The epigenome and top-down causation.

Genes store heritable information, but actual gene expression often depends on many so-called epigenetic factors, both physical and chemical, external to DNA. Epigenetic changes can be both reversible and heritable. The genome is associated with a physical object (DNA) with a specific location, whereas the epigenome is a global, systemic, entity. Furthermore, genomic information is tied to specific coded molecular sequences stored in DNA. Although epigenomic information can be associated with certain non-DNA molecular sequences, it is mostly not. Therefore, there does not seem to be a stored 'epigenetic programme' in the information-theoretic sense. Instead, epigenomic control is-to a large extent-an emergent self-organizing phenomenon, and the real-time operation of the epigenetic 'project' lies in the realm of nonlinear bifurcations, interlocking feedback loops, distributed networks, top-down causation and other concepts familiar from the complex systems theory. Lying at the heart of vital eukaryotic processes are chromatin structure, organization and dynamics. Epigenetics provides striking examples of how bottom-up genetic and top-down epigenetic causation intermingle. The fundamental question then arises of how causal efficacy should be attributed to biological information. A proposal is made to implement explicit downward causation by coupling information directly to the dynamics of chromatin, thus permitting the coevolution of dynamical laws and states, and opening up a new sector of dynamical systems theory that promises to display rich self-organizing and self-complexifying behaviour.

Cancer tumors as Metazoa 1.0: tapping genes of ancient ancestors.

The genes of cellular cooperation that evolved with multicellularity about a billion years ago are the same genes that malfunction to cause cancer. We hypothesize that cancer is an atavistic condition that occurs when genetic or epigenetic malfunction unlocks an ancient 'toolkit' of pre-existing adaptations, re-establishing the dominance of an earlier layer of genes that controlled loose-knit colonies of only partially differentiated cells, similar to tumors. The existence of such a toolkit implies that the progress of the neoplasm in the host organism differs distinctively from normal Darwinian evolution. Comparative genomics and the phylogeny of basal metazoans, opisthokonta and basal multicellular eukaryotes should help identify the relevant genes and yield the order in which they evolved. This order will be a rough guide to the reverse order in which cancer develops, as mutations disrupt the genes of cellular cooperation. Our proposal is consistent with current understanding of cancer and explains the paradoxical rapidity with which cancer acquires a suite of mutually-supportive complex abilities. Finally we make several predictions and suggest ways to test this model.

AFM stiffness nanotomography of normal, metaplastic and dysplastic human esophageal cells.

The mechanical stiffness of individual cells is important in tissue homeostasis, cell growth, division and motility, and the epithelial-mesenchymal transition in the initiation of cancer. In this work, a normal squamous cell line (EPC2) and metaplastic (CP-A) as well as dysplastic (CP-D) Barrett's Esophagus columnar cell lines are studied as a model of pre-neoplastic progression in the human esophagus. We used the combination of an atomic force microscope (AFM) with a scanning confocal fluorescence lifetime imaging microscope to study the mechanical properties of single adherent cells. Sixty four force indentation curves were taken over the nucleus of each cell in an 8 x 8 grid pattern. Analyzing the force indentation curves, indentation depth-dependent Young's moduli were found for all cell lines. Stiffness tomograms demonstrate distinct differences between the mechanical properties of the studied cell lines. Comparing the stiffness for indentation forces of 1 nN, most probable Young's moduli were calculated to 4.7 kPa for EPC2 (n = 18 cells), 3.1 kPa for CP-A (n = 10) and 2.6 kPa for CP-D (n = 19). We also tested the influence of nuclei and nucleoli staining organic dyes on the mechanical properties of the cells. For stained EPC2 cells (n = 5), significant stiffening was found (9.9 kPa), while CP-A cells (n = 5) showed no clear trend (2.9 kPa) and a slight softening was observed (2.1 kPa) in the case of CP-D cells (n = 16). Some force-indentation curves show non-monotonic discontinuities with segments of negative slope, resembling a sawtooth pattern. We found the incidence of these 'breakthrough events' to be highest in the dysplastic CP-D cells, intermediate in the metaplastic CP-A cells and lowest in the normal EPC2 cells. This observation suggests that the microscopic explanation for the increased compliance of cancerous and pre-cancerous cells may lie in their susceptibility to 'crumble and yield' rather than their ability to 'bend and flex'.

Searching for a shadow biosphere on Earth as a test of the 'cosmic imperative'.

Estimates for the number of communicating civilizations in the galaxy, based on the so-called Drake equation, are meaningless without a plausible estimate for the probability that life will emerge on an Earth-like planet. In the absence of a theory of the origin of life, that number can be anywhere from 0 to 1. Distinguished scientists have been known to argue that life on Earth is a freak accident, unique in the observable universe and, conversely, that life is almost bound to arise in the course of time, given Earth-like conditions. De Duve, adopting the latter position, coined the phrase that 'life is a cosmic imperative'. De Duve's position would be immediately verified if we were to discover a second sample of life that we could be sure arose from scratch independently of known life. Given the current absence of evidence for life beyond Earth, the best way to test the hypothesis of the cosmic imperative is to see whether terrestrial life began more than once. If it did, it is possible that descendants of a second genesis might be extant, forming a sort of 'shadow biosphere' existing alongside, or perhaps interpenetrating, the known biosphere. I outline a strategy to detect the existence of such a shadow biosphere.

Finding a second sample of life on earth.

If life emerges readily under Earth-like conditions, the possibility arises of multiple terrestrial genesis events. We seek to quantify the probability of this scenario using estimates of the Archean bombardment rate and the fact that life established itself fairly rapidly on Earth once conditions became favorable. We find a significant likelihood that at least one more sample of life, referred to here as alien life, may have emerged on Earth, and could have coexisted with known life. Indeed, it is difficult to rule out the possibility of extant alien life. We offer some suggestions for how an alternative sample of life might be detected.

Does quantum mechanics play a non-trivial role in life?

There have been many claims that quantum mechanics plays a key role in the origin and/or operation of biological organisms, beyond merely providing the basis for the shapes and sizes of biological molecules and their chemical affinities. These range from Schrödinger's suggestion that quantum fluctuations produce mutations, to Hameroff and Penrose's conjecture that quantum coherence in microtubules is linked to consciousness. I review some of these claims in this paper, and discuss the serious problem of decoherence. I advance some further conjectures about quantum information processing in bio-systems. Some possible experiments are suggested.

Does life's rapid appearance imply a Martian origin?

The hypothesis that life's rapid appearance on Earth justifies the belief that life is widespread in the universe has been investigated mathematically by Lineweaver and Davis (Astrobiology 2002;2:293-304). However, a rapid appearance could also be interpreted as evidence for a nonterrestrial origin. I attempt to quantify the relative probabilities for a non-indigenous versus indigenous origin, on the assumption that biogenesis involves one or more highly improbable steps, using a generalization of Carter's well-known observer-selection argument. The analysis is specifically applied to a Martian origin of life, with subsequent transfer to Earth within impact ejecta. My main result is that the relatively greater probability of a Martian origin rises sharply as a function of the number of difficult steps involved in biogenesis. The actual numerical factor depends on what is assumed about conditions on early Mars, but for a wide range of assumptions a Martian origin of life is decisively favored. By contrast, an extrasolar origin seems unlikely using the same analysis. These results complement those of Lineweaver and Davis.

Quantum vacuum noise in physics and cosmology.

The concept of the vacuum in quantum field theory is a subtle one. Vacuum states have a rich and complex set of properties that produce distinctive, though usually exceedingly small, physical effects. Quantum vacuum noise is familiar in optical and electronic devices, but in this paper I wish to consider extending the discussion to systems in which gravitation, or large accelerations, are important. This leads to the prediction of vacuum friction: The quantum vacuum can act in a manner reminiscent of a viscous fluid. One result is that rapidly changing gravitational fields can create particles from the vacuum, and in turn the backreaction on the gravitational dynamics operates like a damping force. I consider such effects in early universe cosmology and the theory of quantum black holes, including the possibility that the large-scale structure of the universe might be produced by quantum vacuum noise in an early inflationary phase. I also discuss the curious phenomenon that an observer who accelerates through a quantum vacuum perceives a bath of thermal radiation closely analogous to Hawking radiation from black holes, even though an inertial observer registers no particles. The effects predicted raise very deep and unresolved issues about the nature of quantum particles, the role of the observer, and the relationship between the quantum vacuum and the concepts of information and entropy. (c) 2001 American Institute of Physics.