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Swiss-born embryologist Wilhelm His, Sr. (1831-1904) was the first scientist to study embryos using paraffin histology, serial sectioning and three-dimensional modelling. With these techniques, His made many important discoveries in vertebrate embryology and developmental neurobiology, earning him two Nobel Prize nominations. He also developed several theories of mechanical and evolutionary developmental biology. His argued that adult form is determined by the differential growth of developmental primordia. Furthermore, he suggested that changes in the growth parameters of those primordia are responsible for generating new phenotypes during evolution. His developed these theories in his book 'Our Bodily Form' (Unsere Körperform). Here, we review His's work with special emphasis on its potential importance to the disciplines of evolutionary developmental biology (evo-devo) and mechanobiology., (© 2022 The Authors. Biological Reviews published by John Wiley & Sons Ltd on behalf of Cambridge Philosophical Society.)

Evolutionary developmental biology (evo-devo) is the study of the evolution of developmental mechanisms. Here, I review some of the theories, models, and laws in evo-devo, past and present. Nineteenth-century evo-devo was dominated by recapitulation theory and archetypes. It also gave us germ layer theory, the vertebral theory of the skull, floral organs as modified leaves, and the "inverted invertebrate" theory, among others. Newer theories and models include the frameshift theory, the genetic toolkit for development, the ABC model of flower development, the developmental hourglass, the zootype, Urbilateria, and the hox code. Some of these new theories show the influence of archetypes and recapitulation. Interestingly, recent studies support the old "primordial leaf," "inverted invertebrate," and "segmented head" theories. Furthermore, von Baer's first three laws may now need to be rehabilitated, and the hourglass model modified, in view of what Abzhanov has pointed out about the maternal-zygotic transition. There are many supposed "laws" of evo-devo but I argue that these are merely generalizations about trends in particular lineages. I argue that the "body plan" is an archetype, and is often used in such a way that it lacks any scientific meaning. Looking to the future, one challenge for evo-devo will be to develop new theories and models to accommodate the wealth of new data from high-throughput sequencing, including single-cell sequencing. One step in this direction is the use of sophisticated in silico analyses, as in the "transcriptomic hourglass" models., (© 2021 The Authors. Journal of Experimental Zoology Part B: Molecular and Developmental Evolution published by Wiley Periodicals LLC.)

Patterns are orders embedded in randomness; they may appear in spatial arrangements or in temporal sequences, and each element may appear identical or with variations. Patterns exist in the physical world as well as in living systems. In the biological world, patterns can range from simple to complex, forming the basic building blocks of life. When we see patterns in peacock feathers, leopard spots or zebra stripes, we are fascinated by the order, the variations and the beauty. The process that generates this ordering in the biological world has been termed Pattern Formation. Since Lewis Wolpert promoted this concept four decades ago, scientists from molecular biology, developmental biology, stem cell biology, tissue engineering, theoretical modeling and other disciplines have made remarkable progress towards understanding its underlying mechanisms. We have learned that both molecular processes and physico-chemical principles are important for biological Pattern Formation and as Guest Editors, felt that it is time to review and re-integrate our understanding of this fundamental and fantastic process.

Basic research in pattern formation is concerned with the generation of phenotypes and tissues. It can therefore lead to new tools for medical research. These include phenotypic screening assays, applications in tissue engineering, as well as general advances in biomedical knowledge. Our aim here is to discuss this emerging field with special reference to tools based on zebrafish developmental biology. We describe phenotypic screening assays being developed in our own and other labs. Our assays involve: (i) systemic or local administration of a test compound or drug to zebrafish in vivo; (ii) the subsequent detection or "readout" of a defined phenotypic change. A positive readout may result from binding of the test compound to a molecular target involved in a developmental pathway. We present preliminary data on assays for compounds that modulate skeletal patterning, bone turnover, immune responses, inflammation and early-life stress. The assays use live zebrafish embryos and larvae as well as adult fish undergoing caudal fin regeneration. We describe proof-of-concept studies on the localised targeting of compounds into regeneration blastemas using microcarriers. Zebrafish are cheaper to maintain than rodents, produce large numbers of transparent eggs, and some zebrafish assays could be scaled-up into medium and high throughput screens. However, advances in automation and imaging are required. Zebrafish cannot replace mammalian models in the drug development pipeline. Nevertheless, they can provide a cost-effective bridge between cell-based assays and mammalian whole-organism models.

Patterns are orders embedded in randomness. They may appear as spatial arrangements or temporal series, and the elements may appear identical or with variations. Patterns exist in the physical world as well as in living systems. In the biological world, patterns can range from simple to complex, forming the basic building blocks of life. The process which generates this ordering in the biological world was termed pattern formation. Since Wolpert promoted this concept four decades ago, scientists from molecular biology, developmental biology, stem cell biology, tissue engineering, theoretical modeling and other disciplines have made remarkable progress towards understanding its mechanisms. It is time to review and re-integrate our understanding. Here, we explore the origin of pattern formation, how the genetic code is translated into biological form, and how complex phenotypes are selected over evolutionary time. We present four topics: Principles, Evolution, Development, and Stem Cells and Regeneration. We have interviewed several leaders in the field to gain insight into how their research and the field of pattern formation have shaped each other. We have learned that both molecular process and physico-chemical principles are important for biological pattern formation. New understanding will emerge through integration of the analytical approach of molecular-genetic manipulation and the systemic approach of model simulation. We regret that we could not include every major investigator in the field, but hope that this Special Issue of the Int. J. Dev. Biol. represents a sample of our knowledge of pattern formation today, which will help to stimulate more research on this fundamental process.

One of the central, unresolved controversies in biology concerns the distribution of primitive versus advanced characters at different stages of vertebrate development. This controversy has major implications for evolutionary developmental biology and phylogenetics. Ernst Haeckel addressed the issue with his Biogenetic Law, and his embryo drawings functioned as supporting data. We re-examine Haeckel's work and its significance for modern efforts to develop a rigorous comparative framework for developmental studies. Haeckel's comparative embryology was evolutionary but non-quantitative. It was based on developmental sequences, and treated heterochrony as a sequence change. It is not always clear whether he believed in recapitulation of single characters or entire stages. The Biogenetic Law is supported by several recent studies -- if applied to single characters only. Haeckel's important but overlooked alphabetical analogy of evolution and development is an advance on von Baer. Haeckel recognized the evolutionary diversity in early embryonic stages, in line with modern thinking. He did not necessarily advocate the strict form of recapitulation and terminal addition commonly attributed to him. Haeckel's much-criticized embryo drawings are important as phylogenetic hypotheses, teaching aids, and evidence for evolution. While some criticisms of the drawings are legitimate, others are more tendentious. In opposition to Haeckel and his embryo drawings, Wilhelm His made major advances towards developing a quantitative comparative embryology based on morphometrics. Unfortunately His's work in this area is largely forgotten. Despite his obvious flaws, Haeckel can be seen as the father of a sequence-based phylogenetic embryology.

Snake lungs show a remarkable diversity of organ asymmetries. The right lung is always fully developed, while the left lung is either absent, vestigial, or well-developed (but smaller than the right). A ‘tracheal lung’ is present in some taxa. These asymmetries are reflected in the pulmonary arteries. Lung asymmetry is known to appear at early stages of development in Thamnophis radix and Natrix natrix. Unfortunately, there is no developmental data on snakes with a well-developed or absent left lung. We examine the adult and developmental morphology of the lung and pulmonary arteries in the snakes Python curtus breitensteini, Pantherophis guttata guttata, Elaphe obsoleta spiloides, Calloselasma rhodostoma and Causus rhombeatus using gross dissection, MicroCT scanning and 3D reconstruction. We find that the right and tracheal lung develop similarly in these species. By contrast, the left lung either: (1) fails to develop; (2) elongates more slowly and aborts early without (2a) or with (2b) subsequent development of faveoli; (3) or develops normally. A right pulmonary artery always develops, but the left develops only if the left lung develops. No pulmonary artery develops in relation to the tracheal lung. We conclude that heterochrony in lung bud development contributes to lung asymmetry in several snake taxa. Secondly, the development of the pulmonary arteries is asymmetric at early stages, possibly because the splanchnic plexus fails to develop when the left lung is reduced. Finally, some changes in the topography of the pulmonary arteries are consequent on ontogenetic displacement of the heart down the body. Our findings show that the left-right asymmetry in the cardiorespiratory system of snakes is expressed early in development and may become phenotypically expressed through heterochronic shifts in growth, and changes in axial relations of organs and vessels. We propose a step-wise model for reduction of the left lung during snake evolution. [ABSTRACT FROM AUTHOR]

Small, early life stages, such as zebrafish embryos are increasingly used to assess the biological effects of chemical compounds in vivo. However, behavioural screens of such organisms are challenging in terms of both data collection (culture techniques, drug delivery and imaging) and data evaluation (very large data sets), restricting the use of high throughput systems compared to in vitro assays. Here, we combine the use of a microfluidic flow-through culture system, or BioWell plate, with a novel motion analysis technique, (sparse optic flow - SOF) followed by spectral analysis (discrete Fourier transformation - DFT), as a first step towards automating data extraction and analysis for such screenings. Replicate zebrafish embryos housed in a BioWell plate within a custom-built imaging system were subject to a chemical exposure (1.5% ethanol). Embryo movement was videoed before (30 min), during (60 min) and after (60 min) exposure and SOF was then used to extract data on movement (angles of rotation and angular changes to the centre of mass of embryos). DFT was subsequently used to quantify the movement patterns exhibited during these periods and Multidimensional Scaling and ANOSIM were used to test for differences. Motion analysis revealed that zebrafish had significantly altered movements during both the second half of the alcohol exposure period and also the second half of the recovery period compared to their pre-treatment movements. Manual quantification of tail flicking revealed the same differences between exposure-periods as detected using the automated approach. However, the automated approach also incorporates other movements visible in the organism such as blood flow and heart beat, and has greater power to discern environmentally-driven changes in the behaviour and physiology of organisms. We suggest that combining these technologies could provide a highly efficient, high throughput assay, for assessing whole embryo responses to various drugs and chemicals. [ABSTRACT FROM AUTHOR]

During cardiogenesis the epicardium, covering the surface of the myocardial tube, has been ascribed several functions essential for normal heart development of vertebrates from lampreys to mammals. We investigated a novel function of the epicardium in ventricular development in species with partial and complete septation. These species include reptiles, birds and mammals. Adult turtles, lizards and snakes have a complex ventricle with three cava, partially separated by the horizontal and vertical septa. The crocodilians, birds and mammals with origins some 100 million years apart, however, have a left and right ventricle that are completely separated, being a clear example of convergent evolution. In specific embryonic stages these species show similarities in development, prompting us to investigate the mechanisms underlying epicardial involvement. The primitive ventricle of early embryos becomes septated by folding and fusion of the anterior ventricular wall, trapping epicardium in its core. This folding septum develops as the horizontal septum in reptiles and the anterior part of the interventricular septum in the other taxa. The mechanism of folding is confirmed using DiI tattoos of the ventricular surface. Trapping of epicardium-derived cells is studied by transplanting embryonic quail pro-epicardial organ into chicken hosts. The effect of decreased epicardium involvement is studied in knock-out mice, and pro-epicardium ablated chicken, resulting in diminished and even absent septum formation. Proper folding followed by diminished ventricular fusion may explain the deep interventricular cleft observed in elephantsThe vertical septum, although indistinct in most reptiles except in crocodilians and pythonidsis apparently homologous to the inlet septum. Eventually the various septal components merge to form the completely septated heart. In our attempt to discover homologies between the various septum components we aim to elucidate the evolution and development of this part of the vertebrate heart as well as understand the etiology of septal defects in human congenital heart malformations. [ABSTRACT FROM AUTHOR]

Denis Duboule is one of the most influential and highly-cited scientists in developmental biology. Born in Geneva in 1955, he holds dual Swiss and French nationality. His undergraduate studies in biology at the University of Geneva included research on mouse embryology. He later learned molecular techniques in the laboratory of Pierre Chambon, becoming a major player in characterising the newly-discovered vertebrate Hox genes. He helped discover their genomic clustering, realising that they had arisen by trans duplication. With Gaunt and Sharpe, he proposed that vertebrate Hox clusters might show spatial colinearity, and subsequently extended this concept to the timing of gene activation (temporal colinearity). Along with the Krumlauf laboratory, he reported the structural and functional conservation of the homeotic systems in flies and vertebrates. His lab was the first to describe nested patterns of Hox gene expression in the developing mouse limb, and later showed that digit-associated Hoxd gene expression was lacking in zebrafish paired fin development. His concept of phylotypic progression helps explain major evolutionary developmental phenomena in terms of Hox gene regulatory networks. His research helped reveal that the genital tubercle may, like the limb, be patterned by Hox genes. His lab developed targeted meiotic recombination (TAMERE), using it to make profound advances in our understanding of Hox gene regulation. Remote enhancers linked to digit patterning have been uncovered, together with a likely mechanism for colinearity. Denis lives in Geneva with his wife Brigitte Galliot, also a scientist, with their four children. [ABSTRACT FROM AUTHOR]

In 1969, Lewis Wolpert published a paper outlining his new concepts of "pattern formation" and "positional information". He had already published research on the mechanics of cell membranes in amoebae, and a series of classic studies of sea urchin gastrulation with Trygve Gustavson. Wolpert had presented his 1969 paper a year earlier at a Woods Hole conference, where it received a very hostile reception: "I wasn't asked back to America for many years!". But with Francis Crick lining up in support of diffusible morphogen gradients, positional information eventually became established as a guiding principle for research into biological pattern formation. It is now clear that pattern formation is much more complex than could possibly have been imagined in 1969. But Wolpert still believes in positional information, and regards intercalation during regeneration as its best supporting evidence. However, he and others doubt that diffusible morphogen gradients are a plausible mechanism: "Diffusible gradients are too messy", he says. Since his retirement, Lewis Wolpert has remained active as a theoretical biologist and continues to publish in leading journals. He has also campaigned for a greater public understanding of the stigma of depression. He was interviewed at home in London on July 26th, 2007 by Michael Richardson. [ABSTRACT FROM AUTHOR]

Patterns are orders embedded in randomness. They may appear as spatial arrangements or temporal series, and the elements may appear identical or with variations. Patterns exist in the physical world as well as in living systems. In the biological world, patterns can range from simple to complex, forming the basic building blocks of life. The process which generates this ordering in the biological world was termed pattern formation. Since Wolpert promoted this concept four decades ago, scientists from molecular biology, developmental biology, stem cell biology, tissue engineering, theoretical modeling and other disciplines have made remarkable progress towards understanding its mechanisms. It is time to review and re-integrate our understanding. Here, we explore the origin of pattern formation, how the genetic code is translated into biological form, and how complex phenotypes are selected over evolutionary time. We present four topics: Principles, Evolution, Development, and Stem Cells and Regeneration. We have interviewed several leaders in the field to gain insight into how their research and the field of pattern formation have shaped each other. We have learned that both molecular process and physico-chemical principles are important for biological pattern formation. New understanding will emerge through integration of the analytical approach of molecular-genetic manipulation and the systemic approach of model simulation. We regret that we could not include every major investigator in the field, but hope that this Special Issue of the Int. J. Dev. Biol. represents a sample of our knowledge of pattern formation today, which will help to stimulate more research on this fundamental process. [ABSTRACT FROM AUTHOR]

Many advanced snakes use fangs—specialized teeth associated with a venom gland—to introduce venom into prey or attacker. Various front- and rear-fanged groups are recognized, according to whether their fangs are positioned anterior (for example cobras and vipers) or posterior (for example grass snakes) in the upper jaw. A fundamental controversy in snake evolution is whether or not front and rear fangs share the same evolutionary and developmental origin. Resolving this controversy could identify a major evolutionary transition underlying the massive radiation of advanced snakes, and the associated developmental events. Here we examine this issue by visualizing the tooth-forming epithelium in the upper jaw of 96 snake embryos, covering eight species. We use the sonic hedgehog gene as a marker, and three-dimensionally reconstruct the development in 41 of the embryos. We show that front fangs develop from the posterior end of the upper jaw, and are strikingly similar in morphogenesis to rear fangs. This is consistent with their being homologous. In front-fanged snakes, the anterior part of the upper jaw lacks sonic hedgehog expression, and ontogenetic allometry displaces the fang from its posterior developmental origin to its adult front position—consistent with an ancestral posterior position of the front fang. In rear-fanged snakes, the fangs develop from an independent posterior dental lamina and retain their posterior position. In light of our findings, we put forward a new model for the evolution of snake fangs: a posterior subregion of the tooth-forming epithelium became developmentally uncoupled from the remaining dentition, which allowed the posterior teeth to evolve independently and in close association with the venom gland, becoming highly modified in different lineages. This developmental event could have facilitated the massive radiation of advanced snakes in the Cenozoic era, resulting in the spectacular diversity of snakes seen today. [ABSTRACT FROM AUTHOR]

Sequence heterochrony (changes in the order in which events occur) is a potentially important, but relatively poorly explored, mechanism for the evolution of development. In part, this is because of the inherent difficulties in inferring sequence heterochrony across species. The event-pairing method, developed independently by several workers in the mid-1990s, encodes sequences in a way that allows them to be examined in a phylogenetic framework, but the results can be difficult to interpret in terms of actual heterochronic changes. Here, we describe a new, parsimony-based method to interpret such results. For each branch of the tree, it identifies the least number of event movements (heterochronies) that will explain all the observed event-pair changes. It has the potential to find all alternative, equally parsimonious explanations, and generate a consensus, containing the movements that form part of every equally most parsimonious explanation. This new technique, which we call Parsimov, greatly increases the utility of the event-pair method for inferring instances of sequence heterochrony. [Developmental sequences; event pairing; heterochrony; Parsimov program; principle of parsimony.] [ABSTRACT FROM AUTHOR]

Does developmental anatomy have a future in the age of molecular biology and digital technologies? Specifically, will morphological characters continue to be used in comparative developmental biology, or will new types of character be defined? Traditionally, comparative embryology was a non-quantitative, 'portrait-gallery' science. Wilhelm His attempted to develop a character-based, more quantitative approach. Quantitative approaches to development have been also been suggested by Meinhardt and others. With the current availability of computing power and the growth of bioinformatics and phylogenetic methodology, quantitative methodologies ate increasingly being applied to studies of embryonic development. Our aim in this article is to examine some of these approaches. In both anatomical and molecular studies, the parameters to be quantified ate temporal and spatial. Temporal data are analysed by techniques, such as event pairing, that analyse developmental sequences. In this case, the characters are developmental events. Spatial information can be analysed using morphometrics, in combination with computer-assisted 3D reconstruction. In spatial analyses, anatomical parts may be used as the characters. A major challenge in the coming years is to develop techniques for analysing 3D patterns of developmental gene expression and to compare them between species or individuals. Such analyses have to be defined in relation to five dimensions: the 3 orthogonal spatial planes; time; and individuals. The difficulties of such analyses are complicated by problems of homology. Some possible solutions ate suggested. For example, it may be possible to use voxels as characters, and to assign to them attributes according to gene expression domains. At first sight, it might seem that traditional morphological characters would no longer be required in comparative embryology. However, we believe that some kind of anatomical framework will always be needed in comparative biology. The... [ABSTRACT FROM AUTHOR]

Heterochrony is important as a potential mechanism of evolutionary change. However, the analysis of developmental timing data within a phylogenetic framework to identify important shifts has proven difficult. In particular, analytical problems with sequence (event) heterochrony revolve around the lack of an absolute time frame in development to allow standardization of timing data across species. An important breakthrough in this regard is the method of "event-pairing," which compares the relative timing of developmental events in a pairwise fashion. The resulting event-pair-encoded data can be mapped onto a phylogeny, which can provide important biological information. However, event-paired data are cumbersome to work with and lack a rigorous quantitative framework under which to analyze them. Critically, the otherwise advantageous relativity of event-pairing prevents an assessment of whether one or both events in a single event-pair have changed position during evolutionary history. Building on the method of event-pairing, we describe a protocol whereby event-pair transformations along a given branch are analyzed en bloc. Our method of "event-pair cracking" thereby allows developmental timing data to be analyzed quantitatively within a phylogenetic framework to infer key heterochronic shifts. We demonstrate the utility of event-pair cracking through a worked example and show how it provides a set of desired features identified by previous authors. [ABSTRACT FROM AUTHOR]

Deals with the manifestations of typologism in evolutionary developmental biology. Approaches to evolutionary and comparative developmental biology; Advantages of the typological approach; Problems with typologism; Alternatives to typologism.

A new study in this issue of Developmental Cell () uses comparative transcriptomics and reveals a stage in nematode development that is enriched for developmental patterning genes. The molecular profile of this phylotypic stage shows similarities with those of vertebrates and flies. The findings have important evolutionary implications. [ABSTRACT FROM AUTHOR]

A preface for the June 2009 issue of the "International Journal of Developmental Biology" is presented.