The Neo‐Darwinian concept of natural selection is plausible when one assumes a straightforward causation of phenotype by genotype. However, such simple 1:1 mapping must now give place to the modern concepts of gene regulatory networks and gene expression noise. Both can, in the absence of genetic mutations, jointly generate a diversity of inheritable randomly occupied phenotypic states that could also serve as a substrate for natural selection. This form of epigenetic dynamics challenges Neo‐Darwinism. It needs to incorporate the non‐linear, stochastic (...) dynamics of gene networks. A first step is to consider the mathematical correspondence between gene regulatory networks and Waddington's metaphoric ‘epigenetic landscape’, which actually represents the quasi‐potential function of global network dynamics. It explains the coexistence of multiple stable phenotypes within one genotype. The landscape's topography with its attractors is shaped by evolution through mutational re‐wiring of regulatory interactions – offering a link between genetic mutation and sudden, broad evolutionary changes. (shrink)

The stunning possibility of “reprogramming” differentiated somatic cells to express a pluripotent stem cell phenotype (iPS, induced pluripotent stem cell) and the “ground state” character of pluripotency reveal fundamental features of cell fate regulation that lie beyond existing paradigms. The rarity of reprogramming events appears to contradict the robustness with which the unfathomably complex phenotype of stem cells can reliably be generated. This apparent paradox, however, is naturally explained by the rugged “epigenetic landscape” with valleys representing “preprogrammed” attractor states that (...) emerge from the dynamical constraints of the gene regulatory network. This article provides a pedagogical primer to the fundamental principles of gene regulatory networks as integrated dynamic systems and reviews recent insights in gene expression noise and fate determination, thereby offering a formal framework that may help us to understand why cell fate reprogramming events are inherently rare and yet so robust. (shrink)

The fateful combination of (i) the Dunning‐Kruger effect (ignorance of one's own ignorance) with (ii) the nonlinear dynamics of the echo‐chamber between reviewers and editors fuels a self‐reinforcing collective delusion system that sometimes spirals uncontrollably away from objectivity and truth. Escape from this subconscious meta‐ignorance is a formidable challenge but if achieved will help correct a central deficit of the peer‐review process that stifles innovation and paradigm shifts.

As a result of the time‐ and context‐dependency of gene expression, gene regulatory and signaling pathways undergo dynamic changes during development. Creating a model of the dynamics of molecular interaction networks offers enormous potential for understanding how a genome orchestrates the developmental processes of an organism. The dynamic nature of pathway topology calls for new modeling strategies that can capture transient molecular links at the runtime. The aim of this paper is to present a brief and informative, but not all‐inclusive, (...) viewpoint on the computational aspects of modeling and simulation of a non‐static molecular network. BioEssays 26:68–72, 2004. © 2003 Wiley Periodicals, Inc. (shrink)

In the tradition of Western medicine that goes back to Hippocrates, we teach medical students to see beyond the disease and to consider the patient as a whole—to take into account the broader context of family, lifestyle, and environmental exposures. For instance, when measuring blood pressure to diagnose hypertension, family history and situational stress must be considered. Moreover, repeated measurements at multiple time points must be performed to avoid a false-positive diagnosis due to temporary fluctuations of blood pressure. The diagnosis (...) then provides, in adherence to standard-of-care guidelines, the indication for antihypertensive therapy. The recommendations have been... (shrink)

[Without a theorising], a man might as well go into a gravel-pit and count the pebbles and describe the colours. How odd it is that anyone should not see that all observation must be for or against some view if it is to be of any service!Recent years have seen a steady shift of funding programs in biomedical research towards data collection, analysis, and management and its computational analysis. A sizable majority of new major funding opportunity announcements call for assembling (...) large sample banks and databases of molecular profiles of diseases or for computational tools for analysis, display, and distribution of the data. Large consortium projects, such as the Cancer Genome Atlas, the UK Biobank (Allen... (shrink)