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William Collins

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This eBook first published in Great Britain by William Collins in 2019

Copyright © Philip Ball 2018

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Source ISBN: 9780008331771

Ebook Edition © May 2019 ISBN: 9780008331795

Version: 2019-05-27

CONTENTS

COVER

TITLE PAGE

COPYRIGHT

PROLOGUE

INTRODUCTION My Brain in a Dish

CHAPTER 1 Pieces of Life Cells past and present

CHAPTER 2 Body Building Growing humans the old-fashioned way

FIRST INTERLUDE The Human Superorganism How cells became communities

CHAPTER 3 Immortal Flesh How tissues were grown outside the body

SECOND INTERLUDE Heroes and Villains Cancer, immunity and our cellular ecosystem

CHAPTER 4 Twists of Fate How to reprogramme a cell

CHAPTER 5 The Spare Parts Factory Making tissues and organs from reprogrammed cells

CHAPTER 6 Flesh of My Flesh Questioning the future of sex and reproduction

CHAPTER 7 Hideous Progeny? The futures of growing humans

THIRD INTERLUDE Philosophy of the Lonely Mind Can a brain exist in a dish?

CHAPTER 8 Return of the Meatware Coming to terms with our fleshy selves

FOOTNOTES

ENDNOTES

BIBLIOGRAPHY

PICTURE CREDITS

INDEX

ACKNOWLEDGEMENTS

ABOUT THE BOOK

ABOUT THE AUTHOR

ABOUT THE PUBLISHER

PROLOGUE

This book arose from an astonishing experiment in which I was invited to take part, and which involved the transformation of a piece of me.

In the course of writing it, as I spoke to scientists about cell biology and fertility, embryology and medicine, philosophy and ethics, it dawned on me just how much science, in these fields especially, is driven by stories.

I don’t mean “human stories” – those tales about people that are said to be so central to keeping general audiences engaged. I mean that our perception of what science means is shaped by narratives about it. There are narratives that society imposes on new discoveries and advances, which are often cut from older cloth. In biology – particularly developmental, cell and reproductive biology – these stories tend to come from myth, science fiction and fantasy, and they are often alarming: they might, for example, draw on Frankenstein, Brave New World, The Island of Doctor Moreau. But there are also narratives that scientists themselves create and recycle. It happens more in the biological sciences than in the others because biology is inherently a science of becoming, where history matters and where we seem compelled to speak about goals and purposes: what organisms, cells and genes “want”, what evolution “seeks to do”.

A significant aspect of this book’s aim is to expose and explore these stories. They are by no means a bad thing. On the contrary, they are essential and often illuminating, for they fit with the way we humans make sense of our world, with our instinct to look for and find causation, reasons behind things. Yet there is a danger to them too, which is that we might begin to mistake them for descriptions of how things are.

One of the classic examples of a framing narrative in biology is Richard Dawkins’s concept of the selfish gene. Dawkins has had to defend this idea against accusations that it attributes a kind of agency and intention to genes, for it is of course just a metaphor. The problem is that, when a metaphor gets this popular, it starts to be understood (and sometimes presented) as a plain account of “what things are like”. When Dawkins speaks of us – individual humans – as the “survival machines” for genes, he is not defining what a human is but is explaining what we are required to be within the narrative of the selfish gene. The narrative serves to convey a particular aspect of how genes function in evolutionary terms. If you don’t like this story, or don’t find it helpful, you are not obliged to accept it; there is nothing “real” about it. Dawkins has said as much: he admits in The Selfish Gene that it should strictly be called The Slightly Selfish Big Bit of Chromosome and the Even More Selfish Little Bit of Chromosome. (He was right to suspect the book would not have been so successful if he’d called it that.) He even admitted much later that the book could equally have been titled The Cooperative Gene. That would have been a different narrative, of course, and it would have served to illustrate another facet of how genes work.

As Dawkins implicitly acknowledges here, biology is too complex and complicated to be reduced to a single story. That’s precisely why we need stories to tell about it: they give us something to cling to, some way of finding a path through the thicket. There is almost always more than one of them.

It’s not just, though, that we must remember this is what we are doing. We must also keep in mind that stories are not neutral vehicles for understanding. When we frame some medical advance within the narrative of Brave New World, we are not simply saying, “hey, doesn’t this sound a bit like the people-growing hatcheries in Aldous Huxley’s book!”, but also “… and we should be suspicious, even frightened, of where it might lead.” Precisely the same applies to The Selfish Gene. The story’s subtext here is that Darwinian evolution is ruthless – that it makes for a dog-eat-dog world, a battle for survival from the bottom up. Dawkins explains that this does not imply that humans are themselves bound to be selfish; indeed, he shows how altruism can arise from “selfish genes”. But the implication remains that there is to nature a redness in tooth and claw, and indeed Dawkins advises that for this very reason we should strive to supersede the default and be kind to one another. The point is, though, that one can talk about Darwinian evolution and genes without invoking “selfishness” at all, and the story then has a different complexion in which all manner of behaviours appear not as emergent and perhaps counter-intuitive consequences of a selfish genetic strategy but simply as aspects of the complexity of biology: cooperation as well as the most beastly predation strategies, war and peace, love and cruelty. Each of those words is equally freighted with narratives that biology itself doesn’t impose.

This is why I will be constantly alert to the narrative, and will ask, “why this story, and not some other?” Whether we are talking about cancer or immunity, cell signalling or tissue engineering, the science becomes packaged right from the outset inside a story, and this means that we impute agency, make choices about what to include and what not to, and suggest certain goals and not others. Even scientists speaking to other scientists need to use metaphors and narratives somewhere along the road, to give the mind purchase on concepts that are otherwise too slippery and too complex to comprehend. The only danger in all this, as in stories about “selfish genes”, is if we tell ourselves that all we are doing is relating objective truths.

I’d suggest that you might want to be alert to the narratives that I shall deploy too – for I am no more immune than anyone else to the tendency, the need, to tell a story, and the habit of using framing devices unconsciously. Challenge me on it. I promise to try not to mind.

It’s for this reason too that I think it is always important to know something about the historical context in which a scientific idea has arisen. We will see that, for example, cell theory was originally deemed to have a political dimension, and tissue culture was driven by social agendas. Some scientists might say, “oh, but that was then, and we have shed that baggage now and are dealing just with plain facts.” But I suspect that few scientists working on fertility and infertility would say this, and certainly they should not. They know very well that whatever they discover will be refracted through a complex social legacy of attitudes to baby-making, sex and gender. Geneticists labour under the shadow of the field’s eugenic past, and this goes beyond the stark fact that such work once led to enforced sterilization of the “unfit” in many countries and was embraced by the Nazis. Unease and dispute remain today over the implications of genetics for incendiary issues like race, class, intelligence and disability. What this means is that culture, past and present, may shape the scientific questions we ask, the models we develop, and the stories we tell.

I know from experience that there is a kind of reader who says, “I don’t care about that, just give me the science!” If you are that kind of reader, I’d humbly reply: I cannot give you “just the science”, because it already comes with a story attached. In this field – which I find breathtaking, perplexing, occasionally disturbing – there is never “just the science”.

When we ask, “how to grow a human”, we cannot possibly be asking “just” a question about science. That’s what makes the question so interesting.

INTRODUCTION
MY BRAIN IN A DISH

In the summer of 2017, a small piece of my arm was removed and turned into a rudimentary miniature brain. This book is my attempt to make sense of that strange experience.

On a hot day that July, I lay on a bed in the Institute of Neurology at University College London while neuroscientist Ross Paterson gouged a little chunk from my shoulder with a kind of miniature surgical apple-corer. A dab of local anaesthetic made it painless; to my great relief, there wasn’t much blood.

Bathed in a nutrient solution in a test-tube, that piece of my flesh was the seed for what, eight months later, would resemble a tiny brain.

It was my own “mini-brain”, a blob of neurons about the size of a lentil. They wired themselves into a dense network and could signal to one another in the way neurons do. I’m not going to say it was thinking; probably these signals were not much more than random sparks, incoherent noise, signifying nothing. But no one really knows how to think about what goes on inside a mini-brain, any more than they know what transpires in the formative brain of a fetus when it is of comparable pea-size.

This process of culturing new tissues from a piece of arm is not the way to create a human. But it could one day become a basis for doing that.

It’s not obvious why anyone, here and now, would think this a good idea. But the point is not that one day humans will, like the citizens of Aldous Huxley’s Brave New World, be cultivated from blobs of cells in the vats of some dystopian people-factory. The point is that such a vision is no longer obviously impossible. That alone should give us cause to revise our ideas about what we think we are. Having a piece of you grown into a mini-brain in an incubator five miles across town brings home to you, rather viscerally, why the need for that revision is upon us now.

My mini-brain under the microscope.

* * *

Let me explain.

My mini-brain was cultivated, nurtured and guided by neuroscientists Selina Wray and Christopher Lovejoy at UCL. That’s their job. They want to understand how brains develop, and in particular why some gene mutations send that process awry and trigger the onset of neurodegenerative diseases such as Alzheimer’s. These conditions, which many of us will confront – close to a million people in the UK are currently thought to be living with some form of dementia – are partly a consequence of ageing, but they can also have genetic roots. Some gene mutations confer particular susceptibility to dementias, and there are inheritable early-onset dementias that can affect people even in their thirties. My “brain in a dish” was grown as part of a large and ambitious project called Created Out of Mind, funded in 2016–18 by the Wellcome Trust to alter public perceptions of dementia and develop new tools for assessing the value of arts-based interventions for people living with these conditions.

Selina and Chris hope that, by studying the activity of genes in mini-brains cultured from the tissues of people with those genetic mutations, they might come to understand more about the causes, and ultimately find clues that could lead to possible cures. Scientists studying the genetic factors behind the neurodegenerative Huntington’s disease have already found that the baleful effect of one particular gene implicated in the condition can be tempered with drugs that intercept the conversion of the gene to a protein that is prone to “misfolding”. It’s this misfolded form that produces scarring and destruction of brain tissue. Others are working on vaccines that might prevent or remove the clumps of misfolded protein in the brain that seem to trigger Alzheimer’s itself.

To my knowledge, I do not have genes that make me susceptible to early-onset Alzheimer’s. But the aim of the Brains In A Dish project, coordinated by artist Charlie Murphy, was to explore and explain research like this through the response of its participants. Well, this book is mine.

I should be very clear what this term “mini-brain” implies. Some researchers reject it, and I see their point. Human neurons grown in a cell culture in this way can’t make a brain, not even in its early fetal form. But these nerve cells do start to create, under the direction of their own genetic programme, some of the features that a real developing brain exhibits. They become specialized into some of the many different cell types – not just neurons – that are found in our mature brains. And they acquire some of the anatomical structure of brains: the well-defined layers of neurons seen in the cortex, the folds and convolutions of the tissues. It’s rather like a very young child’s drawing of a person: not much of a resemblance really, but you can see what they’re getting at. You can see the potential to do a better job. A more neutral term for these lab-grown cell structures is “organoid”: the cells construct something that looks like a crude representation of an organ of the body, reduced in scale. It is possible to grow organoids resembling livers, kidneys, retinas, gut, as well as brains – all in a dish, outside the body. I want to ask what this means, for medicine, fundamental biology, philosophy and our sense of identity.

There was no rulebook to tell me how I should feel about my mini-brain. Certainly, I didn’t lie awake at night fretting over its welfare; this mass of tissue made from my skin didn’t take on the status of an individual. But I felt oddly fond of those cells, doing their best to fulfil a role in the absence of the guiding influence of their somatic source.¹ There was a curious intimacy involved, a sense of potential that wasn’t present initially in the tiny chunk of arm-flesh excised and placed in a test-tube. This was more than a matter of cells subsisting; this was life in all its teeming, multiplying glory, spilling out from a paring of me.

My skin cells (fibroblasts) growing in a petri dish (in vitro) from a piece of skin tissue taken from my arm.

It’s hard not to invest the whole of biology with intentions, purposes, wants and needs, even though cells and simple organisms resemble automata responding without volition to the signals from their environment. (Some would say this applies to humans too.) That’s just how nature works.

Yet seeing these cells do their business in a petri dish is to recognize that life exists in doing. It is a process in which change is the only constant: change imbued with direction, more or less constrained onto a trajectory that evolution has guided and given what looks almost indistinguishable from a purpose, until death makes that change an inexorable slide into decay and entropic dissolution. There is no agreed scientific definition of “life”, but such a thing (if it is possible at all) would mean little if it fails to acknowledge this dynamic aspect, this interplay of predetermined pattern and historical contingency. It feels banal to say that my excised cells took on a life of their own, but what is so new and so remarkable about the science behind organoids is that we have the knowledge and power to influence the direction that life takes.

* * *

What really needs explaining is that my mini-brain was grown from a piece of my arm: in essence, from skin cells. That doesn’t sound like something that should be possible. Until barely more than a decade ago, most biologists thought so too. The discoveries that changed this view have transformed cell biology, raising all manner of medical possibilities for regenerating organs and tissues as well as opening up new avenues for basic research into embryology, development and conception. These discoveries and their applications are at the heart of this book.

But although these cell-transforming technologies have been celebrated, sometimes in breathless and hyperbolic terms, in the popular press, I’m not at all sure that their wider philosophical, one might even say psychic, implications have been acknowledged. Here is one of the profound things they say to us:

Every part of ourselves can potentially be turned into any other part of ourselves – including a complete self.

This, let me add, is more than science has yet proved. There is some small print attached, and further ingredients might be needed to fulfil the last part of the bargain. All the same, we are more plastic than we ever guessed. And that realization is in turn a culmination of medical advances and discoveries that have taken place over the course of the past century, which too we have processed only in the manner that we always process discoveries we don’t know how to think about. That’s to say, we have framed it around fears, fantasies and fiction.

For example: perhaps my “brain in a dish” immediately invokes visions of Frankenstein. And I pointed you also towards Brave New World, that re-envisioning of Mary Shelley’s tale for the age of industrialization and mass culture. These two novels remain today the favourite, off-the-shelf points of cultural reference for biomedical advances that unsettle and boggle the mind. But we are sent back to other speculative fictions by some of the possibilities that I have seen seriously and soberly discussed in the context of cell transformation and organoid growth. For example:

 It may well be possible to grow a human brain in the body of a pig. One reason I find this so disturbing is that I still vividly remember first seeing the scene in Lindsay Anderson’s 1973 film, O Lucky Man!, where … well, if you don’t know it already, don’t let me spoil it for you.

 It might be feasible to grow each organ of the human body separately outside the body itself in some sort of vessel (in vitro), and then surgically assemble them into a person – or enough of a person to be, let’s say, a personoid. And this is precisely how the first robots were made, in Karel Čapek’s 1921 play, R.U.R.

 Philosophers, ethicists and neuroscientists are now compelled to debate what it could mean to create a full-grown human brain in a vat. Could it be conscious? Would it experience a self-contained interior “reality”? The pop-culture reference point here, which philosophers have embraced with nerdy delight, is of course the Matrix movies of the Wachowskis.

Let me make it clear that no researcher sees any prospect of these things happening in the near future, nor any good reason to try to make them happen. I will look at them more closely later, but my point here is not to tell rather shocking and thrillingly grotesque scare stories in a bout of bait-and-switch. What matters is that, confronted with so disorienting and disturbing a set of imaginable possibilities, we seem to need such stories in order to frame our thoughts. That in itself is worth considering. What motivates and shapes these narratives?

Underpinning them, I believe, is a consideration that might at first strike you as odd: We are not at ease with our own flesh.

But surely, you might say, we inhabit our own flesh? I’m putting those words into your mouth because they have a familiar ring to them – it doesn’t seem a strange thing to suggest. Yet such a phrase serves more to disassociate than to unite us with our flesh. We inhabit it? Like a person who inhabits a house? So what, then, are “we”? It’s the old Cartesian dualism: the separation of mind and body, or as some might have once said, of body and soul.

Yet of course we are not at ease in our own flesh! How we recoil from its routine functions, its excrescences and smells and fluids. How hard we try to remodel it, with what horror we watch its decrepitude. How we flock to watch movies like Hellraiser and Saw, or, at the more sophisticated end of the body-horror market, pretty much any of David Cronenberg’s early oeuvre. Gunther von Hagens, with his plasticized corpses, has made a career from an artful exploration of our horrified fascination; artists from Mark Quinn (who has sculpted with his own blood and the placenta of his baby son) to Marina Abramović have made what are often brave, painful and stomach-churning attempts to help us engage with our raw material.

There are many reasons for this ambivalence towards the somatic aspects of human existence, expressed repeatedly in all cultures in all ages: with piercings and tattoos, rituals of embalming and burial, elaborate taboos and the normative strictures of surgery. But the new sciences of culturing and transforming our cellular fabric confront us with perhaps the most fundamental challenge for our relationship with our flesh. They show us the ultimate in dismemberment: a reduction of the person to the cell.

Time was when we could dismiss that. Sure, cells are our building blocks, but no more or less so than proteins, atoms or quarks. If a chunk of our cellular material were removed, well, so what? It was no longer “us”, but a piece of waste, separate and dead, soon to be putrescent and doomed by microbes and entropy.

Having your skin grown into neurons that assemble themselves into a brain organoid is a pretty convincing way to find out how obsolete that notion is. All the more so when you see it through the microscope and realize that this is not merely some trick of preservation. Life on that scale is multitudinous, and thriving, and it has a plan of sorts.

Life? Whose life?

Not mine, exactly – and yet who else’s can it be? Those cells are autonomous – but why any more so than the cells still in my arm, in my real brain (the need for that specifying adjective still makes me blink), my surging blood and beating heart? And so I come by degrees to accept the inevitable truth: I am a colony of cells, whose cooperation lets me draw breath, whose communication produces my sense of identity and uniqueness.

That is what is fundamentally disconcerting about our own flesh. It grew as a colony from a single cell, and we’re not quite sure where (or when) in this teeming morass to pin the label “me”.

The new cell technologies are making it impossible for us any longer to ignore this fact. I won’t pretend that I know how to normalize it, but I think there is a strange kind of liberation that can come from letting ourselves be unsettled by it.

CHAPTER 1
PIECES OF LIFE
CELLS PAST AND PRESENT

“Ex ovo omnia.”

So declared the frontispiece of Exercitationes de generatione animalium (1651) by the seventeenth-century English physician William Harvey, sometime physician to James I. It expressed a conviction (and no more) that all things living come from an egg.

William Harvey’s motto “All things from an egg” in the frontispiece of his 1651 treatise on the “generation of animals”.

It’s not really true: plenty of living organisms, such as bacteria and fungi, do not begin this way. But we do. (At least, we have done so far. I no longer take it for granted that this will always be the case.)

“Egg” is an odd term for our generative particle, and indeed Harvey was a little vague about what he meant by it. Strictly speaking, an egg is just the vessel that contains the fertilized cell, the zygote in which the male genes from sperm are combined with the female genes from the “egg cell” or ovum. Yet it’s easy to overlook how bold a proposal Harvey was making, in a time when no one (himself included) had ever seen a human ovum and the notion that people might begin in a process akin to that of birds and amphibians could have sounded bizarre.

The truth of Harvey’s insight could only be discerned once biology acquired the idea of the cell, the fundamental “atom of biology”. That insight is often attributed to Harvey’s compatriot and near-contemporary Robert Hooke, who made the most productive use of the newly invented microscope in the 1660s and ’70s. Hooke discerned that a thin slice of cork was composed of tiny compartments that he called “cells”. This is often said to be an allusion to the cloistered chambers (Latin cella: small room) of monks, but Hooke drew a parallel instead with the chambers of the bee’s honeycomb, which in turn probably derive from the monastic analogy.

Robert Hooke’s sketch of cells in cork, as seen in the microscope.

The popular notion that Hooke established the cellular basis of all living things is wrong, however. Hooke saw cells, for sure – but he had no reason to suppose that the fabric of cork had anything in common with human flesh. In fact, Hooke imagined that cork cells are mere passages for transporting fluids around the cork tree. The cell here is just a passive void in the plant’s fabric, a very different notion from the modern concept of an entity filled with the molecular machinery of life.

More provocative were the observations of the Dutch cloth merchant Antonie van Leeuwenhoek in 1673 that living organisms can be of microscopic size. Leeuwenhoek saw such “animalcules” teeming in rainwater – mostly single-celled organisms now called protists, which are bigger than most bacteria. You can imagine how unsettling it was to realize that the water we drink is full of these beings – although not nearly so much so as the dawning realization that bacteria and other invisibly small organisms are everywhere: on our food, in the air, on our skin, in our guts.

Leeuwenhoek contributed to that latter perception when he discovered animalcules in sperm. That was one of the substances that the secretary of London’s Royal Society, Henry Oldenburg, suggested the Dutchman study after receiving his communication on rainwater. Leeuwenhoek looked at the semen of dogs, rabbits and men – including his own – and observed tadpole-like entities that “moved forward with a snake like motion of the tail, as eels do when swimming in water.” Were these parasitic worms? Or might they be the very generative seeds themselves? They were, after all, absent in the sperm of males lacking the ability to procreate: young boys and very old men.

Here we can see the recurrent tendency to impose familiar human characteristics on what is evidently “of us” but not “like us”. The French physician Nicolas Andry de Boisregard, an expert on tiny parasites and a microscope enthusiast, claimed in 1701 that “spermatic worms” could be considered to possess the formative shape of the fetus: a head with a tail. In 1694, the Dutch microscopist Nicolaas Hartsoeker drew a now iconic image of a tiny fetal humanoid with a huge head tucked up inside the head of a spermatozoa: not, as sometimes claimed, a reproduction of what he thought he could see, but a figurative representation of what he imagined to be there.

The “homunculus” in sperm, as imagined by Nicolaas Hartsoeker.

This was one of the most explicit expressions of the so-called preformationist theory of human development, according to which the human body was fully formed from the very beginning of conception and merely expands in size: an extrapolation down to the smallest scale of the infant’s growth to adulthood. According to this picture, the female egg postulated by Harvey continued to be regarded in the prejudiced way in which Aristotle had perceived the woman’s essentially passive role in procreation: it was just a receptacle for the homunculus supplied by the man.

That was, though, a different view to the one Harvey envisaged, in which the body developed from the initially unstructured egg. Harvey, like Aristotle, thought that semen triggered this process of emergence, which Aristotle had imagined as a kind of curdling of a fluid within the female. The idea that the embryo unfolds in this way, rather than simply expands from a preformed homunculus, was known as epigenesis. These rival views of embryo formation contended until studies with the microscope, particularly investigations of the relatively accessible development of chicks inside the egg, during the eighteenth and early nineteenth century put paid to the preformation hypothesis. Embryos gradually develop their features, and the question for embryologists was (and still is) how and why this structuring of the tissues comes about.

* * *

The observations of early microscopists did not, then, engender a belief that life is fundamentally cellular. That cells are a general component of living matter was not proposed until the early nineteenth century, when the German zoologist Theodor Schwann put the idea forward. “There is one universal principle of development for the elementary parts of organisms,” he wrote in 1839, “and this principle is in the formation of cells.”

Schwann developed these ideas while working in Berlin under the guidance of physiologist Johannes Müller. One of Schwann’s colleagues in Müller’s laboratory was Matthias Jakob Schleiden, with whom he collaborated on the development of the cell theory. Schleiden’s prime interest was plants, which were more easily seen under the microscope to have tissues made from a patchwork of cells, their walls constituting emphatic physical boundaries. This structure wasn’t always evident for animal tissues (especially hair and teeth), but Schwann and Schleiden were convinced that cell theory could offer a unified view of all living things.

Schleiden believed that cells were generated spontaneously within the organisms – an echo of the notion of “spontaneous generation” of living matter that many scientists still accepted in the early nineteenth century. But he was shown to be wrong by another of Müller’s students, Robert Remak, who showed that cells proliferate by dividing. Remak’s discovery was popularized – without attribution – by yet another Müller protégé, Rudolf Virchow, who tends now to be given the credit for it. All cells, Virchow concluded, arise from other cells: as he put it in Harveian manner, omnis cellula e cellula. New cells are created from the division of existing ones, and they grow between successive divisions so that this series of splittings doesn’t result in ever tinier compartments. Virchow proposed that all disease is manifested as an alteration of cells themselves.

Virchow was the kind of person only the nineteenth century could have produced – and perhaps indeed only then in Germany, with its notion of Bildung, a cultivation of the intellect that encouraged the emergence of polymaths like Goethe and Alexander von Humboldt. Virchow studied theology before taking up medicine in Berlin. While establishing himself as a leading pathologist and physician, he also became a political activist and writer and was involved in the uprisings of 1848. As if to demonstrate that nothing was simple in those times, this eminent biologist and religious agnostic was also profoundly opposed to Charles Darwin’s theory of evolution, of which his student Ernst Haeckel was Germany’s foremost champion.

Virchow thus had fingers in many pies; but in his view they were different slices of the same pie. The influence of politics, ideology and philosophy on science is always clearer in retrospect, and that’s nowhere more apparent than in the physiology of the nineteenth century. For Schwann, “each cell is, within certain limits, an Individual, an independent Whole”: an idea indebted to the Enlightenment celebration of the individual. The cell was a living thing – as the physiologist Ernst von Brücke put it in 1861, an “elementary organism” – which meant that higher organisms were a kind of community, a collaboration of so many autonomous, microscopic lives, in a manner that paralleled the popular notion of the nation state as the collective action of its citizens. Meanwhile, Schwann’s conviction of the cellular nature of all life, implying a shared structural basis for both plants and animals, was motivated by his sympathy for the German Romantic philosophical tradition that sought for universal explanations.

For Virchow, this belief in tissues and organisms as cellular collectives was more than metaphor. It was the expression writ small of a principle that applied to politics and society. He was convinced that a healthy society was one in which each individual life depended on the others and which had no need of centralized control. “A cell … yes, that is really a person, and in truth a busy, an active person,” he wrote in 1885. “What the individual is on a grand scale, the cell is that and perhaps even more on a small one.”

Life itself, then, showed for Virchow how otiose and mistaken was the centrist doctrine of the Prussian statesman Otto von Bismarck, who at that time was working towards the unification of the German states. Virchow attacked Bismarck’s policies at every opportunity and denounced his militaristic tendencies, so enraging the German nobleman that Bismarck challenged Virchow to a duel. The physiologist shrugged it off, making Bismarck’s belligerent bluster seem like the aristocratic posturing of a bygone era.

The idea of the “germ” as a rogue microbial invader was the counterpart to the idea of a body as a community of collaborating cells. It was entirely in keeping with the political connotations of cell theory that germ theory blossomed in parallel. Once Louis Pasteur and Robert Koch showed in the nineteenth century that micro-organisms like bacteria can be agents of disease (“germs”), generations of children were taught to fear them. Germs are everywhere, our implacable enemies: it is “man against germs”, as the title of a 1959 popular book on microbiology put it. After all, hadn’t a bacillus been identified as the cause of cholera in 1854? Hadn’t Pasteur and Koch established bacteria as the culprits behind anthrax, tuberculosis, typhoid, rabies? These germs were nasty agents of death, to be eradicated with a thorough scrub of carbolic. And to be sure, the antiseptic routines introduced by the unjustly ridiculed Hungarian-German physician Ignaz Semmelweis in the 1840s (as if washing your hands before surgery could make any difference!), and later by Joseph Lister in England, saved countless lives.

This new view of disease had profound sociopolitical implications. The old notion of a disease-generating “miasma” – a kind of cloud of bad air – situated illness in a particular locality. But once disease became linked to contagion passed on between people, a different concept of responsibility and blame was established. The politicized and racialized moral framework for germ theory is very clear in the description of a French writer from 1885 who talked of disease as “coming from outside, penetrating the organism like a horde of Sudanese, ravaging it for the right of invasion and conquest.” This was the language of imperialism and colonialism, and disease was often portrayed as something dangerously exotic, coming from beyond the borders to threaten civilization. Those who supported contagion theory tended to be politically conservative; liberals were more sceptical.

From the outset, then, our cellular nature was perceived to entail a particular moral, political and philosophical view of the world and of our place within it.

* * *

We come from a union of special cells: the so-called gametes of our biological parents, a sperm and an egg cell. Perhaps because this fact is taught in primary schools – a reassuringly abstract vision of human procreation, typically presented with no hint of the confusing richness and peculiarity of stratagems and diversions it engenders – we forget to be astonished by it. That we begin as a microscopic next-to-nothing, a pinprick somehow programmed with potential, is remarkable and counter-intuitive. It’s slightly absurd to image that infants will casually accommodate this “fact of life”, which seems on reflection barely conceivable. Only their endless capacity to accept the magical with equanimity lets us get away with it.

And so it continues through the educational grades: cells exist, and that is all we need to know. School children are taught to label their parts: the oddly named bits like mitochondria, vacuoles, endoplasmic reticulum, the Golgi apparatus. What has all this to do with arms and legs, hearts, brains? One thing is sure: the cell is anything but a homunculus. In which case, where does the body come from?

What the cell and the body do have in common is organization. They aren’t random structures; there’s a plan.

But that word, so often bandied about in biology, is dangerous. It doesn’t seem likely that we can ever leach from the notion of a plan its connotations of foresight and purpose. To speak, as biologists do, of an organism’s “body plan” is to lay the ground for the idea that there exists somewhere – in the cell, for where else could it be? – a blueprint for it. But it is not merely by analogy, but rather as a loose parallel, that I would invite you then to wonder where exists the plan, the blueprint, for a snowflake. There’s a crucial distinction between living organisms and snowflakes, and it is this distinction that explains why snowflakes do not evolve one from the other via inheritance but are created de novo from the cold and humid winter sky.¹ But there are good motivations for the comparison, for the body’s organization, like the snowflake’s, is an instantiation of a particular set of rules that govern growth.

Virchow and his contemporaries were already coming to appreciate that cells are more than fluid-filled sacs. In 1831, the Scottish botanist Robert Brown reported that plant cells have a dense internal compartment that he called a nucleus.² By Virchow’s time, cells were considered to have at least three components: an enclosing membrane, a nucleus, and a viscous internal fluid that the Swiss physiologist Albert von Kölliker named the cytoplasm. (Cyto- or cyte means cell, and we’ll see this prefix or suffix a lot.)

Kölliker was one of the first to study cells microscopically using the technique of staining: treating them with dyes that are absorbed by cell components to make their fine structure more visible. He was a pioneer in the field of histology, the study of the anatomy of tissues and their cells. Kölliker was particularly interested in muscle cells, and he showed that these are of more than one type. One variety has a stripy (“striated”) appearance when stained, and Kölliker noticed that striated muscle cells also contain many tiny granules, later identified as another component of animal cells that were named mitochondria in 1898. Around the same time, other substructures of the cell’s interior were recognized: the disorderly, spongelike folded membrane called the endoplasmic reticulum, and the Golgi apparatus, named after the Italian biologist Camillo Golgi. A vigorous debate began about whether the cell’s jelly-like internal medium – called the protoplasm – is basically granular, reticular (composed of membrane networks) or filamentary (full of fibrous structures). All of these options were observed, and the truth is that it depends on when and where you look at a cell.

Images of onion cells drawn in 1900 by the biologist Edmund Beecher Wilson. These show some of the internal structures seen at different times in different cells. The single dense blob in several of these is the nucleus. Sometimes this seemed to break up into threads or blobs, perhaps in the process of cell division. What was going on in there?

All this internal structure led the zoologist Edmund Beecher Wilson to express regret that the term “cell” had ever been coined. It was a misnomer, he said – “for whatever the living cell is, it is not, as the word implies, a hollow chamber surrounded by solid walls.” Some others wondered if the cell was really the fundamental entity it had been supposed to be, not least because a cell membrane was not always visible under the microscope. Perhaps it was actually these organized contents in the protoplasm that were the real stuff of life? “We must be careful,” warned zoologist James Gray in 1931, “to avoid any tacit assumption that the cell is the natural, or even the legitimate, unit of life and function.”³

At any rate, the cell contained so much stuff. What was it all for?

It was becoming clear, too, what some of the key chemical components of cells are. Chemists interested in the processes of life – by the end of the century that topic was known as biochemistry – had figured out that they contain chemical agents called enzymes that carry out its characteristic panoply of metabolic reactions. Some enzymes, for example, allow yeast to ferment sugar into alcohol. In 1897, German chemist Eduard Buchner showed that intact cells weren’t necessary for that to happen: the “juice” that could be extracted from yeast cells could produce fermentation on its own, presumably because it still carried the crucial enzymes, undamaged, within it.

These molecular ingredients, like workers in a city, had to be organized, segregated, orchestrated in the time and place of their actions and motions. Chemical reactions in the cell have to happen in the proper order and in the right location; things can’t be the same everywhere in the cell. And so the “social” view of bodies as communities of cells was repeated for the single cell itself: it was a sort of factory populated by cooperating enzymes and other molecules. This hidden machinery enables a cell to persist and maintain itself, to take in substances and energy from the environment and use them to carry out the metabolic reactions without which there is only death.⁴

At the turn of the century, the substructure and organization on which the animation of cells depends was largely beyond the resolving power of the microscopes. But it was clear enough that not all cells are alike in their composition and structure. Bacteria and protists have rather little in the way of visible internal organization. They belong to a class of micro-organisms called prokaryotes, and they are typically round or elongated and sausage-shaped. The language of biological classification is always a little presumptuous, but it takes nothing away from bacteria to say that their cells are structurally relatively “simple”. They lack a nucleus – hence the label “prokaryotes”, meaning “pre-nucleus”. (More presumption – as though bacteria just haven’t yet discovered the wisdom of having a nucleus but will wake up to it one day. In fact, bacteria have existed for longer than eukaryotes; they and other prokaryotes dominate much of the planet’s ecology, and evidently have no need of “greater sophistication” in order to thrive.)

Human cells, along with those of other animals, plants, fungi and yeast, are said to be eukaryotes: a term that simply connotes that their cells have a nucleus. Eukaryotic organisms may be multicelled, like us, or single-celled, like yeast. The latter is an example of a “lower” eukaryote: more presumption, of course, but meaning that the degree of organization in the cell is less than that evident in the higher eukaryotes like peas, fruit flies and whales.

For now we can set prokaryotes aside. There is, mercifully, no need either to look in detail at what all the complex structure of the human cell is about, other than to say that it can be usefully regarded as a compartmentalization of the processes of existence. Membrane-wrapped substructures of the cell are called organelles, and each can be somewhat crudely considered to carry out a specific task. Mitochondria are the regions where a eukaryotic cell produces its energy, in the form of small molecules that release stored chemical energy when transformed by enzymes. The Golgi apparatus functions as a kind of cellular post office, processing proteins and dispatching them to where they are needed. The nucleus is where the chromosomes are kept: the material encoding the genes that are passed on when a cell divides or an organism reproduces. What we do need to hear more about, very shortly, are those chromosomes, because they are an important part of what defines you as an individual, and absolutely vital for orchestrating the life processes that enabled you to grow and which sustain you daily.

The human cell.

By the early twentieth century, it was clear that what sets living matter apart from the inanimate is not merely a question of composition: of what life is made of. Neither is it just a question of structure. Organisms and cells clearly did have a hierarchy of significant, specific yet hard-to-interpret structures reaching down to the microscopic and beyond. And that mattered. But the real reason living matter is not equivalent to some other state of matter such as liquids and gases is that it is dynamic: always changing, always in the process of doing something, never reaching a steady equilibrium. Staying alive is not a matter of luxuriating in the state of aliveness but is a relentless task of keeping balls in the air.

Researchers today might rightly point out that this dynamic, out-of-equilibrium character is not unique to life. Our planet’s climate system is like that too: a constant channelling of the energies of the sun and of the hot planetary interior into orchestrated cycling movements of the oceans, atmosphere and sluggish rocky mantle, accompanied by flows of chemical elements and heat between the different components of the planetary system. The system is responsive and adaptive. But this is precisely the point: there are parallels between a living organism and the planet itself, which is why the independent scientist James Lovelock pushed the point from analogy to the verge of genuine equivalence in his Gaia hypothesis. Arguments about whether the planet can be truly considered “alive” are moot, because the living systems – rainforests, ocean microfauna, every creature that takes in chemicals and turns them into something else plus heat – are in any case a crucial, active part of the planet’s “physiology”.

This activity of the planetary biosphere commenced close to four billion years ago and has not ceased since. Virchow’s omnia cellula e cellula has a significance barely any lesser than that of Darwinian evolution, which ultimately depends on it (ironically, given Virchow’s views on Darwin). It establishes a basis for what Aristotle imagined as a Great Chain of Being, in which the fundamental unit is no longer the reproducing organism but the dividing cell. All cells are, in evolutionary terms, related to one another, and the question of origin reduces to that of how the first cell came into being. Since that obscure primeval event, to the best of our knowledge no new cell has appeared de novo.

At the same time, Virchow’s slogan is a description, not an explanation. Why is a cell not content to remain as it is, happily metabolizing until its time runs out? One answer just begs the question: if that is all cells did, they would not exist, because their de novo formation from a chemical chaos is far too improbable. Then we risk falling back again on anthropomorphism – cells intrinsically want to reproduce by division – or on tautology, saying that the basic biological function of a cell is to make more cells (“the dream of every cell is to become two cells”, said the Nobel laureate biologist François Jacob). Biological discourse seldom does much better than this. Cell and molecular biologists and geneticists have a phenomenal understanding of how cells propagate themselves. But explaining why they do so is a very subtle affair, and it’s fair to say that most biologists don’t even think about it. Yet that “impulse” is the engine of Darwinian evolution and consequently at the root of all that matters in biology.

There is not a goal to this process of life, towards which all the machinery of the cell somehow strives. We can’t help thinking of it that way, of course, because we are natural storytellers (and because we do have goals, and can meaningfully ascribe them to other animals too). So we persuade ourselves that life aims to make babies, to build organisms, to evolve towards perfection (or at least self-improvement), to perpetuate genes. These are all stories, and they can be lovely as well as cognitively useful. But they do not sum up what life is about. It is a thing that, once begun, is astonishingly hard to stop; actually we do not know how that could be accomplished short of destroying the planet itself.

* * *

Life’s unit is the cell. Nothing less than the complete cell has a claim to be called genuinely alive.⁵ It’s common to see our body’s cells referred to as “building blocks” of tissues, much like assemblies of bricks that constitute a house. To look at the cells in a slice of plant tissue, such as Wilson’s drawing of the onion earlier, you can understand why. But that image fails to convey the dynamic aspect of cells. They move, they respond to their environment, and they have life cycles: a birth and a death. They receive and process information. As Virchow suggested, cells are to some degree autonomous agents: little living entities, making their way in the world.

Anything less than a cell, then, has at best a questionable claim to be alive; from cells, you can make every organism on Earth. We have known about the fundamental status of the cell for about two centuries but have not always acknowledged it. For much of the late twentieth century, the cell was relegated before the supremacy of the gene: the biological “unit of information” inherited between generations. Now the tide has turned again. “The cell is making a particular kind of reappearance as a central actor in today’s biomedical, biological, and biotechnological settings,” writes sociologist of biology Hannah Landecker. “At the beginning of the 21st century, the cell has emerged as a central unit of biological thought and practice … the cell has deposed the gene as the candidate for the role of life itself.”

Cells do more than persist. Crucially, they can replicate: produce copies of themselves. Ultimately, cell replication and proliferation drives evolution. Life is not what makes this propagation of cells possible; rather, that is what life is.

Biologists towards the end of the nineteenth century recognized that reproduction of cells happens not by the spontaneous formation of new cells, as Schwann believed, but by cell division as Virchow asserted: one cell dividing in two. Single-celled organisms such as bacteria simply replicate their chromosomes and then bud in two, a process called binary fission. But in eukaryotic cells the process is considerably more complex. Cell “fission” was first seen in the 1830s and was called mitosis in 1882 by the German anatomist Walther Flemming, who studied the process in detail in amphibian cells.

Flemming was a champion of the filamentary model of cells – the idea that their contents are organized mainly as long fibrous structures. In the 1870s, he showed that as animal cells divide, the dense blob of the nucleus dissolves into a tangle of thread-like structures (mitosis stems from the Greek word for thread). The threads then condense into X-shaped structures that are arranged on a set of star-like protein filaments dubbed an aster. (The word means “star”, but actually the appearance is more reminiscent of an aster flower.) Flemming saw that the aster gets elongated and then rearranged into two asters, on which the chromosomes break in half. As the cell body itself splits in two, these chromosomal fragments are separated into the two “daughter” cells and enclosed once again within nuclei.⁶

Various stages of cell division or mitosis as recorded by Walther Flemming in his 1882 book Zellsubstanz, Kern und Zelltheilung (Cell Substance, Nucleus and Cell Division).

So cell division is preceded by a reorganization of its contents: apparently, they are apportioned rather carefully into two. The thread-like material seen by Flemming unravelling from the nucleus readily takes up a staining dye (so that it is more easily seen under the microscope), leading it to be called, after the Greek word for colour, chromatin. The individual threads themselves were christened chromosomes – “coloured bodies” – in 1888.

In that same year, the German biologist Theodor Boveri discovered that the movement of chromosomes during cell division is controlled by a structure he called the centrosome, from which the strands of asters radiate. The two asters that appear just before a cell splits in two, each with a centrosome at their core, could in fact be seen to be connected by a bulging bridge of fine filaments, called the mitotic spindle. Flemming became convinced that these spindle fibres act as a kind of scaffold to direct the segregation of the chromosome threads into two groups. He was right, but he lacked a sufficiently sharply resolved microscopic technique to prove it.

So the division of animal cells isn’t just like the splitting of a water droplet into two. It has to be accompanied by a great deal of internal reorganization. Flemming and others identified a series of distinct stages along the way. While cells are going about their business with no sign of dividing, they are said to be in the interphase state. The unpacking of the nucleus into filamentary chromosomes is called prophase, and the formation and elongation of the aster is called metaphase. As the aster-like cluster splits in two, the cell enters the anaphase, from where it is downhill all the way to fission and the re-compaction of the nucleus.

This procedure is called the cell cycle, which is an interesting phrase when you think about it. Its implication is that, rather than thinking of biology as being composed of cells that do their thing until they eventually divide, we might regard it as a process of continual replication and proliferation that involves cells. With all due warning about the artificiality of narratives in biology, we might thus reframe the Great Chain of Being as instead a Great Chain of Becoming.

* * *

It was a fundamental – perhaps the fundamental – turning point for modern biology when, around the turn of the century, scientists came to appreciate that much of the complicated reorganization that goes on when cells divide is in order to pass on the genes, the basic units of inheritance, that are written into the strands called chromosomes. What they were seeing here in their microscopes is the underlying principle that enables inheritance and evolution.

The notion of the gene as a physical entity that confers inheritance of traits appeared in parallel with the development of cell theory in the mid-nineteenth century. The story of how “particulate factors” governing inheritance were posited by the Moravian monk Gregor Mendel from his studies on the cultivation of pea plants has been so often told that we needn’t dwell on it. In the 1850s and ’60s Mendel observed that inheritance seemed to be an all-or-nothing affair: peas made by interbreeding plants that make smooth or wrinkly versions are either one type or the other, not a blend (“a bit wrinkly”) of the two. Of course, real inheritance in humans is more complicated: some traits (like hair or eye colour) may be inherited discretely, like Mendel’s peas, others (like height or skin pigmentation) may be intermediate between those of the biological parents. The puzzle Mendel’s observations raised was why inheritance is not always such mix, given that it comes from a merging of the parental gametes.

Charles Darwin didn’t know of Mendel’s work, but he invoked a similar idea of particulate inheritance in his theory of evolution by natural selection. Darwin believed that the body’s cells produced particles that he called gemmules, which influence an organism’s development and are passed on to offspring. In this view, all the cells and tissues of the body play a role in inheritance, whence the term “pangenesis” that Darwin coined for his speculative mechanism of evolution. These gemmules may be modified at random by influences from the environment, and the variations are acquired by progeny. In the 1890s, the Dutch botanist Hugo de Vries and German biologist August Weismann independently modified Darwin’s theory by proposing that transmission of gemmules could not occur between body (somatic) cells and the so-called “germ cells” that produce gametes. Only the latter could contribute to inheritance. De Vries used the term “pangene” instead of gemmule to distinguish his theory from Darwin’s.

At the start of the twentieth century, the Danish botanist Wilhelm Johannsen shortened the word for these particulate units of inheritance to “gene”. He also drew the central distinction between an organism’s genotype – the genes it inherits from the biological parents – and its phenotype, the expression of those genes in appearance and behaviour.

In 1902 Theodor Boveri, working on sea urchins in Germany, and independently the American zoologist Walter Sutton, who was studying grasshoppers, noticed that the faithful passing on of chromosomes across generations of cells mirrored the way that genes were inherited. Perhaps, they concluded, chromosomes are in fact the carriers of the genes. Around 1915, the American biologist Thomas Hunt Morgan established, from painstaking studies of the inheritance of characteristics in fruit flies, that this is so. Moreover, Morgan showed how one could deduce the approximate positions of two different genes relative to one another on the chromosomes by observing how often the two genes – or rather, the manifestation of the corresponding phenotypes – appear together in fruit flies made by mating of individuals with the respective genes. As the chromosomes were divvied up to form egg and sperm cells, genes that sat close together were more likely to remain together in the offspring. Morgan’s work established the idea of a genetic map: literally a picture of where genes sit on the various chromosomes.

The sum total of an organism’s genetic material is called its genome, a word introduced in 1920. For many years after Morgan’s work, it was suspected that genes are composed of the molecules called proteins, in which the much smaller molecules called amino acids are linked together in chains. Proteins, after all, seemed to be responsible for most of what goes on in cells – they are the stuff of enzymes. And chromosomes were indeed found to consist partly of protein. But those threads of heredity were also known to contain a molecule called DNA, belonging to the class known as nucleic acids (that’s what the “NA” stands for).

No one knew what this stuff did until the mid-1940s, when the Canadian-American physician Oswald Avery and his co-workers at the Rockefeller University Hospital in New York reported rather conclusive evidence that genes in fact reside on DNA. That idea was not universally accepted, however, until James Watson, Francis Crick, Maurice Wilkins, Rosalind Franklin and their co-workers revealed the molecular structure of DNA – how its atoms are arranged along the chain-like molecule. This structure, first reported in 1953 by Watson and Crick, who relied partly on Franklin’s studies of DNA crystals, showed how genetic information could be encoded in the DNA molecule. It is a deeply elegant structure, composed of two chain-strands entwined in a double helix.

The double helix of DNA. This iconic image creates a somewhat misleading picture, since for most of the time DNA in a cell’s chromosomes is packaged up quite densely in chromatin, in which it is wrapped around proteins called histones like thread on a bobbin. The “rungs” of the double-helical ladder consist of pairs of so-called nucleotide bases (denoted A, T, C and G) with shapes that complement each other and fit together well.

So beautiful, indeed, was this molecular architecture and the story it seemed to disclose that modern biology was largely seduced by it. It was immediately obvious to Watson and Crick how heredity could be enacted on the molecular scale. The information in genes could be replicated by unzipping the double helix so that each strand could act as the template on which replicas could be assembled.⁷ Here, then, was how genetic information could be copied into new chromosomes when cells divide: a molecular-scale mechanism for the inheritance described by Mendel and Darwin, which Morgan and others had situated on the chromosomes. DNA married genetics with inheritance at the molecular level, bringing coherence to biology.

And Darwinian evolution? If genes govern an organism’s traits, then random copying errors in DNA replication could alter a trait, mostly to the detriment of an organism but occasionally to its advantage. This is the variation on which natural selection acts to make organisms adapted to their environment.

It all seemed to fall into place. All the important questions – about evolution, genetic disease, development – might now be answered by referring to the information in the genome. Cells didn’t seem to be a very important part of the story except as vehicles for genes and as machines for enacting their commands.

To speak of information being “encoded” in DNA is to speak literally. Genes deploy a code: the genetic code. But what exactly do genes encode? On the most part, it is the chemical structure of a protein molecule, typically an enzyme. Because of the ways in which different amino acids “feel” one another and interact with the watery solvent all around them in the cell, a particular sequence of amino acids determines the way most protein chains fold up into a compact three-dimensional shape. This shape enables enzymes to carry out particular chemical transformations in the cell: they are catalysts that facilitate the cell’s chemistry. So the protein’s sequence, encoded in the respective gene, dictates its function.

A protein’s amino-acid sequence is represented in its gene by the sequence of chemical constituents that make up DNA. There are four of these, called nucleotide bases and denoted by the labels A, T, G and C. Different triplets of bases represent particular amino acids in the resultant protein: AAA, for example, corresponds to the amino acid called lysine.

Turning a gene into its corresponding protein is a two step-process. First, the gene on a piece of DNA in a chromosome is used as a template for building a molecule of another kind of nucleic acid, called RNA. This is called transcription. The piece of RNA made from a gene is then used as a template for putting the protein together, one amino acid at a time. This is called translation, and it is performed by a complex piece of molecular machinery called the ribosome, made of proteins and other pieces of RNA.

Chromosomes consist of lengths of DNA double-helix wound around disk-like protein molecules called histones, like the string on a yoyo. This combination of DNA and its protein packaging is what we call chromatin. The genomes of eukaryotes are divided up into a number of chromosomes that is always the same for every cell of a particular species (if they are not abnormal) but can differ between species. Human cells have 46 chromosomes, in sets of 23 pairs.

* * *

It’s common to see genes called the instructions to make an organism. In this view, the entire genome is then the “instruction booklet”, or even the “blueprint”. This is an understandable metaphor, but misleading. Genes are fundamental to the way an organism turns out: the genome of a frog egg guides it to become a frog, not an elephant, and vice versa. But the way genes influence and to some degree dictate that proliferation of cells is subtle, complex, and resistant to any convenient metaphors from the technological world of design and construction. By leaping from genome to finished organism without taking into account the process of development from cells, we risk simplifying biology in ways that can create some deep misconceptions about how life proceeds and evolves.

To the extent that a gene is an “instruction”, it is an instruction to build a protein molecule. It is far from obvious what, in general, this has to do with the growth and form of an organism: with the generation of our flesh. We know of no way to map an organism’s complement of proteins onto its shape, traits and behaviour: its phenotype. The two are worlds apart: it’s rather like trying to understand the meaning of a Dickens novel from a close consideration of the shapes of its letters and the correlations in their order of appearance.

Besides, this conventional “blueprint” description of what genomes do is too simplistic even if we consider only how they dictate that roster of proteins. Here are some reasons why:

 Only about 1.5 per cent of the human genome encodes proteins, and a further 8 to 15 per cent or so is thought to “regulate” the activity of other genes by encoding RNA that turns their transcription up or down. We don’t know what the rest does, and scientists aren’t agreed on whether it is just useless “junk” accumulated, like rubbish in the attic, over the course of evolution, or whether it has some unknown but important biological function. In all probability, it is a bit of both. But at any rate, a lot of this DNA with no known protein-coding or regulatory function is nonetheless transcribed by cells to RNA, and no one is sure why.

 Most protein-coding human genes each encode more than one protein. Genes are not generally simply a linear encoding of protein sequences that start at one end of the protein chain and finish at the other; they are, for example, interspersed with sequences called introns that are carefully snipped out of the transcribed RNA before it is translated. Sometimes the transcribed RNA then gets reshuffled before translation, providing templates for several different proteins.

 Proteins are not just folded chains of amino acids. Sometimes those folded chains are “stapled” in place by chemical bonds, or clipped together by other chemical entities such as electrically charged ions. Most proteins have other chemical groups added to them (by other enzymes) – for example, a group containing an iron atom is needed by the protein haemoglobin to bind oxygen and carry it around the body in the blood. None of these details, essential to the protein’s structure and function, is encoded in DNA. You would not be able to deduce them from a gene sequence.

 We only know what around 50 per cent of gene-encoded proteins do, or even what they look like. The rest are sometimes called “dark” proteins: we assume they have a role but we don’t know what it is.

 Plenty of proteins do not seem to have well-defined folded states but appear loose and floppy. Understanding how such ill-defined “intrinsically disordered proteins” can have specific biological roles is a very active area of current research. Some researchers think that the floppiness may not reflect the state of these proteins in cells themselves – but we don’t really know if that is so or not.

Ah, details, details! How much should we care? Do they really alter the picture of genes dictating the organism?

That depends, to some degree, on what questions you are asking. A genome sequence – the ordered list of nucleotides A, T, C and G along the DNA strands of chromosomes – does specify the nature of the organism in question. From this sequence you can tell in principle if the cell that contains it is from a human, a dog or a mouse (something that may not be obvious from a cursory look at the cell as a whole). These distinctions are found only in some key genes: the human genome differs from that of chimpanzees in just 1 per cent of the sequence, and a third of it is essentially the same as the genome of a mushroom.⁸ The differences between the genomes of individual people are even tinier.

But whereas you can look at a real blueprint, and probably an instruction manual, and figure out what kind of object will emerge from the plan, you can’t do that for a genome. Indeed, you can only deduce that a genome will “produce” a dog at all if you have already decoded the generic dog genome for comparison, laying the two side by side. It’s simply a case of seeing if the two genomes superimpose; there’s nothing intrinsic in the sequence that hints at its “dogness”.

This isn’t because we don’t yet know enough about the “instructions” in a genome (although that is the case too). It’s because there is no direct relationship between the informational content of a gene – which, as I say, typically dictates the structure of a class of protein molecules, or at least of the basic amino-acid fabric of those proteins – and a trait or structure apparent in the organism. Most proteins do jobs that can’t easily be related to any particular trait. Some can be: for example, there’s a protein that helps chloride ions get through the membranes of our cells, and if this protein is faulty – because of a mutation in the corresponding gene – then the lack of chloride transport into cells causes the disease cystic fibrosis. But in general, proteins carry out “low-level” biochemical functions that might be involved in a whole host of traits, and which might have very different outcomes if the protein is produced (“expressed”) at different stages in the development or life cycle of the organism. As microbiologist Franklin Harold has said, “the higher levels of order, form and function are not spelled out in the genome.”

Might we, then, call a genome not a blueprint but a recipe? The metaphor has rather more appeal, not least because many recipes assume implicit knowledge (especially in older cookbooks). But a recipe is still a list of ingredients plus instructions to assemble them. Genomes do not come with users’ instructions, more’s the pity. Harold offers a different image, allusive and poetic and all the more appealing for that:

I prefer to think of the genome as akin to Hermann Hesse’s Magister Ludi [aka The Glass Bead Game]: master of an intricate game of cues and responses, in which he is fully enmeshed and absorbed; a game that is shaped as much by its own internal rules as by the will of that masterful player.

If there was better public communication of the complex, contingent and often opaque relationship of genotype to phenotype, there might be rather less anxiety about the idea that genes affect behaviour. Small variations in each individual’s genetic make-up can have an influence – sometimes a rather strong one – not just what you look like but what your behaviour and personality are like. This much is absolutely clear: there is not a single known aspect of human behaviour so far investigated that does not turn out to show some correlation with what gene variants we have. Even habits or experiences as apparently contingent and environmental as the amount we watch television⁹ or our chance of getting divorced are partly heritable, meaning that the differences between individuals can be partly traced to differences in their genes.

Far from alarming us, this shouldn’t surprise us. We have always been content to believe that, for example, some people seem blessed with talents that can’t obviously be explained by their environment and upbringing alone. By the same token, some seem hardwired to find particular tasks challenging, such as reading or spatial coordination.

Yet perhaps because we have a strong sense of personal agency, autonomy and free will, many people are disturbed by the idea that there are molecules in our cells that are pulling our strings. They needn’t worry. It is precisely because genetic propensities are filtered, interpreted and modified by the process of growing a human cell by cell that they don’t fully determine how our bodies turn out, let alone how our brains get wired … let alone how we actually behave.

Genes supply the raw material for developing our basic cognitive capabilities – to put it crudely, they are a key part of what allows most human embryos to grow into bodies that can see, hear, taste, that have minds and inclinations. But how they exert their effects is very, very complicated. In particular, very few genes affect one trait alone. Most genes have influences on many traits. Some traits, both behavioural and medical (such as susceptibility to heart disease), seem to be influenced – in ways that are imperceptible gene by gene, but detectable when their effects are added up – by most of the genome. That’s why the popular notion of a “gene for” some behavioural trait is misguided. In fact, it means that there may be no meaningful “causal” narrative that can take us from particular genes to behaviours.

* * *

This is precisely why we need to resist seductively simple metaphors in genetics: blueprints, selfish genes, “genes for”. Of course, science always needs to reduce complex ideas and processes to simpler narratives if it is going to communicate to a broader audience. But I’ve yet to see a metaphor in genomics that does not risk distorting or misrepresenting the truth, so far as we currently know it. Fortunately, I do not think this matters for talking about the roles of genes in making a human. We will deal with those roles as they arise, without resorting to any overarching story about what genes “do”.

I haven’t even told you yet the worst of it, though. It’s not simply difficult to articulate clearly what, in the scheme of growing humans the natural way, genes do. For we don’t exactly know how to define a gene at all.

This isn’t a failure of biology, but a strength. It’s tempting to imagine that science can’t be fully coherent if it can’t define its key terms. But the most fundamental concepts are in fact almost invariably a little hazy. Physicists can’t say too precisely or completely what time, space, mass and energy are. Biologists can’t say what a gene or a species is. For that matter, chemists aren’t fully agreed on what an element or a chemical bond is. In all cases, these terms arose because it seemed as though they had a very specific meaning, but when we looked more closely we found fuzzy edges. Yet the reason we coined the terms in the first place was because they were good for thinking with.

That remains true. A gene is a useful idea, perhaps in much the same way as words like “family” and “love” and “democracy” are useful: they are vessels for ideas that enable us to have useful conversations. They are usually precise enough.

Here, then, is a definition good enough to let us talk about genes in the role of growing a human from cells. Think of a gene as a piece of DNA from which a cell is able to make a particular molecule, or group of molecules, that it needs in order to function. By passing on copies of genes, cells can pass on that information so that the progeny doesn’t have to rediscover it from scratch.

If you raised your eyebrows at “so that”, good for you. In such phrases, biology is given a false purpose, an illusory sense that it pursues goals. It is nigh on impossible to talk about biology – about growth, development, evolution – without some mention of aims. Try to remember that this is always mere metaphor. The way that the laws of the physical world have played out on our planet is such that entities called cells have appeared that have a propensity to pass on genes to copies of themselves. This is remarkable and marvellous. No one really understands why it happens – why reproduction, inheritance and evolution is possible – and that’s why we find it necessary to tell stories about it. All we can say is that there is absolutely nothing that forces us to invoke any supernatural explanation for it. The gaps that remain would make an extremely peculiar shape into which such an account might be squeezed.

Here’s another thing worth knowing about genes: a gene on its own is useless. It can’t replicate,¹⁰ it can’t even do the job that evolution “appears” to have given it. Frankly, there is no real point in calling a gene on its own a “gene” at all: the name connotes an ability to (re)produce, but a lone “gene” is sterile, just a molecule that happens to resemble a part of the DNA in a chromosome. It’s common to say that a gene is a piece of DNA with a particular sequence, but the truth is that such a physical entity only becomes a gene in the context of a living system: a cell, at minimum. Genes are central ingredients of life, but by the time you reach the level of the gene there is nothing left that is meaningfully alive.

No, life starts with the cell. And that’s why a gene only has meaning by virtue of its situation in a cell. Does this, then, mean that the cell is more fundamental to biology than the gene? You might as well ask if words are more fundamental to literature than stories. It is “stories” that supply the context through which words acquire meaning, making them more than random sounds or marks on paper.

And by “context” here I don’t just mean that a gene has to be in a cell in order to represent any biologically meaningful information. I mean also that, for example, the history of the cell, and of the entire organism, might matter to the function a gene has. A gene that is “active” at one point in the organism’s growth might represent a quite different message – have a different implication – than at a later or earlier point. Yet the molecular machine (the protein) encoded by the gene may be identical in the two cases. The gene doesn’t change, but the “instruction” it represents does.

You might compare it to the exclamation “Stop it!” Is that an instruction? Well, of course you don’t know from that enunciation alone what it is you are supposed to stop, but perhaps you might regard it as a generic instruction to desist from the activity you’re engaged in. But what if you hear someone shout “Stop it!” as you see a football rolling towards a cliff edge? Is that an instruction to desist in anything, or on the contrary an injunction to action? You need to know the context.

* * *

The gene-centred narrative of life is just one example of our urge to somehow capture the essence of this complicated, astounding process – to be able to say “life starts here!” Science’s reductionist impulse gets a bad press, but breaking complicated things down into simpler ones is a tremendously powerful way of making sense of them. I think that what many people who complain about reductionism are reacting against is not so much this process of analysis – of taking apart – in itself, but the tendency then to assert “this is what really matters”. Science has sometimes been a little slow to recognize the problem with such assertions. When one group of physicists started insisting it was going to find a Theory of Everything – a set of fundamental laws from which the entire physical universe emerged – others pointed out that it would be nothing of the kind, because it would be useless in itself for predicting or explaining most of what we see in the world.

It’s not just that we should resist the temptation to see reductive analysis as a quest to identify what is more important/fundamental/real in the world. Sometimes the phenomenon you’re interested in only exists at a particular level in the hierarchy of scale, and is invisible above and below it. Go to quarks and you have lost chemistry. With genes and life it is not quite that extreme – but at the level of genes you are left with only a rather narrow view of some of the entities and processes that underpin this notion we call “life”. Life remains a meaningful idea from the macro level of the entire biosphere of our planet right down to the micro level of the cell. Within those bounds it encompasses a whole slew of factors: flows of energy and materials, the appearance of order and self-organization, heredity and reproduction. But below the level of the cell, you’ll always be overlooking something vitally important in life. As Franklin Harold has put it:

Something is not accounted for very clearly in the single-minded dissection to the molecular level. Even as the tide of information surges relentlessly beyond anyone’s comprehension, the organism as a whole has been shattered into bits and bytes. Between the thriving catalog of molecules and genes, and the growing cells under my microscope, there yawns a gulf that will not be automatically bridged when the missing facts have all been supplied. No, whole-genome sequencing won’t do it, for the living cells quite fail to declare themselves from those genomes that are already in our databases … The time has come to put the cell together again, form and function and history and all.

It is precisely the multivalent, multiscale implication of the word “life”, too, that creates the tensions, ambiguities and ambivalences about what it means to “grow a human”. We are thereby “making a life”, but not “making life”. That same truth is spoken in jest in a cartoon by Gary Markstein in which two white-coated scientists contemplate IVF embryos. “Life begins at the Petri dish!” exclaims one embryo; “Cloning for research!” demands another. “Even the human embryos are divided”, sighs a scientist.

This is the struggle we face in reconciling our notion of life as human experience with the concept of life as a property of our material substance. We are alive, and so is our flesh. While those two visions of life were synonymous, we could ignore the problem. Having a mini-brain grown in a dish from a piece of one’s arm tends to make that evasion no longer tenable.

It’s no wonder that different cultures at different times have had such diverse attitudes to the connection between the human body in utero, forming in hidden and mysterious fashion from something not remotely human-like, and the human body in the world. The insistence by some people and in some belief systems that “life begins at conception” is a modern utterance, often claiming firm support from the very science that in fact shows how ill-defined the idea is.

But the tension is an old one, as demonstrated by preformation theories of the human fetus. This was an anthropomorphization of the cell as explicit as that in cartoons that attribute voices and opinions to human embryos in petri dishes. Intuition compels us to look for the self in the cell. An insistence on locating it instead in our genes – as cell biologist Scott Gilbert puts it, to see “DNA as our soul” – comes from the same impulse. Perhaps we must be gentle in dispensing with these superstitions. Aren’t old habits always hard to shake off?

CHAPTER 2
BODY BUILDING
GROWING HUMANS THE OLD-FASHIONED WAY

So far, nothing beats sex. Biologically, I mean. If you want to grow a human, you need a sperm and an egg cell – the two cell types called gametes. And you need to get them together. That’s an objective towards which an immense amount of our culture is geared.

In describing the process in which a fertilized egg develops into a person, I hope in this chapter to give back some of the strangeness, the proper unfamiliarity, to embryology: to show how removed our individual origins are from the comforting intimacy of the gracefully curled fetus that is generally our first ultrasonic glimpse of a new human person.

We are folded and fashioned from flesh in its most basic form, according to a set of instructions that is far removed from a kind of genetic step-by-step. We are shaped from living clay according to rules imperfectly known and often imperfectly executed, and which orchestrate a dance between the cell and its environment.

But there are many things you can potentially fashion from clay, if you know how to work the wheel. As we come to understand more about the emergence of the human ex ovo, we perceive new possibilities, new beginnings and routes and directions. And we change from watchers to makers.

* * *

There is no new narrative of human-growing that does not need to reckon with the preconceptions (so to speak) created by sex. Mary Shelley could not, in her day, make that context explicit – but Victor Frankenstein’s terror of his wedding night tells us all about the psychosexual undercurrents in his onanistic act of creation. I won’t therefore attempt the same evasion as the school biology lesson by beginning the embryo’s tale with sperm meeting egg; by that stage sex has, as we’ll see, already imposed itself on the story.

We should in any case be continually amazed, surprised and possibly even a little proud at how imaginatively we have elaborated, ritualized and celebrated the urge to procreate. This shouldn’t be seen so much as proof that evolutionary psychology can “explain” culture – the banal observation that because of our instinct for sexual reproduction we write stories like Romeo and Juliet and create entertainments like Love Island – but rather the opposite. Evolutionary psychology by itself offers a rather threadbare and reductionist narrative for understanding the rich tapestry of culture. Sure, we can attribute to the sexual drive everything from a worship of lingams in Indian tradition to the Tudor enthusiasm for prominent red codpieces,¹ the hegemony and variety of internet porn and the exquisite faux-pheromone concoctions of perfumeries. But then we will have not really said much that illuminates the particulars of any of those diverting cultural phenomena, will we?

It’s tempting to suppose that the bare biology of reproduction is quite distinct from the human mechanics and its attendant rituals, its messiness and epiphanies and calamities. But we rarely make any statement about biology, and least of all about the biology of making humans, that is devoid of a culturally shaped narrative. If we imagine we can start talking about new ways to grow humans (and parts of humans) that do not inherit some aspects of the stories we tell about how we do it already, we are fooling ourselves.

The old ideas of generative male seed quickening the passive female “soil” are evidently invested with patriarchal stereotypes. Within Christian tradition, conception long struggled to find accommodation with religious thought, being simultaneously a miraculous gift of God (and thus a moral obligation) and the fruit of sin. Within this view, the only “pure” conception in the history of humankind was one that took place two thousand years ago without intercourse and without seed, to dwell on the gestation of which was to risk heresy. And medieval theology willingly lent authority to the idea that to expel male seed not directed towards procreative possibility was even worse than to couple in lust, for it was liable to be taken up by demonic succubi and bred into monsters.

These were tales not just about the social side of sex but about its biological and medical aspects too. Until the nineteenth century, the health hazards of masturbation were considered a plain medical fact, as was the idea that a fetus in the uterus could be damaged by a mother’s bad thoughts. Probably every age has imagined itself mature beyond this mixing of science with folk belief and sociopolitical ideology, but let’s not make the same mistake.

So how does the sperm fertilize the egg? Why, the plucky little fellow has to race along the vaginal passage,² out-swimming its (his, surely!) peers in a Darwinian competition for survival. There sits the egg, plump and alluring – and in he dives, kicking off the process of becoming one of us. As Life’s science editor Albert Rosenfeld wrote in 1969, people are made from “the sperm fresh-sprung from the father’s loins, the egg snug in its warm, secret place; the propelling force being conjugal love.” (I think you’ll find it is actually hydrogen ions crossing cell membranes.)

We see this story not just in children’s books about how babies are made, but (less obviously) in some biology textbooks too, where the active role of the sperm and the passivity of the egg cell is typically stressed. It’s wrong. There is now good reason to think, for example, that the sperm’s entry into the egg is actively mediated by the egg (although even this description still somewhat anthropomorphizes the participants, imputing aims and roles). The fastest sperm are not necessarily the victors, because sperm needs conditioning by the female reproductive tract to make it competent to fertilize an egg. There is increasing evidence that in many species the female can influence which sperm is involved in fertilization – for example by storing sperm from several mates under selective conditions, or ejecting it after sex. Some experiments on genetic outcomes of fertilization seem to imply the egg somehow selects sperm with a particular genotype, defying the conventional idea that once it gets to this stage the union of gametes is random.

It’s by means of narratives about sperm and egg getting together that we instruct our children about the “facts of life” – the definitive phrase seemingly designed to fend off the awkward questions they might otherwise ask. Questions like: Why this way? For doesn’t it seem an awfully messy, contingent and chancy way for genes to propagate, requiring a costly investment in wardrobe, grooming products and expensive meals? If children knew that parthenogenesis (development of the ovum without fertilization) was a reproductive option in the animal kingdom, I suspect many would think it dreadfully unfair that it is not available to humans. (Not only children, actually.)

So why these facts? Why go through the rigmarole of sex, if it doesn’t seem to be a biological sine qua non of reproduction?

No one really knows the answer. The usual one is that sexual reproduction, by combining the genes of two individuals, permits a beneficial reshuffling that can help stave off genetic disease. Organisms like bacteria that reproduce by simple cell division, generating clones, will gradually accumulate gene mutations from one generation to the next. As most mutations are detrimental or at best have no discernible effect on fitness, this can’t be a good thing. But bacteria proliferate exponentially and rapidly, and it doesn’t much matter if many genetically disadvantaged lineages die off, so long as there are a few that acquire mutations that improve fitness. In a rapidly growing bacterial colony, the mutations give the population a chance to explore a significant amount of “gene space” and find good adaptations. It’s for much the same reason that bacteria have evolved mechanisms to transfer genes directly from one to the other in a non-hereditary process called horizontal gene transfer.

Organisms that reproduce slowly and sparsely, like humans, don’t enjoy a bacterium’s capacity to “try out” many mutations. But sex is a way to spread them more rapidly, by allowing new combinations of gene variants to be created at a stroke from one generation to the next.

Clonal reproduction is also risky as it tends to put all a population’s eggs in one basket (to rather abuse a metaphor). Along comes some virus that exploits a bacterium’s vulnerabilities, or a change in conditions such as drought or extreme cold, and the whole colony could be wiped out – unless a few individuals are fortunate enough to possess gene variants that can withstand the threat. That’s also why genetic diversity is good for a population. And again, sexual recombination of genomes provides some of that.

So sex is a way for slowly reproducing organisms like us to eject “bad” genes and acquire “good” ones. It recommends that the organisms become dimorphic – that there be two distinct sexes, to ensure that an organism doesn’t end up combining its own sex cells, which would rather defeat the object. Or at any rate, there must be more than one sex: there’s no obvious reason why it should be limited to two, and indeed some fungi have thousands of different “sexes”.³

From this basic requirement for a distinction between types of sex cell (gametes) stems all the rest of the exciting and confusing features of sexual dimorphism. It helps if the two sexes are distinguishable at a glance, to save the wasted effort (since generally it does cost time and effort, sometimes considerably so) of trying to mate with another individual with which that is not possible. (It also makes complete sense that those impulses and signals will not be equally strong, or present at all, in all individuals, making homosexuality a natural and common phenomenon in animals.)

Once those differences exist, they are apt to get amplified, diversify, sometimes way out of proportion. If you’re going to have sex, it’s likely that your behavioural traits will evolve to let you spot the fittest partners and to advertise your own fitness. Each sex will evolve methods of assessing mates, and outward indicators of fitness will elicit attraction in the opposite sex. Some of these make physiological sense: a lot of muscle suggests dominant males with good survival skills, wide hips in females imply superior child-bearing capacity. Other sexual signals may end up being rather arbitrary – it’s not obvious why body hair on our male ancestors would of itself confer any survival advantage. (Perhaps this was an example of “useless” signalling of fitness, like the peacock’s tail?) Some displays are simply about standing out from the crowd, like exotic bird plumage. Other facets of sexual attractiveness may be subtle: it seems likely, for example, that symmetrical facial features indicate that one’s developmental processes, which commonly unfold independently in the mirror-image halves of the body, are robust against random variations, giving the individual better health prospects. For all the elaborateness of some mating rituals in other animals, they might – if they could – count themselves lucky that these sexual signals and responses don’t get refracted through culture as they do with humans to the point where it can all get overwhelmingly confusing.

Now, this is certainly one way to talk about the evolution and origin of sex, but it invokes an uncomfortable amount of teleology. Sex doesn’t really exist in order to create genetic diversity. Nothing happens in evolution in order to produce a particular end result. It makes intuitive sense for us to speak like this, but the fact is that sex evolved because those early organisms that became able to fuse their cells and chromosomes somehow produced more robust populations than those that lacked this ability. Sexual reproduction might be a more or less inevitable consequence of evolution by natural selection, once it gives rise to a particular kind of complex organism, much as snowflakes are an inevitable consquence of the laws of physics and chemistry playing out in a particular environment. Evolutionary biologists say that sex is a successful evolutionary strategy, although this again imputes a sort of foresight to evolution that it doesn’t possess.

While these arguments for the value of sex surely have a lot going for them, they can’t be the whole answer. Sex is not essential for all higher vertebrates. Parthenogenesis occurs in many different types of animal, including insects such as mites, bees and wasps, and some fish, reptiles and amphibians. In a few such cases, reproduction can happen either with sex or without. Sometimes that’s by design – for example, parthenogenesis is thought to be an option for mayflies as a defence against a lack of males. (The same useful trait arises in the women of the male-free society in Charlotte Perkins Gilman’s utopian feminist novel Herland (1915).) In other cases it occurs by accident, unfertilized eggs just happening rarely to develop into embryos. Komodo dragons are among the larger creatures that can reproduce this way.

The reasons and mechanisms for parthenogenesis are varied and sometimes rather complicated. But one thing you can say for sure is that, in organisms for which it can take place, evolution has not seen fit to rule it out. To put it another way, there is nothing obviously necessary about sex, and assessing the benefits of sexual reproduction over other methods of propagating is a subtle and perhaps context-dependent business.⁴ As far as evolution is concerned, it is just a matter of whatever works.

* * *

There’s a complication with sex. Each of our body cells has two sets of chromosomes, and therefore dual copies of each gene, one inherited from each parent. But if one of these cells in a female simply fused with one from a male, the resulting cell would have four sets of chromosomes. That’s too many, and the cell couldn’t function properly. So organisms that reproduce sexually have evolved special kinds of cells that possess only one copy of each chromosome. These are the gametes, and they are found only in the gonads: the ovaries and testes.

Gametes are made from a specialized type of cell called a germ cell. The germ cells have doubled chromosomes (they are said to be diploid) just like somatic cells, but in a special kind of cell division called meiosis they divide into gametes in which these chromosomes have been carefully segregated into two. Cells with just a single set of chromosomes are said to be haploid.

Normal cell division (mitosis) involves replication of the chromosomes accompanied by their separation so that each daughter cell receives the full complement. Meiosis is even more complicated, because the existing chromosomes have to be divided precisely in two and shipped off to their respective destinations.

Actually it’s worse than that. Meiosis happens in two stages, and the overall result is that a single, diploid germ cell replicates its chromosomes once and divides twice to end up with four haploid gametes. As in mitosis, the process by which the chromosomes are divided uses a spindle-like structure made from fibrous protein. The chromosomes become attached to the fibres and are drawn towards opposing poles of the spindle located in the two lobes of the dividing cell.

Crucially, the chromosomes undergo some shuffling in this process. The pre-meiosis germ cell, recall, has one of each of the 23 types of chromosome from the mother, and a second copy of each from the father. Which of the poles of the spindle each chromosome is drawn towards is random, and so the diploid cells made by division of the germ cell have a random combination of maternal and paternal genes.⁵ The haploid gametes that eventually emerge from the process then have a thoroughly scrambled single set of chromosomes: with 23 pairs of chromosomes in all, there are 2²³, or about 8 million, possibilities. These are combined with a similar range of options in the other gamete when egg and sperm unite, so you can see that having sex is a good way to produce genetic diversity.

Formation of the so-called primordial germ cells happens early in the development of a human embryo, around two weeks after fertilization. This is even before the gonads have started to form, which is to say, before the embryo has yet “woken up” to which sex it is. It’s as if the embryo is putting these cells aside while deferring the matter of whether they will be eggs or sperm. The gonads themselves will guide this process, sending out chemical signals that tell the primordial germ cells which sort of gamete to become. They’re ready to do that around week six of gestation, by which time the germ cells have migrated across the developing embryo to their destination. For yes, that development involves not merely cell division but also cell movement, a physical sorting in space to arrange the parts in the proper disposition.

Germ cells were first postulated by the German zoologist August Weismann in his 1892 book The Germ-Plasm: A Theory of Heredity. As that title suggests, this was a hypothesis as much about evolution as about embryology. The “plasm” here reflects the widespread notion, before Boveri and Sutton’s chromosomal theory of inheritance, that heredity was somehow transmitted via the “protoplasm” substance inside cells. As we saw earlier, Charles Darwin speculated that the particles responsible for inheritance, which he called gemmules, were collected from the body’s cells and transmitted via sperm and egg. Weismann was a staunch advocate of Darwinism, but he was convinced that there was a fundamental distinction between the somatic cells that made up the body’s tissues and the special cells called germ cells that gave rise to gametes. Any changes to the “plasm” of somatic cells could therefore play no part in heredity. To demonstrate that changes to the body of an organism are not inherited, Weismann cut off the tails of hundreds of mice and followed their offspring for five generations, each time removing the tails. Not once were any offspring born without tails.⁶ Any notion that “acquired characteristics” could be inherited, as in the pre-Darwinian theory of evolution proposed in the early nineteenth century by Jean-Baptiste Lamarck, could no longer be sustained.

In Weismann’s view, then, somatic cells are irrelevant to evolution. They are destined to die with the organism. But germ cells beget more germ cells – there is an unbroken line of germ cells (the germ line) down through the generations. It’s often said that the germ cells are thus immortal, although that’s an odd formulation – by that definition, we are all immortal simply by virtue of being able (if indeed we are) to produce offspring.

* * *

In the story of how to make a human “the natural way”, the fertilized egg is often portrayed as the end – at least, until the happy day that the baby emerges. All our traditional stories of people-making rely on that quantum leap from fertilization to birth. The dire moral warnings about pregnancy that loomed over adolescence (and in some cultures still do) make this the equation: bring together sperm and egg and you’ll get a baby! It’s a warning (sometimes needed, for sure) to experimenting teenagers, but becomes more like a promise in the narrative of IVF: to make that longed-for baby, all you need to do is unite the gametes. And if it doesn’t turn out that way, something has gone wrong. There is a single and inevitable road from fertilized egg to infant, and anything else is an aberration.

This is misleading. To put it starkly, most acts of non-protected penetrative sexual intercourse do not produce a baby – and when I say most, I mean 99.9 per cent. Even most fertilized eggs do not become babies – about 2 to 3 in 10 confirmed pregnancies abort spontaneously in miscarriage, but even those figures mask the 75 per cent or so of fertilized eggs that never get to the point of registering as a pregnancy at all, either because they don’t develop into a multi-celled embryo or because the embryo fails to implant in the uterus. That’s a puzzling thing about humans: we are unusually poor, within the animal kingdom, at reproducing. You have to wonder whether all the attention we give to sex is because we are so spectacularly bad at getting results from it.

Even to say “bad” is perhaps to collude with the moral imperative of the fertilized-egg-to-infant story; let’s just say that we are an anomaly, for reasons imperfectly understood. This calls into question the idea that sex really is “for” reproduction, as some religious moralists insist. If we were inclined to see procreation as a divine gift and imperative, one would at least need to grant that God expects us to have a heck of a lot of rehearsal.

The baby grows, of course, from a fetus: even children’s books tell us that. But in the common view the fetus is simply a baby – a person – that has not yet fully developed. Its proportions might be a little odd, its limbs blunter, but it is recognizably human. The classic images made in the mid-1960s by Swedish photographer Lennart Nilsson and presented in the book A Child Is Born (1965), have defined the view of our in utero existence ever since. They show the fetus floating freely in space, often lacking even an umbilical cord, like the iconic image from Stanley Kubrick’s 2001: A Space Odyssey three years later. Perhaps this “child” even sucks its thumb. But these images were actually made by artful arrangement of aborted fetuses – they were not in fact living organisms at all, much less in utero. They were curated to tell a reassuring story. (At least, so it might seem until you realize that it’s a story in which the mother has been edited out.)

By the time a fetus looks even vaguely human (which is what, loosely speaking, distinguishes it from an embryo), most of the important stuff has happened. Most of the dangerous hurdles have been cleared. And most importantly, the developing organism is already anthropomorphic, relieving us from any need to grapple with the strangeness of an entity evidently made of cells, which we might want to call human but would struggle to justify that intuition.

Yet it is the early embryo that reveals the true versatility, the genius, of our cells – and the unfamiliarity of the moment when those cells are not merely what we are made of, but what we are.

It might surprise you to discover – it surprised me – that when a woman first has a fertilized egg (a zygote) inside her body she is not technically pregnant. This is not some perverse biomedical fine print; it simply makes no sense to see things otherwise. A pregnancy test would show nothing, nor will it for the first four days or so after fertilization. The zygote divides by mitosis into two, then four, then eight cells and so on, and at this point these cells can form all the tissues needed in the embryo: they are called stem cells and are said to be totipotent.

In other words, every one of these cells could potentially become a separate embryo. In the early days of embryology, that was by no means clear. The German zoologist Wilhelm Roux thought, for example, that cells are headed towards different fates from the first division of the zygote. In 1888, he reported experiments on frog embryos at the two and four-cell stage, in which he destroyed one of the cells by lancing it with a hot needle. A single remaining cell from a two-cell embryo would then, he said, grow into a half-embryo, suggesting that it had even at that stage become assigned as the progenitor of that part of the body plan alone.

But Roux’s method was flawed, because he could not detach the remains of the ruptured cell from the intact one. This debris interfered with the subsequent growth of the embryo. In the 1920s and ’30s, German embryologist Hans Spemann performed a cleaner act of surgery on salamander embryos. By using a noose made from a single hair taken from a baby, he pinched early embryos in two and found that each of the resulting parts is able to grow into a complete embryo.⁷ In effect, Spemann made identical twins by artificial means. Because he produced two genetically identical embryos from a single initial one, you could also call this a process of cloning.⁸ Spemann and his co-workers used amphibian cells, because they are so large that the delicate manipulation could be done by hand – albeit an impressively steady one.

The ball of totipotent stem cells that is the human embryo floats freely in the fallopian tube (also called the oviduct), borne slowly towards the uterus. By day five, the embryo has become a ball of around 70 to 100 cells and has rearranged itself into a structure known as the blastocyst. By the time it arrives at the uterus, it has shed the protein coat called the zona pellucida that formed the protective shell of the original egg – it has “hatched” and is ready to implant.

The human embryo at around five days, called a blastocyst.

That ball of cells is not exactly the nucleus of a person. Most of the cells of the blastocyst became the mere housing and life support. Some of them form an outer layer enclosing a fluid-filled void: these are trophoblast cells, comprising the tissue called trophectoderm which will become the placenta. Others congregate into a clump on the inside, called the inner cell mass, which separates into the epiblast from which the fetus will grow, and the hypoblast that will eventually become the yolk sac. The epiplast consists of embryonic stem cells, capable of forming all the tissues of the body (but not the placenta): a capacity called pluripotency. Identical twins grow from two separate inner cell masses in a single blastocyst, whereas non-identical twins grow from two separate blastocysts, formed from distinct eggs fertilized by different sperms. Within a few days of implanting, the epiblast is covered in a layer of specialized cells called the primitive endoderm, derived from the hypoblast.

The human embryo at around day 10–11.

The fate of the embryo wholly depends on a successful implantation in the lining of the uterus. If this does not happen – which is the case around 50 per cent of the time – the embryo will be expelled in the menstrual cycle. Failure to implant is one of the common reasons why an IVF cycle does not work. No wonder, then, the division of labour in the blastocyst makes it seem that its priority is to those cells surrounding the epiblast, which won’t be a part of the fetus at all. For without implantation, it’s game over.

Implantation is a delicate and complex process involving a dialogue of hormones and proteins between the embryo and the cells of the uterine lining. In some ways it is more delicate and complex than fertilization itself. The placenta, for example, is made not just from the trophoblast layer of the blastocyst but also from tissues from the mother, called the decidua. The two types of cell, with different genetic makeup, have to work together to create a single, vital organ. Emotive and anthropomorphic metaphors suggest themselves, presenting implantation as an intimate collaboration between the tissues of mother and her “child”. But one might equally choose to speak of the blastocyst “invading” the uterine tissue: one “organism” colonizing another for its survival.⁹ Both are stories; neither is a neutral description of events (which story ever is?).

* * *

The best is about to come. Calling the part of the embryo fated to become the baby an “inner cell mass” is no euphemism: it really does seem to be a shapeless conglomerate. If we want to insist that baby-making is a miracle, what seems truly miraculous is not just that the inner cell mass makes a body but that, most often, it makes exactly the same type of body, with five fingers on each hand, with all facial features in the right place and fully functional, and with its battery of correctly positioned organs. It’s no surprise that development of the embryo occasionally goes awry; it is astonishing that it does so rather rarely.

When embryos start off as single cells, they have no plan to consult. Cells are programmed to grow and divide, but it isn’t meaningful to think of a human being as somehow fully inherent in a fertilized egg, any more than one can regard the complex convolutions of a towering termite mound as being programmed into each termite. The growth of an organism is a successive elaboration of interactions within and between cells: a kind of collaborative computation whose logic is obscure and convoluted, and the outcome of which is incompletely specified and subject to chance disturbances and digressions.

In this way, the job evolution has devised for those formative cells is an architectural one: a challenge of coordination in time and space. They have to move into position, to acquire the right fate at the right time, and to know when it is time to stop growing or to die.

Developmental biologists talk of this as “self-organization”. It could make the process sound quasi-magical, calling as it does upon the image of the cell as an autonomous being with aims and purposes. But many of the rules are now broadly understood.

Two key factors are at work. First, as the cells divide and multiply, they take on increasingly specialized roles, a process called differentiation. Thus, totipotent cells in a two or four-cell embryo become trophoblasts or the pluripotent stem cells of the epiblast. The latter go through further stages of differentiation that ultimately produce the specialized cell types found in muscle, skin, blood and so forth. We will see shortly how that happens.

Second, particular spatial arrangements may arise from cells actively moving through or across the growing organism or organ, or becoming sorted into clumps of different cell types by preferential stickiness, often between cells that are alike.

That cells have adhesive qualities joining them into aggregates was suggested in the 1890s by Wilhelm Roux. He was also able to disrupt frog embryos by vigorous shaking, which separated them into single cells. He found that those cells would join back together, which he attributed to some kind of attractive force.

Such “disaggregation” experiments were taken further in the early 1900s by marine biologist Henry V. Wilson, who found that sponges kept for a long time in an aquarium became “loose” and could be teased apart into individual cells. He achieved the same thing in fresh sponges by the simple measure of squeezing them through a piece of silk, which acted as a sieve that separated the cells. Again, those cells would reassemble if brought into contact to regenerate a living sponge. It was like a recapitulation of the evolution of primitive multi-celled organisms from colonies of single-celled ones (see the First Interlude, here). When Wilson did the experiment with different species of sponge, he found that cells from the same species would stick together selectively. Ernest Everett Just discerned in the 1930s that the reason for this selectivity had something to do with the cell membranes. The truth is that cells adhere via protein molecules protruding at their membrane surface (especially those belonging to the class called cadherins), which will bind to one another discerningly.

This notion of “tissue affinity” was developed around the same time by the German-American embryologist Johannes Holtfreter. In 1955, he and Philip Townes studied how the cells of amphibian tissues that had been disaggregated by exposing them to alkalis could reassemble from solution. Holtfreter largely outlined the concept of cell sorting that allows tissues of several cell types to adopt particular structures and arrangements.

The process of body formation (morphogenesis) is orchestrated by genes, and no wonder then that genes have been attributed such determinative power. Some researchers have made more apt comparisons to a musical score: genes tightly constrain but do not fully prescribe the performance. This is still a limited metaphor, because you can look at the score and figure out (if you’re a musician) pretty much how things will go. Not so with genes. Sometimes it is better simply to tell the story as it is, as simply as you can, rather than trying to pretend it is some other story.

Morphogenesis literally means shape-formation, but equally it is a question of cell specialization: the embryonic stem cells gradually lose their versatility as they divide, becoming geared instead to do the task of specific tissue types. Heart muscle cells must execute synchronized beating, pancreatic cells must secrete insulin, the nerve cells of the eye’s retina must respond to light, and so on. This happens not by cells gaining new properties, but rather by narrowing the possibilities inherently available to them by shutting down genes that aren’t needed. That’s what differentiation is all about.

The cells must know how and where to switch genes on and off as differentiation proceeds. How do they know? The cues come from the other cells and tissues around them.

Some of these signals are delivered as chemical messages, which, diffusing through the mass of cells, serve to define a kind of spatial grid that lets cells know where they are in the overall embryo and thus what their fate should be.

Imagine that a cell, or group of cells, at one place in the embryonic mass switches on a gene that produces some protein. And suppose that this protein can diffuse out of the cell, like water leaking out of a paper bag, and into other cells. Then the concentration of the protein throughout the embryo varies gradually from place to place, being greater nearest the cells that produce it and slowly diminishing with distance. If you could measure the protein concentration, you’d have some notion of where you are in the embryo relative to the source cells. You’d be able to sense your position. Think of it in the same way as finding your way to the kitchen of a large house by following the smell: the stronger it is, the closer you are.

These “position-marker” proteins are called morphogens, and cells are able to “sense” their concentrations. Morphogen concentration gradients allow regions of the embryo to become distinct from one another.

To see how this can work, let’s forget the human body for a moment and look at the development of a simpler embryo: that of the fruit fly. This humble creature became the paradigmatic representative of “complex life” in the early twentieth century, when its robustness and ease of breeding made it the ideal subject to study the mechanisms of genetic inheritance – an art of which Thomas Hunt Morgan was the master. There are, of course, substantial differences between humans and fruit flies, extending to their genetic and developmental fine print. In particular, fruit-fly embryos, unlike those of mammals, are not initially clusters of separate cells at all. Once fertilized, the ovoid fly egg starts to replicate chromosome-carrying cell nuclei, but just accumulates these around the edges of the egg. The nuclei only acquire their own cell membrane once the embryo has amassed 6,000 or so. This lack of cell membranes in the early embryo makes it particularly easy for morphogens to diffuse through it.

One simple way that gradients of diffusing molecular morphogens can mark boundaries is to think in terms of concentration contours. A contour denotes a threshold: a point where the concentration exceeds a certain value.

The fruit-fly embryo acquires its initial pattern features from morphogen threshold concentrations. Pretty much the first thing it does is to define which end will become the head and thorax, and which end the abdomen. In other words, the embryo acquires a front–rear axis. That is defined by a morphogen protein called bicoid. At the tip of the “head” (so-called anterior) end, the embryo produces bicoid, and this begins to diffuse down to the rear (posterior) end. The concentration falls smoothly from the anterior to the posterior end. Where it exceeds certain values, the bicoid protein will bind to the DNA within the embryo and activate other genes with vivid names like hunchback, sloppypaired 1 and giant (typically named because of the developmental defects that mutations in the genes can produce). How this switching occurs is complicated, not least because it also seems to depend on a gradient of another protein called caudal that diffuses from the opposite (posterior) end. But the outcome is that the embryo becomes quite sharply segmented into regions where different genes are expressed or not. Thus the uniformity of the embryo is destroyed: an anterior– posterior axis is established, along with the segments that will develop into the fly’s head, thorax and abdomen. It seems that similar gradients cause segmentation of the neural tube of vertebrates: the tissues that will become our brain and spinal column.

Gradients in the concentration of proteins bicoid and caudal from opposite ends of the fruit-fly embryo switch on genes at different positions that cause segmentation of the body plan.

Other diffusing morphogens produce other kinds of gradient, defining different axes of the emerging body. For example, a protein called dorsal is involved in setting up the top-to-bottom (dorsoventral) axis of the fruit-fly embryo that distinguishes the region that will become the back (where the larva will ultimately grow wings) from that which will become the belly. In each case, the gradient thresholds may turn particular genes on and off in a series of elaborations that begins with the crudest determinants of shape – the front/back and top/bottom axes, say – and works its way to the fine details.

The idea that chemical concentration gradients might control the development of embryos was first proposed at the start of the twentieth century by Theodor Boveri. By producing a chemical patterning signal that spreads into the rest of the embryo, one cell can determine the fate of other cells nearby. In 1924 Hans Spemann, together with Hilde Mangold, called such groups of cells “organizers”.¹⁰ Mangold transplanted groups of cells in amphibian embryos from one position to another and saw that they could induce the development of “out of place” features.

The British biologists Julian Huxley and Gavin de Beer verified the idea of organizers in the 1930s by manipulating the embryos of birds. They proposed that Spemann’s organizers create “developmental fields” of some kind that influence the course of development. Spemann had imagined this “field” as something like the magnetic or electrical fields of physics, but Huxley, de Beer and their contemporaries in this fledgling field of developmental biology suspected that the agent was a chemical one. The notion that these organizing centres define a sense of position within the emerging body plan through the action of morphogen concentration gradients was crystallized in the late 1960s by biologist Lewis Wolpert.

There’s a crucial part of this story that I’ve skipped over so far. The patterning of the fruit-fly embryo is kicked off by the production of the bicoid protein at the anterior tip of the egg. But what causes that production in the first place? How does the bicoid gene know it is at the anterior end?

The answer is that “mother tells it”. While the unfertilized egg is attached to the follicle of the mother fly, specialized cells called nurse cells deposit material needed to make bicoid – specifically, the RNA molecules that mediate the gene-to-protein conversion – into the anterior tip of the egg, so that developmental patterning is all ready to go when the egg is fertilized. Right from the outset, cells in the embryo are dependent on other cells around it to know what to do. It’s for similar reasons that a fertilized human egg can’t develop fully in isolation, if cultured in a test-tube. Implantation in the uterus wall is needed to give it a “sense of up and down”. Ectopic pregancies (within the fallopian tubes) show that such a signal doesn’t have to come from the uterus, however, and we’ll see later whether there might be other ways to do produce it in vitro.

This is why it is strictly incorrect to say – although it often is said – that all the information needed to grow a human being is in the genome of the fertilized egg, which is in turn supplied by the gametes that combined to make it. You could say that the human embryo also needs positional information supplied by its environment – specifically by the uterus lining. Furthermore, any particular cell in the developing embryo depends on receiving information from the surrounding cells in order to keep embryo growth on track. As the transplantation experiments of Huxley and de Beer showed, if you mess with that information then you screw up development, despite the fact that every cell retains its complete “genetic programme”.

Embryo development is thus not encoded from the outset in the genome, as if in some blueprint or instruction book. It relies on a precise expression of genetic information in time and space, which in turn depends on the proper coordination of many cells (including maternal ones) and is subject to chance events during the execution. To understand embryology and the growth of complex tissues and organisms, we shouldn’t 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.

* * *

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.

* * *

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 Genome Project got underway, biologists estimated the number of genes the project would find as being somewhere between 140,000 and a lower limit, proposed by a few bold souls, of 26,000. Most put the figure at around fifty to seventy thousand.

The answer turned out to be 23,000.

This is often presented as a sobering example of how experts can get things wrong. It’s certainly that, but rarely does anyone identify the real moral: that the genome doesn’t work the way it was thought to.

Zoologist Fred Nijhout is one of the few to have come properly to terms with the implications. “A more balanced and useful view of the role of genes in development,” he says, “is that they act as suppliers of the material needs of development and … as context-dependent catalysts of cellular changes … they simply provide efficient ways of ensuring that the required materials are supplied at the right time and place.” They are less like Baltimore’s executive directors, and more like stewards guiding a crowd. It’s no coincidence that Nijhout sees things this way, because he is an expert on the genetics of butterfly wing patterns, where it is clear that just a few genes, creating interacting fields of influence through the diffusion and spreading of morphogens, can generate a startlingly diverse array of patterns and forms, dictated by the details of how the genes are expressed in time and space. It’s somewhat meaningless, in such a situation, to say what a gene does (beyond “encode a class of proteins”) without specifying where and when it acts.

The view now emerging is that a relatively small number of genes is able to generate the complexity of the human form, with its many different tissue types so precisely arranged and coordinated, because they act in networks that produce distinct patterns of gene expression varying over time. With 23,000 genes, the number of possible networks of influence is astronomical.

How do genes acquire and change their patterns of behaviour? The control, activation and silencing of genes in different cell types and at different stages of development is called epigenetics. The word literally implies something additional to genetics, but what it really connotes is that the observable outcome of genetic activity – the phenotype, such as the tissue type of a cell – isn’t determined by the genotype (that is, which genes are present), but by the question of which genes are active. Epigenetics is all about how genes become modified to alter whether, or how much, they are expressed.

There are several ways in which this can happen. One is by the attachment of molecular “tags” to the respective genes, which might act as markers that deter the machinery of transcription, suppressing gene expression. Some genes can be switched off, for example, by proteins that stick a so-called methyl group – a carbon atom with three hydrogen atoms attached – onto DNA bases in the gene, which forms a sort of “shield” that protects the gene against being transcribed and translated into a protein. Another molecular mechanism of epigenetic regulation involves chemical changes to the histone proteins around which a stretch of DNA is wrapped in the chromosomes.

Harder to understand than this attachment of “leave me alone” labels to genes, but equally important for epigenetics, are processes that involve the packaging of DNA in chromosomes. Remember that the combination of DNA and histone proteins in chromosomes goes by the name of chromatin. This stuff is rather systematically coiled up and stowed when the chromosomes are in the compact form (typically X-shaped) found in dividing cells. At other points in the cell cycle, chromatin can be unwoven and loosely strewn, in which case the transcription machinery can get to it more easily. So how “active” genes are can depend on how the corresponding regions of the chromosomes are packaged.

An example of this epigenetic gene regulation happens in female cells, which contain two copies of the X chromosome, one passed on from each parent. If both of them were active, they would produce more proteins from this chromosome than the cell needs, and that would cause problems. So one X chromosome is inactivated early in the development of the embryo. The choice of whether to silence the maternal or paternal X chromosome is made by each cell at random and then passed on to daughter cells when they divide. The result is that females end up with an equal blend of two types of cell throughout their body. This process of X-chromosome inactivation was first identified by geneticist Mary Lyon in the 1960s. It took many years to figure out how “X-silencing” occurs, but we now know that it involves a gene that switches on a series of events resulting in the packaging of the inactive chromosome into a tight bundle, inaccessible to transcription. All the genes are still there and are faithfully copied and passed on when cells divide, but the shape of the chromosome keeps them hidden.

Some epigenetic changes to DNA that regulate gene activity happen automatically as cells divide and mature: each cell type will have its own characteristic pattern of epigenetic modifications. This too is why development of a fertilized egg into an embryo and then a mature organism isn’t exactly just a matter of reading out a genetic programme. It involves a continual, ever-changing process of epigenetic editing of that programme, taking place through time and space.

* * *

In the mid-twentieth century, British embryologist Conrad Hal Waddington offered a metaphor for the process of epigenetic cell differentiation. He imagined cells in the early embryo traversing a landscape of possibilities: they begin their journey at a mountain peak and descend into valleys that branch like the channels of a river. At each branching point, the cell (more properly, the lineage of dividing cells) makes a decision about its subsequent fate: to become a progenitor of lung or heart, say. The consensus was that, once a lineage has descended into a valley, it can never reverse direction and go back uphill again.

The Waddington landscape. The balls represent the trajectories of different cell lineages, which begin in the single valley of totipotency as the zygote first begins to divide, and end in valleys representing different types of mature, differentiated cell.

Differentiation begins early. Indeed, it has happened even in the pluripotent embryonic stem cells of the epiblast, which have lost the totipotency of the earliest cells made from the dividing zygote. Already some of those first cells have been directed down the valley in Waddington’s landscape that leads to a placenta or a yolk sac, not to a part of the fetal body. The cells that make up the three layers of endoderm, mesoderm and ectoderm in the gastrulated embryo have undergone a further degree of differentiation, a further narrowing of choice.

It’s because of this specification of cell “fates” early in embryogenesis that the germ cells need to be formed so soon. Evidently a barely formed embryo doesn’t yet “need” eggs or sperm – but it must put aside the cells from which they will grow before they lose too much of their pluripotency. The germ cells, after all, have to make a totipotent zygote, so it won’t do if their chromosomes have already been heavily modified and silenced. Germ cells do have some epigenetic silencing of genes, although this too must be stripped away when the gametes combine to make a totipotent zygote.

This special dispensation for germ cells aside, epigenetic changes appear to be one-way. They partly account for how our body tissues remember and maintain their identity as they grow: why skin cells divide to produce more skin cells, and don’t spontaneously become muscle cells or stem cells. In other words, cell replication is somewhat more complex than merely a matter of copying the chromosomes. It’s necessary also to copy the epigenetic chromosomal modifications that give the cell its identity.

What this means is that each cell in our bodies, like each one of us, has a lineage: an ancestral history that starts with the zygote – and, except for a handful of germ cells (if we have children), ends in the grave. A liver cell has arisen from an embryonic stem cell via a succession of ancestors with intermediate characteristics, reflecting an ever greater specialization and loss of versatility. This notion of cell lineages was first articulated clearly by August Weismann when he drew up his fundamental distinction between somatic (“mortal”) and germ (“immortal”) cells.

When we tell the story this way, a new possibility becomes apparent. In cells during development, just as in organisms during evolution, genes can change. Every time a cell divides, there is a chance that some of the three billion base pairs in the genome will be miscopied – that the daughter cells will acquire mutations. Cells put a great deal of effort into avoiding such mistakes, employing a kind of molecular proofreading to check for errors in replication. All the same, the numbers are so vast that mutations are inevitable. It’s estimated that distributed within the chromosomes of our 37 trillion or so cells are about ten thousand trillion genomic mutations.¹³ Every one of our genes experiences somatic mutations at some point in our lives.

Most of these mutations, fortunately, don’t matter – they don’t affect a gene’s ability to do its job(s). But some have consequences. Most notoriously, gene mutations can lead to the cell dysfunctions that cause cancer (see here). Even potentially harmful mutations, though, might not matter if they happen late in development and so appear only in a few cells. Somatic mutations that arise during early embryo growth, on the other hand, may be passed on to all subsequent cells in that lineage, making the developing body a patchwork or “mosaic” with slightly but perhaps significantly different genomes. There are many diseases related to “mosaicism”, of which cancer is just one class. Somatic mutations leading to mosaicism are particularly common in brain neurons, and they are thought to be responsible for a range of brain and cognitive disorders, including some types of autism. Even benign mutations can manifest themselves in outward appearance (that is, phenotypically): for example, causing striped skin pigmentation called Blaschko’s lines or the red skin blotches called port-wine stains.

One particularly unusual but very rare kind of mosaicism happens when a cell in a male embryo fails to pass on its Y chromosome to the daughter cells, which, inheriting only the X, then develop as “female cells” by default. This can lead to a mixture of male and female characteristics in the embryo. Rare it may be, but this condition serves to remind us of the cell’s autonomy. Even in a body “meant” (to judge from the zygote) to be male, there is no global command that cells obey, and the “feminized” cells will feel no obligation to conform to the nature of their “male” neighbours.

Genetic variations along a cell lineage are, therefore, random. Epigenetic modifications that give rise to different cell types and tissues, on the other hand, are generally systematic and preordained in the genes – not in the sense that they will happen come what may, but that they are destined to be a part of the developmental programme so long as it proceeds without mishap. Some epigenetic changes aren’t preordained at all, though. They may take place in response to the contingent environment of a cell or organism, including unpredictable events arising from randomness within the network of interacting genes themselves. This is one reason why identical twins, who have the same genomes, may look rather different later in life. They have different environmental nudges, and this affects the epigenetic programming of their genes. Some dietary chemicals such as curcumin (found in curry spices) and resveratrol (in grapes) seem to have epigenetic effects on the folding-up of chromatin in cancer cells, while deficiencies of folate (a chemical in pulses and grains) can alter epigenetic patterns of methyl attachment to DNA. (Whether this means that red wine and tikka masala protect against cancer is another matter.) Drugs and pollutants can also act, for better or worse, via their influences on the epigenetic (as well as genetic) programming of cells.

Given that Waddington proposed the idea of an “epigenotype” – which he called a “whole complex of developmental processes between the genotype and phenotype” – in 1942, it is a little odd that epigenetics has been portrayed in recent years as a field that is “revolutionizing” biology. Perhaps that’s just how it looks if you’re starting from a simplistic view in which cells are nothing more than player-pianos orchestrated by their punched-hole genetic scripts – that’s to say, if you had a faulty story to begin with.

All the same, it is only in the past several decades that we have had a more detailed understanding of how epigenetics works at the scale of cells and molecules. There are still many holes in that understanding. Some researchers now talk in terms of an epigenetic code that imposes itself on and modulates the “all-powerful” genetic code. But epigenetics is a dynamic process, for which a “code” might be the wrong metaphor. Sure, there may be an epigenetic signature characteristic of, say, a fibroblast cell. But the epigenetic status of a human being is constantly changing and depends on our personal history.

It is the recognition of contingency in a cell’s epigenetic state that underpins the real revolution in biology. For, as the growth of my mini-brain from skin cells attests, the specification of cell fate is not irreversible. If we cling too strongly to the evolutionary metaphor of cell lineage, that sounds crazy: it’s like saying that you could be transformed back to a pre-human Australopithecus (more properly, to the common ancestor we Homo sapiens shared with that early hominid).

But for cells, such things are possible. The history of our flesh can be reversed and revised, and this completely transforms the possibilities for what it can become – and what we might do with it. We will see later how this can be achieved.

* * *

It should come as no surprise that there’s plenty of contingency and circumstance involved in the way genes, epigenetics and cell interactions combine to create a human being. Of course the environment can play a major and perhaps even catastrophic part. Drugs (licit and otherwise), alcohol, hormones and environmental contaminants entering the mother’s bloodstream during pregnancy can disrupt the process, for example, in ways that are transformative to the embryo or fetus.

We might tend to imagine that this is just a matter of a “plan for a person” that either proceeds as it should or gets thrown off course. But I will end this chapter by looking at one more way in which a simplistic picture of the person being a kind of “read-out” of the genes in a zygote can be profoundly misleading. The person – their body, their chromosomal inheritance of propensities – is not so easily condensed into a single type of cell. For just as human societies can be diverse, so can the cell societies that comprise a human individual.

Non-identical twins, for instance, may each have a mixture of red blood cells from both twins. Red blood cells are unique in the human body in having no chromosomes: they are produced not by cell division but by transformation of a special kind of cell in bone marrow. They fall into particular general classes – blood groups – depending on the chemical structure of protein molecules on the surface of the cells. Normally, each individual has red blood cells of a specific blood group, but twins can have a mixture of each twin’s blood group.

This was first discovered in non-identical twinned cattle calves by the American biologist Ray Owen in the 1940s. In 1953, British physicians Ivor Dunsford and Robert Race found a similar case of two distinct blood groups in a human, a patient denoted Mrs McK who was tested before donating blood. Mrs McK had no living twin, but she told the puzzled doctors that she had had a twin brother who had died at three months old. The mixture of blood types here come from the fact that twins share a blood circulation system in the uterus, and so may exchange blood-forming cells that continue to produce blood long after birth and perhaps for a lifetime.

This presence of cells from more than one “biological individual” persisting and carrying out their biological function in a single organism is said to make it a chimera. Robert Race coined the term in describing the case of Mrs McK, admitting that he was simply looking to give his paper a catchy title.

People can be chimeric in much more dramatic ways than this. Their entire bodies can be patchworks of cells that seem to come from two different people. One way this can arise is by the fusing, at a very early stage of development, of non-identical twin embryos in utero. In a demonstration of how our cells can adjust to “unforeseen circumstances”, these fusions can give rise to an anatomically normal individual whose cells got their genetic material from two different pairs of gametes: they are said to be tetragametic. This can happen even if the embryos that fused were of different sexes: the reproductive organs will then be decided by which set of cells in the merged embryo happens to produce them. But the chimeric person’s body as a whole is not specifically gendered one way or the other in terms of the usual XX/XY chromosomal distinction: it is a bit of both.

Chimerism can also arise from exchange of cells between an embryo and the mother carrying it. These two “individuals” are conjoined via the placenta, which, as I explained earlier, is a mixture of cells from both of them. But the placenta is a rather leaky barrier. So cells from the mother can become incorporated into the embryo and fetus, while the developing child’s cells may enter the body of the mother.

In fact, some degree of exchange, known as microchimerism, is normal. Many women who are pregnant with sons, for example, acquire some cells with Y chromosomes. What surprised researchers when this exchange came to light in the 1990s is that these fetal cells may persist and remain active, albeit at a low level, in the mother for many years after the child is born. But while microchimerism affects just a small proportion of the body’s cells, a process like embryo fusion to create a tetragametic chimera makes a person who is genetically heterodox through and through: some organs and body parts come from one embryo, some from another.

If I were a mixture of the flesh of “two people”, what would that make me? It is tempting to say that such an individual is indeed a mixture of two people in one. But that seems a profoundly odd and unhelpful way to look at the matter, for in what meaningful sense were those twin embryos “people” before they fused? These clusters of cells have only given rise to a single individual. This is just one of the ways in which quirks of developmental and reproductive biology undermine a simplistic determination to invest an embryo with unique personhood. A “person” is a higher-order concept, not to be reduced to genes or cells.

Still, our habits of thought and even our laws are challenged by these discoveries. DNA analysis of a tissue sample from a tetragametic woman may fail to confirm that her biological children are “hers”, if the sample does not happen to share chromosomes with her gametes. Such cases have come to light through genetic testing to confirm maternity in applications for social welfare benefits in the United States, leading to harrowing accusations of false claims of parentage. Some of these cases have highlighted how strongly we invest notions of personhood and identity in the character of our flesh and genes. In his book She Has Her Mother’s Laugh, science writer Carl Zimmer describes two such cases, saying that the discovery of their chimerism left these women with “haunting questions not only about their families but about themselves”. One woman wondered if she was only partly the mother of her children, despite having given birth to them, and partly their aunt. “I felt that part of me hadn’t passed on to them,” said the other woman. As Zimmer explains:

We use words like sister and aunt as if they describe rigid laws of biology. But despite our genetic essentialism, these laws are really only rules of thumb. Under the right conditions, they can be readily broken.

Yet I wonder. Not all cultures do use these words this way. It is common in Chinese society, for example, to call a close female friend of the family “aunt” even without any blood relation, and in the West “sisterhood” and “brotherhood” are widely used to express sympathetic bonds irrespective of sibling connections. Many cultures have a flexibility of familial relations that does not inevitably reduce them to blood and birth.

No, the problem here is not that biology destroys our traditional categories and concepts of human life, but that we too often now fall into the trap of imagining that biology can and should arbitrate on socially mediated questions of self and identity, family and kinship, sex and gender. Biology has a habit of declining that role, handing back (so I like to see it) the responsibility and saying, “you, not I, are the ones who care about these issues, so you must decide them for yourself.”

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