Epigenetic Regulation of the Mammalian Cell

BACKGROUND: Understanding how mammalian cells are regulated epigenetically to express phenotype is a priority. The cellular phenotypic transition, induced by ionising radiation, from a normal cell to the genomic instability phenotype, where the ability to replicate the genotype accurately is compromised, illustrates important features of epigenetic regulation. Based on this phenomenon and earlier work we propose a model to describe the mammalian cell as a self assembled open system operating in an environment that includes its genotype, neighbouring cells and beyond. Phenotype is represented by high dimensional attractors, evolutionarily conditioned for stability and robustness and contingent on rules of engagement between gene products encoded in the genetic network. METHODOLOGY/FINDINGS: We describe how this system functions and note the indeterminacy and fluidity of its internal workings which place it in the logical reasoning framework of predicative logic. We find that the hypothesis is supported by evidence from cell and molecular biology. CONCLUSIONS: Epigenetic regulation and memory are fundamentally physical, as opposed to chemical, processes and the transition to genomic instability is an important feature of mammalian cells with probable fundamental relevance to speciation and carcinogenesis. A source of evolutionarily selectable variation, in terms of the rules of engagement between gene products, is seen as more likely to have greater prominence than genetic variation in an evolutionary context. As this epigenetic variation is based on attractor states phenotypic changes are not gradual; a phenotypic transition can involve the changed contribution of several gene products in a single step

The Chernobyl Accident 20 Years On: An Assessment of the Health Consequences and the International Response

BACKGROUND: The Chernobyl accident in 1986 caused widespread radioactive contamination and enormous concern. Twenty years later, the World Health Organization and the International Atomic Energy Authority issued a generally reassuring statement about the consequences. Accurate assessment of the consequences is important to the current debate on nuclear power. OBJECTIVES: Our objectives in this study were to evaluate the health impact of the Chernobyl accident, assess the international response to the accident, and consider how to improve responses to future accidents. DISCUSSION: So far, radiation to the thyroid from radioisotopes of iodine has caused several thousand cases of thyroid cancer but very few deaths; exposed children were most susceptible. The focus on thyroid cancer has diverted attention from possible nonthyroid effects, such as mini-satellite instability, which is potentially important. The international response to the accident was inadequate and uncoordinated, and has been unjustifiably reassuring. Accurate assessment of Chernobyl’s future health effects is not currently possible in the light of dose uncertainties, current debates over radiation actions, and the lessons from the late consequences of atomic bomb exposure. CONCLUSIONS: Because of the uncertainties over the dose from and the consequences of the Chernobyl accident, it is essential that investigations of its effects should be broadened and supported for the long term. Because of the problems with the international response to Chernobyl, the United Nations should initiate an independent review of the actions and assignments of the agencies concerned, with recommendations for dealing with future international-scale accidents. These should involve independent scientists and ensure cooperation rather than rivalry

Crick’s sequence hypothesis - a review

Health care based on gene sequencing and genomics is increasingly becoming a reality: it is timely to review Crick’s sequence hypothesis for its fitness for this purpose. The sequence hypothesis is central to the prediction and correction of disease traits from gene sequence information. Considerable success in this respect has been achieved for rare diseases, but for the dominant part of the human disease burden, common diseases, little progress has been made since the completion of the sequencing of the human genome. It is argued here that the sequence hypothesis, namely the assumption that peptides will fold spontaneously to the native state protein, thus retaining the information coded in the originating genes, is not supported by a realistic physics-based assessment of the peptide to protein folding process

Comments on Rithidech, K.N.; et al. Lack of Genomic Instability in Bone Marrow Cells of SCID Mice Exposed Whole-Body to Low-Dose Radiation. Int. J. Environ. Res. Public Health 2013, 10, 1356–1377

I would like to take issue with Rithidech et al., authors of the paper entitled “Lack of genomic instability in mice at low doses” [1] who claim to have shown that their results on the measurement of late occurring chromosome aberrations after irradiation of SCID mice with X-rays show that lower doses (0.05 Gy) do not induce genomic instability. Their earlier work at higher doses (0.1 and 1.0 Gy) on the same strain of mouse indicated that de novo chromosome aberrations were detected at 6 months post-irradiation. This was taken, almost certainly correctly, to be an indication of the presence of genomic instability: late appearing chromosome damage, as the authors note, seems to be a reliable indicator of the process. The lack of de novo chromosome aberrations at 6 months post-irradiation, however, cannot be taken as evidence of the absence of genomic instability. In drawing their conclusion of a “lack of genomic instability ….” the authors have committed two category errors