How to Build a Human: Adventures in How We Are Made and Who We Are. Philip Ball
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imagine that we will find a set of instructions packed like a homunculus inside the zygote. Rather, we will need to discern and interpret the patterns of information flow (and the various sources of that information) as the process unfolds.
It’s rather as if the genome is a list of the words that feature in a book, but you need other information to put the words in the right order so that they become more than just assemblages of letters and may take on meanings. Those meanings are not inherent in the words themselves but may be determined by the words nearby, by allusions and interactions that leap from one part of the text to another – by context. Again, there is no perfect metaphor for illustrating how genes work in building an organism; doubtless this one would collapse too under pressure, so use it gently.
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I won’t explain in detail how human embryogenesis differs from that of the fruit fly, but it’s worth understanding one of the most basic distinctions. For the human body doesn’t simply emerge imprinted on the inner cell mass of the blastocyst like stripes on an embryonic zebra.11 Rather, the cells in the embryo move around, and the tissues grow, buckle and fold, to shape the body. It’s a highly active process, a kind of auto-origami happening in parallel with the appearance of distinctions between cell types. The first stage of this process, which for humans occurs around day 14 after fertilization (around the time that a pregnant woman might first notice a missing menstrual period), is called gastrulation. Some scientists regard this as the point where a mass of cells begins to produce an organism: as the beginning of personhood.
There is a lame joke that scientists still seem to find amusing about how, if a physicist were to study the cow, she would first simplify the question by approximating it as a sphere. It is rendered all the lamer by the fact that this is not so far from how nature approximates the human body – or the bovine one for that matter – in the first instance. For the most rudimentary idealization of our body might run thus: an inner tube for digestion from mouth to gut to anus, an outer layer of skin to create a boundary, and everything else packed into the space in between. At one end we’ll put the head – the anterior – and at the other end is of course the posterior. Gastrulation creates a structure very much like this (the word actually means “gut formation”). In some creatures, such as species of worms and molluscs, it really is that simple: gastrulation folds the embryo into a sort of fat tube or doughnut shape in which an inner tube connects mouth to anus, and the job is nearly done at a stroke.
For humans, it is rather more complicated. The embryo develops a central groove called the primitive streak, which will become the axis of the backbone and central nervous system: the beginning of the aforementioned neural tube. The subsequent folding is not easy to describe in words, but it creates the crescent-shaped structure that will become the fetus, connected to a yolk sac (involved in early embryonic blood supply) and attached to the placenta via the umbilical cord. The key point is that initially this gastrulated human embryo develops distinct types of tissue: its cells lose their pluripotency and start to specialize. The innermost layer, which will form the lining of the gut, is called the endoderm (“inner skin”). The outer layer, or ectoderm, generates the surface layer of the skin as well as the brain and nervous system. Between these layers is the mesoderm (“middle skin”), which is the primal fabric of the inner organs and tissues: the heart, kidneys, bone, muscles, ligaments and also the blood. At this stage, some of the embryonic stem cells are also set aside to become the germ cells: the precursors to the gametes (eggs and sperm).
Gastrulation of the human embryo and formation of the primitive streak.
And there you have it: the schematic human body, its cells launched on their road to specialization. The rest is refinement. For example, some neural cells in the head region develop (around week five of gestation) not into neurons but into the retinal cells of the eye. Some cells don’t differentiate where they first sit, but actively migrate through the embryo to where they need to be – we saw that the primordial germ cells do this. The sex organs develop identically at first in both sexes, becoming female organs unless triggered into the structures of the male if the cells have a Y chromosome instead of a second X. On the Y chromosome sits a gene denoted SRY, which controls other genes needed to develop male characteristics.
All of this refinement happens through cell dialogue. Molecular messages pass from cell to cell, each at the proper stage of development, so that cells get assigned their roles in collaboration with their neighbours. “The parts of each organ help the other parts to form,” explains cell biologist Scott Gilbert. It is because organoids like my mini-brain lack this information from surrounding tissues that their development – their morphology – is imperfect. To make a body or even a mature organ, cells need community.
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The idea that genes involved in development interact and control one another via diffusing morphogens is only a part of the story of how embryos take on their form. The distinctions between cell types initiated by such signals become permanently imprinted on the cells as they develop into different tissues.
How can that be, if they still all share the same genome?
That problem was recognized by Thomas Hunt Morgan and others in the early days of molecular genetics, but no one really knew how to address it. So it was largely put to one side. The discovery of DNA’s genetic code in the 1950s and ’60s all but eclipsed the question, seeming as it did to promise an underlying simplicity in the way cells function. Already in 1941, Morgan’s former student George Beadle, along with biochemist Edward Tatum, had shown that genes (whatever they were – it wasn’t yet clear) encode protein enzymes. This became understood to mean that each gene has a unique corresponding protein. The key question was then how a gene made a protein. Crick and Watson’s double helix, zipped together with information-bearing nucleotide bases, seemed to deliver the answer: DNA carries the coded plan, and RNA and ribosomes are the machinery that does the translation.
But how do you get from a protein to the phenotypic effect of a gene on the unfolding organism? That wasn’t at all obvious. By the 1960s, the general idea was that genes act in some vague way to dictate the developmental programme, which was then envisaged merely as “an unfolding of pre-existing instructions encoded in the nucleotide sequences of DNA”, as American biologist-cum-historian-cum-philosopher Evelyn Fox Keller has put it. According to the French biochemist Jacques Monod, as far as gene action is concerned, “what’s true for [the bacterium] E. coli is true for the elephant.” What seemed to matter was establishing the common basis by which gene becomes protein. Somehow the rest – meaning the living organism itself – followed. Which would be all very well, if E. coli looked like an elephant.
In this picture, then, the answer to the question of development must reside in the gene sequence, and the ultimate goal of biology becomes the decoding of that sequence. This picture has been burnished for a remarkably long time, culminating in the Human Genome Project, which began in the 1990s and announced the almost complete sequencing of the human genome between 2001 and 2003.12 The objective was simply to get the code, which took on the status of the “fundamental” information directing all biological activity. Meanwhile, genetics more broadly looked for correlations between genes and phenotypic outcomes. Exactly how and why genes exert their effects was a question long bundled up in the vague concept of “gene action” that, as Keller says, allowed scientists “to get on with their work despite almost complete ignorance of what that ‘action’ consisted of.” There was an implied hierarchy of causation in which genes were paramount, as reflected in Nobel laureate David Baltimore’s comment that the development of an organism involved the “greasy machines” of the cell directed by the “executive suite” of the genome. (Engineers are very familiar with this kind of prejudice.)
The resulting view was that development was a kind of painting by numbers of the plan in the genome. For a complex organism like us, that left an awful lot of instructions to be packed into the genes. As the Human