Substantia. An International Journal of the History of Chemistry 4(2): 7-13, 2020 Firenze University Press www.fupress.com/substantia ISSN 2532-3997 (online) | DOI: 10.13128/Substantia-865 Citation: L. Schwartz, A. Devin, F. Bouillaud, M. Henry (2020) Entropy as the Driving Force of Pathogenesis: an Attempt of Classification of the Dis- eases Based on the Laws of Physics. Substantia 4(2): 7-13. doi: 10.13128/ Substantia-865 Received: Feb 27, 2020 Revised: May 14, 2020 Just Accepted Online: May 27, 2020 Published: Sep 12, 2020 Copyright: © 2020 L. Schwartz, A. Devin, F. Bouillaud, M. Henry. This is an open access, peer-reviewed article published by Firenze University Press (http://www.fupress.com/substantia) and distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distri- bution, and reproduction in any medi- um, provided the original author and source are credited. Data Availability Statement: All rel- evant data are within the paper and its Supporting Information files. Competing Interests: The Author(s) declare(s) no conflict of interest. Research Article Entropy as the Driving Force of Pathogenesis: an Attempt of Classification of the Diseases Based on the Laws of Physics Laurent Schwartz1,*, Anne Devin2, Frédéric Bouillaud3, Marc Henry4 1 Assistance Publique des Hôpitaux de Paris, Paris, France 2 Université Bordeaux, IBGC, UMR 5095, 33077 Bordeaux cedex, France 3 Institut Cochin, INSERM, CNRS, Université de Paris, Paris, France 4 Laboratoire de Chimie Moléculaire de l’Etat Solide, UMR 7140 UDS-CNRS, Université de Strasbourg, France *Corresponding author: dr.laurentschwartz@gmail.com Abstract. In nature, every physical process involving matter is ruled by the second law of thermodynamics (the total entropy of an isolated system can never decrease over time, and is constant if and only if all processes are reversible). The living cell being a material system should comply by releasing entropy either into the body or into the outside environment. In case of pathologies, entropy cannot be fully exported out- side the body and stays inside the body either in the form of intracellular biomass, of extracellular waste products. We propose hereafter, a new way of classifying diseases by looking at the kind of entropy which cannot be easily excreted outside the body. In such a classification, inflammatory diseases play with entropy through increased heat, biomass synthesis (proliferation of lymphocytes and neutrophils) and secretion of pro-inflammatory proteins (waste products from the cell’s point of view). In the case of chronic inflammation, it induces mitochondrial impairment, owing to the increased osmotic pressure associated to hyper-osmolarity leading to cancer and degenerative diseases (DDs). In the special case of degenerative diseases, cellular entropy is mostly released in the form of wastes, such as amyloid plaques or Lewy’s bodies, and not as proliferating cells as in cancer. Consequently, despite quite different symptoms, these two diseases are proposed to be Janus-like twins, meaning that a remedy active against cancer, should also be active against various forms of DDs. Keywords: entropy, inflammation, cancer, extracellular pressure, classification of dis- eases. INTRODUCTION Life appeared on earth over 3,6 billions years ago. Life is a robust phe- nomenon with similar concentrations of sodium, potassium and chloride in every living cell. Moreover, similar lipoproteins constitute the membranes and the nucleic acids are always built with the same bases.1 Metabolism corresponds to a set of life-sustaining reactions that are doomed to generate entropy. Conversion of food into energy and heat (catabo- http://www.fupress.com/substantia http://www.fupress.com/substantia mailto:dr.laurentschwartz@gmail.com 8 Laurent Schwartz, Anne Devin, Frédéric Bouillaud, Marc Henry lism) generates a large entropy flux. Heat is then released in the environment. Entropy can also be transduced into the building blocks of life such as proteins, membranes or nucleic acids (anabolism) with elimination of wastes. In a previous paper,1 we have shown how it is possible to classify biological molecules into food and wastes, according to their intrinsic entropy content. From such a standpoint, secretion of hormones, growth factors or any other small molecules should be considered as generation of wastes, triggering a mandatory response of the cell. It follows that any kind of “waste” should be considered as a potential signaling molecule. This new positive inter- pretation of “wastes” is a key step allowing deep-rooting of life processes into thermodynamics. As previously stated, in order to be a spontane- ous chemical process, metabolism should always lead to a global increase of entropy. This has allowed deriv- ing a fundamental law of life1 stating that the sum of the entropy of the biomass created added to the entropy of the wastes secreted by the cell added to the heat released should be higher than the entropies of the ingested nutrients. If one considers the cell as being the inside, to comply with the second law of thermodynamics, the excess entropy has to be exported outside the original cell. The excess entropy can be exported either in the form of radiation (heat) or in the form of matter named in biology: biomass. Biomass can be exported in the form of the extracel- lular secretion of molecules. The secreted molecules can be simple deposits of proteins such as amyloid plaques or can be released in the blood and absorbed by other cells. Some of these molecules have special signaling proper- ties and modify the activity of the target cell. Hormones are secreted by the sexual organs and are secreted, first, in the extracellular space then in the blood stream. These hormones bind to specific receptors and are taken up by target cells whose genetic activity they modulate. Similarly, lactate released by glial cells is secreted by the glial cells. Lactate is uptaken by the adjacent neurons, enters the Kreb’s cycle and is burnt releasing entropy outside the body in the form of heat. Entropy of the primary cell can also be released in the form of a daughter cell. The division of the primary cell in two different entities decreases by two the entropy of the original cell. Thus entropy can be released either in the form of heat or in the form of supplementary cells and/or cel- lular waste. Heat will be released outside the body but waste and biomass will stay outside the original cell but inside the body. Taking these premises for granted, it follows that diseases are also regulated by the second law of thermo- dynamics. Accordingly, it appears that diseases are simi- lar across species. For example, cancer,2 but also inflam- mation and degenerative diseases3 have been described across species in almost every metazoan. Life expectan- cy, physiology and metabolism are deeply linked. This was demonstrated through allometry, the study of the relationship of body size to anatomy as first outlined by D’Arcy Thompson.4 Thus, Atanasov has evidenced a line- ar relationship between the total metabolic energy per life span and the body mass of 95 mammals5. Similarly, Lev- ine correlates the life expectancy with the rest heart rate.6 Today diseases are understood by the biologist as a cascade of events resulting in organ failure or in cancer. In deep contrast with biology, physics and thermody- namics do not look for detailed mechanisms, diseases being the mere consequences of fundamental laws. The goal of this paper is to better understand diseases by classification according to the second law of thermo- dynamics. Hereafter, by focusing on clinical symptoms such as the ones described by the physician, it is possible deducing the physical laws at stake. As of today changes in the cycle of life are under- stood as the staightforward consequences of biologi- cal mishaps. They can also be described by the way the affected cells release entropy. Most common diseases (if not all) and conditions can be understood by the modulation of entropy secret- ed by the cell. Entropy synthesized by the cell can either be exported outside the body in the form of heat or be secreted outside the cell in the extracellular space or stay inside the cell. From the cell’s point of view the synthesis of another cell is a way to decrease the entropy by two. 1) Conditions with heat release: circadian rhythm and ovulation During the circadian rhythm, there is an oscillation of the body temperature. Temperature is higher in the evening and lower in the morning.7 At night a decrease in body temperature and cell proliferation as well as the release of hormones such as steroids are observed.7 At time of ovulation, there is an increase in body tem- perature. The sexual hormones are released by the ovaries as cholesterol derived, entropy rich, molecules. The hormone will bind to the receptor and interact with the genome. Entropy will be released mostly in the form of heat. 2) Conditions with biomass synthesis: childhood growth Infancy and childhood are characterized by body growth. Growth starts with fecundation and suddenly 9Entropy as the Driving Force of Pathogenesis: an Attempt of Classification of the Diseases Based on the Laws of Physics stops shortly after puberty. Body growth is harmonious and is partially controlled by mechanical constraints.8 ATTEMPT OF CLASSIFICATION OF DISEASES As of today, diseases are classified by symptoms and affected sites. We will try to classify the pathologies by the typologies of entropy. In a few rare diseases, the amount of entropy can be increased or lowered. Diseases with increased entropy synthesis: drug abuse, hyperthyroidism. During hyperthyroidism there is increased heart rate, weight loss, diarrhea, ner vousness, irritabil- ity, increased perspiration and hand tremors. All these symptoms are caused by increased metabolism second- ary to enhanced hormone secretion. During drug abuse like cocaine or heroin, there is increased heart rate, res- piration and euphoria. Diseases with decreased entropy synthesis: hypothy- roidism, hibernation, abuse of sedative On the contrary, during hypothyroidism, constipa- tion, feeling of tiredness, depression and slow heart rate are observed. Abuse of sedative may result in somno- lence, amnesia and possibly dementia. DISEASES WITH INCREASED BIOMASS SYNTHESIS AND WASTE SECRETION Some benign tumors secrete proteins that are excret- ed in the blood stream. These proteins secreted by the cell could be considered as waste-signaling products. Other proteins have no peculiar biological functions. Benign prostatic adenoma secretes a glycoprotein: Pro- tein Specific Antigen (PSA) which can be measured in the blood stream and used as a diagnostic tool. When present in the blood, this PSA has no known biological function. Other benign tumors can secrete hormones which can be toxic. Best known are the thyroid adeno- ma. Some of these benign tumors secrete high level of T3 and T4 thyroid hormones which can, in turn, be tox- ic to the heart or the brain (thyreotoxicosis). Sclerosis, cancer and neurodegenerative diseases also experience increased biomass synthesis and waste products secretion. They will be discussed later in the paper as they are the direct consequence of inflamma- tion. Diseases with increased waste secretion and tempera- ture: infection and cell death Hyperthermia is present in most acute infections, but also during tissue necrosis (like cardiac infarct). During infection or cell death there is an increase secre- tion of pro-inflammatory proteins or CRP. During car- diac infarct, multiple proteins present in the myocardial cells such as troponin are released in the blood stream. DISEASES WITH INCREASED TEMPERATURE AND BIOMASS SYNTHESIS We were not able to isolate any disease display- ing increased temperature, biomass synthesis and no increased waste production. Diseases with increased heat, biomass and waste syn- thesis: This is the signature of every kind of inflamma- tory disease. a) Acute inflammation As stated by Galen about two thousand years ago, inflammation can be stated as «tumor, dolor and calor». During the inflammatory process there is increased heat, synthesis of biomass and increased waste secretion. Inflammation can be caused by a different set of cir- cumstances such as heat, cold, chemical or bacterial and viral injuries. The name of the inflammatory diseases varies upon the affected organ (Table 1 and 2). To name a few, hepatitis, Crohn’s disease, ulcerative colitis, men- ingitis or bronchitis… Some inflammatory diseases are confined to one organ (for example asthma or psoriasis) but may also extend to several organs (scleroderma, rheumatoid arthritis…). Inf lammatory diseases have all in common an increase in extracellular osmolarity. In every inflamma- tory fluid there is increased osmotic pressure (9, 10, 11 and references therein). The increased osmotic pressure results from an increased oncotic (and osmotic) pressure because of the presence of abnormal level of proteins in the extracellular fluid. This is in line with the fact that the concentration of protein in the extracellular fluid is pathognomonic with inflammation.12 Increased osmotic pressure results in cy tokine and lymphokine secretion as well as the immune response.13,14 The waste products secreted during the inflamma- tory process are well documented. They are the C-Reac- 10 Laurent Schwartz, Anne Devin, Frédéric Bouillaud, Marc Henry tive Proteins (CRP) and numerous cytokines and lym- phokines which can be assessed in the blood.10 This increased secretion of lymphokine and cytokine will result in vasodilatation, increased vascular perme- ability and leukocyte extravasation. The activation of the immune system caused by these lymphokines and cytokines results in phagocytosis and cell death. b) Chronic inflammation  and its consequence: scle- rosis Chronic inflammation is secondary to the persis- tence of the inflammatory agent. For example, hepatitis because of persistent alcohol consumption or unrelent- ing auto immune disease will result into cirrhosis (scle- rosis of the liver). Similarly, persistent bronchitis sec- ondary to excessive smoking will result in change in the Table 1. Entropy release by the affected cell. Heat Biomass Waste Circadian rhythm: day night yes no no yes no yes Growth no yes no Glands no no hormones Infection yes no pro-inflammatory cytokines Cell death (infarct) yes no yes (troponin) Benign tumors no yes PSA/ hormones Degenerative diseases no yes (inflammation) yes (amyloid plaques, Loewy’s body) Cancer no cell multiplication yes (tumor markers) Inflammation yes immune system activation yes (CRP) Ageing no yes (inflammation) yes (CRP) Table 2. classification of diseases. Organ Inflamatory disease Sclerosis Diseases resulting from metabolic rewiring CNS Encephalitis Meningitis Multiple sclerosis Lateral amyotrophic sclerosis, Schizophrenia Glioma, neuroblastoma, Alzheimer, Parkinson, Huntington’s disease CV Myocarditis Pericarditis Atherosclerosis Heart failure GI Crohn’s, Ulcerative colitis Dysfunctional colonic syndrom Adenocarcinoma, Squamous cell carcinoma Reproductive Organs Salpingitis, Orchitis Endometriosis Infertility Seminoma, Adenocarcinoma Liver Hepatitis Cirrhosis Heart failure, hepatocarcinoma Breast Mastitis Adenoma, Fibroma Adenocarcinoma Skin Erysepelas, sun burn Lupus, Psoriasis, sclerodermia Basal cell carcinoma, melanoma Lung Flu, bronchitis Chronic bronchitis Emphysema Pulmonary fibrosis Squamous cell carcinoma, respiratory failure Joints and Bone Arthristis Arthrosis Osteopenia Sarcoma Muscle Myositis Sclerosis Sarcopenia, Sarcoma Eye Inflammation Glaucoma, Cataract, Near sightedness Macular degeneration Immune system Infection Cytopenia, Myelofibrosis Lymphoma, Leukaemia General Inflammation Ageing Ageing 11Entropy as the Driving Force of Pathogenesis: an Attempt of Classification of the Diseases Based on the Laws of Physics lung architecture with lung fibrosis and/or emphysema15 (Table 2). In the confined environment of the affected organ, the intracellular pressure must be equal to the pressure in the extracellular space. The increased multiplication of the epithelial cells will increase mechanical loads on the surrounding fibroblasts. This increased pressure results in the secretion of collagen by the fibroblasts.16 Chronic inflammation has another consequence: the occurrence of cancer17 and neurodegenerative diseas- es.18 This may be in part because of the change in tissue architecture secondary to fibrosis.19 Cancer cells usually originate from the epithelium on the lumen of an organ. In the case of sclerosis, the architecture is distorted resulting in loss of polarity of the epithelial cell. Numerical models demonstrate that the loss of cell polarity alone, is enough to induce an invasive, fractal, dendritic pattern such as seen in can- cer. This transition shows a sequence of morphologies in the following order as a function of loss of polarity: first an apparently normal but already diseased tissue, then metaplastic followed by a dysplastic tissue, and eventu- ally carcinoma first, in situ, then invasive carcinoma.19 c) Cancer and neurodegenerative diseases Because of the Warburg’s effect, cancer has a defec- tive metabolism.20,21 The glucose is mostly degraded into lactic acid which is secreted, as a waste, in the extracel- lular space. Lactic acid is a nutrient for the surrounding benign cells (inflammatory cells, fibroblast or vascular cells).22 Lactic acid is an energy rich molecule. Its release by the cancer cell results in a drastic drop in energy yield1. A molecule of glucose fully burnt by a normal cell releases 36 molecule of ATP. The same molecule of ATP releases only 2 molecules of ATP in a cancer cell. The energy yield is divided by at least 10 times resulting in a decrease in heat export outside the cancer cell1. To compensate this decrease energy yield, there is increase uptake of glucose such as seen in PET scan.1 Cancer could be viewed as the consequence of increased osmotic or oncotic pressure. Recently Ham- raz23 has demonstrated that increased osmotic pressure such as seen in inflammation is enough to induce the Warbug’s effect. The addition to the cell culture medium of mannitol or other osmotic agents induce an increase in glucose uptake and an inhibition of the mitochondrial respiration. Moreover, treatments aiming at restoring the normal metabolic profile inhibit tumor growth.24 Degenerative diseases are also induced by inflam- mation. For example, Alzheimer’s disease can be caused by repeated trauma over a long period.25 In Alzheimer’ s disease the waste products stay in the vicinity of the neurons to form the amyloid plaques. Upon examination under the microscope there is a coexistence of intense apoptosis of neurons and proliferation of the inflamma- tory and the glial cells (increased biomass synthesis). In cancer and in degenerative diseases there is meta- bolic rewiring with decreased ATP synthesis.20,21,26,27 The main difference between cancer and degenerative diseases is the intracellular pH. In cancer cells the intra- cellular pH is alkaline.20,21 There is decrease synthesis of CO2 and carbonic acid resulting in the alkalinisation of the intracellular medium. Alkaline pH is responsible of unrelenting cellular growth.28 To the difference of cancer cells, the main nutrient of neurons is not glucose but lac- tic acid.29 Accumulation of lactic acid results in an acidic pH and cell death.30 CONCLUSION Modern medicine is characterized by a hyper-spe- cialization with the consequence of classifying the vari- ous diseases of the body into unrelated categories. For instance, the rheumatologist takes care of the bones and joints while the pulmonologist considers only the lung. Such a wide diversification of medicine goes in the opposite direction of physics which eagerly looks for unification. This is a very strange situation as both med- icine and physics play with systems made of matter. It follows that if the race for unification observed in phys- ics is a wise goal, the same goal of unification should apply to medicine. In this paper, we proposed a very first step towards unification and classification of diseases. The red lead of our classification was the entropy con- cept, the single known concept ruling time evolution for every kind of material system. We do hope that the use- fulness of the proposed classification will be demonstrat- ed in a very near future. We are sincerely convinced that deep-rooting biology into physics, as done here, should not only be useful for healing diseases but also crucial for the survival of humanity. This is because our mod- ern civilization is currently overwhelmed by wastes with the consequence of heavy pollution of air, water and soils. But, as explained here, wastes management should be synonymous of entropy management. Accumulation of wastes, i.e. entropy that is not released in the form of heat into the intergalactic space, means accumulated disorders with only one possible outcome: death. This applies to a human body, as well as to the whole earth. Time is then ripe enough to put entropy management at the very heart of any kind of living system. 12 Laurent Schwartz, Anne Devin, Frédéric Bouillaud, Marc Henry REFERENCES 1. Henry, M., Schwartz, L. (2019). Entropy export as the driving force of evolution. Substantia, 29-56. 2. Aktipis, C. A., Boddy, A. M., Jansen, G., Hibner, U., Hochberg, M. E., Maley, C. C., Wilkinson, G. S. (2015). Cancer across the tree of life: cooperation and cheating in multicellularity. Philosophical Trans- actions of the Royal Society B: Biological Sciences, 370(1673), 20140219. 3. Schwartz, L., Lafitte, O., da Veiga Moreira, J. (2018). Toward a Reasoned Classification of Diseases Using Physico-Chemical Based Phenotypes. Frontiers in physiology, 9, 94. 4. D›Arcy, W. T. (1952). On growth and form Cam- bridge university press. 5. Atanasov, A. T. (2007). The linear allometric relation- ship between total metabolic energy per life span and body mass of mammals. Biosystems, 90(1), 224-233. 6. Levine, H. J. (1997). Rest heart rate and life expec- tancy. Journal of the American College of Cardiology, 30(4), 1104-1106. 7. Refinetti, R., Menaker, M. (1992). The circadian rhythm of body temperature. Physiology and Behav- ior, 51(3), 613-637. 8. Wertz, X., Schoëvaërt, D., Maitournam, H., Chassig- net, P., Schwartz, L. (2006). The effect of hormones on bone growth is mediated through mechanical stress. Comptes rendus biologies, 329(2), 79-85. 9. Tubiana, M., Attie, E., Flamant, R., Gérard-Marchant, R., Hayat, M. (1971). Prognostic factors in 454 cases of Hodgkin›s disease. Cancer research, 31(11), 1801- 1810. 10. Arai, K. I., Lee, F., Miyajima, A., Miyatake, S., Arai, N., Yokota, T. (1990). Cytokines: coordinators of immune and inflammatory responses. Annual review of biochemistry, 59(1), 783-836. 11. Schwartz, L., Guais, A., Pooya, M., Abolhassani, M. (2009). Is inflammation a consequence of extracellu- lar hyperosmolarity?. Journal of inflammation, 6(1), 21. 12. Fleck, A. (1989). Clinical and nutritional aspects of changes in acute-phase proteins during inflamma- tion. Proceedings of the Nutrition Society, 48(3), 347- 354. 13. Binger, K. J., Gebhardt, M., Heinig, M., Rintisch, C., Schroeder, A., Neuhofer, W.,Voelkl, J. (2015). High salt reduces the activation of IL-4–and IL-13–stimu- lated macrophages. The Journal of clinical investiga- tion, 125(11), 4223-4238. 14. Schwartz, L., Abolhassani, M., Pooya, M., Steyaert, J. M., Wertz, X., Israël, M., Chaumet-Riffaud, P. (2008). Hyperosmotic stress contributes to mouse colonic inflammation through the methylation of protein phosphatase 2A. American Journal of Physi- ology-Gastrointestinal and Liver Physiology, 295(5), G934-G941. 15. Schwartz, L., Balosso, J., Baillet, F., Brun, B., Amman, J. P., Sasco, A. J. (2002). Cancer: the role of extracel- lular disease. Medical hypotheses, 58(4), 340-346. 16. Bishop, J. E., Laurent, G. J. (1995). Collagen turnover and its regulation in the normal and hypertrophying heart. European heart journal, 16(suppl C), 38-44. 17. Coussens, L. M., Werb, Z. (2002). Inflammation and cancer. Nature, 420(6917), 860. 18. Holmes, C., Cunningham, C., Zotova, E., Woolford, J., Dean, C., Kerr, S. U., Perry, V. H. (2009). Systemic inflammation and disease progression in Alzheimer disease. Neurology, 73(10), 768-774 19. Fleury, V., Schwartz, L. (2003). Numerical investiga- tion of the effect of loss of cellular polarity on cancer invasiveness and geometry. Fractals, 11(04), 397-414. 20. Schwartz, L., T Supuran, C., O Alfarouk, K. (2017). The Warburg effect and the hallmarks of cancer. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents), 17(2), 164-170. 21. Seyfried, T. N. (2015). Cancer as a mitochondrial metabolic disease. Frontiers in cell and developmental biology, 3, 43. 22. Warburg, O. (1956). On the origin of cancer cells. Science, 123(3191), 309-314. 23. Hamraz, M., Abolhassani, R., Andriamihaja, M., Ransy, C., Lenoir, V., Schwartz, L., Bouillaud, F. (2019). Hypertonic external medium represses cel- lular respiration and promotes Warburg/Crabtree effect. The FASEB Journal. 24. Schwartz, L., Guais, A., Israël, M., Junod, B., Stey- aert, J. M., Crespi, E., Abolhassani, M. (2013). Tumor regression with a combination of drugs interfering with the tumor metabolism: efficacy of hydroxyci- trate, lipoic acid and capsaicin. Investigational new drugs, 31(2), 256-264. 25. Nogueira, M. L., Hamraz, M., Abolhassani, M., Bigan, E., Lafitte, O., Steyaert, J. M., Schwartz, L. (2018). Mechanical stress increases brain amyloid β, tau, and α-synuclein concentrations in wild-type mice. Alzheimer›s & Dementia, 14(4), 444-453. 26. Gibson, G. E., Sheu, K. F., Blass, J. P. (1998). Abnor- malities of mitochondrial enzymes in Alzheimer dis- ease. Journal of neural transmission, 105(8-9), 855- 870. 27. Kösel, S., Hofhaus, G., Maassen, A., Vieregge, P.,Graeber, M. B. (1999). Role of mitochondria in 13Entropy as the Driving Force of Pathogenesis: an Attempt of Classification of the Diseases Based on the Laws of Physics Parkinson disease. Biological chemistry, 380(7-8), 865-870. 28. Shrode, L. D., Tapper, H., Grinstein, S. (1997). Role of intracellular pH in proliferation, transformation, and apoptosis. Journal of bioenergetics and biomem- branes, 29(4), 393-399. 29. Smith, D., Pernet, A., Hallett, W. A., Bingham, E., Marsden, P. K., Amiel, S. A. (2003). Lactate: a pre- ferred fuel for human brain metabolism in vivo. Jour- nal of Cerebral Blood Flow & Metabolism, 23(6), 658- 664. 30. Ruffin, V. A., Salameh, A. I., Boron, W. F., Parker, M. D. (2014). Intracellular pH regulation by acid-base transporters in mammalian neurons. Frontiers in physiology, 5, 43. Substantia An International Journal of the History of Chemistry Vol. 4, n. 2 - 2020 Firenze University Press Some Thoughts Written on ‘Juneteenth’ of 2020, the Day Commemorating the End of Slavery in the United States, June 19, 1865, at the End of our Civil War Richard G. Weiss Entropy as the Driving Force of Pathogenesis: an Attempt of Classification of the Diseases Based on the Laws of Physics Laurent Schwartz1,*, Anne Devin2, Frédéric Bouillaud3, Marc Henry4 Early Industrial Roots of Green Chemistry - II. International “Pollution Prevention” Efforts During the 1970’s and 1980’s Mark A. Murphy, Ph.D., J.D. …And All the World a Dream: Memory Outlining the Mysterious Temperature-Dependency of Crystallization of Water, a.k.a. the Mpemba Effect Evangelina Uskoković1, Theo Uskoković1, Victoria Wu1,2, Vuk Uskoković1,3,* The Strange Case of Professor Promezio: A Cold Case in the Chemistry Museum Marina Alloisio, Andrea Basso*, Maria Maddalena Carnasciali, Marco Grotti*, Silvia Vicini Estonian scientist in USSR (Memories and reflections about Endel Lippmaa, 1930-2015) Alexandr Vladimirovich Kessenikh The Eminent French Chemist Claude-Louis Berthollet (1748-1822) in the Literature between the 19th and 21th Centuries Aleksander Sztejnberg Communicating Science: a Modern Event Antonio Di Meo