Keith Baverstock

Radiation-induced genomic instability: a paradigm-breaking phenomenon and its relevance to environmentally induced cancer.

The existing paradigm governing radiobiology which is fundamental to the estimation of environmental radiation risk, cannot explain the phenomena of radiation induced genomic instability and the bystander effect. Both effects can, however, be understood in terms of the dynamical genome concept, qualitatively described herein. The dynamical genome concept may find further application in better understanding other aspects of biology, most notably the cancer process in general and the consequences of genetic modification.

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 UK Committee on Radioactive Waste Management

The UK Committee on Radioactive Waste Management is charged with recommending to Government, by July 2006, options for the long term management of the UKs radioactive waste legacy. These options should inspire public confidence. Now, more than halfway into the time allotted, we, as two former members of the Committee, express our concerns at the wayward approach that has been adopted. The Committee has placed emphasis on gaining public confidence but this has been done at the expense of recruiting the best scientific expertise in the management of radioactive waste, an act which we believe will actually undermine public confidence. Furthermore, given also the immense importance of this decision to public safety, national security and the national interest, we believe urgent steps should be taken to review the Committees process, its management and its sponsorship.

Towards a unifying theory of late stochastic effects of ionizing radiation

The traditionally accepted biological basis for the late stochastic effects of ionizing radiation (cancer and hereditary disease), i.e. target theory, has so far been unable to accommodate the more recent findings of non-cancer disease and the so-called non-targeted effects, genomic instability and bystander effect, thus creating uncertainty in radiation risk estimation. We propose that ionizing radiation can give rise to these effects through two distinct and independent routes, one essentially genetic, termed here type A, and the other essentially epigenetic, termed type B. Type B processes entail envisaging phenotype as represented by a dynamic attractor and radiation acting as an agent that stresses cellular processes leading to the adoption of a variant attractor/phenotype. Evidence from the literature indicates that type B processes can lead to the inheritance of variant cell attractors and mediate a category of trans-generational effects quite distinct from classical Mendelian inherited disease, which is type A. The causal relationships for radiation-induced somatic human health detriment, i.e., cancer and non-cancer (e.g., cardiovascular) disease, are discussed from the point of view of the proposed classification. This approach unifies at a fundamental level the heritable and late somatic effects of radiation into a single causal framework that has the potential to be extended to the effects of the other environmental agents damaging to health.

Genes without prominence: a reappraisal of the foundations of biology

The sequencing of the human genome raises two intriguing questions: why has the prediction of the inheritance of common diseases from the presence of abnormal alleles proved so unrewarding in most cases and how can some 25 000 genes generate such a rich complexity evident in the human phenotype? It is proposed that light can be shed on these questions by viewing evolution and organisms as natural processes contingent on the second law of thermodynamics, equivalent to the principle of least action in its original form. Consequently, natural selection acts on variation in any mechanism that consumes energy from the environment rather than on genetic variation. According to this tenet cellular phenotype, represented by a minimum free energy attractor state comprising active gene products, has a causal role in giving rise, by a self-similar process of cell-to-cell interaction, to morphology and functionality in organisms, which, in turn, by a self-similar process entailing Darwins proportional numbers are influencing their ecosystems. Thus, genes are merely a means of specifying polypeptides: those that serve free energy consumption in a given surroundings contribute to cellular phenotype as determined by the phenotype. In such natural processes, everything depends on everything else, and phenotypes are emergent properties of their systems.

Understanding of anesthesia - Why consciousness is essential for life and not based on genes.

ABSTRACT Anesthesia and consciousness represent 2 mysteries not only for biology but also for physics and philosophy. Although anesthesia was introduced to medicine more than 160 y ago, our understanding of how it works still remains a mystery. The most prevalent view is that the human brain and its neurons are necessary to impose the effects of anesthetics. However, the fact is that all life can be anesthesized. Numerous theories have been generated trying to explain the major impact of anesthetics on our human-specific consciousness; switching it off so rapidly, but no single theory resolves this enduring mystery. The speed of anesthetic actions precludes any direct involvement of genes. Lipid bilayers, cellular membranes, and critical proteins emerge as the most probable primary targets of anesthetics. Recent findings suggest, rather surprisingly, that physical forces underlie both the anesthetic actions on living organisms as well as on consciousness in general.

Life as physics and chemistry: A system view of biology.

Cellular life can be viewed as one of many physical natural systems that extract free energy from their environments in the most efficient way, according to fundamental physical laws, and grow until limited by inherent physical constraints. Thus, it can be inferred that it is the efficiency of this process that natural selection acts upon. The consequent emphasis on metabolism, rather than replication, points to a metabolism-first origin of life with the adoption of DNA template replication as a second stage development. This order of events implies a cellular regulatory system that pre-dates the involvement of DNA and might, therefore, be based on the information acquired as peptides fold into proteins, rather than on genetic regulatory networks. Such an epigenetic cell regulatory model, the independent attractor model, has already been proposed to explain the phenomenon of radiation induced genomic instability. Here it is extended to provide an epigenetic basis for the morphological and functional diversity that evolution has yielded, based on natural selection of the most efficient free energy transduction. Empirical evidence which challenges the current genetic basis of cell and molecular biology and which supports the above proposal is discussed.

Chernobyl and public health.

In 1992, when the first effects of the Chernobyl accident on the prevalence of thyroid cancer in children were reported,1 they were met with scepticism by the radiological community. 2 3 Some of this scepticism was undoubtedly scientific (“iodine-131 has a low carcinogenic potential”), though some was not. These reservations have now mostly been resolved by re-examination of the data on the relation of exposure to x rays and thyroid cancer and a realisation of just how many children were exposed. It is a cautionary tale of how scientific instinct can mislead: help could have been provided more quickly had it not been for this debate. Nevertheless, similar debates are now obscuring our ability to learn longer term lessons from Chernobyl and provide further help to its victims. Some sceptics, relieved that the fallout had not originated and fallen in western Europe or America, where populations are litigious, were reluctant to concede that environmental sources of radiation could be strongly associated with serious disease. Childhood thyroid cancer has a very low spontaneous incidence in most countries (<1/1 000 000/year). Thus, the appearance of several tens of cases in the region round Chernobyl from a population of under half a million children, giving relative annual incidences of ≥100/1 000 000, should have left little room for doubt that something was seriously amiss. Today there is little dispute that a real increase in thyroid cancer occurred among young people in Belarus, …

Radiation-induced genomic instability in Caenorhabditis elegans

Radiation-induced genomic instability has been well documented, particularly in vitro. However, the understanding of its mechanisms and their consequences in vivo is still limited. In this study, Caenorhabditis elegans (C. elegans; strain CB665) nematodes were exposed to X-rays at doses of 0.1, 1, 3 or 10Gy. The endpoints were measured several generations after exposure and included mutations in the movement-related gene unc-58, alterations in gene expression analysed with oligoarrays containing the entire C. elegans genome, and micro-satellite mutations measured by capillary electrophoresis. The progeny of the irradiated nematodes showed an increased mutation frequency in the unc-58 gene, with a maximum response observed at 1Gy. Significant differences were also found in gene expression between the irradiated (1Gy) and non-irradiated nematode lines. Differences in gene expression did not show clear clustering into certain gene categories, suggesting that the instability might be a chaotic process rather than a result of changes in the function of few specific genes such as, e.g., those responsible for DNA repair. Increased heterogeneity in gene expression, which has previously been described in irradiated cultured human lymphocytes, was also observed in the present study in C. elegans, the coefficient of variation of gene expression being higher in the progeny of irradiated nematodes than in control nematodes. To the best of our knowledge, this is the first publication reporting radiation-induced genomic instability in C. elegans.

The evolutionary origin of form and function

We regard the basic unit of the organism, the cell, as a complex dissipative natural process functioning under the second law of thermodynamics and the principle of least action. Organisms are conglomerates of information bearing cells that optimise the efficiency of energy (nutrient) extraction from its ecosystem. Dissipative processes, such as peptide folding and protein interaction, yield phenotypic information from which form and function emerge from cell to cell interactions within the organism. Organisms, in Darwins ‘proportional numbers’, in turn interact to minimise the free energy of their ecosystems. Genetic variation plays no role in this holistic conceptualisation of the life process.