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.

Impoverished Conceptions of Gene Causation and Therapy in Developmental Neurology.

We offer a primer to the modifiability of genetic neurological disease, particularly during development. One goal is to harness several unexpected observations made in the course of experimental gene modification or therapy into an explanatory conceptual context based on biological first principles. To this end, we anchor growing, disparate reports of unusual or untoward effects to a plausible framework wherein genes exhibit different degrees of modifiability and may result, when mutated or therapeutically modified, in unsuspected consequences. We propose that genetic pathogenic variant effects and modifiability depend on the number and complexity of associated protein-protein or higher-order interactions. Thus, gene malleability may range from that characteristic of the favorably modifiable primarily structural genes that subserve relatively invariant or circumscribed phenomena such as cell shape to that typical of some transcription factors, which are less functionally predictable when altered. The latter may be expressed developmentally, in compartmentalized manner, or only intermittently and yet exert vastly ramified influences sometimes circumscribed only to select species. We also argue that genetic diseases may steer the organism toward often poorly understood biological end points and co-opt multiple processes into hardly modifiable biology. Addition or modification of genes to approximate a normal state not previously experienced by the organism may lead to further aberration due to extraneous interference with the native biology of the disease state. Therefore, an understanding as perspicuous as possible of gene function, regulation, modifiability, and biological directionality down to seemingly minute but disease-relevant consequences is a prerequisite to intervention. Although we provide some groundwork steps to such an understanding, this may occasionally prove unattainable.

Silvio Weidmann: laying the foundations for unravelling the mechanism of heart rhythm.

Silvio Weidmann laid the basis of cardiac electrophysiology and was the forerunner in the search for mechanisms governing the electrical activity of the heart in his legendary first studies of Purkinje fibres in the 1950s. His work was the cornerstone of research in this field for many generations, and countless cardiologists and electrophysiologists have based their studies on the knowledge generated by Weidmann's pioneering data. This review summarizes his key contributions from the first intracellular recordings of cardiac membrane potentials in 1949 to the publication of his monograph in 1956. That summary is followed by an imagined dialogue between the authors and Silvio Weidmann himself, in the format of a one-act play. Both of us have such good recollections of our real-life conversations with Silvio Weidmann that we decided we could achieve a better feel for the history and issues by using a dialogue format. We hope that, in that way, we may transmit the character of Silvio Weidmann better for those readers who will not have known him personally. Silvio Weidmann was an extraordinarily sensitive and conversational person as well as a great scientist, and we feel it is worth the effort to convey that fact here. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

Origins and demise of selfish gene theory.

The idea of The Selfish Gene, first published in 1976, grew out of the Modern Synthesis of evolutionary biology formulated by Julian Huxley in 1942, and more specifically from George Williams' Adaptation and Natu - ral Selection in 1966. It presents a severely narrowed down version of Huxley's synthesis, which developed in the 1960s following the formulation of the Cen tral Dogma of molecular biology by Francis Crick. The idea rests on three assumptions: the isolation of the genome from any influences by the soma and its development in interaction with the environment (the Weis - mann Barrier), one-way causation from DNA to proteins (The Central Dogma), and the autoreplication of DNA (Schrödinger's aperiodic crystal). All three of these assumptions have now been shown to be incorrect. The 'replicator' (DNA) is not independent of the 'vehicle', the organism itself, so that The Selfish Gene can no longer be regarded as a valid scientific hypothesis.

Biological relativity revisited: the pre-eminent role of values.

Multilevel interpretations of development and evolution take to heart the contextual nature of both those processes, and so necessarily assume top-down causation occurs, right down to the physics level. In this article we revisit the Principle of Biological Relativity proposed by Noble in 2012, where all emergent levels of organisation are equally causally valid. While this is true in general for physical interactions between levels, we argue that in the case of conscious organisms making rational choices, there is indeed a preferred causal origin - namely the overall embracing influence of meaning and values. This is the opposite of what is suggested by a reductionist viewpoint, where it is the bottom-most physical level that is stated to be causally preferred (by some physicists), or the genetic level (by some evolutionary theorists). Charles Darwin was therefore correct to distinguish between Artificial (conscious) Selection, where values enter, and Natural Selection. The Modern Synthesis was wrong to exclude Darwin's distinction.

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.

Review of historic article: Huxley 1957 Muscle Structure and theories of contraction. Progress in Biophysics and biophysical chemistry, 7, 255-318.

The article by Andrew Huxley in this journal in 1957, "Muscle Structure and theories of Contraction" is much more than a standard review of a field. It is itself a major theoretical modelling achievement: the first mathematical model of the contractile process in skeletal muscle. That model was based on careful microscopic analysis of the striation patterns in skeletal muscles. Cited 4456 times, it holds the record for this journal.

Review of historic article: Butler, J.A.V., Johns, E.W. and Philips, D. M. P. 1968. Recent investigations on histones and their functions. Progress in Biophysics and molecular biology, 18, 209-244.

This Historic Article was based on pioneering work by the laboratory of the Founding Editor of the journal to characterise the different forms of histones in the nucleus and their relationship with DNA. The classification determined in 1968 bears strong relationship to that known today. Most importantly, the work clarified that the inhibitory effect of histones on DNA is a general one and would not explain the subsequent differentiation of cells during development in multicellular organisms. Extensive work on the amino acids in histones leads to the understanding that negatively charged DNA naturally attaches itself to positively charged histones.

Review of historic article: Skou 1964 enzymatic aspects of active linked transport of Na+ and K+ through the cell membrane. Progress in Biophysics and Molecular Biology, 14, 133-166.

In this historic article we witness the author's own account of his great discovery: the nature and location of the enzyme system enabling sodium-potassium exchange across membranes in living cells, particularly nerve cells. That discovery has stood the test of time. active ion transport of sodium and potassium ions through cell membranes is ubiquitous.

Review of historic article: Ebashi, S & Endo, M. 1968 Calcium Ion and Muscle Contraction. Progress in Biophysics and Molecular Biology, 18, 123-183.

The 1968 review article on Calcium ion and muscle contraction by Setsuro Ebashi and Makoto Endo is one of the highest cited in the journal since it was required reading in the early days of understanding what triggers contraction of the myofilaments. It correctly identified the major steps in excitation-contraction coupling and still inspires mathematical models of muscle activity today. It also successfully identified the role of troponin.