The Master Builder: How the New Science of the Cell is Rewriting the Story of Life

If you haven’t yet met a gastruloid, it’s probably time you did, especially if you cover aspects of embryology, genetics, or evolution in your classes. Gastruloids are small (<1mm) groups of cells that go through significant changes that result in their having a body axis, a more-or-less head end and a more-or-less tail end, and even some apparent tissue concentrations that look like early heart cells—all despite the fact that they’re not embryos and did not result from a fertilization. Over the last decade or so, they have been produced from embryonic stem cells (tissue cells that have been transformed into pluripotent embryonic stem cells by exposure to a small cocktail of transcription factors) derived from tissues of humans, mice, frogs, and zebrafish—and they all look more or less the same.

With that, I’ve just given away the climactic conclusion of The Master Builder: How the New Science of the Cell is Rewriting the Story of Life, by Alfonso Martinez Arias. On the way to introducing gastruloids, Martinez Arias wants to convince us that we’re on the verge of much deeper understanding of how complex multicellular animals develop, and how they evolved, but to accomplish this he has to move us beyond our gene-centered view of life to learn more about the behavior of cells. Early in the book he claims that “[g]eneticists have been so successful at finding changes to genes associated with dysfunction that we’ve fallen into the trap of equating correlation with causation” (p. 6). This is not the assertion of an armchair biology enthusiast. Martinez Arias is the ICREA Research Professor in the department of Medicine and Life Sciences of the Universitat Pompeu Fabra in Barcelona, Spain. From 2003 to 2021, he was Professor of Developmental Mechanics in the University of Cambridge Department of Genetics.

The Master Builder is a three-part report from a frontier of knowledge, one in the midst of which many researchers know something of huge significance is going on, but for which existing language is not yet adequate to explain precisely what. Part One cites evidence that cells actively employ genes to send messages among themselves and to direct activities that result in building important structures. Part Two narrows the focus to the spectacular cell behaviors that occur during gastrulation, especially the “choreography” by which vertebrate embryos set up their body plans and axes. Part Three introduces the discovery of a new sort of “creature,” the gastruloids, that hold out hope for new research pathways to understand just how organisms develop and how they evolved.

In Part One, Martinez Arias replaces the “blueprint” analogy commonly applied to genes and DNA with a “hardware store catalog” image: the genome is better viewed as the catalog from which the cell orders up the appropriate plans for the protein tools and materials it needs. He repeatedly asks us to consider that genes are used by cells to generate three dimensional, sometimes symmetrical, complex structures, emphasizing always that genes themselves have no concept or perception of space or time. Knowing that the movements of cells during gastrulation are spectacular and not yet well explained, Martinez Arias spends Part Two digging in to evidence that cells respond to all sorts of things—their physical substrate, its hardness, softness, geometry, the number and density of adjacent cells, and even the order of cellular events—as they reach into their catalog of available genes to accomplish complex multicellular constructions. The astonishing activity of the neural crest cells provides his strongest example:

Martinez Arias doesn’t see evidence that the neural crest cells are simply gene-driven. Rather, they snap into streaming migratory behavior just after vertebrate gastrulation, establish resident populations at particular locations, and set about building vital, complex structures (e.g., the complex, integrated anatomy of our head and face). Traditionally, the language used to describe this involves movements of neural crest cells to locations adjacent to epithelial cells where the migrants then receive signals that “induce” them to transform their activities and create a specific organ or shape. Martinez Arias sees these neural crest cell movements as far more dependent on the “choices” of the cells. He asks why, and how, the neural crest cells “choose” to migrate in the first place.

In Part Three, Martinez Arias engagingly tells the story of how a number of different researchers stumbled on the conditions that stimulate formation of gastruloids, little “creatures” with a predictable shape and a predictable gene expression geography. They’re not embryos, they don’t represent a known stage of embryonic development, and they won’t proceed through full development. Instead, they seem to present a bare “outline” of a bilaterian vertebrate body plan. Manipulating them in the lab allows the probing of questions about just what sort of conversations are going on among the cells to get them to this point, and what conversations are not going on, thwarting their further development. They present a gold mine of possible laboratory investigations (and, for now at least, avoid the political/legal complications of studying human embryos).

Throughout the book, Martinez Arias hints strongly at how his view of cellular activity fits with evolution. He sees the advent of multicellularity, at least among animals, as the watershed moment at which genes—which had been functioning as “simple” tools of single-celled organisms, providing appropriate responses to certain environmental limitations and opportunities—began to be used in cell-to-cell conversations using new gene products as signals, creating unlimited levels of complexity. He believes those conversations led to the movements of gastrulation and the resultant great diversity of animal body plans, likely happening during the Cambrian period.

A major problem for The Master Builder is that we don’t yet have adequate language to describe what’s happening in and among cells as they go through complex embryonic development. Martinez Arias regularly employs active verbs that imply intelligence and will, using “choose” and “decide” frequently as cells order up the appropriate tool or material from the genomic catalog, then selectively employ the molecular product to accomplish an essential end. Unless we think cells are conscious, there must be some mechanistic link that looks like the “choosing” that’s going on. Martinez Arias has observed that many features of a cell’s immediate environment (the number, type, density, or texture of the neighboring cells, and physico-chemical properties of any substrate along which or in which the cells are acting) seem to trigger specific cell responses. But is that an example of the cell choosing or simply reacting? The mechanisms for these interactions are not fully known, as he freely admits. Despite the difficulty of talking of cells’ agency in developmental processes, Martinez Arias never suggests that there is some vital force behind development, and he is not sympathetic with any sort of intelligent design argument (p. 177). Martinez Arias simply suggests that we are only beginning to figure out how cells work together in the processes of building multicellular organisms. (For a quick information-packed introduction to this line of research, see Gorfinkiel and Martinez Arias, 2021.¹ But reading The Master Builder is a lot more fun.)

Gastruloids open a window into asking a series of new questions that couldn’t be asked before. The Master Builder is a great read and an exciting introduction to this field of study.