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Gregor Mendel is generally presented as the ‘ignored and solitary founder of genetics’. This Moravian friar would have worked in strict isolation on the heredity of peas in the garden of his monastery, and his experiments would have been ignored by his contemporaries, before being ‘rediscovered’ independently by three botanists in 1900, 34 years after their publication. Historians have contributed to replace the genesis of Mendel’s work in the context of his time, questioning the mythical image that prevailed in academic circles and the public perception. This paper recalls that Mendel benefitted from a very favourable context for the development of his experiments at St Thomas Monastery in Brno and was not isolated from the scientific community of his time. Although the notions on which his work was based were already present in scientific publications, this does not diminish the importance of Mendel’s contribution to the development of modern biology. We provide a detailed analysis of the results of his experiments on the development of hybrid plants that he presented in two lectures at the Brno Society of Natural History in 1865, demonstrating that beyond his major contribution to the foundation of genetics, Mendel was one of the pioneers of systems biology.

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’.

The Weismann Barrier and the Central Dogma do not protect the assumptions of The Modern Synthesis.

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.

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.

40 years ago a single experiment upset a decade of painstaking research on the mechanisms of rhythm generation in the heart. It did so by turning a theory of pacemaker activity upside down. Instead of attributing rhythm to decaying potassium current carrying outward current, it attributed the pacemaker depolarization to the slow activation of a channel conducting sodium ions into cardiac cells. But this was no standard upset of a theory. Like the replacement of Newtonian mechanics by relativity theory, the new theory explained every minute detail of the experimental observations that had established the theory it was replacing. Computational modelling of the heart achieved one of the major successes, the complete mapping of one theory onto another without challenging the correctness of any of the experimental findings. This review details the way in which this transition occurred and draws some important lessons for modelling of biological processes today.

The extensive range and depth of the twenty commentaries on my target article (Noble, 2021) confirms that something has gone deeply wrong in biology. A wide range of biologists has more than met my invitation for “others to pitch in and develop or counter my arguments.” The commentaries greatly develop those arguments. Also remarkably, none raise issues I would seriously disagree with. I will focus first on the more critical comments, summarise the other comments, and then point the way forward on what I view as a necessary and long-overdue transition in the foundations of biology.

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.

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.

Stochastic processes at molecular, cellular and higher levels in organisms are not simply noise. Organisms also use stochasticity at all levels to generate new DNA sequences, as in the immune system, and new forms of behaviour, as in the nervous system. The harnessing of stochasticity therefore endows organisms with the means to actively influence the direction of their development and evolution.

Ukazanie powiązań między genotypem a fenotypem jest problematyczne nie tylko ze względu na ogromną złożoność interakcji między genami, białkami i funkcjami fizjologicznymi wyższych rzędów, ale również dlatego, że paradygmatom przyczynowości genetycznej w systemach biologicznych towarzyszy duże zamieszanie. W tym artykule przeanalizuję niektóre związane z tym błędne przekonania, zaczynając od zagadnienia definicji genu. W toku rozwoju biologii uległa ona zasadniczej zmianie - pierwotnie gen rozumiano jako przyczynę cech fenotypowych, obecnie definiuje się go jako fragment DNA. Następnie przejdę do następujących zagadnień: czy "cyfrowa" natura sekwencji DNA gwarantuje im pierwszeństwo w ciągu przyczynowym w porównaniu z dziedzicznością niezwiązaną z DNA, czy koncepcja programów genetycznych jest sensowna i użyteczna oraz jaka jest rola przyczynowości na wyższych poziomach (przyczynowości odgórnej). Metafory, które dobrze spełniały swoją funkcję podczas molekularnej fazy rozwoju biologii w ostatnich dziesięcioleciach, mają ograniczone zastosowanie w wielopoziomowym świecie biologii systemowej, a nawet mogą pro-wadzić do nieporozumień. Wyjaśnienie wieloczynnikowej przyczynowości genetycznej związanej z funkcjami fizjologicznymi wyższych rzędów wymaga nowych paradygmatów, które zarazem pozwolą zrozumieć zjawiska badane pierwotnie przez genetykę. Modelowanie funkcji biologicznych umożliwia rozwiązanie "problemu genetycznego efektu różnicowego" i odegra istotną rolę również w wyjaśnieniu przyczynowości genetycznej.

The Modern Synthesis has dominated biology for 80 years. It was formulated in 1942, a decade before the major achievements of molecular biology, including the Double Helix and the Central Dogma. When first formulated in the 1950s these discoveries and concepts seemed initially to completely justify the central genetic assumptions of the Modern Synthesis. The Double Helix provided the basis for highly accurate DNA replication, while the Central Dogma was viewed as supporting the Weismann Barrier, so excluding the inheritance of acquired characteristics. This article examines the language of the Modern Synthesis and reveals that it is based on four important misinterpretations of what molecular biology had shown, so forming the basis of the four Illusions: 1. Natural Selection; 2. The Weismann Barrier; 3. The Rejection of Darwin’s Gemmules; 4. The Central Dogma. A multi-level organisation view of biology avoids these illusions through the principle of biological relativity. Molecular biology does not therefore confirm the assumptions of the Modern Synthesis.

Life is purposefully creative in a continuous process of maintaining integrity; it adapts to counteract change. This is an ongoing, iterative process. Its actions are essentially directed to this purpose. Life exists to exist. Physiology is the study of purposeful living function. Function necessarily implies purpose. This was accepted all the way from William Harvey in the 17th century, who identified the purpose of the heart to pump blood and so feed the organs and tissues of the body, through many 19th and early 20th century examples. But late 20th century physiology was obliged to hide these ideas in shame. Teleology became the ‘lady who no physiologist could do without, but who could not be acknowledged in public.’ This emasculation of the discipline accelerated once the Central Dogma of molecular biology was formulated, and once physiology had become sidelined as concerned only with the disposable vehicle of evolution. This development has to be reversed. Even on the practical criterion of relevance to health care, gene-centrism has been a disaster, since prediction from elements to the whole system only rarely succeeds, whereas identifying whole system functions invariably makes testable predictions at an elemental level.

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.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.

In this paper, we demonstrate (1) how harnessing stochasticity can be the basis of creative agency; (2) that such harnessing can resolve the apparent conflict between reductionist (micro-level) accounts of behaviour and behaviour as the outcome of rational and value-driven (macro-level) decisions; (3) how neurophysiological processes can instantiate such behaviour; (4) The processes involved depend on three features of living organisms: (a) they are necessarily open systems; (b) micro-level systems therefore nest within higher-level systems; (c) causal interactions must occur across all the boundaries between the levels of organization. The higher levels constrain the dynamics of lower levels. The experimental evidence and theoretical arguments are shown to be consistent with previous research on the neuronal mechanisms of conscious choice, and with the interconnected multi-level processes by which organisms harness stochasticity, whether conscious or unconscious.

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.