How to Build a Human: Adventures in How We Are Made and Who We Are

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 (#litres_trial_promo) 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.”

FIRST INTERLUDE (#ulink_b43af3e2-d1a0-56b2-8cff-9e5c0cd570de)

THE HUMAN SUPERORGANISM (#ulink_b43af3e2-d1a0-56b2-8cff-9e5c0cd570de)

HOW CELLS BECAME COMMUNITIES (#ulink_b43af3e2-d1a0-56b2-8cff-9e5c0cd570de)

To insist xthat the embryo is “us” from its first instants is to some degree a displaced religious impulse. It announces a moment of creation, as profound and abrupt as the fiat lux of the Old Testament. Because, let’s face it, the world did begin when you did, and it will end when you do: that’s a universal, experiential human truth. Symmetry alone then seems to demand a beginning that is as abrupt and all-encompassing as the end – a moment, in those monotheistic traditions, when the soul enters the body to match the one when it leaves.

But this concept of the embryo denies the true wonder of our origin, and is another expression of the flight from flesh that has been going on for centuries. The assertion of the soul as an immaterial thing, pre-existing and eternal, is a pre-scientific attempt to deal with the incommensurability between the life we lead and the life in our cells.

For the latter is truly something to be astonished at. It is contiguous with the moment life first appeared on Earth. Life is passed like a baton between living things and is not created afresh with their own beginning. In arguments about abortion and embryo research, we talk about “when life begins”, but that’s not what we mean. Life only began once, around four billion years ago, and no one knows how. It continued in an unbroken thread from primal slime and algae to the oddly shaped metazoans of the Cambrian, through to the shrew-like ancestors of all mammals, and on to our apelike forebears walking upright and wielding stone tools, and finally – for this brief, glorious moment – here you are. Life is just passing through you, so enjoy it while you can.

The ambiguity, anxiety and angst that arise when we contemplate the life of the one-cell zygote and try to reconcile it with the human form in order to formulate laws and moral codes are consequences of our being assemblies of cells living in community. So it’s worth considering how that came about.

* * *

If there was to be a competition for the least appealing organism in the world, slime moulds would be a strong contender. Bacteria get a bad press as mere “germs” to be expunged, but they also have a certain cachet too now that we know their presence in our gut is so beneficial and that they have such superpowers: metabolizing radioactive waste and oil spills, surviving in hot springs and so forth. Slime moulds, meanwhile, appear to be nothing more than their name suggests: a slightly disgusting smear of living matter whose purpose seems incidental to anything useful or inspiring in nature.

These organisms are members of a group called Mycetozoa. They are a type of amoebae, single-celled entities so “primitive” that for years microbiologists argued about whether they were closer to animals, fungi or plants. Modern genetic studies suggest that in evolutionary terms they are most closely related to the former two kingdoms, but they sit right at the boundaries – which is to say, the Mycetozoa became a distinct group around the same time in evolutionary history that animals, fungi and plants went their separate ways.

This is what makes slime moulds in fact deeply interesting. They offer a glimpse of what might have gone on when life began to get truly complex: when single-celled organisms evolved into multi-celled ones. In other words, when cell communities started to become superorganisms like us.

Amoebae played a significant role in the history of how we came to understand living matter. The word was coined originally to denote any microscopic organism that doesn’t have a fixed shape. Bacteria do: typically they are cigar-shaped, like round-ended tubes. But amoebae are shape-shifting blobs that move by extending a part of their bodies into pseudopods (“false feet”). The term “amoeboid” has entered everyday speech to denote that kind of amorphous, oozy mass.

The amoeba Proteus: a cell of no fixed shape.

But amoebae aren’t really a well-defined class of organism at all. There are types of amoebae that are truly animals, or fungi, or plants, as well as protozoans, which are single-celled organisms more “complicated” than bacteria. (I’ll say shortly what I mean by that.) Some amoebae are parasites; some are slime moulds. Even some of our own cells display amoeboid behaviour, such as white blood cells that “eat” bacteria and other pathogens by engulfing and absorbing them.

Amoebae were first reported in the eighteenth century in studies of seawater under the microscope. In 1841, the French biologist Félix Dujardin christened the jelly-like contents of amoebae “sarcode”. Renamed as “protoplasm”, this stuff became regarded as the fundamental living material. Amoebae came to be seen as the exemplar of the living cell, and to some scientists of the late nineteenth century it seemed that complex organisms like us were little more than sophisticated versions of their colonies: English physiologist Michael Foster wrote in 1880 that “The higher animals, we learn (#litres_trial_promo) from morphological studies, may be regarded as groups of amoebae peculiarly associated together.” The German biologist Ernst Haeckel, a Darwinian committed to finding similarities and analogies among living things, attested that the amoeba was a sort of egg cell that needed nothing but itself to multiply: a “permanent ovum (#litres_trial_promo)”, as he put it.

That was the heyday of the amoeba, which by and by came to be seen as too primitive a creature to take us very far in understanding life in all its variety. But if you suspected that amoebae don’t seem likely to hold much of interest in their gelatinous lives, Dictyostelium discoideum will set you right. It lives in soils and consumes bacteria, helping to maintain a balance in the microbial ecosystem that is as important for the health of the soil as harmony among our gut microbiota is for our own well-being. It’s appropriate, then, that Dictyostelium discoideum – which I shall call Dicty – was discovered by the son of a farmer, working during the years of the Great Depression when soils were under threat from drought and wind erosion on the American prairies. That man was Harvard microbiologist Kenneth Raper.

What fascinated Raper was that Dicty has a peculiar life cycle. When food or moisture becomes scarce, the cells give up their individuality and turn into a multi-cellular superorganism. They send out chemical signals that attract one another, and the amoeboid cells gather into a “slug” a few millimetres long that contains hundreds of thousands of them. The slug undergoes some shape changes before narrowing at one end and ballooning at the other, becoming a tiny plant-like structure standing upright on a stalk. The bulbous head is the “fruiting body”, filled with cells that have become robust spores in suspended animation, ready to be released when conditions are conducive to start the cycle again. In the fruiting body, cells that were once identical have become distinct: they have differentiated, acquiring specialized skills.

Left: The life cycle of Dictyostelium discoideum.Some of these forms are shown in sequence under the microscope on the right.

There is sacrifice involved. The spores will survive, but the supporting tissue of the fruiting body will die. That seemed curious to Raper: these autonomous cells make a choice, some voluntarily renouncing immortality for the sake of the others. It’s not unlike the way, during the development of the human embryo, a ball of identical cells apportions into tissues with separate fates. Some become body (somatic) cells, which will die with the person. Others become germ cells, which can in principle keep propagating forever.

What’s more, just as this cooperative behaviour of our cells depends on their exchanging chemical signals that allow them to self-organize into pattern and shape, so we see that too in Dicty. There the patterns are remarkable, even beautiful, and certainly adequate to make the case that slime moulds deserve a bit more respect. Some of the cells in the community become pacemakers, exuding pulses of a chemical that diffuses out into the surroundings and induces neighbouring cells to start moving, pseudopod by pseudopod, towards the signalling cell. Because the attractive chemical comes in pulses, the cells advance in waves, resembling the concentric patterns of ripples on water. Eventually these motions coalesce into streams that converge on the place where the fruiting body will grow.

The patterns formed by Dicty cells as they aggregate into multi-celled fruiting bodies.

This behaviour supplies a model system for understanding the appearance of pattern in cell biology more generally. It’s not really what human cells do, but there are resemblances. The way Dicty’s signalling molecules travel in waves through the cell community is also mathematically analogous to how waves of electrical excitation pass through the cells of the human heart, inducing a steady heartbeat.

Still, Dicty seems deeply alien. Blurring our categories even more, the cells sometimes reproduce by simple division, like bacteria, but sometimes by sex between two of the three different “mating types” – three different genders, if you will.

But as I watched my skin cells turn into a mini-brain in a dish, I had to wonder if we are really so unlike Dicty after all. We are single, autonomous beings, but we are also aggregates of microscopic entities that might each one give rise to another entire organism. Here were my swarming cells, making their individual ways in the world. They may divide and proliferate, they may cluster into clumps from which organs will grow. They’re a part of me, but they can live apart too.

We are not, though, superorganisms in quite the way that Dicty is. For one thing, any pieces of us that become detached will normally perish fast, whereas if you cut off a piece of Dicty’s fruiting body it will grow into another fruiting body. Our own cells need to stay and work together for our entire life cycle, whereas when the Dicty spores are revived, they can grow into communities in which single cells can do their own thing again. For Dicty, multi-celled existence is just a passing phase.

Yet the origin of multi-cellularity must have looked a little like this: single cells finding out the benefits of forming temporary unions, of taking specialized tasks, of reproducing sexually. That history used to seem so distant from us – perhaps a billion years ago – that it barely seemed part of our human heritage at all. Now we can see under the microscope that this past has never quite gone away.

As much as a recent shared ancestry with simian cousins, the origin of humans as colonies of cooperating cells was what seemed so unsettling about Charles Darwin’s evolutionary theory, which implied a chain of being extending all the way back to amoebic “protoplasmic slime”. That we possessed ape-like ancestors might have been deemed undignified. But to collapse the human body to the cell and turn identity into unstructured living matter – that seemed an absurd affront. To some people, it still does.

* * *

Slime moulds are one of the simplest members of the domain of living organisms called eukaryotes, which also includes plants, fungi and animals. What else does that leave in nature? Just single-celled organisms: bacteria and archaea, the so-called prokaryotes.

It has taken much of the century and a half since Darwin to shake off the notion that these distinctions imply a hierarchy of status, with evolution being a progressive elaboration and improvement of living matter at the pinnacle of which is … guess who? The simplest way to dispel that illusion is to recognize that all the other types of organism are still with us, many of them thriving (if we let them). Cell for cell, bacteria outnumber us humans by a factor of several tens of millions. So who is truly the most successful?

The question is then why bacteria and other prokaryotes have stayed resolutely single-celled, while many eukaryotes are multi-cellular organisms.

Being a eukaryote is a necessary but not sufficient criterion for getting multi-cellular. The word comes from the Greek for “true/good kernel”. It reflects the fact that eukaryotic cells have a kind of kernel, while prokaryotes don’t – namely the dense cell nucleus where the gene-laden chromosomes reside. Prokaryotes have genes too, but they are not sequestered in a separate cell compartment, and neither are the genes apportioned between several chromosomes as they are in eukaryotes. The genes of bacteria are mostly housed on one double-helical loop of DNA, wound into coils and floating freely in the cytoplasm, sometimes along with several smaller, circular segments of DNA called plasmids.

The organization of chromosomes is just one respect in which the structure of eukaryotic cells is more complex than that of prokaryotes. Along with the nucleus, eukaryotes generally also contain a host of other compartments or “organelles”, bounded by membranes, that carry out particular functions: the mitochondrion, the chloroplast, the endoplasmic reticulum and so on. We know what roles these organelles fulfil, but there’s a puzzle about that “good kernel”, the nucleus itself.

The usual story is that it protects the DNA. But as biochemist Nick Lane asks, protects it from what? What is there to fear in the rest of the cell?

Well, it could be from viruses. But another hypothesis has been suggested by evolutionary biologists Eugene Koonin and Bill Martin: the nucleus is there to slow down the process of protein production from the genome. Recall that the genome of eukaryotic cells (but not that of prokaryotes) is full of rogue bits of DNA called introns that interrupt the gene sequences encoding proteins. It’s thought that these introns might be the remnants of an infestation of so-called “jumping genes” – pieces of DNA that are adept at splicing themselves at random places in the genome. Many eukaryotic introns are ancient: they appear in the same places in equivalent genes in a variety of eukaryotic organisms ranging from humans to yeast. This suggests that there was an episode far in the evolutionary past when the genomes of eukaryotes became particularly vulnerable to infestation by jumping genes.

Whatever the reason, introns now need to be cut out before proteins are made. This happens after the transcription of DNA into RNA, the intermediary molecules that serve as the templates for protein synthesis on the structure called the ribosome. An RNA transcript of a gene is made from DNA, and then it is edited by special enzymes before being used by the ribosome to guide protein synthesis.

In bacteria, this sequence of transcription to ribosomal RNA followed by translation to proteins happens all at once; the RNA is translated even while it is being transcribed. If that happened in eukaryotes, there would be no time for proper intron editing. But the nucleus separates the process of transcription, which happens inside its membrane, from translation, which happens outside. Maybe, say Koonin and Martin, this spatial separation of transcription from translation ensures that the job is done properly.

* * *

Since eukaryotes are more complex than prokaryotes, it seems natural to suppose that the latter cells appeared first and eukaryotes evolved from them. This is indeed what is suggested by both the fossil record (even single-celled organisms leave fossils of a kind) and studies of DNA, from which we can deduce how the “tree” of evolution branched.