Genome

— The Autobiography of a Species in 23 Chapters

Chromosome	Theme	Gene	Note
1	Origin of life	5S rRNA	One of the first molecules to catalyze steps of its own replication Origin of life Continuity
2	Human evolution	Chromosome 2	Two ape chromosomes were fused Species vs Other Species
3	Heredity & the code	HGD	Alkaptonuria (black urine) caused by one copying error Central Dogma
4	Genetic fatalism	HTT	Single-factor explanation for Huntington’s Disease (CAG repeat >35) Neurodegenerative
5	Complex & interact	Many asthma-related genes	Chain of reaction, no single-factor explanation Immune Disorders
6	GxE interplay	IGF2R ‘for IQ’	Difficulty of separating nature & nurture Heritability
7	Language instinct	SLI (hearing vs speech)	Cultural influence vs innate (linguistic/social) instincts Language
X/Y	Sex	SRY on Y (triggers male)	Conflict between the chromosomes & sexes Homosexuality
8	Self-interest	DNA parasites	Noncoding sequences exploit cell machinery to propagate Parasites
9	Dynamic Equilibrium	ABO blood group	Infectious disease resistance ↔︎ genetic variability Fluctuating Selection Opposites Attract
10	Stress	CYP17 (converts cholesterol)	No single factor (world/brain/body/gene/selection) is in charge Decentralized Systems Status & Heart Disease
11	Personality	DRD4 (dopamine, novelty-seeking)	Neurotransmitter ↔︎ behavior, mutual shaping Categorical Thinking
12	Embryo development	Hox genes	Incredible conservatism of embryological genetics Evolutionary History
13	Pre-History	Alcohol/lactose digestion	Gene-culture coevolution Human Evolution
14	Aging	Telomerase	Maintains chromosome ends; associated with aging and cancer Aging
15	Imprinting	UBE3A	M/F imprinted genes for different things Sexual Conflict
16	Learning	CREB	Intelligence requires forgetting; flexibility is innate Neuroplasticity
17	Cancer	TP53	Treatment works by inducing damage that trigger suicide Cancer
18	GMO	DCC (colon cancer)	Genetic manipulation is norm, while people’s ideology resists GMO
19	Genetic testing	APOE (Alzheimer’s)	Ethics surrounding testing, insurance, privacy
20	Prions	PRP	Non-DNA self-replication, misfolding leads to neurodegenerative disease
21	Eugenics	3 copies (Down syndrome)	Individual choice vs state coercion Eugenics
22	Free Will	COMT (again, with dopamine link)	Breaks down dopamine; linked to decision-making and free will Determinism

Select Quotes

Preface

the first time in the story of life on earth that a species has read its own recipe.

But most geneticists are too busy mining nuggets of intellectual gold from the laboratory to give up their time to explaining their science to the public. So it falls to commentators like me to try to translate the arcane stories of genes into something more like entertainment than education.

I think knowledge is a blessing, not a curse.

Introduction

(Incidentally, you will not find the tired word ‘blueprint’ in this book, after this paragraph, for three reasons. First, only architects and engineers use blueprints and even they are giving them up in the computer age, whereas we all use books. Second, blueprints are very bad analogies for genes. Blueprints are two-dimensional maps, not one-dimensional digital codes. Third, blueprints are too literal for genetics, because each part of a blueprint makes an equivalent part of the machine or building; each sentence of a recipe book does not make a different mouthful of cake.)

All rules have exceptions (including this one).

Chromosome 1 - Life

The word eventually blossomed and became sufficiendy ingenious to build a porridgy contraption called a human brain that could discover and be aware of the word itself. My porridgy contraption boggles every time I think this thought. In four thousand million years of earth history, I am lucky enough to be alive today. In five million species, I was fortunate enough to be born a conscious human being. Among six thousand million people on the planet, I was privileged enough to be born in the country where the word was discovered. In all of the earth’s history, biology and geography, I was born just five years after the moment when, and just two hundred miles from the place where, two members of my own species discovered the structure of DNA and hence uncovered the greatest, simplest and most surprising secret in the universe.

The secret of life has nothing to do with quantum states. The answer will not come from physics.

Life, to a rough approximation, consists of the chemistry of three atoms, hydrogen, carbon and oxygen, which between them make up ninety-eight per cent of all atoms in living beings. But it is the emergent properties of life—such as heritability—not the constituent parts that are interesting. Avery cannot conceive what it is about DNA that enables it to hold the secret of heritable properties. The answer will not come from chemistry.

Anything that can use the resources of the world to get copies of itself made is alive; the most likely form for such a thing to take is a digital message-a number, a script or a word.

The word was not DNA. That came afterwards, when life was already established, and when it had divided the labour between two separate activities: chemical work and information storage, metabolism and replication.

This short paragraph is perhaps as close as we can get to an echo of the original word. This ‘paragraph’ is a small gene, probably the single most active gene in the human body. Its 120 letters are constantly being copied into a short filament of RNA. The copy is known as 5S RNA.

Protein represents chemistry, living, breathing, metabolism and behaviour-what biologists call the phenotype. DNA represents information, replication, breeding, sex-what biologists call the genotype. Neither can exist without the other.

RNA is a chemical substance that links the two worlds of DNA and protein.

By repeatedly selecting random RNA molecules in the test tube based on their ability to catalyse reactions, it is possible to ‘evolve’ catalytic RNAs from scratch-almost to rerun the origin of life. And one of the most surprising results is that these synthetic RNAs often end up with a stretch of RNA text that reads remarkably like part of the text of a ribosomal RNA gene such as the 5S gene on chromosome 1.

Carl Woese points out, the organism was not yet an enduring entity. It was a temporary team of genes. The genes that ended up in all of us may therefore have come from lots of different ‘species’ of creature and it is futile to try to sort them into different lineages. We are descended not from one ancestral Luca, but from the whole community of genetic organisms.

The very first modern organisms were not like bacteria; they did not live in hot springs or deep-sea volcanic vents. They were much more like protozoa: with genomes fragmented into several linear chromosomes rather than one circular one, and ‘polyploid’-that is, with several spare copies of every gene to help with the correction of spelling errors. Moreover, they would have liked cool climates. As Patrick Forterre has long argued, it now looks as if bacteria came later, highly specialised and simplified descendants of the Lucas, long after the invention of the DNA-protein world. Their trick was to drop much of the equipment of the RNA world specifically to enable them to live in hot places.

Bacteria dropped the old RNAs when they invaded hot places like hot springs or subterranean rocks where temperatures can reach 170 ° C-to minimise mistakes caused by heat, it paid to simplify the machinery. Having dropped the RNAs, bacteria found their new streamlined cellular machinery made them good at competing in niches where speed of reproduction was an advantage—such as parasitic and scavenging niches.

Unlike the massively competitive world of bacteria, we—that is all animals, plants and fungi—never came under such fierce competition to be quick and simple. We put a premium instead on being complicated, in having as many genes as possible, rather than a streamlined machine for using them. 11

if it is alive, it will use the same dictionary and know the same code. All life is one. The genetic code, bar a few tiny local aberrations, mostly for unexplained reasons in the ciliate protozoa, is the same in every creature. We all use exactly the same language.

The genes in the cells of your little finger are the direct descendants of the first replicator molecules; through an unbroken chain of tens of billions of copyings, they come to us today still bearing a digital message that has traces of those earliest struggles of life.

Chromosome 2 - Species

Sometimes the obvious can stare you in the face. Until 1955, it was agreed that human beings had twenty-four pairs of chromosomes. It was just one of those facts that everybody knew was right. They knew it was right because in 1921 a Texan named Theophilus Painter had sliced thin sections off the testicles of two black men and one white man castrated for insanity and ‘self-abuse’, fixed the slices in chemicals and examined them under the microscope. Painter tried to count the tangled mass of unpaired chromosomes he could see in the spermatocytes of the unfortunate men, and arrived at the figure of twenty-four. ‘I feel confident that this is correct,’ he said. Others later repeated his experiment in other ways. All agreed the number was twenty-four. For thirty years, nobody disputed this ‘fact’. One group of scientists abandoned their experiments on human liver cells because they could only find twenty-three pairs of chromosomes in each cell. Another researcher invented a method of separating the chromosomes, but still he thought he saw twenty-four pairs. It was not until 1955, when an Indonesian named Joe-Hin Tjio travelled from Spain to Sweden to work with Albert Levan, that the truth dawned. Tjio and Levan, using better techniques, plainly saw twenty-three pairs. They even went back and counted twenty-three pairs in photographs in books where the caption stated that there were twenty-four pairs. There are none so blind as do not wish to see.

Single-celled creatures still dominated, but these great unwieldy forms of giant survival machines were carving out a niche for themselves.

In thirteen chromosomes no visible differences of any kind exist.

There is nothing about chimpanzees that looks ninety-eight per cent like me. Oh really? Compared with what? If you took two Plasticene models of a mouse and tried to turn one into a chimpanzee, the other into a human being, most of the changes you would make would be the same.

our need for water, our tendency to sweat, our peculiar adaptation to a diet rich in the oils and fats of fish and other factors (even our love of beaches and water sports) hint at something of an aquatic preference. We are really rather good at swimming. Were we at first to be found in riverine forests or at the edges of lakes?

Big brains, meat eating, slow development, the ‘neotenised’ retention into adulthood of childhood characters (bare skin, small jaws and a domed cranium)—all these went together. Without the meat, the protein-hungry brain was an expensive luxury. Without the neotenised skull, there was no cranial space for the brain. Without the slow development, there was no time for learning to maximise the advantages of big brains.

Females were getting big relative to males.

What it means is that the mating system of the species was changing.

And so on, round and round the theories we go in a spiral of comforting justification, proving how we came to be as we are. We have built a scientific house of cards on the flimsiest foundations of evidence, but we have reason to believe that it will one day be testable.

The genes are the negative; the womb is the developer. Just as a photograph needs to be immersed in a bath of developer before the picture will appear, so the recipe for a chimpanzee, written in digital form in the genes of its egg, needs the correct milieu to become an adult—the nutrients, the fluids, the food and the care—but it already has the information to make a chimpanzee. The same is not quite true of behaviour.

Chromosome 3 - History

Every single protein in the body is made from a gene by a translation of the genetic code.

There is no mingling of fluids, no blending of blood; there is instead a temporary joining together of lots of little marbles.

Crick also had an idea that was so good it has been called the greatest wrong theory in history.

it excludes all words that can be misread if you start in the wrong place.

Chromosome 4 - Fate

Like Alzheimer’s disease and BSE, it is this accumulation of a sticky lump of protein within the cell that causes the death of the cell, perhaps because it induces the cell to commit suicide.

Anticipation means that the longer the repetition, the longer it is likely to grow when copied for the next generation. We know that these repeats form little loopings of DNA called hairpins. The DNA likes to stick to itself, forming a structure like a hairpin, with the Cs and Gs of the C* G ‘words’ sticking together across the pin. When the hairpins unfold, the copying mechanism can slip and more copies of the word insert themselves.

But above all the tale drives home the uselessness of diagnosing without curing.

Alice chronicled the discussions in a diary that later became a soul-searching book called Mappingfate,

Chromosome 5 - Environment

Mendelian genetics is no more relevant to understanding heredity in the real world than Euclidean geometry is to understanding the shape of an oak tree.

The theory goes that dirt contains bacteria, especially mycobacteria, which stimulate one part of the immune system, whereas routine vaccination stimulates a different part of the immune system. Since these two parts of the immune system (the Th1 cells and the Th2 cells respectively) normally inhibit each other, the modern, sanitised, disinfected and vaccinated child is bequeathed a hyperactive Th2 system, and the Th2 system is specially designed to flush parasites from the wall of the gut with a massive release of histamine. Hence hay fever, asthma and eczema. Our immune systems are set up in such a way that they ‘expect’ to be educated by soil mycobacteria early in childhood; when they are not, the result is an unbalanced system prone to allergy.

The trouble seems to be that there are so many ways of altering the sensitivity of the body to asthma triggers, all along the chain of reactions that leads to the symptoms, that all sorts of genes can be ‘asthma genes’, yet no single one can explain more than a handful of cases.

Chromosome 6 - Intelligence

Mother Nature has plainly not entrusted the determination of our intellectual capacities to the blind fate of a gene or genes; she gave us parents, learning, language, culture and education to program ourselves with.

Science is supposed to advance by erecting hypotheses and testing them by seeking to falsify them. But it does not. Just as the genetic determinists of the 1920s looked always for confirmation of their ideas and never for falsification, so the environmental determinists of the 1960s looked always for supporting evidence and averted their eyes from contrary evidence, when they should have been actively seeking it. Paradoxically, this is a corner of science where the ‘expert’ has usually been more wrong than the layman. Ordinary people have always known that education matters, but equally they have always believed in some innate ability. It is the experts who have taken extreme and absurd positions at either end of the spectrum.

Howard Gardner has argued forcefully for a theory of multiple intelligence that recognises each talent as a separate ability. Robert Sternberg has suggested instead that there are essentially three separate kinds of intelligence-analytic, creative and practical.

the speed with which an infant habituates to a new stimulus correlates quite strongly with later IQ, as if it were almost possible to predict the adult IQ of a baby when only a few months old, assuming certain things about its education. IQ scores correlate strongly with school test results. High-I Q children seem to absorb more of the kind of things that are taught in school.

No study of the causes of intelligence has failed to find a substantial heritability.

Amy was placed in the family of a poor, overweight, insecure and unloving mother; sure enough, Amy grew up neurotic and introverted, just as Freudian theory would predict. But so—down to the last details—did Beth, whose adoptive mother was rich, relaxed, loving and cheerful. The differences between Amy’s and Beth’s personalities were almost undetectable when they rediscovered each other twenty years later.

But the astonishing result is the correlation between the scores of adopted children reared together: zero. Being in the same family has no discernible effect on IQ at all.

The influence upon our intelligence of events that happened in the womb is three times as great as anything our parents did to us after our birth.

Not only does your IQ change with age, but so does its heritability. As you grow up and accumulate experiences, the influence of your genes increases.

As you grow up, you gradually express your own innate intelligence and leave behind the influences stamped on you by others. You select the environments that suit your innate tendencies, rather than adjusting your innate tendencies to the environments you find yourself in. This proves two vital things: that genetic influences are not frozen at conception and that environmental influences are not inexorably cumulative.

If you accept the criticism that these studies mildly exaggerate heritability because they are of families from a single social class, then it follows that heritability will be greater in an egalitarian society than an unequal one. Indeed, the definition of the perfect meritocracy, ironically, is a society in which people’s achievements depend on their genes because their environments are equal. We are fast approaching such a state with respect to height:

The discovery of genetic mutations behind conditions like dyslexia has not led teachers to abandon such conditions as incurable—quite the reverse; it has encouraged them to single out dyslexic children for special teaching. Indeed, the most famous pioneer of intelligence testing, the Frenchman Alfred Binet, argued fervently that its purpose was not to reward gifted children but to give special attention to less gifted ones.

The fact that people with high IQs have more symmetrical bodies suggests that they were subject to fewer developmental stresses in the womb or in childhood. Or rather, that they were more resistant to such stresses. And the resistance may well be heritable. So the heritability of IQ might not be caused by direct ‘genes for intelligence’ at all, but by indirect genes for resistance to toxins or infections—genes in other words that work by interacting with the environment. You inherit not your IQ but your ability to develop a high IQ under certain environmental circumstances. How does one parcel that one into nature and nurture? It is frankly impossible.

The environment that a child experiences is as much a consequence of the child’s genes as it is of external factors: the child seeks out and creates his or her own environment. If she is of a mechanical bent, she practises mechanical skills; if a bookworm, she seeks out books. The genes may create an appetite, not an aptitude. After all, the high heritability of short-sightedness is accounted for not just by the heritability of eye shape, but by the heritability of literate habits. The heritability of intelligence may therefore be about the genetics of nurture, just as much as the genetics of nature. What a richly satisfying end to the century of argument inaugurated by Galton.

Chromosome 7 - Instinct

No matter that the social sciences set about reinventing much more alarming forms of determinism to take the place of the genetic form: the parental determinism of Freud; the socio-economic determinism of Marx; die political determinism of Lenin; the peer-pressure cultural determinism of Franz Boas and Margaret Mead; the stimulus—response determinism of John Watson and B. F. Skinner; the linguistic determinism of Edward Sapir and Benjamin Whorf. In one of the great diversions of all time, for nearly a century social scientists managed to persuade thinkers of many kinds that biological causality was determinism while environmental causality preserved free will; and that animals had instincts, but human beings did not. Between 1950 and 1990 the edifice of environmental determinism came tumbling down. Freudian theory fell the moment lithium first cured a manic depressive, where twenty years of psychoanalysis had failed. (In 1995a woman sued her former therapist on the grounds that three weeks on Prozac had achieved more than three years of therapy.) Marxism fell when the Berlin wall was built, though it took until the wall came down before some people realised that subservience to an all-powerful state could not be made enjoyable however much propaganda accompanied it. Cultural determinism fell when Margaret Mead’s conclusions (that adolescent behaviour was infinitely malleable by culture) were discovered by Derek Freeman to be based on a combination of wishful prejudice, poor data collection and adolescent prank-playing by her informants. Behaviourism fell with a famous 1950s experiment in Wisconsin in which orphan baby monkeys became emotionally attached to cloth models of their mothers even when fed only from wire models, thus refusing to obey the theory that we mammals can be conditioned to prefer the feel of anything that gives us food—a preference for soft mothers is probably innate. 1 In linguistics, the first crack in the edifice was a book by Noam Chomsky, Syntactic structures, which argued that human language, the most blatantly cultural of all our behaviours, owes as much to instinct as it does to culture. Chomsky resurrected an old view of language, which had been described by Darwin as an ‘instinctive tendency to acquire an art’. The early psychologist William James, brother of the novelist Henry, was a fervent protagonist of the view that human behaviour showed evidence of more separate instincts than animals, not fewer.

Pinker (who has been called the first linguist capable of writing readable prose) persuasively gathered the strands of evidence for the innateness of language skills. There is first the universality of language. All human people speak languages of comparable grammatical complexity, even those isolated in the highlands of New Guinea since the Stone Age. All people are as consistent and careful in following implicit grammatical rules,

Second, if these rules were learnt by imitation like the vocabulary, then why would four-year-olds who have been happily using the word ‘went’ for a year or so, suddenly start saying ‘goed’?

But the most startling evidence for a language instinct comes from a series of natural experiments in which children imposed grammatical rules upon languages that lacked them.

A sensitive period during which something can be learnt, and outside which it cannot, is a feature of many animals’ instincts.

Yet even bad ideas take a lot of killing, and the notion that language is a form of culture that can shape the brain, rather than vice versa, has been an inordinate time a-dying. Even though the canonical case histories, like the lack of a concept of time in the Hopi language and hence in Hopi thought, have been exposed as simple frauds, the notion that language is a cause rather than consequence of the human brain’s wiring survives in many social sciences. It would be absurd to argue that only Germans can understand the concept of taking pleasure at another’s misfortune; and that the rest of us, not having a word for Schadenfreude, find the concept entirely foreign.

The Broca-homologue is used for controlling the muscles of the monkey’s face, larynx, tongue and mouth. The Wernicke-homologue is used for recognising sound sequences and the calls of other monkeys.

The main goal of twentieth-century social science has been to trace the ways in which our behaviour is influenced by the social environment; instead, we could turn the problem on its head and trace the ways in which the social environment is the product of our innate social instincts. Thus the fact that all people smile at happiness and frown when worried, or that men from all cultures find youthful features sexually attractive in women, may be expressions of instinct, not culture.

Chromosome X And Y - Conflict

Thus, a pair of middle-sized chromosomes, once home to all sorts of ‘normal’ genes, was hijacked by the process of sex determination and became the sex chromosomes,

Sexual selection is thus an expression of sexual antagonism between genes for seduction and genes for resistance. 9 Rice and Holland come to the disturbing conclusion that the more social and communicative a species is, the more likely it is to suffer from sexually antagonistic genes, because communication between the sexes provides the medium in which sexually antagonistic genes thrive.

among fifty-four gay men who were fraternal twins, there were twelve whose twin was also gay; and among fifty-six gay men who were identical twins, there were twenty-nine whose twin was also gay.

Homosexuality seemed to run in the female line. If a man was gay, the most likely other member of the previous generation to be gay was not his father but his mother’s brother. That immediately suggested to Hamer that the gene might be on the X chromosome, the only set of nuclear genes a man inherits exclusively from his mother. By comparing a set of genetic markers between gay men and straight men in the families in his sample, he quickly found a candidate region in Xq28, the tip of the long arm of the chromosome. Gay men shared the same version of this marker seventy-five per cent of the time; straight men shared a different version of the marker seventy-five per cent of the time. Statistically, that ruled out coincidence with ninety-nine per cent confidence. Subsequent results reinforced the effect, and ruled out any connection between the same region and lesbian orientation.

Trivers argued that, because an X chromosome spends twice as much time in women as it does in men, a sexually antagonistic gene that benefited female fertility could survive even if it had twice as large a deleterious effect on male fertility.

A man with one or more elder brothers is more likely to be gay than a man with no siblings, only younger siblings, or with one or more elder sisters. The birth order effect is so strong that each additional elder brother increases the probability of homosexuality by roughly one-third

(The old Freudian idea that homosexuality was caused by a protective mother and a distant father almost certainly confused cause and effect: the boy’s developing effeminate interests repel the father and the mother becomes overprotective in compensation.)

An important clue lies in the fact that there is no such birth-order effect for lesbians, who are randomly distributed within their families.

The reason these gene products are called antigens is because they are known to provoke a reaction from the immune system of the mother. As a result, the immune reaction is likely to be stronger in successive male pregnancies (female babies do not produce H-Y antigens, so do not raise the immune reaction). Ray Blanchard, one of those who studies the birth-order effect, argues that the H-Y antigens’ job is to switch on other genes in certain tissues, in particular in the brain-and indeed there is good evidence that this is true in mice. If so, the effect of a strong immune reaction against these proteins from the mother would be partly to prevent the masculinisation of the brain, but not that of the genitals.

Chromosome 8 - Self-Interest

Nobody suspected this. Nobody predicted that when we read the code for life we would find it so riddled with barely controlled examples of selfish exploitation. Yet we should have predicted it, because every other level of life is parasitised.

Meet the ‘hypervariable minisatellite’. This neat little sequence is found on all the chromosomes; it crops up at more than one thousand locations in the genome. In every case the sequence consists of a single ‘phrase’, usually about twenty ‘letters’ long, repeated over and over again many times. The ‘word’ can vary according to the location and the individual, but it usually contains the same central ‘letters’: GGGCAGGAXG (where X can be any ‘letter’). The significance of this sequence is that it is very similar to one that is used by bacteria to initiate the swapping of genes with other bacteria of the same species, and it seems to be involved in the encouragement of gene swapping between chromosomes in us as well. It is as if each sequence is a sentence with the words ‘SWAP ME ABOUT’ in the middle.

at each of one thousand locations, there might be fifty or five repeats of the same phrase. Following instructions, the cell starts swapping the phrases with the equivalent series on the other copy of the same chromosome. But in doing so it makes fairly frequent mistakes, adding or subtracting to the number of repeats. In this way each series of repeats gradually changes length, fast enough so that it is different in every individual, but slowly enough so that people mostly have the same repeat lengths as their parents.

Chromosome 9 - Disease

‘Neutralists’ and ‘selectionists’ for a while grew quite exercised about their respective beliefs, and when the dust settled Kimura was left with a respectable following. Much variation does indeed seem to be neutral in its effects. In particular, the closer scientists look at how proteins change, the more they conclude that most changes do not affect the ‘active site’ where the protein does its chemical tricks.

AB children, who will be resistant. In other words, the advantage will always lie with the rare version of the gene, so neither version can become extinct because if it becomes rare, it comes back into fashion. This is known, in the trade, as frequency-dependent selection, and it seems to be one of the commonest reasons that we are all so genetically diverse.

Wherever you look, the reasons behind genetic variability seem to have something to do with infectious disease.

men and women most prefer (or least dislike) the body odour of members of the opposite sex who are most different from them genetically. Wederkind and Füri looked at MHC genes on chromosome 6, which are the genes involved in the definition of self and the recognition of parasitic intruders by the immune system.

Only women on the contraceptive pill failed to show a clear preference for different MHC genotypes in male-impregnated T-shirt armpits. But then the pill is known to affect the sense of smell.

Variation is an inherent and integral part of the human - or indeed any — genome. Nor does it make sense to take a snapshot at this particular moment in 1999 and believe that the resulting picture somehow represents a stable and permanent image. Genomes change. Different versions of genes rise and fall in popularity driven often by the rise and fall of diseases. There is a regrettable human tendency to exaggerate stability, to believe in equilibrium. In fact the genome is a dynamic, changing scene.

Chromosome 10 - Stress

From cholesterol at least five crucial hormones are made, each with a very different task: progesterone, aldosterone, cortisol, testosterone and oestradiol.

The truth is that nobody is in charge. It is the hardest thing for human beings to get used to, but the world is full of intricate, cleverly designed and interconnected systems that do not have control centres.

The status of a person’s job was more able to predict their likelihood of a heart attack than obesity, smoking or high blood pressure. Somebody in a low-grade job, such as a janitor, was nearly four times as likely to have a heart attack as a permanent secretary at the top of the heap. Indeed, even if the permanent secretary was fat, hypertensive or a smoker, he was still less likely to suffer a heart attack at a given age than a thin, non-smoking, low-blood-pressure janitor.

high cholesterol is a risk factor, but only in those with genetic predispositions to high cholesterol, and even in these people the beneficial effects of eating less fat are small

Testosterone levels correlate with aggression, but is that because the hormone causes aggression, or because release of the hormone is caused by aggression? In our materialism, we find the first alternative far easier to believe. But in fact, as studies of baboons demonstrate, the second is closer to the truth. The psychological precedes the physical. The mind drives the body, which drives the genome.

Testosterone is just as good at suppressing the immune system as Cortisol.

Chromosome 11 - Personality

The tension between universal characteristics of the human race and particular features of individuals is what the genome is all about. Somehow the genome is responsible for both the things we share with other people and the things we experience uniquely in ourselves. We all experience stress; we all experience the elevated Cortisol that goes with it; we all suffer from the immune-suppressive effects thereof. We all have genes switched on and off by external events in this way. But each of us is unique, too.

Curiously, understanding that it is innate seems to help to cure it. One trio of therapists, reading about the new results emerging from genetics, switched from trying to treat their clients’ shyness to trying to make them content with whatever their innate predispositions were. They found that it worked. The clients felt relieved to be told that their personality was a real, innate part of them and not just a bad habit they had got into. ‘Paradoxically, depathologising people’s fundamental inclinations and giving group members permission to be the way they are seemed to constitute the best insurance that their self-esteem and interpersonal effectiveness would improve.’ In other words, telling them they were naturally shy helped them overcome that shyness.

Most job advertisements require candidates with ‘good interpersonal skills’-something that is probably partly innate. Yet it would plainly be a repellent world in which we were picked for jobs on the basis of our eye colour. Why? Physical discrimination is so much less acceptable than psychological. Yet psychological discrimination is just chemical discrimination. It is just as material as any other discrimination.

You eat cookies on winter evenings to cheer yourself up by raising your brain serotonin.

It has been known for twenty years that impulsive, antisocial and depressed people—including prisoners, violent offenders and failed suicides-have generally lower cholesterol levels than the population at large.

Monkeys fed on low-cholesterol diets become more aggressive and bad-tempered (even if they are not losing weight), and the cause seems to be a drop in serotonin levels.

The higher your self-esteem and social rank relative to those around you, the higher your serotonin level is. Experiments with monkeys reveals that it is the social behaviour that comes first. Serotonin is richly present in dominant monkeys and much more dilute in the brains of subordinates. Cause or effect? Almost everybody assumed the chemical was at least partly the cause: it just stands to reason that the dominant behaviour results from the chemical, not vice versa. It turns out to be the reverse: serotonin levels respond to the monkey’s perception of its own position in the hierarchy, not vice versa.

There is little doubt that the monkey’s mood is set by its high serotonin levels. If you artificially reverse the pecking order so that the monkey is now a subordinate, not only does its serotonin drop, but its behaviour changes, too.

Social influences upon behaviour work through the switching on and off of genes.

Chromosome 12 - Self-Assembly

But, astonishingly, each of these has the opposite effect in mice that its equivalent has in flies: BMP4 is ventralising, and chordin is dorsalising. This means that arthropods and vertebrates are upside-down versions of each other.

From the basic asymmetry of chemicals injected into the egg all else follows. Genes turn each other on, giving the embryo a head and a rear. Other genes then get turned on in sequence from bow to stern giving each compartment an identity. Other genes then polarise the compartments into front and rear halves. Other genes then interpret all this information and make ever more complicated appendages and organs. It is a rather basic, chemical—mechanical, step-by-step process that would have appealed more to Aristotle than Socrates. From simple asymmetry can grow intricate pattern.

Chromosome 13 - Pre-History

there is undoubtedly a family connection between these three linguistic families: Indo-European, Altaic and Uralic. They derive from a single language spoken throughout Eurasia maybe 15,000 years ago by hunter-gathering people who had, to judge by the words in common in their descendant tongues, not yet domesticated any animals, except possibly the wolf (dog).

Cavalli-Sforza uncovered five different contour maps of gene frequencies within Europe. One was a steady gradient from south-east to north-west, which may reflect the original spread of neolithic farmers into Europe from the Middle East: it echoes almost exactly the archaeological data on the spread of agriculture into Europe beginning about 9,500 years ago. This accounts for twenty-eight per cent of the genetic variation in his sample. The second contour map was a steep hill to the north-east, reflecting the genes of the Uralic speakers, and accounting for twenty-two per cent of genetic variation. The third, half as strong, was a concentration of genetic frequencies radiating out from the Ukrainian steppes, reflecting the expansion of pastoral nomads from the steppes of the Volga—Don region in about 3,000 BC. The fourth, weaker still, peaks in Greece, southern Italy and western Turkey, and probably shows the expansion of Greek peoples in the first and second millennium BC. Most intriguing of all, the fifth is a steep little peak of unusual genes coinciding almost exactly with the greater (original) Basque country in northern Spain and southern France. The suggestion that Basques are survivors of the pre-neolithic peoples of Europe begins to seem plausible.

fermented liquids are relatively clean and sterile.

But foraging, nomadic people not only could not grow the crops to ferment; they did not need the sterile liquid. They lived at low densities and natural water supplies were safe enough. So it is little wonder that the natives of Australia and North America were and are especially vulnerable to alcoholism and that many cannot now ‘hold their drink’.

Chromosome 14 - Immortality

they suffer more damage and need more repair. Repair involves cell copying, which uses up the ends of telomeres.

Natural selection carefully weeds out all genes that might allow damage to the body before or during reproduction. It does so by killing or lowering the reproductive success of all individuals that express such genes in youth. All the rest reproduce. But natural selection cannot weed out genes that damage the body in post-reproductive old age, because there is no reproduction of the successful in old age. Take Dunnet’s fulmar, for instance. The reason it lives far longer than a mouse is because in the life of the fulmar there is no equivalent of the cat and the owl: no natural predators. A mouse is unlikely to make it past three years of age, so genes that damage four-year-old mouse bodies are under virtually no selection to die out. Fulmars are very likely to be around to breed at twenty, so genes that damage twenty-year-old fulmar bodies are still being ruthlessly weeded out.

The most famous of them, the HeLa cell line, originated in the cervical tumour of a patient named Henrietta Lacks, a black woman who died in Baltimore in 1951. Her cancer cells are so wildly proliferative when cultured in the laboratory that they often invade other laboratory samples and take over the Petri dish.

Chromosome 15 - Sex

In the two-mothers case, the embryo itself was properly organised, but it could not make a placenta with which to sustain itself. In the two-fathers case, the embryo grew a large and healthy placenta and most of the membranes that surround the foetus. But inside, where the embryo should be, there was a disorganised blob of cells with no discernible head. 3 These results led to an extraordinary conclusion. Paternal genes, inherited from the father, are responsible for making the placenta; maternal genes, inherited from the mother, are responsible for making the greater part of the embryo, especially its head and brain.

However, in most cases, before that stage is reached, the body has a way of dealing with this triplet problem. It ‘deletes’ one chromosome altogether, leaving two, as intended. The difficulty is that it does so at random.

Chimeras are fused bodies of two genetically distinct individuals. They occur naturally—you may have met some or even be one yourself, though you will not know it without a detailed study of the chromosomes. Two genetically distinct embryos happen to fuse together and grow as if they were one.

if we are to believe that the placenta is an organ that the father’s genes do not trust the mother’s genes to make, then the cerebral cortex is an organ that the mother’s genes do not trust the father’s genes to make.

paternal X chromosomes are found only in females. Therefore, behaviour that is characteristically required of females should be expressed only from paternal chromosomes. If they were also expressed from maternal X chromosomes, they might appear in males, or they might be overexpressed in females. It therefore makes sense that maternal behaviour should be paternally imprinted.

The twenty-five girls missing the maternal chromosome were significantly better adjusted, with ‘superior verbal and higher-order executive function skills, which mediate social interactions’ than the fifty-five girls missing the paternal chromosome.

Chromosome 16 - Memory

teleological

Just as we underestimate the degree to which human brains rely upon instincts, so we have generally underestimated the degree to which other animals are capable of learning.

Eric Kandel, had a motive other than bothering slugs. He wanted to understand the basic mechanism by which learning occurred. What is learning?

And he soon developed a strain of fly that learnt so fast that it got the message after a single lesson whereas other flies needed ten lessons to learn to fear a smell that was reliably followed by an electric shock. Tully described these flies as having photographic memories; far from being clever, they over-generalised horribly, like a person who reads too much into the fact that the sun was shining when he had a bicycle accident and refuses thereafter to bicycle on sunny days. (Great human mnemonists, such as the famous Russian Sherashevsky, experience exactly this problem. They cram their heads with so much trivia that they cannot see the wood for the trees. Intelligence requires a judicious mixture of remembering and forgetting.

They had carefully arranged the two so that the volado gene only worked when the heat-shock gene was on. At cool temperatures, the flies could not learn. Three hours after a heat shock, however, they suddenly became good learners. A few hours after that, as the heat shock faded into the past, they again lost the ability to learn.

It seems probable that the transmission of memory from the medial temporal lobe to the neo-cortex happens at night during sleep:

In every way, it seems, conscious, willed life has advantages over automatic, gene-determined life. Yet, as James Mark Baldwin realised and modern Artificial-Intelligence nerds appreciate, the dichotomy is a false one. The brain is created by genes. It is only as good as its innate design. The very fact that it is a machine designed to be modified by experience is written in the genes. The mystery of how is one of the great challenges of modern biology. But that the human brain is the finest monument to the capacities of genes there is no doubt. It is the mark of a great leader that he knows when to delegate. The genome knew when to delegate.

Chromosome 17 - Death

close genetic relatives discovered they could reproduce more effectively if they did so vicariously, delegating the task to germ cells in the cells’ case, or to a queen in the case of bees.

each cell is descended from a long line of reproducing cells;

Tumours, like populations of rabbits, are prone to rapid and strong evolutionary pressures. Just as the offspring of the fastest-breeding rabbits soon dominate a rabbit warren, so the fastest dividing cells in each tumour come to dominate at the expense of more stable cells. Just as mutant rabbits that burrow underground to escape buzzards soon come to dominate at the expense of rabbits that sit in the open, so mutations in tumour-suppressor genes that enable cells to escape suppression soon come to dominate at the expense of other mutations. The environment of the tumour is literally selecting for mutations in such genes as the external environment selects rabbits.

The suicide of cells in this way is known as apoptosis, from the Greek for the fall of autumn leaves. It is the most important of the body’s weapons against cancer, the last line of defence. Indeed, so important is apoptosis that it is gradually becoming clear that almost all therapeutic cancer treatment works only because it induces apoptosis by alerting p53 and its colleagues. It used to be thought that radiation therapy and chemotherapy worked because they preferentially killed dividing cells by damaging their DNA as it was being copied.

These treatments do indeed cause a little DNA damage, he says, but not enough to kill the cells. Instead, the DNA damage is just sufficient to alert p53, which tells the cells to commit suicide. So chemotherapy and radiation therapy are actually, like vaccination, treatments that work by helping the body to help itself.

the most intractable tumours—melanoma, lung, colorectal, bladder and prostate—are the ones in which TP53 is usually mutated already. Certain kinds of breast cancer resist treatment: the ones in which TP53 is broken.

Chromosome 18 - Cures

The discovery in 1970 that retroviruses could make DNA copies from RNA suddenly made ‘gene therapy’ seem, nonetheless, a feasible goal. A retrovirus contains a message written in RNA which reads, in essence: ‘Make a copy of me and stitch it into your chromosome.’ All a gene therapist need do is take a retrovirus, cut out a few of its genes (especially those that make it infectious after the first insertion), put in a human gene, and infect the patient with it. The virus goes to work inserting the gene into the cells of the body and, lo, you have a genetically modified person.

He injected retroviruses directly into brain tumours of twenty people. Injecting anything into the brain sounds horrifying enough, let alone a retrovirus. But wait till you hear what was in the retrovirus. Each one was equipped with a gene taken from a herpes virus. The tumour cells took up the retrovirus and expressed the herpes gene.

The opposition to genetically modified crops, motivated more by hatred of new technology than love of the environment, largely chooses to ignore the fact that tens of thousands of safety trials have been done with no nasty surprises; that gene swapping between different species, especially microbes, is now known to be far more common than was once believed, so there is nothing ‘unnatural’ about the principle; that before genetic modification, plant breeding consisted of deliberate and random irradiation of seeds with gamma rays to induce mutations; that the main effect of genetic modification will be to reduce dependence on chemical sprays by improving resistance to diseases and pests; and that fast increases in yields are good for the environment, because they take the pressure off the cultivation of wild land.

We have grown cautious. Or at least we have as voters. As consumers, we may well act differently. Cloning may well happen not because the majority approves, but because the minority acts. That, after all, was roughly what happened in the case of test-tube babies. Society never decided to allow them; it just got used to the idea that those who desperately wanted such babies were able to have them.

Chromosome 19 - Prevention

Asymetrix

When you eat a plate of bacon and eggs, you absorb much fat and with it cholesterol, the fat-soluble molecule from which so many hormones are made (see the chapter on chromosome 10). The liver digests this stuff and feeds it into the bloodstream for delivery to other tissues. Being insoluble in water, both triglyceride fats and cholesterol have to be carried through the blood by proteins called lipoproteins. At the beginning of the journey, laden with both cholesterol and fats, the delivery truck is called VLDL, for very-low-density lipoprotein. As it drops off some of its triglycerides, it becomes low-density lipoprotein, or LDL (‘ bad cholesterol’). Finally, after delivering its cholesterol, it becomes high-density lipoprotein, HDL (‘ good cholesterol’) and returns to the liver for a new consignment.

If genetic testing were to become routine for lots of genes, the entire concept of pooled risk, on which insurance is based, would be undermined. Once my exact fate is known, I would be quoted a premium that covered the exact cost of my life.

Chromosome 20 - Politics

The fuel on which science runs is ignorance. Science is like a hungry furnace that must be fed logs from the forests of ignorance that surround us. In the process, the clearing we call knowledge expands, but the more it expands, the longer its perimeter and the more ignorance comes into view.

A true scientist is bored by knowledge; it is the assault on ignorance that motivates him-the mysteries that previous discoveries have revealed.

Let us take stock of this strange tale as it appeared in about 1980. Sheep, mink, monkeys, mice and people could all acquire versions of the same disease by the injection of contaminated brain. The contamination survived almost all normal germ-killing procedures and remained wholly invisible to even the most powerful electron microscopes. Yet it was not contagious in everyday life, did not seem to pass through mother’s milk, raised no immune response, stayed latent for sometimes more than twenty or thirty years and could be caught from tiny doses—though the likelihood of contracting the disease depended strongly on the size of the dose received. What could it be?

Chromosome 21 - Eugenics

if we think them not enlightened enough to exercise that control with a wholesome discretion, the remedy is not to take it from them, but to inform their discretion.

he had identified the central flaw in the whole eugenic project. This was not that it was based on faulty science, nor that it was impractical, but that it was fundamentally oppressive and cruel, because it required the full power of the state to be asserted over the rights of the individual.

This brief history of eugenics leads me to one firm conclusion. What is wrong with eugenics is not the science, but the coercion. Eugenics is like any other programme that puts the social benefit before the individual’s rights. It is a humanitarian, not a scientific crime.

genetic screening is about giving private individuals private choices on private criteria. Eugenics was about nationalising that decision to make people breed not for themselves but for the state. It is a distinction frequently overlooked in the rush to define what ‘we’ must allow in the new genetic world. Who is ‘we’? We as individuals, or we as the collective interest of the state or the race?

Many modern accounts of the history of eugenics present it as an example of the dangers of letting science, genetics especially, out of control. It is much more an example of the danger of letting government out of control.

Chromosome 22 - Free Will

Hume’s fork: Either our actions are determined, in which case we are not responsible for them, or they are the result of random events, in which case we are not responsible for them. Oxford Dictionary of Philosophy

Because virtually no studies had controlled for heritability, there was no proof of causation at all in any study. Not even lip service was being paid to this omission: correlation was being routinely presented as causation. Yet in each case, from behaviour genetics studies, there was new, strong evidence against what Rich Harris calls ‘the nurture assumption’. Studies of the divorce rate of twins, for example, reveal that genetics accounts for about half of the variation in divorce rate, non-shared environmental factors for another half and shared home environment for nothing at all.

it is now clear that children probably have more non-genetic effect on parents than vice versa. As I argued in the chapter on chromosomes X and Y, it used to be conventional wisdom that distant fathers and over-protective mothers turn sons gay. It is now considered much more likely to be the reverse: perceiving that a son is not fully interested in masculine concerns, the father retreats; the mother compensates by being overprotective, Likewise, it is true that autistic children often have cold mothers; but this is an effect, not a cause: the mother, exhausted and dispirited by years of unrewarding attempts to break through to an autistic child, eventually gives up trying.

people get their personalities from their genes and from their peers, not from their parents.

But children do not seem to let the home environment influence their personality outside the home, nor to let it influence their personality in later life as an adult.

The reason the equation of determinism with fatalism is a fallacy is as follows. Suppose you are ill, but you reason that there is no point in calling the doctor because either you will recover, or you won’t: in either case, a doctor is superfluous. But this overlooks the possibility that your recovery or lack thereof could be caused by your calling the doctor, or failure to do so. It follows that determinism implies nothing about what you can or cannot do. Determinism looks backwards to the causes of the present state, not forward to the consequences.

As Sam Brittan has argued, ‘the opposite of freedom is coercion, not determinism.’

So does every criminal who uses the defence of insanity or diminished responsibility. So does every jealous spouse who uses the defence of temporary insanity or justifiable rage after murdering an unfaithful partner. So does the unfaithful partner when justifying the infidelity. So does every tycoon who uses the excuse of Alzheimer’s disease when accused of fraud against his shareholders. So indeed does a child in the playground who says that his friend made him do it. So does each one of us when we willingly go along with a subtle suggestion from the therapist that we should blame our parents for our present unhappiness. So does a politician who blames social conditions for the crime rate in an area. So does an economist when he asserts that consumers are utility maximisers. So does a biographer when he tries to explain how his subject’s character was forged by formative experiences. So does everybody who consults a horoscope. In every case there is a willing, happy and grateful embracing of determinism. Far from loving free will, we seem to be a species that positively leaps to surrender it whenever we can.

A religious instinct may be no more than a by-product of an instinctive superstition to assume that all events, even thunderstorms, have willful causes. Such a superstition could have been useful in the Stone Age.

The philosopher A. J. Ayer put it this way:
“If I suffered from a compulsive neurosis, so that I got up and walked across the room, whether I wanted to or not, or if I did so because somebody else compelled me, then I should not be acting freely. But if I do it now, I shall be acting freely, just because these conditions do not obtain; and the fact that my action may nevertheless have a cause is, from this point of view, irrelevant.
A psychologist of twins, Lyndon Eaves, has made a similar point:
“Freedom is the ability to stand up and transcend the limitations of the environment. That capacity is something that natural selection has placed in us, because it’s adaptive … If you’re going to be pushed around, would you rather be pushed around by your environment, which is not you, or by your genes, which in some sense is who you are.”
Freedom lies in expressing your own determinism, not somebody else’s. It is not the determinism that makes a difference, but the ownership. If freedom is what we prefer, then it is preferable to be determined by forces that originate in ourselves and not in others.

Bibliography And Notes

For the studies that led to the conclusion that homosexuality was partly genetic, see Dean Hamer and Peter Copeland’s The science of desire (Simon and Schuster, 1995) and Chandler Burr’s A separate creation: how biology makes us gay (Bantam Press, 1996).