Nature via Nurture: Genes, experience and what makes us human

That figure has meandered a little since the 1970s. Most estimates place it at 98.5 per cent, although two recent detailed studies of actual stretches of genome came to a figure of 98.76 per cent.

(#litres_trial_promo) However, just as the 98.5 per cent was seeping into the public consciousness, Roy Britten wrote a dramatic paper in 2002 showing that it was out by a mile. He confirmed that if you count only substitutions – i.e., letters in the text that are different between human and chimpanzee genes—you do indeed get a figure of 98.6 per cent. But if you then add in the textual insertions or deletions, the figure drops to 95 per cent.

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Whatever. It was still a terrible shock to science to discover just how small was the genetic distance between the two species. ‘The molecular similarity between chimpanzees and humans is extraordinary because they differ far more than many other [closely related] species in anatomy and way of life,’ wrote King and Wilson.

(#litres_trial_promo) An even greater shock was in store in 1984, when Charles Sibley and Jon Ahlquist at Yale found that chimpanzee DNA was more like human DNA than it was like gorilla DNA.

(#litres_trial_promo) This was a moment of human dethronement similar to Copernicus placing the Earth within the solar system as just another planet. Sibley and Ahlquist placed the human species within the ape family as just another ape. From having our own distinct ape lineage stretching back 16 million years, we were now forced to admit that not only did we share a common ancestor not much more than five million years ago, but that we were the most recent branch of the family. Our common ancestor with the chimp lived after the common ancestor of both with the gorilla and long after the common ancestor of all three with the organg-utan. Incredible as it may seem, chimpanzees are more closely related to human beings than they are to gorillas (a conclusion that Britten’s reanalysis of the precise number does not alter). Nothing in the anatomy or fossil record of the African apes suggested such a possibility. Human beings are not the odd ones out.

Time has dulled these shocks. But there are more coming. Reading the DNA of a human being, alongside that of a chimpanzee, might once and for all define the difference between them. At the time of writing, the complete genome of the chimpanzee is not yet available. Even when it is, it may prove tricky to work out which differences are the ones that matter. The human genome contains about three billion ‘letters’ of code. Strictly speaking, these are chemical bases on a molecule of DNA, but since it is their order, not their individual properties, that determines what they produce, they can be treated as digital information. The difference between two individual human beings amounts, on average, to 0.1 per cent, so there are three million different letters between me and my neighbour. The difference between a human being and a chimpanzee is about 15 times as great, or 1.5 per cent. That equates to 45 million different letters. That is about ten times as many letters as there are in the whole Bible, or 75 books the length of this one. The book of digital differences between our two species, unannotated, would fill eleven feet of bookshelf. (The bookshelf of similarities, by contrast, would stretch to 250 yards.)

Look at it another way. Scientists now reckon that there are about 30,000 human genes. That is, scattered throughout the genome are 30,000 distinct stretches of digital information that are directly translated into protein machinery to run and build the body: a gene being a recipe for a protein. Chimpanzees almost certainly have roughly the same number of genes. Since 1.5 per cent of 30,000 is 450, then it seems to follow that we have 450 different, uniquely human genes. Not such a big number. The other 29,550 genes are identical in us and chimps. But this is actually most unlikely. It could instead be that every single human gene is different from every single chimp gene, but only 1.5 per cent of its text is different. The truth is bound to lie somewhere between the two. Many genes will be identical in closely related species; many will be slightly different. A very few will be utterly different.

The most visible difference is that all apes have one more pair of chromosomes than people do. The reason is simple enough to find: at some point in the past, two middle-sized ape chromosomes fused together in the ancestors of all human beings to form the large human chromosome known as chromosome 2. This is a surprising rearrangement, and it almost certainly means that chimp-human hybrids would be sterile if they could survive at all. It may have helped create what evolutionists delicately call ‘reproductive isolation’ between the species in the past.

But the rearrangement of the chromosomes does not necessarily imply a difference in genetic text at that spot. Although the chimpanzee genome is still largely terra incognita, already there are significant textual differences known between human and chimp (or other ape) genes. For example, whereas people have a mixture of A, B and O blood groups, chimpanzees have only A and O, while gorillas have only B. Likewise, there are three common variants of a human gene called APOE, and chimpanzees only have one – the one most associated with Alzheimer’s disease in people. There seems to be a distinct difference in the way thyroid hormones work in people compared with other apes. The significance of this is unknown. And a family of genes on chromosome 16 has undergone several bursts of duplication in the apes after they had separated from the monkey lineage 25 million years ago. Each set of these so-called ‘morpheus’ genes in human beings has diverged rapidly in sequence from each other and from those in other apes – evolving at nearly 20 times the normal rate. Some of these morpheus genes might indeed be described as uniquely human genes. But exactly what these genes do, or why they are evolving apart so rapidly in apes, remains mysterious.

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Most of these differences are also variable among people; there is nothing here unique to human beings as a whole. In the mid-1990s, however, the first genetically unique feature universal to all people and absent from all apes was discovered. Several years before, a medical professor in San Diego named Ajit Varki became intrigued by a unique form of human allergy: an allergy to a particular kind of sugar (a certain ‘sialic acid’) found attached to proteins in animal serum. This immune reaction is partly responsible for the severe reaction that people often have to horse serum used as a snake-bite antidote, for example. We human beings simply cannot tolerate this ‘Gc’ version of sialic acid, because we do not have it in the human body. Varki, together with Elaine Muchmore, soon discovered the cause by first noting that unlike human beings, chimpanzees and other great apes did have Gc. The human body does not manufacture Gc sialic acid because it lacks the enzyme for making it from Ac sialic acid. Without the enzyme, human beings cannot add an oxygen atom to the Ac form. All human beings lack the enzyme, but all apes have it. This was the first universally true biochemical difference between us and them. Fittingly, at the end of a millennium that saw us humiliatingly demoted from the centre of the universe and the apple of God’s eye to just another ape, Varki now seemed to suggest that we differ by just a single atom on a humble sugar molecule: and an omission at that! Not a promising locus for the soul.

By 1998 Varki knew why we were peculiar: a 92-letter sequence was missing from a gene called CMAH on chromosome 6 in human beings, a gene that codes for the enzyme that makes Gc. Next he discovered how it had gone missing. Right in the middle of the gene was an Alu sequence, a sort of ‘jumping gene’ of a kind that infests our genome. In the ape genome there is a different and more ancient Alu, but the one in the human gene was of a sequence known to be unique to human beings.

(#litres_trial_promo) So some time after the divergence of the human and chimp lineage, this Alu had done what it does best, which is to jump into the CMAH gene, swap places with the older Alu and accidentally remove the 92-letter chunk of the gene while it was about it. (If this all sounds like double genetic Dutch, try thinking of it this way: a computer virus has destroyed one of your files.)

Varki’s discovery initially raised a big yawn from the scientific establishment. So what, they cried, you have found a gene that is bust in human beings but not in apes. Big deal. Varki is not easily discouraged, and by now he was interested by the whole subject of human-ape difference. The first issue was to pinpoint when the mutation had occurred. DNA cannot be recovered from ancient fossils of human ancestors, but sialic acid can be. He found that Neanderthals were like us, in having Ac, but no Gc, but older fossils (from Java and Kenya) were all from warmer climates and their sialic acids had degraded too far. However, by counting the number of changes in the defunct human CMAH gene, and using a molecular clock, his colleague Yuki Takahata has been able to estimate that the change happened about 2.5 or 3 million years ago in some human being who is now one of the ancestors of all people alive.

Varki began to investigate other possible consequences of the mutation. Most other animals seemed to have the working gene, even sea urchins, but if the gene is ‘knocked out’ in the embryo of a mouse, the mouse grows up healthy and fertile. Sialic acid is a sugar found on the outside of cells, like a sort of flower growing from the cell surface. It is one of the first targets for infectious pathogens including botulism, malaria, influenza and cholera. Lacking one of the common forms of sialic acid might make us more or less vulnerable to these diseases than our ape relatives (cell-surface sugars seem to be a sort of first line of defence in the immune system). But the most intriguing thing about the Gc form of sialic acid is that it is easily found throughout the body of mammals except in the brain. Varki’s gene is almost entirely switched off in the brains of mammals. There must be some reason why you cannot operate a mammalian brain properly unless you switch this gene off almost completely. Perhaps, muses Varki’s, the expansion of the human brain, which accelerated about two million years ago, was made possible by going one further and switching the gene off altogether throughout the body. He admits it is a ‘wild idea’ for which he has no evidence; he is in uncharted territory. Intriguingly, he has since found another gene concerned with processing sialic acid that is also knocked out in human beings.

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Even esoteric research like this may have practical consequences. It gives a strong reason to abandon the idea of xeno-transplantation, the transplanting of animal organs into people: allergic reactions to the Gc sugars in animal organs are almost inevitable. Since you can find traces of Gc sialic acid in human tissues, presumably from animal food, Varki has been drinking diluted Gc sialic acid recently to test how his own body handles it. He wonders if some of the diseases that are caused by eating ‘red meat’ may be associated with encountering this animal version of the sugar. But Varki is the first to admit that the vast range of differences between human beings and apes cannot be boiled down to one kind of sugar molecule.

We use roughly the same set of genes as other mammals, but we achieve different results with them. How can this be? If two sets of near-identical genes can produce such different-looking animals as a human being and a chimpanzee, then it seems superficially obvious that the source of the difference must lie elsewhere than in the genes. Nurtured as we are in nature–nurture dichotomies, the obvious alternative that occurs to us is nurture. Well, then, do the obvious experiment. Implant a fertilised human egg into the womb of an ape, and vice versa. If nurture is responsible for the difference, the human will give birth to a human and the chimp to a chimp. Any volunteers?

It has been done, though not in apes. In zoos, surrogate mothers have been made to lend their wombs to foetuses from other species in the cause of conservation. The results have been mixed at best. Wild oxen called gaur and banteng have been gestated in cattle, but until now they have died soon after birth. Similar failures have been achieved in wild moufflon gestated in sheep; bongo antelope in eland antelope; Indian desert cat and African wild cat in domestic cats; and Grant’s zebra in domestic horses. The failure of these zoo experiments suggests that a surrogate human mother could not carry a chimpanzee foetus to term. But they do at least prove that in every case, the baby comes out looking like its biological parent, not like its gestational parent. That, indeed, is the point of the experiment: to save rare species by mass-producing them in domestic animals’ wombs.

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It is such an obvious outcome that the experiment seems pointless. We all know that a donkey embryo in a horse womb would develop into a donkey, not a horse. (Donkeys and horses are slightly more similar, genetically, than people and chimps. Like the two ape species, they also differ from each other in that horses have one more pair of chromosomes. This mismatch in chromosome number accounts for the sterility of mules and implies that a man mated to a female chimp just might produce a viable baby who would grow into a sterile ape-person with considerable hybrid vigour. Rumours of Chinese experiments in the 1950s notwithstanding, nobody seems to have tried this simple, but unethical experiment.)

So the conundrum only deepens. The genes, not the womb, determine our species. Yet despite having roughly the same set of genes, human beings and chimpanzees look different. How do you get two different species from one set of genes? How can we have a brain that is three times the size of a chimp’s, and is capable of learning to speak, and yet not have an extra set of genes for making it?

THROWING SWITCHES

I cannot resist a literary analogy. The opening sentence of Charles Dickens’s novel David Copperfield reads: ‘Whether I shall turn out to be the hero of my own life, or whether that station will be held by anybody else, these pages must show.’ The opening sentence of J.D. Salinger’s novel The Catcher in the Rye reads: ‘If you really want to hear about it, the first thing you’ll probably want to know is where I was born, and what my lousy childhood was like, and how my parents were occupied and all before they had me, and all that David Copperfield kind of crap, but I don’t feel like going into it.’ In the pages that follow, to a close approximation, Dickens and Salinger use the same few thousand words. There are words that Salinger uses but not Dickens, like elevator or crap. There are words that Dickens uses but not Salinger, like caul and pettish. But they will be few compared with the words they share. Probably there is at least 90 per cent lexical concordance between the two books. Yet they are very different books. The difference lies not in the use of a different set of words, but in the same set of words used in a different pattern and order. Likewise, the source of the difference between a chimpanzee and a human being lies not in the different genes, but in the same set of 30,000 genes used in a different order and pattern.

I say this with confidence for one main reason. The most stunning surprise to greet scientists when they first lifted the lid on animal genomes was the discovery of the same sets of genes in wildly different animals. In the early 1980s, fly geneticists were thrilled to discover a small group of genes they called the hox genes that seemed to set out the body plan of the fly during its early development – roughly telling it where to put the head, the legs, the wings and so on. But they were completely unprepared for what came next. Their mouse-studying colleagues found recognisably the same hox genes, in the same order, doing the same job. The same gene tells a mouse embryo where (but not how) to grow ribs as tells a fly embryo where to grow wings: you can even swap them between species. Nothing had prepared biologists for this shock. It meant, in effect, that the basic body plan of all animals had been worked out in the genome of a long-extinct ancestor that lived more than 600 million years before and preserved ever since in its descendants (and that includes you).

Hox genes are the recipes for proteins called ‘transcription factors’, which means that their job is to ‘switch on’ other genes. A transcription factor works by attaching itself to a region of DNA called a promoter.

(#litres_trial_promo) In creatures such as flies and people (as opposed to bacteria, say), promoters consist of about five separate stretches of DNA code, usually upstream of the gene itself, sometimes downstream. Each of those sequences attracts a different transcription factor, which in turn initiates (or blocks) the transcription of the gene. Most genes will not be activated until several of their promoters have caught transcription factors. Each transcription factor is itself a product of another gene somewhere else in the genome. The function of many genes is therefore to help switch other genes on or off. And the susceptibility of a gene to being switched on or off depends on the sensitivity of its promoters. If its promoters have shifted, or changed sequence so that the transcription factors find them more easily, the gene may be more active. Or if the change has made the promoters attract blocking transcription factors rather than enhancing ones, the gene may be less active.

Small changes in the promoter can therefore have subtle effects on the expression of the gene. Perhaps promoters are more like thermostats than switches. It is here in the promoters that scientists expect to find most evolutionary change in animals and plants – in sharp contrast to bacteria. For example, mice have short necks and long bodies; chickens have long necks and short bodies. If you count the vertebrae in the neck and thorax of a chicken and a mouse, you will find that the mouse has 7 neck and 13 thoracic vertebrae; the chicken has 14 and 7 respectively. The source of this difference lies in one of the promoters attached to one of the hox genes, Hoxc8, a gene found in both mice and chickens whose job is to switch on other genes that lay down details of development. The promoter is a 200-letter paragraph of DNA and it has just a handful of letters different in the two species. Indeed, changes in as few as two of these letters may be enough to make all the difference. The effect is to alter the expression of the Hoxc8 gene slightly in the development of the chicken embryo. In the chicken embryo the gene is expressed in a more limited part of the spine, giving the animal a shorter thorax compared with a mouse.

(#litres_trial_promo) In the python, Hoxc8 is expressed right from the head and goes on being expressed for most of the body. So pythons consist of one long thorax – they have ribs all down the body.

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The beauty of the system is that the same gene can be reused in different places and at different times simply by putting a set of different promoters beside it. The ‘eve’ gene in fruit flies, for example, whose job is to switch on other genes during development, is switched on at least ten separate times during the fly’s life, and it has eight separate promoters attached to it, three upstream of the gene and five downstream. Each of these promoters requires 10–15 proteins to attach to it to switch on expression of the eve gene. The promoters cover thousands of letters of DNA text. In different tissues, different promoters are used to switch on the gene. This, incidentally, seems to be one reason for the humiliating fact that plants usually have more genes than animals. Instead of reusing the same gene by adding a new promoter to it, a plant reuses a gene by duplicating the whole gene and changing the promoter in the duplicated version. The 30,000 human genes are probably used in at least twice as many contexts during development thanks to batteries of promoters.

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To make grand changes in the body plan of animals, there is no need to invent new genes, just as there is no need to invent new words to write an original novel (unless your name is Joyce). All you need to do is switch the same ones on and off in different patterns. Suddenly, here is a mechanism for creating large and small evolutionary changes from small genetic differences. Merely by adjusting the sequence of a promoter, or adding a new one, you could alter the expression of a gene. And if that gene is itself the code for a transcription factor, then its expression will alter the expression of other genes. Just a tiny change in one promoter will produce a cascade of differences for the organism. These changes might be sufficient to create a wholly new species without changing the genes themselves at all.

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In one sense, this is a bit depressing. It means that until scientists know how to find gene promoters in the vast text of the genome, they will not learn how the recipe of a chimpanzee differs from that of a person. The genes themselves will tell them little, and the source of human uniqueness will remain as mysterious as ever. But in another sense it is also uplifting, reminding us, more forcefully than ever, of a simple truth that is all too often forgotten, that bodies are not made, they grow. The genome is not a blueprint for constructing a body; it is a recipe for baking a body. The chicken embryo is marinaded for a shorter time in the Hoxc8 sauce than the mouse embryo. This is a metaphor I shall return to frequently in the book, for it is one of the best ways of explaining why nature and nurture are not opposed to each other, but work together.

As the hox story illustrates, DNA promoters express themselves in the fourth dimension: their timing is all. A chimp has a different head from a human being not because it has a different blueprint for the head, but because it grows the jaws for longer and the cranium for less long than does the human being. The difference is all timing.

The process of domestication, by which the wolf was turned into the dog, illustrates the role of promoters. In the 1960s, a geneticist named Dmitri Belyaev was running a huge fur farm near Novosibirsk in Siberia. He decided to try to breed tamer foxes, because however well they had been handled and however many generations they had been kept in captivity, foxes were nervous and shy creatures in the fur farm (with good reason, presumably). So Belyaev started by selecting as breeding stock the animals that allowed him closest before fleeing. After 25 generations he did indeed have much tamer foxes, which, far from fleeing, would approach him spontaneously. The new breed of foxes not only behaved like dogs, they looked like dogs: their coats were piebald, like collies, their tails turned up at the end, the females came on heat twice a year, their ears were floppy, their snouts shorter and their brains smaller than in wild foxes. The surprise was that merely by selecting tameness, Belyaev had accidentally achieved all the same features that the original domesticator of the wolf had got – and that was probably some race of the wolf itself, which had bred into itself the ability not to run away too readily from ancient human rubbish dumps when disturbed. The implication is that some promoter change had occurred which affected not one, but many genes. Indeed, it is fairly obvious that what happened in both cases was that the timing of development had been altered so that the adult animals retained many of the features and habits of pups: the floppy ears, the short snout, the smaller skull and the playful behaviour.

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What seems to happen in these cases is that young animals do not yet show either fear or aggression, these developing last during the forward growth of the limbic system at the base of the brain. So the most likely way for evolution to produce a friendly or tame animal is to stop brain development prematurely. The effect is a smaller brain and especially a smaller ‘area 13’, a late-developing part of the limbic system that seems to have the job of disinhibiting adult emotional reactions such as fear and aggression. Intriguingly, such a taming process seems to have happened naturally in bonobos since their separation from the chimpanzee more than two million years ago. For its size the bonobo not only has a small head, but also reduced aggression and several juvenile features retained into adulthood including a white anal tail tuft, high-pitched calls and unusual female genitals. Bonobos have unusually small area 13s.

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So do human beings. Surprisingly, the fossil record suggests that there has been a rather steep decline in human brain size during the past 15,000 years, partly but not wholly reflecting a shrinking body size that seems to have accompanied the arrival of dense and ‘civilised’ human settlement. This followed several million years of more or less steady increases in brain size. In the Mesolithic (around 50,000 years ago) human brains averaged 1,468 cc (in females) and 1,567 cc (in males). Today the numbers have fallen to 1,210 cc and 1,248 cc, and even allowing for some reduction in body weight, this seems to be a steep decline. Perhaps there has been some recent taming of the species. If so, how? Richard Wrangham believes that once human beings became sedentary, living in permanent settlements, they could no longer tolerate anti-social behaviour and they began to banish, imprison or execute especially difficult individuals. In the past in highland New Guinea, more than one in ten of all adult deaths were by the execution of ‘witches’ (mostly men). This might have meant killing the more aggressive and impulsive – hence more developmentally mature and bigger-brained – people.

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Such self-taming, however, seems to be a recent phenomenon in our species and is not able to explain the selective pressures that led to the divergence of human beings from chimp-like ancestors more than five million years ago. But it does support the idea of evolution happening through the adjustment of gene promoters rather than genes themselves: hence the alteration of several irrelevant features caught in the slipstream of a reduction in impulsive aggression.

(#litres_trial_promo) Meanwhile, it is suddenly looking possible to understand how the human brain achieved its enlarged size in the first place, thanks to a newly discovered gene on chromosome 1. Following the completion of a dam in Mirpur, in Pakistani-controlled Kashmir in 1967, a large number of local people, displaced from their homes, migrated to Bradford in England. They included some who had married cousins, and among the offspring of these cousin marriages were a few people born with abnormally small, though otherwise normal brains – so-called microcephalics. The family pedigrees allowed scientists to pin down the cause as four different mutations in different families, but all affecting the same gene: the ASPM gene on chromosome 1.

On further investigation, a team of scientists led by Geoffrey Woods in Leeds discovered something rather extraordinary about the gene. It is a large gene, 10,434 letters long and split into 28 paragraphs (called exons). The 16th to 25th paragraphs contain a characteristic motif repeated over and over again. The phrase, usually 75 letters long, begins with the code for the amino acids isoleucine and glutamine, the significance of which I will reveal in a moment. In the human version of the gene, there are 74 such motifs, in the mouse 61, in the fruit fly 24 and in the nematode worm just 2 repetitions. Remarkably, these numbers seem to be in proportion to the number of neurons in the adult brain of the animal.

(#litres_trial_promo) Even more remarkably, the standard abbreviation for isoleucine is ‘I’ and the abbreviation for glutamine is ‘Q’. Therefore, the number of IQ repeats may determine the relative IQ of the species, which, according to Woods, ‘is a proof of God’s existence since only someone with a sense of humour could have arranged for the correlation’.

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ASPM seems to work by regulating the number of times neuronal stem cells divide inside the vesicles of the young brain about two weeks after conception. This in turn decides how many neurons the adult brain will have. To have stumbled on a gene with the power to decide brain size in such a simple manner seems almost too good to be true, and complications will undoubtedly crowd in upon this simple story as more comes to be known. But the ASPM gene vindicates that young man who was so startled by the Fuegians: evolution is a difference of degree, not kind.

The startling new truth that has emerged from the human genome – that animals evolve by adjusting the thermostats on the fronts of genes, enabling them to grow different parts of their bodies for longer – has profound implications for the nature–nurture debate. Imagine the possibilities in a system of this kind. You can turn up the expression of one gene, the product of which turns up the expression of another, which suppresses the expression of a third, and so on. And right in the middle of this little network, you can throw in the effects of experience. Something external – education, food, a fight, or requited love, say – can influence one of the thermostats. Suddenly nurture can start to express itself through nature.