Perspective.

I am a developmental biologist, but I started off as a civil engineer. I did some research on soil mechanics but decided to change to biology. A friend changed my life when he told me about the mechanics of cell division, on which I did my PhD at Kings College. I then worked on the morphogenesis of the sea urchin embryo and became interested in how embryos are patterned, and I proposed positional information as a basic mechanism. I was a professor at the Middlesex Hospital Medical School, where we concentrated on how the chick limb developed.

'Neighbourhood watch' model: embryonic epiblast cells assess positional information in relation to their neighbours.

In many developing and regenerating systems, tissue pattern is established through gradients of informative morphogens, but we know little about how cells interpret these. Using experimental manipulation of early chick embryos, including misexpression of an inducer (VG1 or ACTIVIN) and an inhibitor (BMP4), we test two alternative models for their ability to explain how the site of primitive streak formation is positioned relative to the rest of the embryo. In one model, cells read morphogen concentrations cell-autonomously. In the other, cells sense changes in morphogen status relative to their neighbourhood. We find that only the latter model can account for the experimental results, including some counter-intuitive predictions. This mechanism (which we name the 'neighbourhood watch' model) illuminates the classic 'French Flag Problem' and how positional information is interpreted by a sheet of cells in a large developing system.

An interview with Lewis Wolpert.

Lewis Wolpert is a retired developmental biologist who, over his long career, has made many important contributions to the field, from his French Flag model and the concept of positional information to the famous quote that it is "not birth, marriage or death, but gastrulation which is truly the most important time in your life." In addition to his scientific contributions, Lewis is also a prolific writer, from the textbook 'Developmental Biology' to books about popular science, religion and his battle with depression. Although born in South Africa, it was in the United Kingdom that Lewis spent most of his scientific career. We met Lewis at the Spring Meeting of the British Society for Developmental Biology, where he was awarded the Waddington Medal.

The amniote primitive streak is defined by epithelial cell intercalation before gastrulation.

During gastrulation, a single epithelial cell layer, the ectoderm, generates two others: the mesoderm and the endoderm. In amniotes (birds and mammals), mesendoderm formation occurs through an axial midline structure, the primitive streak, the formation of which is preceded by massive 'polonaise' movements of ectoderm cells. The mechanisms controlling these processes are unknown. Here, using multi-photon time-lapse microscopy of chick (Gallus gallus) embryos, we reveal a medio-lateral cell intercalation confined to the ectodermal subdomain where the streak will later form. This intercalation event differs from the convergent extension movements of the mesoderm described in fish and amphibians (anamniotes): it occurs before gastrulation and within a tight columnar epithelium. Fibroblast growth factor from the extraembryonic endoderm (hypoblast, a cell layer unique to amniotes) directs the expression of Wnt planar-cell-polarity pathway components to the intercalation domain. Disruption of this Wnt pathway causes the mesendoderm to form peripherally, as in anamniotes. We propose that the amniote primitive streak evolved from the ancestral blastopore by acquisition of an additional medio-lateral intercalation event, preceding gastrulation and acting independently of mesendoderm formation to position the primitive streak at the midline.

Positional information and patterning revisited.

The concept of positional information proposes that cells acquire positional values as in a coordinate system, which they interpret by developing in particular ways to give rise to spatial patterns. Some of the best evidence for positional information comes from regeneration experiments, and the patterning of the leg and antenna in Drosophila and the vertebrate limb. Central problems are how positional information is set up, how it is recorded, and then how it is interpreted by the cells. A number of models have been proposed for the setting up of positional gradients, and most are based on diffusion of a morphogen and its interactions with extracellular molecules. It is argued that diffusion may not be reliable mechanism. There are also mechanisms based on timing. There is no good evidence for the quantitative aspects of any of the gradients and details how they are set up. The way in which a signalling gradient regulates differential gene expression in a concentration-dependent manner also raises several mechanistic issues.

There is no place for the psychoanalytic case report in the British Journal of Psychiatry.

As evidence-based mental health and the randomised controlled trial come to dominate the content of major psychiatric journals, the status and clinical utility of single case reports have been increasingly questioned. Arguably, owing to their subjective, anecdotal nature and unsuitability for rigorous scientific testing, this is particularly true of psychoanalytic case studies. Professor Peter Fonagy and Professor Lewis Wolpert debate here whether or not there is a place for such case reports in the British Journal of Psychiatry.

From soil mechanics to chick development.

Here, I provide some recollections of my life, starting as a civil engineer in South Africa and how I gradually became interested in biology, particularly pattern formation. In retrospect, I think that my decision to work on chick embryos to study limb development back in 1966 turned out to be the right one. The principles discovered in these 50 years, both by my collaborators and by other colleagues, have established the principles of how the limb develops in higher vertebrates, including humans.

Limb patterning: reports of model's death exaggerated.

The progress zone model for the specification of positional values for patterning the proximodistal axis of the vertebrate limb has been questioned, but the results can be largely reconciled with the old model.

Left-right asymmetry: all hands to the pump.

How do embryos establish differences between their left and right sides? Previous studies have implicated various signaling molecules and directional beating of cilia. Now, a new player enters the scene: the proton-potassium pump.

Head-tail patterning of the vertebrate embryo: one, two or many unresolved problems?

When, where and how is the head-tail axis of the embryo set up during development? These are such fundamental and intensely studied questions that one might expect them to have been answered long ago. Not so; we still understand very little about the cellular or molecular mechanisms that lead to the orderly arrangement of body elements along the head-tail axis in vertebrates. In this paper, we outline some of the major outstanding problems and controversies and try to identify some reasons why it has been so difficult to resolve this important issue.

Positional Information and Pattern Formation.

The concept of positional information proposes that cells acquire positional values as in a coordinate system, which they interpret by developing in particular ways to give rise to spatial patterns. Some of the best evidence for positional information comes from regeneration experiments, and the patterning of the leg and antenna in Drosophila, and the vertebrate limb. Central problems are how positional information is set up, how it is recorded, and then how it is interpreted by the cells. A number of models have been proposed for the setting up of positional gradients, and most are based on diffusion of a morphogen and its interactions with extracellular molecules; however, diffusion may not be reliable mechanism. There are also mechanisms based on timing. There is no good evidence for the quantitative aspects of any of the proposed gradients and details how they are set up. The way in which a signaling gradient regulates differential gene expression in a concentration-dependent manner also raises several technical and quite difficult issues. A key feature of positional information being the basis for pattern formation is that there is no prepattern in the embryo.

Much more from the chicken's egg than breakfast--a wonderful model system.

The chick embryo has played a major role in the advance of our understanding of embryonic development. It has been particularly helpful in relation to amniotes like the mouse, for unlike the mouse in the early embryo the epiblast is beautifully flat, while in the mouse it is all curled up. Here I briefly describe some history and a few of the major achievements that came from the chick embryo.

The progress zone model for specifying positional information.

The Progress Zone Model proposes that positional information in a growing system can be specified by the time the cells spend in a zone where growth occurs. In the vertebrate limb, the Progress Zone is specified by the Apical Ectodermal Ridge. The best evidence for the model is that killing cells in the zone at an early stage leads to loss of proximal structure as cells remain much longer in the zone as it becomes repopulated.

Lewis Wolpert discusses development and depression. Interview by Joanne Clough.

Lewis Wolpert is Professor of Biology as Applied to Medicine in the Department of Anatomy and Developmental Biology at University College, London, UK. His research interests focus on the mechanisms that are involved in embryonic development. Lewis originally trained as a civil engineer in South Africa but in 1955 made the move to research in cellular biology at King's College, London. He was made a Fellow of the Royal Society in 1980 and awarded the CBE in 1990. Lewis was also made a Fellow of the Royal Society of Literature in 1999 and has presented science on both radio and TV for several years. He was awarded The Royal Society Michael Faraday Prize in 2000 for his contribution to the public understanding of science, most notably through his Chairmanship of the Committee for the Public Understanding of Science (COPUS; 1993-1998). He is the author of numerous books, including Malignant Sadness: The Anatomy of Depression, Principles of Development, The Unnatural Nature of Science and The Triumph of the Embryo. He also writes a regular column for The Independent.