of the participants in elaboration of the General Project. Of course, this does not suppose ceasing the communication among the participant scientists. They are available for each other via skype or other means of communication to discuss instant matters connected with COVID-19 and the Project.
!!! “The comparative study of dose-dependent effects of hydroxychloroquine and new therapeutic chemical and physical factors on metabolic control of tissue hydration in Sarcoma-180 tumor carrying mice” has been chosen as a General Project for two years. As the UNITWIN Network has research and postgraduate character, the necessary requirement for all the daughter-projects is to have minimum 3 PhD-students and to consider gender equality issues.