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What happens in Cancer? Cancer can develop when something goes haywire and affects the regulators or mechanisms that are responsible for homeostasis - the maintenance of steady physical, chemical and biological conditions within the body. It is thus fairly apparent that cancer is the outcome of a failure of the body to cope with threats and challenges with an appropriate response, and altered processes that bring about sustained changes from the normal have the potential to lead to cancer. Several hallmarks of cancer have been clearly identified today; these are critical processes which, when altered, can give rise to uncontrolled cell division and ultimately to cancer. The hallmarks encompass processes that bring about sustained proliferation signaling, evasion of growth suppression, resistance to cell death, replicative immortality, induction of angiogenesis, and activation of invasion and metastasis (Hanahan & Weinberg, 2011; figure 4). Thus in cancer it is seen that cells keep dividing, they do not respond to signals that suppress growth, they resist cell death, they show signs of immortality, new blood vessels are set up to provide growth factors and energy to the growing tissue, and invasion to neighboring or distant organs and fresh tumour growth at the new site takes place. 75

More recently, sustained inflammation, altered stress response favouring survival, a favouring microenvironment, immune modulation, and resistance to cell death have been added to the list of hallmarks. Through this article, the first of a three part series, the author aims to provide fundamental information about normal life processes and what goes wrong during the development of cancer. In the next article, the author will discuss the causative factors at the root of cancer. References Weinberg, RA: How cancer arises. [Special Issue: What you need to know about cancer.] Scientific American 275 (3): 62-70, September 1996. Cooper GM. The cell: a molecular approach. 2nd edition. Sunderland (MA): Sinauer Associates; 2000. The development and causes of cancer. https://www.ncbi.nlm.nih.gov/books/NBK9963/ Zhivotovsky B, Orrenius S: Carcinogenesis and apoptosis: paradigms and paradoxes. Carcinogenesis 27 (10): 1939‑1945, October 2006. https://doi.org/10.1093/carcin/bgl035 (Published 10 April 2006) Hanahan, D, Weinberg, RA (4 March 2011). Hallmarks of cancer: the next generation. Cell 144 (5): 646–674. DOI:10.1016/j. cell.2011.02.013. PMID 21376230 ***** 76

CHEMOPREVENTION OF CANCER Lubna Ahmed [email protected] Keywords: Cancer chemoprevention, hormonal, medication, dietary, vaccines. Abstract Cancer chemoprevention involves the usage of various agents for the inhibition, delay, or reversal of the carcinogenic process before cancer invasion takes place. This review provides an overview of various agents - classified as hormonal, medication, dietary agents and vaccines, which are being studied or are in use for cancer chemoprevention. Introduction Cancer is one of the principal reasons for death across the globe. Many types of cancer are poorly controlled through treatment which in itself can cause serious side effects. Due to the unavoidable limitations of cancer screening programs, chemoprevention of cancer has generated great interest and hope in the past few years. Cancer chemoprevention can be achieved through intervention using pharmacologically active agents that can block or hinder the carcinogenic process. Chemopreventive agents can be divided into four categories: hormonal, medication, dietary agents, and vaccines. Hormonal chemopreventive agents are found to be useful in steroid-related cancers. They are classified into two subcategories: anti-estrogens and anti-androgens. • Anti-estrogens: Selective estrogen receptor modulators (SERMs) form a group of compounds that exhibit a varying level of tissue-specific estrogen receptor (ER) activity which can be antagonistic but also agonistic on the target tissue. A meta-analysis of data from nine clinical trials compared the use of SERMs (tamoxifen, raloxifene, arzoxifene, or lasofoxifene) with placebo controls reported a big decrease in carcinoma incidence, but not in carcinoma mortality. The use of SERMs 77

as primary prevention drugs for breast cancer in clinical practice is limited. Reasons include the fear of adverse effects, the absence of reasonably accurate and feasible methods for assessing individual risk, insufficient public and professional information, and medication costs. Another group of anti‑estrogens are the aromatase inhibitors (AIs) that convert androgens into estrogens by inhibiting the enzyme aromatase, which catalyzes the aromatization procedure. • Anti-androgens: Both testosterone and dihydrotestosterone (DHT) are essential for normal growth and functioning of the prostate. The role of anti-androgens in prostate cancer prevention relies on the hypothesis that androgens may be implicated in the etiology of prostate cancer and that suppressing DHT synthesis may inhibit carcinogenesis. 5-alpha-reductase is the enzyme that converts testosterone to the more active intracellular androgen DHT; the anti‑androgens 5-alpha-reductase inhibitors (5-ARIs) block the process by inhibiting this enzyme. Two 5-ARIs - finasteride and dutasteride, have been tested as chemopreventive agents for prostate cancer. Medication: Besides Aspirin and other anti-inflammatory drugs, Statins and Metformin feature under this category of chemopreventive agents. Aspirin: Since inflammation is linked to carcinogenesis, agents with anti-inflammatory effects such as non-steroidal anti‑inflammatory drugs (NSAIDs) like aspirin could have cancer chemopreventive effect. Evidence from randomized trials and observational epidemiological studies suggests that regular prophylactic aspirin use reduces the mortality from colorectal cancer in the general population. Statins are used as cholesterol-lowering drugs but have also drawn attention as potential cancer chemopreventive agents. In meta-analysis studies, a modest decrease in colorectal cancer risk with statin use was indicated; there is currently no conclusive evidence for cancer chemopreventive effect of statins. Metformin is a drug prescribed for type 2 diabetes. The crucial role of energy metabolism in cell growth and proliferation implies 78

that anti-diabetic or metabolism-altering drugs may hold cancer chemopreventive or even therapeutic value. Epidemiologic studies indicate a decreased cancer risk in diabetics treated with metformin versus other anti-diabetic medication. Dietary agents: A large number of dietary micronutrients have interested the scientific community as potential cancer chemopreventive agents. • Carotenoids are fat-soluble red/orange pigments with antioxidant properties. Fruits and vegetables provide around 50 carotenoids, only half of which are absorbable. Alpha and beta carotene, lutein and lycopene are the most common dietary carotenoids. Beta-carotene is the most widely studied protective carotenoid. Of concern is the recent finding that high dose beta-carotene supplements increase the carcinoma risk in current smokers. Dietary lycopene found mainly in tomatoes is inversely related to adenocarcinoma risk. • Vitamin A or retinol is required for the upkeep of normal cell growth and differentiation. Retinoids (vitamin A along with its dietary precursor beta-carotene) were the first agents to be tested in large population-based trials. The CARET trial within the United States did not derive any gain from retinol or beta- carotene supplementation among smokers. • Folic acid or folate, a water-soluble vitamin B, is a crucial cofactor in one-carbon metabolism. There is not enough evidence about its potential tumor-promoting effect in humans. Folate shows dual modulatory effect on colorectal carcinogenesis depending on timing and dosage, and is not recommended for colorectal cancer chemoprevention. • Vitamin C is a water-soluble antioxidant and enzyme cofactor. Humans cannot synthesize it and must obtain it through diet. Vitamin C exists in a reduced ascorbic acid form and an oxidized dehydroascorbic acid form. Expert panels at the World Cancer Research Fund (WCRF) and the American Institute for Cancer Research had concluded in 1997 that dietary vitamin C could reduce cancer risk at several sites including the esophagus, but only the evidence for reduced esophageal cancer risk was 79

considered probable in their updated 2007 report. Vitamin C supplements do not modify cancer risk. • Vitamin D plays a crucial role in calcium metabolism and various other physiological functions. Results from randomized trials did not demonstrate an effect of vitamin D supplementation on colorectal cancer risk. Hence, there are suggestions for a minimum vitamin D intake within the context of colorectal cancer prevention. • Vitamin E is a fat-soluble vitamin with antioxidant activity. The Physicians’ Health Study had reported null results for vitamin E supplementation vis a vis prostate and overall cancer risk. In the Selenium and Vitamin E Cancer Prevention Trial (SELECT) in men, vitamin E taken alone or with selenium did not decrease prostatic adenocarcinoma risk. A subsequent report noted a rise in adenocarcinoma risk in people who received vitamin E. Current evidence does not support the role of vitamin E for cancer prevention. • Calcium is a vital nutrient that plays a crucial role in muscle contraction, cellular growth, cell adhesion and bone formation. There is concern that high calcium intake may increase glandular cancer incidence. The evidence on diets rich in calcium or dairy products is limited but suggestive, while evidence on calcium supplements is limited. • Flavonoids are polyphenolic compounds that inhibit carcinogen-activating enzymes and possess antioxidant properties. Over 5,000 flavonoids have been classified into subclasses based on their range and structural complexity. Fruits, vegetables, tea and wine are the primary dietary sources of flavonoids. Epidemiologic data though not conclusive suggest a protective role of flavonoids on cancers of the lung, breast, colon, and prostate. • Multivitamin/ multi-mineral supplements: A meta-analysis of randomized controlled trials had in 2013 concluded that multivitamin/ multi-mineral use had no effect on cancer prevention. The expert panel of the WCRF report concluded from the evidence from its review of trials failed to show 80

that micronutrient supplements have any benefits in cancer survivors, and in fact suggested that high-dose supplements may be harmful. Vaccines for cancer prevention: Two vaccines against infectious agents are currently being utilized in clinical practice for the prevention of cancer; the vaccine against the hepatitis B virus (HBV) and the vaccine against human papillomavirus (HPV). The HBV vaccine was developed in the late 1960s. Chronic HBV infection is a major cause of hepatocellular carcinoma, and by preventing the infection and chronic carriage state, the HBV vaccine provides protection against hepatocellular carcinoma. HPV vaccination was introduced much later than HBV vaccination, approved by the FDA in the mid-2000s. There are more than 40 HPV types that infect human mucosal surfaces, but most infections are asymptomatic and transient. However, certain oncogenic types that persist can cause cervical cancer and other, less common, cancers, including cancers of the anus, penis, vulva, vagina, and oropharynx. Although history of use of this vaccine is not long, current evidence suggests that it is both effective and safe. Conclusions The notion of chemoprevention is appealing because it implies evasion of suffering caused by the diagnosis of cancer - the disease itself and its treatment. As chemoprevention refers to the widespread and long-term use of compounds by the “healthy” population, safety is an issue that must be addressed in studies with long follow-up in large segments of the population to identify even the rarest side effects. At present there are limitations to the documented effectiveness of cancer chemopreventive agents, and dissension about the efficacy of aspirin. It is clear that a diet rich in vegetables and fruits extends more protection than individual micronutrients. Hormonal agents and vaccines are likely to show positive outcome as cancer chemopreventive agents in the coming years. References Cuzick J, Sestak I, Cawthorn S, et al.: Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. Lancet Oncol. 2015;16(1):67–75. 10.1016/S1470-2045(14)71171-4 81

Thorat MA, Cuzick J: Role of aspirin in cancer prevention. Curr Oncol Rep. 2013;15(6):533–40. 10.1007/s11912-013-0351-3 Bonovas S: Statins: do they have a potential role in cancer prevention and modifying cancer-related outcomes? Drugs. 2014;74(16):1841–8. 10.1007/s40265-014-0309-2 DeCensi A, Puntoni M, Goodwin P, et al.: Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila). 2010;3(11):1451–61. 10.1158/1940- 6207.CAPR-10-0157 Omenn GS, Goodman GE, Thornquist MD, et al.: Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334(18):1150–5. 10.1056/NEJM199605023341802 Zhang X, Giovannucci E: Calcium, vitamin D and colorectal cancer chemoprevention. Best Pract Res Clin Gastroenterol. 2011;25(4‑5):485–94. 10.1016/j.bpg.2011.10.001 Lippman SM, Klein EA, Goodman PJ, et al.: Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2009;301(1):39–51. 10.1001/jama.2008.864 Romagnolo DF, Selmin OI: Flavonoids and cancer prevention: a review of the evidence. J Nutr Gerontol Geriatr. 2012;31(3):206‑38. 10.1080/21551197.2012.702534 Macpherson H, Pipingas A, Pase MP: Multivitamin-multimineral supplementation and mortality: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2013;97(2):437–44. 10.3945/ ajcn.112.049304 Monographs on the Evaluation of Carcinogenic Risks to Humans: HPV. IARC Scientific Publications No. 90. International Agency for Cancer Research. Lyon,2005 World Cancer Research Fund/American Institute for Cancer Research. Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Washington DC: AICR, 2007 ***** 82

Epigenetics in Radiation Biology: Potential targets for better clinical outcome Asmita Sharda 1, 2 and Sanjay Gupta 1, 2, # 1Epigenetics and Chromatin Biology Group, Gupta Lab, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai- 410210, MH, India. 2Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, MH 400085, India. # [email protected] With the discovery of radiation in the early 1900s, radiotherapy has become an indispensable part of the healthcare sector. Radiotherapy is an important therapeutic intervention in many tumor types and it has been utilized to treat different type of cancers as either a primary therapy or an adjuvant treatment. However, local recurrence after radiation continues to be a major hindrance. This has been termed as cellular radio-resistance, which might be acquired during the course of radiotherapy or could be influenced by multiple biological factors (1). Ionizing Radiation (IR) leads to hydrolysis of water molecules and generation of Reactive Oxygen Species (ROS). These ROS act in a direct mode and damage the phosphodiester backbone of the DNA, mostly causing DNA Double Strand Breaks (DSBs). DSBs are the most deleterious form of DNA damage. If a DSB is un- and/ or misrepaired, it compromises the genomic stability of the cell by causing gross chromosomal aberrations like translocation and deletion. Such genetic abnormalities could lead to chromosomal instabilities and subsequently maladies such as cancer. Apart from genetic anomalies, epigenetic deregulation also occurs during cancer development and progression. Epigenetics term basically defines “above” or “on top of” genetics. It is an evolving field that studies heritable changes without any 83

change in the underlying DNA sequence of the organism (2). Fortunately epigenetic modifications are readily reversible in nature, unlike genetic alterations which are irreversible. The major modifications include chromatin remodeling, histone modifications, DNA methylation and non-coding RNA mechanisms (Figure 1). The both environment and distinct lifestyle can directly impact epigenetic phenomena. These changes may be mirrored at several stages through an individual’s life and even in future generations. Figure 1. Factors affecting epigenetic phenomena (Adapted from Reference 3) Epigenetic changes determine whether genes are turned ‘on’ or ‘off’ and thereby regulate the synthesis of RNA and proteins in cells, confirming that only required proteins are synthesized. For example, RNA and proteins that function in liver cells are not produced in brain cells. Thus, the arrangements of epigenetic modification differ between individuals, different tissues within an individual, and even different cells. The best described example is of monozygotic twins. Monozygotic twins (also known as identical twins) develop from a single fertilized egg that separate in two during early stages of development, and have hundred percent identical DNA sequence, but substantial phenotypic changes exist between them. Also, cloned animals provide another example of how epigenetics provide phenotypic alterations in organisms that have identical genetic sequences (3). 84

Histone modifications, one of the key epigenetic mechanisms, are indispensable to modulate chromatin architecture and have a very important role to play in cellular processes such as transcription, replication, cell cycle and DNA repair. Chromatin is a nucleoprotein complex, comprising of functional units called nucleosomes. A nucleosome is formed when negatively charged DNA wraps around an octamer of special proteins called histones. The highly basic nature and small size of histones helps in facilitating this histone- DNA interaction and subsequently packages the DNA in a micron scale nucleus. Histones that form the octamer are called core histones and are of 4 types - Histones H2A, H2B, H3 and H4 (Figure 2). Figure 2. DNA packaging to chromosomes: a hindrance in gene function The incorporation or removal of Post-Translational Modifications (PTMs) like acetylation, methylation on specific amino acid residues of histones are known to alter charge of histone proteins and thereby modulate global and/or local chromatin architecture, thus influencing critical cellular processes (2). Several studies have shown the association between epigenetic changes and disorders like cancers, mental retardation associated disorders, immune disorders, neuropsychiatric disorders and pediatric disorders. Several studies have shown that the chromatin organization changes during different phases of the cell cycle (G1, S, G2 and M), affecting gene expression and thus the cell fate. Cells in G1 phase have preferentially accessible chromatin and during G2 phase nucleosomes condense to form chromosomes (4). 85

Figure 3. Differential chromatin organization in different phases of cell cycle (Adapted from Reference 4) Cell cycle is an important determinant for achieving success in radiotherapy, as different cell cycle phases have variable survival towards radiation. Interestingly, each cell cycle phase responds differently to radiation induced DNA damage, with mitosis being the most radio-sensitive and S-phase being the most radio- resistant in nature, intrinsically. DNA Damage Response (DDR) is one of the most indispensable processes for the cell. There are various histone PTMs like histone methylation, acetylation and ubiquitination that change in response to DNA damage (5). One of the key histone PTM that plays an important role in DDR is histone phosphorylation. A very extensively studied and important example is that of histone H2AX phosphorylation (γH2AX) in response to DNA damage. Therefore, it may be possible that the application of new therapies to target the epigenetic machinery of cancer cells with cell cycle specificity could be used to switch resistant cancer cells to more sensitive phenotypes for radiotherapy. Extensive understanding is required in the field of chromatin architecture modulation that takes place in each phase of the cell cycle after radiation induced DNA damage to provide better therapies. Thus, it may be interesting to understand how changes in chromatin can influence DNA repair response in each phase of the cell cycle. This may lead to a better understanding if there is actually any epigenetic basis to radio resistance. Our group had initiated a study to find out cell cycle phase specific 86

changes in histone modifications in response to DNA damage. Our published findings elucidated the complete kinetics of histone modification H3S10ph (Histone H3 seine 10 phosphorylation) and demonstrated its decrease in response to DNA damage only in the G1 phase of the cell cycle. Additionally, there was a down- regulation of the responsible enzymes, MAPK (Mitogen activated protein kinase) and pERK (phosphorylated extracellular signal- regulated kinase) in response to DNA damage (6, 7). Mitosis is the most radiosensitive phase of the cell cycle. In mitotic cells, histone marks H3S10ph do not decrease in response to DNA damage contrasting to G1 phase cells. However, the levels of H3S10ph decreased in a cell cycle dependent manner, but did not recover only in damaged mitotic cells. A population consisting of bi- nucleated tetraploid cells was generated after radiation of mitotic cells, and had potentially decreased survival. Our and other studies suggest how differential behavior of histone PTMs in response to genotoxic stresses affects the cellular outcome in terms of cell survival, in a cell cycle phase dependent manner. Studies strongly suggest that key epigenetic differences between mitotic and interphase cells could lead to differences in their DDR. Therefore, an understanding of the epigenetic landscape during acquirement of resistance during cancer and features of surviving cells could open up new avenues for utilization of next- generation mitotic inhibitor therapy or combinatorial therapies with epi-drugs like HDAC inhibitors to target the intrinsically radio-resistant cell cycle population. References 1. Chang D S, Lasley F D, Das I J, Mendonca M S and Dynlachts J R. Basic radiotherapy, physics and biology. 2014; Springer International Publishing, New York. 2. Felsenfeld G. A brief history of epigenetics. Cold Spring Harbor perspectives in biology. 2014 Jan 1;6(1):a018200. 3. Kanherkar R R, Bhatia-Dey N, Csoka A B. Epigenetics Across the Human Lifespan. Frontiers in Cell and Developmental Biology. 2014; 2:49. 87

4. Ma Y, Kanakousaki K and Buttitta L. How the cell cycle impacts chromatin architecture and influences cell fate. Front. Genetics, 2015; 6:19. 5. Soria G, Polo SE, Almouzni G. Prime, repair, restore: the active role of chromatin in the DNA damage response. Molecular cell. 2012 Jun 29;46(6):722–34. 6. Sharma AK, Bhattacharya S, Khan SA, Khade B, Gupta S. Mutation Research / Fundamental and Molecular Mechanisms of Mutagenesis Dynamic alteration in H3 serine 10 phosphorylation is G1-phase specific during ionization radiation induced DNA damage response in human cells. Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis. 2015;773:83–91. 7. Sharma AK, Khan SA, Sharda A, Reddy D V, Gupta S. Mutation Research / Fundamental and Molecular Mechanisms of Mutagenesis MKP1 phosphatase mediates G1-specific dephosphorylation of H3Serine10P in response to DNA damage. Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis. 2015;778:71–9. ***** 88

About the Author Dr. Sanjay Gupta Dr. Sanjay Gupta is the head of Epigenetics and Chromatin Biology Group at Tata Memorial Centre, Navi Mumbai. He obtained his Ph.D. from the Banaras Hindu University in the area of aging, chromatin biology and gene regulation. Dr. Gupta, after his post- doctoral and DST-young scientist fellowships, is deciphering ‘how epigenetic component, histones and histone modifying enzymes are involved in the pathogenesis of cancer, resistance mechanisms and DNA repair’. His group is exploiting these epigenetic changes for biomarker development and epi-drugs for their therapeutic potential. Dr. Sanjay is an active contributor to global epigenetics science and innovation. Ms. Asmita Sharda is a senior research scholar in his group. 89

SPILLWAY OF SOULS

WINSOME WINTER Dr. Nikhat Bano Our cajoleries of wintry nights, our meetings between silky whites; The witness is that silent morning star, hiding behind sun after a rumour of war; Our each night is like a fresh footprint, carved with the knife of this frosty wind; O’ Winter! Do visit our love nest faithfully, bellowing life into our love even more zestfully. 91

WINTERY WARMTH Dr. Nikhat Bano Often the way of this world agonised me, swept my entity with its wintery wind, sending chills in my spine as dead men’s graves. Making me sleep once more in dejection, in the cruel world of hope and despair, where the bubbles of joy and sorrow merge with life. But it’s only you my love, who is an eternal sunshine, in the mist-ladden world of mine. I’ve craved more for these wintery chills, to get warmth of your love more than ever. As I wish to count my blessings on me by my lord, by comparing the two worlds of mine - with you and without you. 92

ENCHANTING WINTER Renette Peterson Dsouza These icy cold wintry days of the year I find so enchanting and delightful Especially when you are here, my dear To love and life I find myself grateful. The snow man outside our window keeps watch The blustery winds whistles a soft tune And snowflakes fall softly onto our porch Glittering bright as the silvery moon. The cold somehow brings out the warmth in me As we huddle close by the fireplace I pray that time stands still and let me be All snug and cuddled in your warm embrace. Enthralling, captivating and so grand Our romance in this winter wonderland. Renette Dsouza - an economics graduate from Mumbai, is a writer, editor, entrepreneur, social activist and the co-founder of Astra Foundation, a charitable organization that works for the empowerment of women. A strong believer in the simple policy of ‘Live and let live in peace and love’, and with a passion for travelling, photography and writing poetry from a very young age, her work has been published in many National as well International Anthologies on a broad range of subjects. A recipient of many awards, her poems have also aired on live shows and featured in various e-magazines. 93

LOVE IN WINTER Naghma Shaikh time strives to fulfil the yearnings of a dynamic mind in need of peace and stillness which will change this fretfulness into a muted prelude winter will muffle it with the coldness and the endlessness of the snow and this soft mellowed music of the earth will slowly reach its crescendo with flakes turning into hail and breath forming icicles yet love will not elude those who are in search of it but will find its way noiselessly, mysteriously it will raise its resilient and resurgent spirit in an unwelcoming world defiantly and tenaciously till it suffuses the very air around and infuses the lovers with an all-pervading warmth... Naghma Shaikh expresses her emotions spontaneously. Her freeversepoemswithoutcapitalisation andotherpunctuation (except for commas and the final ellipsis) are based on love, longing, life, faith, passion, despair, disenchantment, pain, suffering, resilience, determination and hope. 94

Literature in Context

Quantum Mechanics and Vedanta Philosophy - Dr. Biswadeep Choudhury -

about the author Dr Biswadeep Choudhury is an Associate Professor of Biochemistry at Silchar Medical College & Hospital. He obtained his MD degree from the prestigious Assam Medical College (formerly Berry White Medical School) and was subsequently awarded with PhD from Assam University, Silchar, for his work related to squamous cell cancers. He has published a number of research papers in national and international journals and his papers have been extensively cited. He has been engaged in biomedical research work in various projects sponsored by the Government of India and its funding agencies. Though his research interests are primarily in the field of cancer genomics and biomarkers, he also has avid interest in diverse areas pertaining to psychology, philosophy and theoretical physics. Dr Biswadeep Choudhury is a member of Lions Club and has always been an enthusiastic participant in various television and radio programmes, awareness cam-paigns, and social activities related to education. He is also a newspaper columnist apart from being a distinguished participant and presenter of research papers in conferences and workshops. An avid reader himself, he loves writing, loves to listen to music, and plays a few musical instruments too. 97

About the Author The Book written by the author This self-published book DEVIL’S NIGHTMARE MONK’S DREAM (published in 2016) is an attempt to explore the neurodynamic basis of hu¬man consciousness through a multidisciplinary approach involving principles of physics, molecular biology, neuroscience and psychology. It offers a refreshingly new perspective of human emotion, perception, and behavior. Rational principles, based on latest scientific discoveries and theories, have been extensively discussed and plenty of ideas, which have taken shape as a result of some decisive out-of-box thinking, have been incorporated in this book. To what extent every¬thing is illusory? What is that mathematical equation which explains the relation be¬tween mental states and circumstances? To what extent are we responsible for what we are and our conditions? How crucial is the role of genetic polymorphisms? Is spirituality the answer, or is something else required? Such questions have been discussed in a lucid language in the book. This book tries to bring about a paradigm shift in our way of thinking. The fascinating fact is that, happiness and sustained well-being actually seem attaina¬ble when we consider the new philosophical paradigm. This book is not a typical self-help manual; it is a book on deep-knowledge. It is not about methods and techniques but about broad based and relevant scientific prin¬ciples that are invaluable for all individuals who desire to live life to the full. 98

Quantum Mechanics and Vedanta Philosophy Dr Biswadeep Choudhury [email protected] The 19th century was proving to be a great one for science. The laws of mechanics had already taken a firm foothold. The heavens no longer seemed mysterious. Causality of events had been explained. Practical applications of all sorts were making people more and more convinced about the truth and reliability of the scientific method. The theory related to the building blocks of matter had taken a definite shape. People started believing that matter was composed of tiny indestructible real particles. Dualism became the dominant thought – matter and mind were considered as separate entities. Physicists got busy with matter, leaving the intangible mind to psychologists and philosophers. The final realization, it seemed, was just round the corner. Leading scientists were certain that very soon, mankind would have complete understanding about a materialistic world and a mechanistic Universe where everything, from tiny electrons to massive stars, operated on the basis of simple deterministic laws. In the hyper-charged environment, consciousness, the very essence of existence, was conveniently forgotten. There were, however, some brilliant rebels who weren’t comfortable with the ideas that were in vogue. They were even less comfortable with the finality of the prevailing theories. They were confident that the theories of Rene Descartes, Sir Isaac Newton and other classical physicists couldn’t be ultimate. The 20th century challengers had arrived. Bohr, Schrodinger and Heisenberg started questioning the established order. Far from reaching the “end of knowledge”, new conundrums opened up and things took an unexpected turn – so unexpected that even the proponents had a hard time believing the implications of their own findings! Pandemonium broke out, initiated by none other than Schrodinger and Heisenberg. Both were maverick scientists and geniuses. Both were voracious readers and faithful believers of Vedanta philosophy. What had actually started as an exploration of eastern spirituality and 99

mysticism gradually developed into a concerted effort to explain the universe on those terms. The outcome was pure beauty! What’s it between the Vedanta and Quantum Mechanics? Just why did ancient scriptures influence brilliant scientific minds to such an extent that a whole new science emerged? Vedanta, the literal translation of which means “end of Vedas”, contains explicit expression of the nature of Ultimate Truth as perceived by seekers of ancient India, written with such perfection and authority that one is left wondering about the source of such profound knowledge and the methods employed in derivation. Vedanta refers to the comprehensive collection of writings called the Upanishads and these were affixed to the Vedas as their final segment. In this broader interpretation, Vedanta includes not only the Upanishads but also covers the whole body of literature which explains and elaborates the teachings of the Upanishads. The Shlokas of Vedanta have been variously interpreted by scholars thereby leading to the emergence of diverse schools of thoughts. Among the different schools, it is Shankaracharya’s Advaita philosophy, with its theoretical mainstay of non-dualism, which has become hugely popular. In totality, Vedanta is synonymous with a perennial philosophy. It’s a universal knowledge of the broad principles and represents a culmination of the searching process. Therefore, it’s no wonder that Vedanta gets recurrently discovered by genuine seekers of truth in every age and culture. The shloka “Brahma Satyam Jagath Mithya, Jivo Brahmaiva Naparah” is, in my opinion, the entire Advaita philosophy summed up within a capsule. It basically means that Brahma is the only truth and the universe is unreal; there is ultimately no difference between the Brahma and Atman. In the terminology of Vedanta, Brahma refers to the Cosmos and Atman refers to the individual consciousness or self. Brahma, Cosmos, God, cosmic force, Absolute Truth are all synonymous as far as interpretation of Vedanta is concerned. Vedanta defines Brahma as the universal spirit, the ultimate reality, and pure consciousness. It is the absolute, beyond which the Universe which cannot be defined. Neti Neti (not this not this) is another expression from Vedanta that attempts a definition of the indefinable Brahma. It means that Brahma has no 100

name, no form, no heterogeneity or qualities that can be ascribed. It’s such a brilliant way to explain a concept that’s so indescribable. It has been used in an all-inclusive sense so as to eliminate every possible specification that may occur! Two other shlokas, both from Chandogya Upanishad, reinforce the philosophical concept of Brahma: “Ekam Evadvitiyam Brahma” and “Sarvam Khalvidam Brahma”. The first shloka essentially means that “Brahma is without a second” while the second shloka means “all this is Brahma”. Another expression from the Aitreya Upanishad, “Prajnanam Brahma”, sums up the primacy of consciousness. It literally means that consciousness is the ultimate reality. It’s obvious that Vedanta philosophy considers the Cosmos and everything in it as an illusion. Consciousness is considered to be primary and all matter is considered as secondary – resulting from the interpretations of the consciousness. Vedanta regards absolute truth as unknowable by the human mind. It can neither be envisioned nor expressed in language. The reality that we see is the apparent reality or the truth pertaining to appearances. This apparent reality is the one which can be described and explained. Vedanta philosophy doesn’t regard apparent reality to be independent of consciousness and the human experience. The world and everything else exists only because we exist as subjective entities to make the observation. And what we observe, according to Vedanta, is not real but merely illusions. The known world cannot exist without us to observe it and therefore it’s a subjective world. The absolute world is never perceived by our senses. It’s the phenomenon of Maya that connects the subjective world with the absolute world, the apparent Cosmos with the actual Cosmos, the perceived reality with absolute reality. Ever since Swami Vivekananda had laid bare the subtle message of Vedanta before the modern audience, the surprising parallels between quantum physics and the philosophy of Vedanta started becoming evident. The discoveries of quantum physics have shaken the very foundations of both epistemology and ontology. However, Vedanta philosophy doesn’t seem to be inconsistent with the newly discovered radical truths. On the contrary, the discoveries have made it clear that the conclusions of Vedanta, enshrined in the Upanishads, are more about real 101

science rather than mystic mumbo-jumbo. The equivalence is in fact striking! Most students of science are familiar with Young’s double- slit experiment with light where it was shown that light creates interference patterns whenever it passes through an opaque plate with two slits and allowed to strike a screen behind. That in fact was the verification of the concept that light has wave like properties. Interference pattern is inexplicable otherwise. Later, curious scientists performed a modified double-slit experiment with electrons instead of light. Interestingly, they noticed interference patterns. It unmistakably indicated that an electron has to be a wave despite being a particle. The electron wave, just like light waves, passes through the double slits and splits into two smaller waves. As the two waves continue to travel, they simultaneously reinforce and cancel out each other at certain points thereby giving rise to the interference patterns. But, why does an electron behave like a wave when it passes through double slits? Does an electron split into two when it reaches the first screen and travels through both slits simultaneously? That cannot be possible if an electron is a particle. It can however be possible if an electron is considered to be a wave. It would then interfere with itself thereby causing an interference effect on the screen. The thing that goes through the slits is not a real particle but a probability wave! The probability wave of each individual electron interferes with itself. But the story doesn’t end there. If the double-slit experiment with electrons is further modified, so as to allow single electrons to pass through at a time and further allowed to be monitored by a suitable detecting device placed strategically at the slits, we get perplexing results. The detector detects single electrons as they pass and interference pattern is no longer formed even though electrons are allowed to pass through the two slits as “waves”. Somehow and mysteriously, the presence of the detector destroys the wave property of the electron and it gets registered as a real particle by the electron detector device. Each single electron manifests as a single real particle when confronted with the observer (i.e. the electron detector). If we do know by any means which of the two slits the electron goes through, it loses its wave character. The very act of measuring or observing makes 102

the electron a particle! Observation (or interaction) collapses the wave function simply by observing (or interacting). What this implies is that: when there’s an “observer” in the form of a mechanical detector or even a conscious human being which is “looking”, electron behaves like a particle. When we are not looking, it behaves as a wave. The laws of quantum mechanics say that interference pattern must disappear if we measure particle properties of the electrons i.e. if interaction with electrons occurs. And this is so irrespective of the experimental set-up. The individual physical effects that may be present in one experiment or another are subservient to the laws of quantum mechanics. In other words, changing over from a probability wave to a real particle, whenever there’s an observation, is inherent in Cosmos. This applies to every single one of the zillions and zillions of electrons in the universe as well as to all sub-atomic particles. We cannot even call them particles anymore because their particulate nature seems to be true only in the context of an observation by an observer. Otherwise, each particle seems to be an omnipresent nebulous entity that’s only energy but not “real” matter. This nebulous entity becomes matter only when it interacts with other nebulous entities. The interaction between two such, or many such, conglomerates of nebulous energy-entities create “outcomes”. The outcome is observable matter in its various forms. Quantum physics therefore implies that matter and all material objects including rocks, soil, wood, leaves, ants, viruses and humans have no real existence but are only “phenomenon” created through the interaction of energy entities. Each electron is an energy entity just as photons and other particles are energy entities. They are not real material entities as we understand matter in the ordinary and intuitive sense. It therefore follows that particles are potentiali¬ties rather than actual physical entities. They exist as potentials, until somebody decides to look. Upon “actual looking” or interacting, it sort of forces the universe to make a determination about which potential is going to be actualized. All this flows from Heisenberg’s Uncertainty Principle. In Heisenberg’s own words: “we have to remember that what we observe is not nature herself, but nature exposed to our method of questioning”. All of existence 103

is fundamentally an unlimited quantum field of energy, a sea of infinite possibilities waiting to happen. Consciousness collapses the wave functions of fundamental particles into actual matter particles that now come into existence in our conceptual space and time. Consciousness seems to be the mysterious entity that influences probability waves. Our Consciousness experiences energy as matter. The observer is not apart from the observa-tion. The observer simultaneously plays a part in creating the reality he is observing. Quantum physics implicates that a conscious observer is required to create reality (real matter) by interacting with energy and unequivocally suggests that nature remains non‑manifest unless we participate. Without nature, we cannot create. Without us, nature would not manifest. It seems that we are all co-creators of reality with nature. This is conceptually very disturbing but the science behind it seems pretty convincing. Something only appears as matter when it’s being observed – observed by sentient beings like us. The mind creates and controls Reality; that’s the quantum mechanics paradigm. It’s however a different matter that this implication becomes rather hard to digest because it goes against our gut feelings about the universe in which we live. Quantum physics has changed the way we view our universe. It’s true that the implications are difficult to comprehend owing to the limitations of our intellect as well as due to the overwhelming suggestions coming from our common sense. Because we humans cannot comprehend the implications easily and take everything for granted, it becomes difficult for us to acknowledge that we may actually be living in an illusory universe where the reality is not what it seems. Perhaps it’s an inherent property of nature to maintain a veil over the Truth. Vedanta philosophy does have a strong argument in its favor because it’s backed by a concrete scientific theory. The confluence of Vedanta philosophy and modern physics is too palpable to be denied. 104

References 1. Swami Vivekananda. The Vedanta Philosophy, An Address Before the Graduate Philosophical Society of Harvard University: March 25, 1896. Published by the Vedanta Society, 1901. 2. Albert Einstein. Physics and Reality: 1936. 3. Robert G Jahn, Brenda J Dunne. On the Quantum Mechanics of Consciousness with Application to Anomalous Phenomenon. 1986. Foundations of Physics. Volume 16, Number 8, August 1986. 4. Swami Jitatmananda. Modern Physics and Vedanta. 6th Edition: 2006. Published by Bharatiya Vidya Bhavan 5. Leonid I Perlovsky. Toward physics of the mind: Concepts, emotions, consciousness, and symbols. Physics of Life Reviews 3 (2006) 23–55. 6. Andy Karr. Reality Isn’t What You Think. Shambhala Sun, July 2007 7. Thomas Filk and Albrecht von Muller. Quantum Physics and Consciousness: The Quest for a Common Conceptual Foundation. 2009. Mind & Matter Vol. 7(1), pp. 59—79 8. Kashyap Vasavada. Concepts of Reality in Hinduism and Buddhism from the perspective of a physicist ***** 105

Existentialism and the Coronavirus - Neeti Parti -

NEETI PARTI Neeti Parti, is an educationist, a prize-winning poetess and writer, an artist, an editor and a trainer. She is Deputy Director, Academic Practices, of a renowned chain of schools and has more than forty schools in India under her charge. As Founder Principal of a well reputed Senior Secondary School, she received the ‘Award for Best Upcoming School in Uttar Pradesh’. She has contributed to more than thirty anthologies, compiled two and edited three. She is an RJ and a television artist. She loves to paint and has exhibited her paintings. She is a keen environmentalist, a nature photographer and associated with many ‘green’ causes. She lives in Gurgaon, India and believes that ‘When the Universe smiles, a child is born, nature’s greatest tribute to itself!’ 107

EXISTENTIALISM AND THE CORONAVIRUS “It’s fun to think that one day our great, great grandchildren may get that much closer to understanding what the hell creation is doing here in the first place, and glimpsing the underlying structure and nature of matter itself. Hopefully they won’t live with the same existential horrors we all quietly face today in our own lives.” The Prince of Milk by Exurb1a Existentialism and its existence is not easily definable. Existentialism is not a school of thought nor can it be reduced to any set of tenets. It is a philosophic as well as a literary movement which flourished in Europe in the nineteenth and twentieth century. It developed in Germany after the country was defeated in World War I and in France after its subjugation in World War II. It is a movement of the dangerous period which completely destroyed man’s faith in the future. Existentialism is also a protest against the impersonal nature of the industrial and technological world when the individual becomes subordinate to the machine. The extreme example of this is probably Ford’s method of production of automobiles during which process man becomes a part of the machine. The conveyor- belt brings a skeleton of a car to where the worker stands and he performs one single mechanical operation like an automaton before the belt moves it on to the next worker. Meanwhile the belt brings on the next car, the worker repeats automatically the same operation as before and so on. It’s a very efficient way of putting together a car but takes apart the man. A car is assembled but an individual is fragmented. Existentialists do not belong to a self-consciously defined homogenous school. They include the Danish protestant theologian and philosopher Soren Kierkegaard, the iconoclastic German atheist Friedrich Nietzsche, the German ontologist Martin Heidegger, the French catholic philosopher Gabriel Marcel, German psychiatrist and philosopher Karl Jaspers, the French philosopher Jean Paul Sartre, the French feminist philosopher and novelist Simone De Beauvoir and the French phenomenologist 108

Maurice Merbeau-Ponty to name a few. Existentialist themes are salient in the literature of Mikhail Lermontov, Fydor Dostoyevsky, Andre Malraux, Anteine de Sain - Exupery, Samuel Bechett, Albert Camus, Jean Genet. Of all existentialists, Kierkegaard, Nietzsche, Heidegger, Marcel, Jaspers and Sartre are the most well-known. Soren Kierkegaard, regarded as the father of modern existentialism said, “Truth is not introduced into the individual from without, but was within him all the time.” Man’s existence, Kierkegaard observed, cannot be discovered in logical existence. It can be discovered in the various modes in which man tries to realize his existence. Kierkegaard expressed individual existence in a manner in which man is not simply a biological, psychological or social animal. “Man is a human being, an actual existent whose life presents more exciting moments, than that of a biological organism which continues to spend its life in a mechanical manner. It is the existence of an individual being who wishes to realize the uniqueness of his existence through his freedom, despair and commitment.” Friederich Nietzsche put forward his philosophical thought in a similar way as Kierkegaard but the difference between Kierkegaard and Nietzsche is that Kierkegaard is preoccupied with becoming a ‘believer’, while Nietzsche does not believe in a ‘higher power’. Nietzsche considered faith to be ‘a continuous suicide of reason’. As an existentialist he gave importance to total liberation of man. According to Nietzsche, “God is dead! God remains dead! And we have killed him!” Existentialists are opposed to all forms of objectivity. The emphasis is on subjective awareness. It is a turning inward, a probing of the self to penetrate to the very centre. Says Sartre, “Assume that existentialism is a new basis for humanism in which man instead of God is the divine creator and in which subjectivity is the sole universe man must explore.” THE PSYCHOLOGICAL EFFECTS OF COVID-19 The world as we knew it ended a few months ago. What we have now is a seemingly alien muddle that we are all trying to make sense of. Aside from an unprecedented global public 109

health crisis, COVID-19 is a ‘not so gentle nudge’ for humanity to rethink things pertinent for our very existence. It brings focus on the manner in which people are dealing with the current situation leading to a ‘person-situation’ analysis as to how the Corona virus is influencing our mind and behaviour. Skinner, an American psychologist believed behaviour is a stimulus-response dynamic. Stimuli are most easily located in the environment we find ourselves in. For many at this time of the Coronavirus, the said environment is simply our home. We have further been advised to be at least six feet away from others, especially while outside and must respond to others within these deterministic guidelines. Freedom is now defined on how we respond to our situation’s stimuli – our home confinement! Many commentators refer to the coronavirus as an existential threat to life as it threatens liberty. Albert Camus, a Nobel Prize-winning existentialist, penned words that fit our present tumultuous times: “The first progressive step for a mind overwhelmed by the strangeness of things is to realize that his feelings of strangeness are shared with all men and that human reality, in its entirety, suffers from the distance which separates it from the rest of the universe. The malady experienced by a single man becomes a mass plague.” While the virtual world is helping people stay in touch with friends, families, and colleagues, most people have reported that they are suffering as they miss the physicality of meeting another human being. For others, the fear of losing their job, being laid off, or not being able to find work is their biggest source of anxiety. Even the ones who have been lucky to keep their jobs are finding themselves in a situation where they have to clock in many more hours of work than they used to. All this is adding to the pandemonium the virus has already created, and the big question now is what will get to people first - the pandemic, or the fear instilled by it?! The coronavirus pandemic is challenging our health, work, family, food and fun. It’s disturbing our peace of mind and forcing us to ask existential questions: Why is this happening to me? Why can’t I go on with my usual life? 110

Who created the problem and why? According to the Indian Psychiatry Society, the number of mental health cases including anxiety and depression has risen 20% since the lockdown was first announced, mostly attributable to the decline in social activity and restricted movement. “The virus thus creates a pandemic of anxiety and depression. The losses incurred as a result of the lockdown imposed by the governments has led to many cases of anxiety, depression and in extreme cases, suicide.” “There are two main problems triggering anxiety in people – loneliness and the fear of death. We are now faced with a one of a kind disease that even researchers and medical practitioners have not figured out . We don’t know of the exact properties of the virus, what its exact symptoms are or whether it is capable of genetic mutation.” says Dr Mohan, a renowned Indian psychiatrist, currently practicing in Australia. ADAPT AND ADJUST TO FIND A NEW MEANING TO LIFE! When the capacity to respond outwardly is limited, as in the case of COVID-19, existentialists teach us to respond inwardly and that when it comes to the great problems of life, attitude is an immeasurable asset. Existential thinkers have a long history of poignant responses to crises and a sampling of these may be of help to us now. In the winter of 1974, cultural anthropologist and Pulitzer Prize winning author Ernest Becker lay dying in a Canadian hospital. At the tender age of 49, Becker had just completed his masterwork Denial of Death and agreed to meet with Sam Keen of Psychology Today magazine for what was to be his final public statement. After several rich interchanges, Keen then posed the clincher: “You have thought harder and more about death than most anybody in the modern world and now I would like to ask you what you can add as a person….” Becker paused a moment, gathered his thoughts, and replied with one of the most spellbinding death-bed reflections ever heard, “The most important thing to know is that beyond the absurdity of one’s life, beyond the apparent injustice of things, beyond the human 111

viewpoint, there is the fact of the tremendous creative energies of the cosmos which are using us for some purposes we don’t know and to be used for divine purposes, however we may be misused, is the thing that I think consoles.” Concepts from Buddhism can provide some solace for our overburdened minds. Some 2,500 years ago in ancient India. Mālunkyaputta, a disciple kept troubling Buddha to answer a series of complex questions. One particular day, he walked up to the Buddha and insisted he be given the answers. Buddha responded with an anecdote of a man wounded with a poisonous arrow coming to see a physician for medication. The man insisted that he would not let the arrow be taken out until he knew who shot him and how. Buddha said by the time all the answers had been given the man would be dead. Buddha’s answer focused solely on the existential facts and aimed at its understanding. We all have the inner freedom to respond positively rather than collapse passively before a tragedy. Existential psychiatrist Viktor Frankl’s ordeal at Auschwitz, the notorious Nazi death camp, is powerfully described in his seminal book ‘Man’s Search for Meaning’. In this work, Frankl elaborates the most dehumanizing circumstances imaginable - daily mass executions, pervasive excrement and disease, harrowing terror and despair. But Frankl found an inner resolve, a wider vision, and a notable capacity to choose his responses to calamity rather than enabling calamity to dictate its terms to him. Hence, Frankl, virtually overcame the horrors by ‘imagining’ his wife. He ‘heard’ her ‘answer’ him, ‘saw’ her smile, and ‘noticed her frank and encouraging look.’ “Real or not,” he concluded, “her look was more luminous than the sun which was beginning to rise.” Soren Kierkegaard wrote profoundly about despair and anxiety. He also pointed to inner choices to approach calamity rather than vain efforts to deny or eradicate it. He believed that inner choices lead to fresh ways to experience life and the improvement of overall health. To reduce the pressure on the overworked primary and secondary mental health task force, our focus should be on self, family, community and primary care. Group psychological support for the 112

unemployed through non-profits and the community will help too. Training as many as possible in suicide prevention techniques and combining crisis intervention by providing psychological first‑aid will help save lives and reduce emotional distress, preventing long-term trauma. We must sit back and reflect at this crucial moment by taking stock of those around us and how our lives are intertwined. If we stay in touch with our inner self while staying at home, we’ll have done our best to fight the virus that is not only biological in nature but is also sociocultural. We must retain our sanity and be flexibly attuned to what the present situation calls for. We have to be vigilant in how we go about our daily lives, taking care not to let anxiety of the future or depression of the past drag us into despondency or hopelessness. All of this is inherently existential. Our authentic, responsible and meaningful response will lead to the best outcome possible. The best way to combat depression is to ingest the beauty that is all around us. Here is a short extract from the inspiring poem ‘Ode on Melancholy’ by John Keats that tells us how…… But when the melancholy fit shall fall Sudden from heaven like a weeping cloud, That fosters the droop-headed flowers all, And hides the green hill in an April shroud; Then glut thy sorrow on a morning rose, Or on the rainbow of the salt sand-wave, Or on the wealth of globed peonies; References: 1. http://www.igntu.ac.in/eContent/IGNTU-eContent- 341445947762-MA-PoliticalScience-2-Dr.GeorgeT.Haokip-Pa per202ContemporaryPoliticalTheory-Unit3.pdf 2. “Existentialism Is a Humanism” Jean-Paul Satre - First published in French in 1946, the book was translated by Philip Mairet and published in English in 1948. 113