James E. Trosko, Ph.D., Professor Emeritus, Dept. Pediatrics & Human Development, Cllege of Human Medicine, Michigan State University, East Lansing, Michigan 48824, USA, E-mail: [email protected]

 

Understanding human health and acute & chronic diseases depends on understanding the nature of homeostatis in multi-cellular organism and how three mechanisms of toxicity can cause disruption of cell proliferation, differentiation, apoptosis, gene regulation and aging, namely, mutagenesis; cytotoxicity and alteration of gene expression( “epigentic toxicity”). All normal and abnormal human phenotypes are the result of a complex gene & environmental interacts, while heritary and somatic mutations do occur in the three fundamental cells of the human body, namely, the few organ-specific adult stem cells, their finite dividing progenitor cells and the non-dividing terminally-differentiated cells, the rate limiting step in converting the individual mutated stem cell depends on the clonal amplification of that single stem cell by epigenetic endogenous agents ( growth factors, hormones and cytokines) or exogenous agents ( pollutants, nutritional and dietary components; drugs, behaviorial factors, such as exercise; smoking, alcohol) that must exceed “threshold” levels; being present for regular and extended periods of time; and in the absence of “anti-promoters”. One classic disease example illustrates how biological and cultural evolutionary changes in the global metabolic diseases are on a “collision” course because of nutrition and dietary changes that have dramatically changed in the last 100 years. Studying the role of the pre- and post- dietary customs after  the atomic bomb survivors illustrates the powerful role they had on incidences had on cancers. One of the major implications of these studies is a potential mechanistic explanation of the Barker hypothesis, namely , exposures to the adult organ-specific adult stem cells to epigenetic agents diuring early embryonic development can modulate risks to diseases later in life.  Finally, while current use of the concept of “Precision Medicine” has primarily focused on genomic mutations, understanding the mechanisms of “epigenesis” will be more important. In addition, while current focus of these epigenetic mechanisms has been at the ultimate down-stream level  ( DNA and nuclear protein methylation/ethylation changes), the pentultimate studies that trigger these changes occur at the up-stream level or at the adult stem cell and cell-cell communication levels).

Reference: Upham, B.L. and Trosko, J.E., “Carcinogenic tumor promotion, induced oxidative stress signaling, modulated gap junction function and altered gene expression”. Antioxidants & Redox Signaling 11: 297-308, 2009. & . Trosko, J.E. Global Health Crisis Caused by the Collision of Biological and Cultural Evolution: Pre-Natal Influences on Acute and Chronic Diseases in Later Life. Planet@risk 2: 271-280, 2014.