Responses to commentaries on "The gene: An appraisal".

The central conclusions of "The Gene: An Appraisal" are that genetic variance does not underpin biological evolution, and, therefore, that genes are not Mendel's units of inheritance. In this response, I will address the criticisms I have received via commentaries on that paper by defending the following statements: 1. Epistasis does not explain the power-law fitness profile of the Long-Term Evolution Experiment (LTEE). The data from the evolution of natural systems displays the power-law form ubiquitously. Epistasis plays no role in evolution. 2. The common characteristics of living things (natural systems) are described by the principle of least action in de Maupertuis's original form, which is synonymous with the 2nd law of thermodynamics and Newton's 2nd law of motion in its complete form, i.e., F = dp/dt. Organisms strive to achieve free energy balance with their environments. 3. Based on an appraisal of the scientific environment between 1880 and 1911, I conclude that Johannsen's genotype conception was perhaps, the only option available to him. 4. The power-law fitness profile of the LTEE falsifies Fisher's Genetical Theory of Natural Selection, Johannsen's genotype conception, and the idea that 'Darwinian evolution' is an exception to the generic thermodynamic process of evolution in natural systems. 5. The use of the technique of genome-wide association to identify the causes and the likelihoods of inherited common diseases and behavioural traits is a 'wild goose chase' because genes are not the units of inheritance.

The Gene: An appraisal.

The gene can be described as the foundational concept of modern biology. As such, it has spilled over into daily discourse, yet it is acknowledged among biologists to be ill-defined. Here, following a short history of the gene, I analyse critically its role in inheritance, evolution, development, and morphogenesis. Wilhelm Johannsen's genotype-conception, formulated in 1910, has been adopted as the foundation stone of genetics, giving the gene a higher degree of prominence than is justified by the evidence. An analysis of the results of the Long-Term Evolution Experiment (LTEE) with E. coli bacteria, grown over 60,000 generations, does not support spontaneous gene mutation as the source of variance for natural selection. From this it follows that the gene is not Mendel's unit of inheritance: that must be Johannsen's transmission-conception at the gamete phenotype level, a form of inheritance that Johannsen did not consider. Alternatively, I contend that biology viewed on the bases of thermodynamics, complex system dynamics, and self-organisation, provides a new framework for the foundations of biology. In this framework, the gene plays a passive role as a vital information store: it is the phenotype that plays the active role in inheritance, evolution, development, and morphogenesis.

Evolution in two parts: as seen in a new fram ework for biology.

The case has been made that the-gene-centric approach to biology, which has prevailed over the past ~100 years, should be replaced by a fundamental framework based on the cell being a far from equilibrium complex dissipative system, regulated and governed by its phenotype (1, 2), the metaphor for which is a brain. This independent attractor (IA) model is a radical departure from the conventional view based on Wilhelm Johannsen's genotype-conception which has prevailed since 1910. In this prevailing paradigm the gene and the genotype are fundamental in accounting for inheritance, evolution, development, and morphogenesis: the phenotype, upon which natural selection is deemed to act, plays little or no role in these crucial aspects of biology. Here I discuss how the process of evolution might be viewed under the IA model. Based on empirical evidence, evolution can be seen as a two-part process, one part based on thermodynamics and resulting in increased resilience to perturbation of the cellular phenotype (conditioning), and the other part, based on agency exhibited by the evolving organisms. A crucial open question is: should we view the realisation of the phenotype as a matter for biochemistry, or physics.

The gene: An appraisal.

The gene can be described as the foundational concept of modern biology. As such, it has spilled over into daily discourse, yet it is acknowledged among biologists to be ill-defined. Here, following a short history of the gene, I analyse critically its role in inheritance, evolution, development, and morphogenesis. Wilhelm Johannsen's genotype-conception, formulated in 1910, has been adopted as the foundation stone of genetics, giving the gene a higher degree of prominence than is justified by the evidence. An analysis of the results of the Long-Term Evolution Experiment (LTEE) with E. coli bacteria, grown over 60,000 generations, does not support spontaneous gene mutation as the source of variance for natural selection. From this it follows that the gene is not Mendel's unit of inheritance: that must be Johannsen's transmission-conception at the gamete phenotype level, a form of inheritance that Johannsen did not consider. Alternatively, I contend that biology viewed on the bases of thermodynamics, complex system dynamics and self-organisation, provides a new framework for the foundations of biology. In this framework, the gene plays a passive role as a vital information store: it is the phenotype that plays the active role in inheritance, evolution, development, and morphogenesis.

Polygenic scores: Are they a public health hazard?

I argue here that polygenic scores are a public health hazard because the underlying methodology, genome wide association, from which they are derived, incorrectly assumes that the information encoded in the genomic DNA sequence is causal in terms of the cellular phenotype. This is not so when the cell is viewed from the perspective of a) fundamental physics, b) the protein chemistry that characterises the cellular cytoplasm and c) the fundamental requirement for evolution to yield unlimited species diversity.

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.

Discourse on order vs. disorder.

The second law of thermodynamics is on one hand understood to account for irrevocable flow of energy from the top down, on the other hand it is seen to imply irreversible increase of disorder. This tension between the 2 stances is resolved in favor of the free energy consumption when entropy is derived from the statistical mechanics of open systems. The change in entropy is shown to map directly to the decrease in free energy without any connotation attached to disorder. Increase of disorder, just as order, is found to be merely a consequence of free energy consumption. The erroneous association of disorder with entropy stems from an unwarranted assumption that a system could undergo changes of state without concomitant dissipation, i.e., a change in energy.

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

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.

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 Darwin's '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.

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 Darwin's 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.

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.

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.

The role of information in cell regulation.

The organised state of living cells must derive from information internal to the system; however, there are strong reasons, based on sound evidence, to reject the base sequence information encoded in the genomic DNA as being directly relevant to the regulation of cellular phenotype. Rather, it is argued here that highly specific relational information, encoded on the gene products, mainly proteins, is responsible for phenotype. This regulatory information emerges as the peptide folds into a tertiary structure in much the same way as enzymic activity emerges under the same circumstances. The DNA coding sequence serves as a "data base" in which a second category of relational information is stored to enable accurate reproduction of the cellular peptides. In the context of the cell, therefore, information is physical in character and contributes, through its ability to dissipate free energy, to the maximisation of the entropy of the cell according to the 2nd law of thermodynamics.

What mechanisms/processes underlie radiation-induced genomic instability?

Radiation-induced genomic instability is a modification of the cell genome found in the progeny of irradiated somatic and germ cells but that is not confined on the initial radiation-induced damage and may occur de novo many generations after irradiation. Genomic instability in the germ line does not follow Mendelian segregation and may have unpredictable outcomes in every succeeding generation. This phenomenon, for which there is extensive experimental data and some evidence in human populations exposed to ionising radiation, is not taken into account in health risk assessments. It poses an unknown morbidity/mortality burden. Based on experimental data derived over the last 20 years (up to January 2012) six mechanistic explanations for the phenomenon have been proposed in the peer-reviewed literature. This article compares these hypotheses with the empirical data to test their fitness to explain the phenomenon. As a conclusion, the most convincing explanation of radiation-induced genomic instability attributes it to an irreversible regulatory change in the dynamic interaction network of the cellular gene products, as a response to non-specific molecular damage, thus entailing the rejection of the machine metaphor for the cell in favour of one appropriate to a complex dissipative dynamic system, such as a whirlpool. It is concluded that in order to evaluate the likely morbidity/mortality associated with radiation-induced genomic instability, it will be necessary to study the damage to processes by radiation rather than damage to molecules.

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.