Embryogenesis Explained is a fascinating book. Its authors, Natalie and Richard Gordon, expound a theory of embryogenesis based on the mechanical properties of the cell cytoskeleton. This theory is associated with epistemological thought developed in an entire chapter suggesting a holistic conception of life and in a series of remarks dispersed throughout the book. In the preface, the authors stipulate the three conditions that, in their view, must be met by a developmental theory. First, universality; as they write, “For any theory of embryogenesis to be the ‘right’ theory, it must have certain key elements. First and foremost, the right theory must be universal” (p. vii). Second, “it must be traceable in some form back in time to before embryogenesis was required” (p. xi). The reason for that is that “nature is conservative.” It uses only mechanisms that have been successfully tested. Thus embryogenesis must rely on mechanisms that were already, at least partially, present in single-celled organisms. Third, for the same reason, embryogenesis must rely on a simple mechanism, because life began with very simple single-celled forms in which the mechanism must have already been present. In the preface, Natalie and Richard Gordon also attack frontally the prevalent theory based on morphogen gradients and inductive interactions. Their argument relies on the requirement for universality. They recall that organisms such as wasps have a morphology similar to Drosophila although there are no gradients in their embryo. They also point to developmental stages during which morphogen gradients are absent, even in the fly. Since the book is written for the widest possible audience, including the curious non-expert, the authors have tried as much as possible to avoid jargon. It is composed of three types of chapters. Some chapters give the indispensable background in different areas of biology that are necessary to understand the problems of embryogenesis. A series of chapters are devoted to explanation of the different facets of the theory. The last chapters put it in a wider context and touch on issues such as evolution or the holistic conception of life. All chapters are well documented with large bibliographies and a wealth of illustrations that make the book easier to read.

Chapter 1 traces “How Embryogenesis Began in Evolution.” The authors go back to the origin of life and the early steps in life history to understand the conditions of embryogenesis’ emergence. They stress the importance of basic cellular mechanisms that appeared in single-celled organisms, and the evolutionary constraints that forced the evolution of life. They also stress the need to perceive food and to be able to move towards it or to escape from predators. And they point to sporulation and the first forms of multicellularity (for example, colonial cyanobacterium), showing that they already possessed major properties such as the coordination of cells’ behavior or size regulation. Most importantly for the authors’ theory, they point to the fact that some prokaryotes have a cytoskeleton similar to the eukaryotic cytoskeleton that is involved in sporulation. Chapter 2 deals with the “Developmental Anatomy of the Axolotl.” In this chapter the authors recall the basic facts of early development, focusing on the axolotl, which is their model organism. They start at fertilization up to gastrulation and the germ layers’ formation. Although the content of this chapter may seem trivial to developmental biologists (the authors themselves suggest that some readers may skim ahead in the book), it remains interesting because of the side comments that give it a particular tone bearing an original perspective absent from classical textbooks. It starts with a strong antireductionist commitment:

In order to understand how embryogenesis works, you must understand what embryogenesis is. This obvious statement evades many people who begin and end their studies with molecular developmental biology. It is as if understanding architecture required only a deep appreciation of bricks and mortar, i.e., in our case, molecules and their interactions…. Embryogenesis encompasses anatomy versus time. This includes molecular events that may be causes. However, the events may also be consequences of other processes at size scales bigger than molecules. (p. 75)

The authors also explain what a model organism is, why they chose the axolotl, and compare it with a series of other model organisms. The axolotl presents three characteristics that allowed the authors to discover the differentiation waves underlying their theory. Axolotl’s embryo is big, develops slowly, and has variegated pigmentation making it easy to observe with a microscope the contraction and expansion of the apical surfaces of cells when pigment granules come closer together or move farther apart.

Entitled “Developmental Genetics: A Flying Tour,” Chap. 3 provides an account of the current state of knowledge achieved in genetics and how it impacts embryogenesis. Phenomena such as the molecular biology of the cell cycle, gene expression, chromosome organization, and mitosis are reviewed. Again the emphasis is put on the mechanical aspects rather than the more classical interpretation of genetics and molecular biology that gives genes the power to direct life. In their words:

Unfortunately expressions like “gene A regulates gene B” can also lead to sloppy thinking. Sometimes people (including scientists) will start referring to genes as if the DNA itself has mystical magical properties or that DNA is somehow able to do all kinds of neat thinking-style stuff all by itself. (p. 191)

The authors provide a list of things that genes or their products can’t do, such as direct, determine, mediate, instruct, coordinate, control, etc. Consequently, when it comes to the crucial problem of gene expression they do not emphasize a causal role of gene networks functioning with specific activating or repressive regulatory proteins. Instead, Natalie and Richard Gordon simply remark that some genes are available for transcription while others are not, depending on whether they are located in opened or closed regions of the chromatin. As they write, “In eukaryotes we can make a broad classification of all genes in a given cell type into exposed and sequestered” (p. 198, emphasis in original). Among exposed genes some are shared by several cell types while others are specific to a particular one. The latter define cell types and are called differons. Chapter 4 deals with epigenetics understood as higher-order gene control. The chapter is largely devoted to the role of DNA methylation in chromosome X inactivation and more generally in gene control. As in the preceding chapters, the subject is reviewed at sufficient length to give the reader a solid knowledge of it, but again it is put in the theoretical perspective the authors wish to develop. The beginning of the chapter reviews the effects of genetic accidents such as DNA segments duplications, rearrangements, or chromosomal imbalance. These accidents result in an abnormal copy number for certain genes (for example, the APP gene linked to down syndrome), which is not followed by a proportional change in gene expression. In a manner reminiscent of Richard Goldschmidt who, before World War II, considered that the units of heredity are not the genes but the whole chromosomes, the authors point to gene dosage and compensation and argue that the genome must be taken as a functional whole. At the end of the chapter, they conclude that epigenetic mechanisms result in the sequestration of some parts of the genomes while other parts are left exposed and available for transcription. However, they insist that detailed knowledge of these mechanisms does not provide an answer to the crucial question of knowing which specific parts of a genome will be sequestered or exposed in a particular cell type.

As the last of the “background chapters,” Chap. 5 deals with the cytoskeleton, describing its structure and functioning. The chapter explains the cytoskeleton’s role in various phenomena ranging from motility, fertilization, or early unequal divisions in embryogenesis to nuclear organization. This is an important chapter because the differentiation waves theory is based on the mechanical properties of a cytoskeletal structure named the cell state splitter. The authors stress that somehow the cytoskeleton should be rehabilitated and given back the status it deserves in the understanding of development:

If one consults any of the standard developmental biology textbooks, the cytoskeleton will be briefly presented as the support structure of the cell and about as interesting to most biologists as the floor struts in a ballet school would be to an artistic director seeking the next prima ballerina. (p. 329)

This view is rooted in the theoretical analysis started in Chap. 1. For the authors, cytoskeletal evolution led from cell division to movement and to cell differentiation.

Chapter 6 is the first chapter describing the core of the differentiation waves theory. In it the cell state splitter, which is located at the apical end of the cells, plays a key role. Its organization can be observed by electron microscopy. It has three components made of the cytoskeletal elements: a microfilament ring, a mat of microtubules, and an intermediate filament ring. This characteristic organization endows the cell state splitter with a property allowing it to direct cell differentiation. It is a bistable structure that can go in two opposite and exclusive directions: either the contraction of the microfilament ring or the expansion of the microtubule mat. Each of these events occurring in specific cells at a specific stage of development can be mechanically propagated to adjacent cells in an epithelium, acting as a signal inducing a specific change of gene expression (a change in the differon expressed in these cells). The propagation of the contraction or of the expansion of cells corresponds to the differentiation waves that can readily be observed by microscopy throughout the axolotl’s development. Chapter 7, entitled “The Differentiation Tree and the Fate Map of the Axolotl,” shows how the differentiation waves theory can be used to explain the axolotl’s development by correlating the differentiation waves in various tissues at various stages of development with cellular fates. The sequence of waves on the embryo is what Natalie and Richard Gordon refer to as the differentiation tree of the axolotl. Chapters 8 and 9 explain how the cell state splitter could control gene expression. The argument is based on the reinterpretation of a wealth of data concerning signal transduction and nuclear organization. Classically, it was thought that differentiating cells exchange signals, inducing signal-transduction cascades inside cells that end in the nuclei of these cells, with specific signals activating or repressing genes. Instead, a model based on mechanotransduction is proposed. According to this model, the mechanical properties of the cell state splitter are converted into signals regulating gene expression. Extending the views introduced in Chaps. 3 and 4, the conception of gene regulation proposed here departs from the classical view inasmuch as it is not a matter of tuning gene activity by means of specific transcription factors but rather of global nuclear conformation allowing different sets of genes to be exposed or sequestered. This leads to another new concept: what happens in the nucleus is called the nuclear state splitter. Thus, in the end, the differentiation waves theory is radically different from the classical view brought about by genetics and molecular biology. It is primarily based on the physical properties of the cytoskeleton. In the authors’ words:

The cytoskeleton is consistently treated in the scientific literature as merely a structural protein complex whose rearrangements are side effects to induction that are of no relevance in embryogenesis. We have moved the cytoskeleton from irrelevance to being the single most important component. The cytoskeleton is the starting point that allows the individual cell to become the right kind of cell, in the right place, at the right time. (p. 593)

In the last three chapters the theory is put in a broader context. Chapter 10 looks back at history. Swiss physiologist Albrecht von Haller,who lived in the 18th century, is cited as the author of an idea that was the first forerunner to differentiation waves with his notion of an irritable protoplasm characteristic to life. Other names discussed include Thomas H. Morgan, when he was still an embryologist prior to his work in genetics, and Ralph S. Lillie and his research from the beginning of the 20th century. Chapter 11 deals with the relationship of the differentiation waves theory to evolution. Natalie and Richard Gordon argue that in the main it is coherent with a progressive conception of evolution, and, finally, Chap. 13 puts the theory in an even broader context by discussing the holistic and reductionist approach to embryogenesis. The discussion goes beyond purely biological issues, touching on subjects like the implications of quantum physics. After discussing the limitations of a purely physical approach, the authors endorse a form of “cybernetic holism” according to which the embryo as a whole could be compared to self-regulated cybernetic objects.

Overall, Embryogenesis Explained is a very interesting book. Although it is primarily intended to be theoretical, it provides a large overview of the data collected on various subjects of developmental biology and could thus also be used as a complementary textbook. Of course, it raises a number of questions. The main question concerns the differentiation waves theory itself. I am typically one of those biologists referred to by the authors who usually does not put the cytoskeleton and mechanical forces at the forefront for understanding development. So, was I convinced that the cell state splitter is the driver of development? The theory is certainly coherent. It is based on data and it suggests testable hypotheses. In this regard it should be accepted, and its research program should be developed. Natalie and Richard Gordon undoubtedly point to something very important, and molecular biologists focused on gene expression will benefit from reading this book.

Am I entirely convinced, however? When reading this book, a question will inevitably arise in the mind of any reader: could it be that simple? In the preface, the authors argue that a theory of embryogenesis has to be simple. But, I am perplexed. Although I agree that the physics of biology has not been sufficiently taken into account, and this is why Embryogenesis Explained is valuable, I have some reservations about the purely mechanical theory proposed here and the broader holistic philosophy in which it is inserted. First, the differentiation waves theory is totally deterministic, whereas the stochastic aspects of cellular physiology, notably in gene expression, are amply documented now. Integrating the randomness of cells into the picture will produce a radical change. Because of this inherent stochasticity in cellular behavior, cell fate cannot be determined exclusively by the cell state splitter as described here in a purely deterministic way. I would rather see the physics of biology as imposing constraints that give a direction to cells but not as acting as their first causal mover. Second, I am not at ease either with the holistic philosophy the authors wrap their theory in. I even find it to be paradoxical. Mechanism is philosophically associated with reductionism. There is no doubt that if Descartes were alive today he would enthusiastically approve and applaud the authors’ mechanistic theory. But, I think there is a widespread confusion among a number of biologists today. Because they reject genetic reductionism they tend to reject reductionism in general and adopt a holistic perspective. However, there are different forms of reductionism. Natalie and Richard Gordon’s theory is physicalist, and physicalism is an even more radical form of reductionism than genetic reductionism. In my mind this is not an infamy. Historically reductionism has been (and still is) the prima philosophy and methodology of science. It is beyond the scope of this review to analyze these issues in depth. I mention them only to show possible further discussions. It does not diminish the merit of Natalie and Richard Gordon. Clearly, they are successful writers, and I enthusiastically recommend their book. Embryology Explained is a pleasure to read, presenting difficult concepts clearly and effectively. It carries deep biological thought, and whether one agrees with the differentiation waves theory or not, it is inspiring and stimulating.