Speciation by physiological selection of environmentally acquired traits.

A chance mutation affecting a single or extremely few individuals in a continuous population will be quickly diluted through interbreeding. Charles Darwin fully appreciated this difficulty with relying on natural selection alone, and suggested an enabling role for geographical isolation in the origin of species. However, Darwin also believed in evolution by the inheritance of acquired traits and in populations of interbreeding animals, both of which would need a different isolating mechanism to overcome dilution and play a role in animal evolution. Historically disputed, the inheritance of acquired characters is now increasingly accepted as a phenomenon, and Charles Darwin himself is acknowledged as closely pre-empting the type of physiology necessary to mediate it in his hypothesis of 'pangenesis'. In this article, we question how the inheritance of acquired traits might overcome the problem of dilution by interbreeding and contribute to evolution. Specifically, we describe how Darwin's young protégé, George Romanes, developed ideas he discussed with Darwin and extended pangenesis to include a conceivable solution published after Darwin's death: physiological selection of fertility. In light of the 'rediscovery' of pangenesis, here we recount physiological selection as a testable hypothesis to explain how environmentally acquired characteristics could become coupled to the generation of species.

Bubbling beyond the barrier: exosomal RNA as a vehicle for soma-germline communication.

'Weismann's barrier' has restricted theories of heredity to the transmission of genomic variation for the better part of a century. However, the discovery and elucidation of epigenetic mechanisms of gene regulation such as DNA methylation and histone modifications has renewed interest in studies on the inheritance of acquired traits and given them mechanistic plausibility. Although it is now clear that these mechanisms allow many environmentally acquired traits to be transmitted to the offspring, how phenotypic information is communicated from the body to its gametes has remained a mystery. Here, we discuss recent evidence that such communication is mediated by somatic RNAs that travel inside extracellular vesicles to the gametes where they reprogram the offspring epigenome and phenotype. How gametes learn about bodily changes has implications not only for the clinic, but also for evolutionary theory by bringing together intra- and intergenerational mechanisms of phenotypic plasticity and adaptation.

Modern physiology vindicates Darwin's dream.

NEW FINDINGS: What is the topic of this review? Revisiting the 2013 article 'Physiology is rocking the foundations of evolutionary biology'. What advances does it highlight? The discovery that the genome is not isolated from the soma and the environment, and that there is no barrier preventing somatic characteristics being transmitted to the germline, means that Darwin's pangenetic ideas become relevant again. ABSTRACT: Charles Darwin spent the last decade of his life collaborating with physiologists in search of the biological processes of evolution. He viewed physiology as the way forward in answering fundamental questions about inheritance, acquired characteristics, and the mechanisms by which organisms could achieve their ends and survival. He collaborated with 19th century physiologists, notably John Burdon-Sanderson and George Romanes, in his search for the mechanisms of transgenerational inheritance. The discovery that the genome is not isolated from the soma and the environment, and that there is no barrier preventing somatic characteristics being transmitted to the germline, means that Darwin's pangenetic ideas become relevant again. It is time for 21st century physiology to come to the rescue of evolutionary biology. This article outlines research lines by which this could be achieved.

A Quantitative Systems Pharmacology Perspective on the Importance of Parameter Identifiability.

There is an inherent tension in Quantitative Systems Pharmacology (QSP) between the need to incorporate mathematical descriptions of complex physiology and drug targets with the necessity of developing robust, predictive and well-constrained models. In addition to this, there is no "gold standard" for model development and assessment in QSP. Moreover, there can be confusion over terminology such as model and parameter identifiability; complex and simple models; virtual populations; and other concepts, which leads to potential miscommunication and misapplication of methodologies within modeling communities, both the QSP community and related disciplines. This perspective article highlights the pros and cons of using simple (often identifiable) vs. complex (more physiologically detailed but often non-identifiable) models, as well as aspects of parameter identifiability, sensitivity and inference methodologies for model development and analysis. The paper distills the central themes of the issue of identifiability and optimal model size and discusses open challenges.

Harnessing stochasticity: How do organisms make choices?

Choice in the behavior of organisms involves novelty, which may be unpredictable. Yet in retrospect, we can usually provide a rationale for the choice. A deterministic view of life cannot explain this. The solution to this paradox is that organisms can harness stochasticity through which they can generate many possible solutions to environmental challenges. They must then employ a comparator to find the solution that fits the challenge. What therefore is unpredictable in prospect can become comprehensible in retrospect. Harnessing stochastic and/or chaotic processes is essential to the ability of organisms to have agency and to make choices.

Cardiac action potential repolarization revisited: early repolarization shows all-or-none behaviour.

In healthy mammalian hearts the action potential (AP) waveform initiates and modulates each contraction, or heartbeat. As a result, AP height and duration are key physiological variables. In addition, rate-dependent changes in ventricular AP duration (APD), and variations in APD at a fixed heart rate are both reliable biomarkers of electrophysiological stability. Present guidelines for the likelihood that candidate drugs will increase arrhythmias rely on small changes in APD and Q-T intervals as criteria for safety pharmacology decisions. However, both of these measurements correspond to the final repolarization of the AP. Emerging clinical evidence draws attention to the early repolarization phase of the action potential (and the J-wave of the ECG) as an additional important biomarker for arrhythmogenesis. Here we provide a mechanistic background to this early repolarization syndrome by summarizing the evidence that both the initial depolarization and repolarization phases of the cardiac action potential can exhibit distinct time- and voltage-dependent thresholds, and also demonstrating that both can show regenerative all-or-none behaviour. An important consequence of this is that not all of the dynamics of action potential repolarization in human ventricle can be captured by data from single myocytes when these results are expressed as 'repolarization reserve'. For example, the complex pattern of cell-to-cell current flow that is responsible for AP conduction (propagation) within the mammalian myocardium can change APD and the Q-T interval of the electrocardiogram alter APD stability, and modulate responsiveness to pharmacological agents (such as Class III anti-arrhythmic drugs).

Rate-dependent activation failure in isolated cardiac cells and tissue due to Na+ channel block.

While it is well established that class-I antiarrhythmics block cardiac sodium channels, the mechanism of action of therapeutic levels of these drugs is not well understood. Using a combination of mathematical modeling and in vitro experiments, we studied the failure of activation of action potentials in single ventricular cells and in tissue caused by Na(+) channel block. Our computations of block and unblock of sodium channels by a theoretical class-Ib antiarrhythmic agent predict differences in the concentrations required to cause activation failure in single cells as opposed to multicellular preparations. We tested and confirmed these in silico predictions with in vitro experiments on isolated guinea-pig ventricular cells and papillary muscles stimulated at various rates (2-6.67 Hz) and exposed to various concentrations (5 × 10(-6) to 500 × 10(-6) mol/l) of lidocaine. The most salient result was that whereas large doses (5 × 10(-4) mol/l or higher) of lidocaine were required to inhibit action potentials temporarily in single cells, much lower doses (5 × 10(-6) mol/l), i.e., therapeutic levels, were sufficient to have the same effect in papillary muscles: a hundredfold difference. Our experimental results and mathematical analysis indicate that the syncytial nature of cardiac tissue explains the effects of clinically relevant doses of Na(+) channel blockers.

Evolution beyond neo-Darwinism: a new conceptual framework.

Experimental results in epigenetics and related fields of biological research show that the Modern Synthesis (neo-Darwinist) theory of evolution requires either extension or replacement. This article examines the conceptual framework of neo-Darwinism, including the concepts of 'gene', 'selfish', 'code', 'program', 'blueprint', 'book of life', 'replicator' and 'vehicle'. This form of representation is a barrier to extending or replacing existing theory as it confuses conceptual and empirical matters. These need to be clearly distinguished. In the case of the central concept of 'gene', the definition has moved all the way from describing a necessary cause (defined in terms of the inheritable phenotype itself) to an empirically testable hypothesis (in terms of causation by DNA sequences). Neo-Darwinism also privileges 'genes' in causation, whereas in multi-way networks of interactions there can be no privileged cause. An alternative conceptual framework is proposed that avoids these problems, and which is more favourable to an integrated systems view of evolution.

Conrad Waddington and the origin of epigenetics.

Denis Noble discusses Conrad Waddington's classic paper, "The genetic assimilation of the bithorax phenotype", published in Evolution in 1956.

LEONARDO DA VINCI AND THE ORIGIN OF SEMEN.

It is well known that Leonardo da Vinci made several drawings of the human male anatomy. The early drawings (before 1500) were incorrect in identifying the origin of semen, where he followed accepted teaching of his time. It is widely thought that he did not correct this mistake, a view that is reflected in several biographies. In fact, he made a later drawing (after 1500) in which the description of the anatomy is remarkably accurate and must have been based on careful dissection. In addition to highlighting this fact, acknowledged previously in only one other source, this article reviews the background to Leonardo's knowledge of the relevant anatomy.

Physiology is rocking the foundations of evolutionary biology.

The 'Modern Synthesis' (Neo-Darwinism) is a mid-20th century gene-centric view of evolution, based on random mutations accumulating to produce gradual change through natural selection. Any role of physiological function in influencing genetic inheritance was excluded. The organism became a mere carrier of the real objects of selection, its genes. We now know that genetic change is far from random and often not gradual. Molecular genetics and genome sequencing have deconstructed this unnecessarily restrictive view of evolution in a way that reintroduces physiological function and interactions with the environment as factors influencing the speed and nature of inherited change. Acquired characteristics can be inherited, and in a few but growing number of cases that inheritance has now been shown to be robust for many generations. The 21st century can look forward to a new synthesis that will reintegrate physiology with evolutionary biology.