Hox and hedgehog genes are not by any means the only genes that control development. Scores of other genes doing ingenious things to signal where and how bits of the body should grow make up a system of brilliant self-organisation: 'pax genes' and 'gap genes', genes with names like radical fringe, even-skipped, fushi tarazu, hunchback, Kruppel, giant, engrailed, knirps, windbeutel, cactus, huckebein, serpent, gurken, oskar and tailless. Entering the new world of genetic embryology sometimes feels like dropping into a Tolkien novel; it requires you to learn a massive vocabulary. But - and here is the wonder of it
— you do not need to learn a new way of thinking. There is no fancy physics, no chaos theory or quantum dynamics, no conceptual novelties. Like the discovery of the genetic code itself, what seemed initially to be a problem that could only be solved with new concepts turns out to be just a simple, literal and easily understood sequence of events. 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.
Indeed, so simple is embryonic development in principle - though not in detail — that it is tempting to wonder if human engineers should not try to copy it, and invent self-assembling machines.
C H R O M O S O M E 1 3
P r e - H i s t o r y
Antiquitas saeculi juventus mundi (Ancient times were the youth of the world) Francis Bacon
The surprising similarity of embryological genes in worms, flies, chicks and people sings an eloquent song of common descent. The reason we know of this similarity is because D N A is a code written in a simple alphabet — a language. We compare the vocabulary of developmental genes and find the same words. On a completely different scale, but with direct analogy, the same is true of human language: by comparing the vocabularies of human languages, we can deduce their common ancestry. Italian, French, Spanish and Romanian share word roots from Latin, for instance. These two processes — linguistic philology and genetic phylogeny - are converging upon a common theme: the history of human migrations.
Historians may lament the lack of written records to document the distant, prehistoric past, but there is a written record, in the genes, and a spoken one, too, in the very vocabulary of human language.
For reasons that will slowly emerge, chromosome 13 is a good place to discuss the genetics of genealogy.
1 8 6 G E N O M E
In 1786 Sir William Jones, a British judge in Calcutta, announced to a meeting of the Royal Asiatic Society that his studies of the archaic Indian language Sanskrit had led him to conclude that it was a cousin of Latin and Greek. Being a learned fellow he also thought he saw similarities between these three languages and Celtic, Gothic and Persian. They had all, he suggested, 'sprung from some common source'. His reasoning was exactly the same as the reasoning which led modern geneticists to propose the existence of the Roundish Flat Worm of 530 million years ago: similarities of vocabulary. For instance, the word for three is 'tres' in Latin, 'treis' in Greek and
'tryas' in Sanskrit. Of course, the great difference between spoken languages and genetic languages is that there is much more horizontal borrowing of words in spoken language. Perhaps the word for three had somehow been inserted into Sanskrit from a western tongue.
But subsequent research has confirmed that Jones was absolutely right and that there was once a single people, speaking a single language in a single place and that descendants of those people brought that language to lands as far apart as Ireland and India, where it gradually diverged into modern tongues.
We can even learn something about these people. The Indo¬
Europeans, as they are known, expanded at least 8,000 years ago from their homeland, which some think was in the modern Ukraine, but was more likely in a hilly part of modern Turkey (the language had words for hills and fast-flowing streams). Whichever is correct, the people were undoubtedly farmers - their language also had words for crops, cows, sheep and dogs. Since this dates them to soon after the very invention of agriculture in the so-called fertile crescent of Syria and Mesopotamia, we can easily picture that their immense success in stamping their mother tongue on two continents was due to their agricultural technology. But did they impose their genes in the same way? It is a question I shall have to attack indirectly.
Today in the Indo-European homeland of Anatolia, people speak Turkish, a non-Indo-European tongue brought later by horse-riding nomads and warriors from the steppes and deserts of central Asia.
These 'Altaic' people owned a superior technology, too - the horse P R E - H I S T O R Y 187
- and their vocabulary confirms as much: it is full of common words for horses. A third family of languages, the Uralic, spoken in northern Russia, Finland, Estonia and, bizarrely, Hungary, bears witness to a previously successful expansion of people, before and after the Indo-Europeans, using an unknown technology - herding of domestic animals, perhaps. Today the Samoyede reindeer herders of northern Russia are perhaps typical Uralic speakers. But if you delve deeper, 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). There is disagreement about where to draw the boundaries that contain the descendants of these 'Nostratic' people. The Russian linguists Vladislav Illich-Svitych and Aharon Dolgopolsky prefer to include the Afro-Asiatic family of languages spoken in Arabia and North Africa, whereas Joseph Greenberg of Stanford University omits them but includes the Kamchatkan and Chukchi languages of north-east Asia.
Illich-Svitych even wrote a little poem in phonetic Nostratic, having deduced what the root words sounded like.
The evidence for this linguistic super-family lies in the simple little words that change least. Indo-European, Uralic, Mongol, Chukchi and Eskimo languages, for example, almost all use or used the 'm' sound in the word for 'me' and the 't' sound in the word for 'you' (as in the French 'tu'). A string of such examples stretches to breaking point the coincidence hypothesis. Remarkable as it seems, the languages spoken in Portugal and Korea are almost certainly descended from the same single tongue.
Quite what the Nostratic people's secret was we may never know.
Perhaps they had invented hunting with dogs or stringed weapons for the first time. Perhaps it was something less tangible, like demo-cratic decision making. But they did not altogether wipe out their predecessors. There is good evidence that Basque, several languages spoken in the Caucasus mountains and now-extinct Etruscan do 1 8 8 G E N O M E
not belong to the Nostratic super-family of languages, but share an affinity with Navajo and some Chinese tongues in a different super-family known as Na-Dene. We are getting into highly speculative ideas here, but Basque, which survived in the Pyrenees (mountains are backwaters of human migration, bypassed by the main flows), was once spoken in a larger area, as shown by place names, and the area coincides neatly with the painted caves of Cro-Magnon hunters. Are Basque and Navajo linguistic fossils of the first modern people to oust the Neanderthals and spread into Eurasia? Are speakers of these tongues actually descended from mesolithic people, and surrounded by neighbours of neolithic descent speaking Indo-European languages? Probably not, but it is a delicious possibility.
In the 1980s Luigi Luca Cavalli-Sforza, a distinguished Italian geneticist, watched these unfolding discoveries of linguistics and decided to ask the obvious question: do linguistic boundaries coincide with genetic ones? Genetic boundaries are inevitably more blurred, because of intermarriage (most people speak only one language, but share the genes of four grandparents). The differences between French and German genes are much less definite than the difference between the French and the German languages.
None the less, some patterns emerge. By gathering data on the common, known variations in simple genes - the 'classical polymorphisms' — and doing clever statistical tricks called principal-components analysis with the resulting data, 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 archaeo-logical 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 P R E - H I S T O R Y 1 8 9
pastoral nomads from the steppes of the Volga-Don region in about 3,000 B C. 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 B C . 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.1
Genes, in other words, support the evidence from linguistics that expansions and migrations of people with novel technological skills have played a great part in human evolution. The gene maps are fuzzier than the linguistic maps, but this enables them to be subtler.
On a smaller scale, too, they can pick out features that coincide with linguistic regions. In Cavalli-Sforza's native Italy, for instance, there are genetic regions that coincide with the ancient Etruscans, the Ligurians of the Genoa region (who spoke a non-Indo-European ancient language) and the Greeks of southern Italy. The message is plain. Languages and peoples do, to some extent, go together.
Historians speak happily of neolithic people, or herdsmen, or Magyars, or whoever, 'sweeping into' Europe. But what exactly do they mean? Do they mean expanding, or migrating? Do these newcomers displace the people already there? Do they kill them, or merely out-breed them? Do they marry their women and kill their men? Or do their technology, language and their culture merely spread by word of mouth and become adopted by the natives? All models are possible. In the case of eighteenth-century America, the native Americans were displaced almost completely by whites —
both in genetic and linguistic terms. In seventeenth-century Mexico, something much more like mixing happened. In nineteenth-century India, the language of English spread, as a whole procession of Indo-European languages such as Urdu/Hindi had done before, but in this case with very little genetic admixture.
The genetic information allows us to understand which of these models applies best to pre-history. The most plausible way to account for a genetic gradient that grows steadily more dilute towards the 1 9 0 G E N O M E
north-west is to imagine a spread of neolithic agriculture by diffusion.
That is, the neolithic farmers from the south-east must have mixed their genes with those of the 'natives', the influence of the invaders'
genes growing steadily less distinct the further they spread. This points to intermarriage. Cavalli-Sforza argues that the male cultivators probably married the local hunter-gatherer women, but not vice versa, because that is exactly what happens between the pygmies and their cultivator neighbours in central Africa today. Cultivators, who can afford more polygamy than hunter-gatherers, and tend to look down on foraging people as primitive, do not allow their own women to marry the foragers, but the male cultivators do take forager wives.
Where invading men have imposed their language upon a land but married the local women, there should be a distinct set of Y-chromosome genes but a less distinct set of other genes. This is the case in Finland. The Finns are genetically no different from the other western Europeans who surround them, except in one notable respect: they have a distinct Y chromosome, which looks much more like the Y chromosome of northern Asian people. Finland is a place where the Uralic language and the Uralic Y chromosomes were imposed on a genetically and linguistically Indo-European population some time in the distant past.2
What has all this to do with chromosome 13 ? It so happens that there is a notorious gene called BRCA2 on chromosome 13 and it, too, helps to tell a story of genealogy. BRCA2 was the second
'breast cancer gene' to be discovered, in 1994. People with a certain, fairly rare version of BRCA2 were found to be much more likely to develop breast cancer than is usually the case. The gene was first located by studying Icelandic families with a high incidence of breast cancer. Iceland is the perfect genetic laboratory because it was settled by such a small group of Norwegians around AD 900, and has seen so little immigration since. Virtually all of the 270,000 Icelanders trace their descent in all lines from those few thousand Vikings who reached Iceland before the little ice age. Eleven hundred years of chilly solitude and a devastating fourteenth-century plague have rendered the island so inbred that it is a happy genetic hunting P R E - H I S T O R Y 1 9 1
ground. Indeed, an enterprising Icelandic scientist working in America returned to his native country in recent years precisely to start a business helping people to track down genes.
Two Icelandic families with a history of frequent breast cancer can be traced back to a common ancestor born in 1711. They both have the same mutation, a deletion of five 'letters' after the 999th
'letter' of the gene. A different mutation in the same gene, the deletion of the 6,174th 'letter', is common in people of Ashkenazi Jewish descent. Approximately eight per cent of Jewish breast-cancer cases under the age of forty-two are attributable to this one mutation, and twenty per cent to a mutation in BRCA1, a gene on chromosome 17. Again, the concentration points to past inbreeding, though not on the Icelandic scale. Jewish people retained their genetic integrity by adding few converts to the faith and losing many people who married outsiders. As a result, the Ashkenazim in particular are a favourite people for genetic studies. In the United States the Committee for the Prevention of Jewish Genetic Disease organises the testing of schoolchildren's blood. When matchmakers are later considering a marriage between two young people, they can call a hotline and quote the two anonymous numbers they were each assigned at the testing. If they are both carriers of the same mutation, for Tay-Sachs disease or cystic fibrosis, the committee advises against the marriage. The practical results of this voluntary policy —
which was criticised in 1993 by the New York Times as eugenic — are already impressive. Cystic fibrosis has been virtually eliminated from the Jewish population in the United States.3
So genetic geography is of more than academic interest. Tay-Sachs disease is the result of a genetic mutation comparatively common in Ashkenazi Jews, for reasons that will be familiar from chromosome 9. Tay—Sachs carriers are somewhat protected against tuberculosis, which reflects the genetic geography of Ashkenazi Jews.
Crammed into urban ghettos for much of the past few centuries, the Ashkenazim were especially exposed to the 'white death' and it is little wonder that they acquired some genes that offer protection, even at the expense of lethal complications for a few.
1 9 2 G E N O M E
Although no such easy explanation yet exists for the mutation on chromosome 13 that predisposes Ashkenazis to develop breast cancer, it is quite possible that many racial and ethnic genetic peculiarities do indeed have a reason for their existence. In other words, the genetic geography of the world has a functional as well as a mapping contribution to make to the piecing together of history and pre-history.
Take two striking examples: alcohol and milk. The ability to digest large amounts of alcohol depends to some extent on the overproduc-tion by a certain set of genes on chromosome 4 of enzymes called alcohol dehydrogenases. Most people do have the capacity to pump up production by these genes, a biochemical trick they perhaps evolved the hard way — that is, by the death and disabling of those without it. It was a good trick to learn, because fermented liquids are relatively clean and sterile. They do not carry germs. The devastation wrought by various forms of dysentery in the first millennia of settled agricultural living must have been terrible. 'Don't drink the water', we westerners tell each other when heading for the tropics.
Before bottled water, the only supply of safe drinking water was in boiled or fermented form. As late as the eighteenth century in Europe, the rich drank nothing but wine, beer, coffee and tea. They risked death otherwise. (The habit dies hard.) 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'.
A similar story is taught by a gene on chromosome 1, the gene for lactase. This enzyme is necessary for the digestion of lactose, a sugar abundant in milk. We are all born with this gene switched on in our digestive system, but in most mammals - and therefore in most people — it switches off during infancy. This makes sense: milk is something you drink in infancy and it is a waste of energy making the enzyme after that. But some few thousand years ago, human P R E - H I S T O R Y 1 9 3
beings hit on the underhand trick of stealing the milk from domestic animals for themselves, and so was born the dairy tradition. This was fine for the infants, but for adults, the milk proved difficult to digest in the absence of lactase. One way round the problem is to let bacteria digest the lactose and turn the milk into cheese. Cheese, being low in lactose, is easily digestible for adults and children.
Occasionally, however, the control gene which switches off the lactase gene must suffer a mutation and the lactase production fails to cease at the end of infancy. This mutation allows its carrier to drink and digest milk all through life. Fortunately for the makers of Corn Flakes and Weetabix, most western people have acquired the mutation. More than seventy per cent of western Europeans by descent can drink milk as adults, compared with less than thirty per cent of people from parts of Africa, eastern and south-eastern Asia and Oceania. The frequency of this mutation varies from people to people and place to place in a fine and detailed pattern, so much so that it enables us to pose and answer a question about the reason people took up milk drinking in the first place.
There are three hypotheses to consider. First and most obvious, people took up milk drinking to provide a convenient and sustainable supply of food from herds of pastoral animals. Second, they took up milk drinking in places where there is too little sunlight and there is therefore a need for an extra source of vitamin D, a substance usually made with the help of sunlight. Milk is rich in vitamin D. This hypothesis was sparked by the observation that northern Europeans traditionally drink raw milk, whereas Mediterranean people eat cheese. Third, perhaps milk drinking began in dry places where water is scarce, and was principally an extra source of water for desert dwellers. Bedouin and Tuareg nomads of the Saharan and Arabian deserts are keen milk drinkers, for example.
By looking at sixty-two separate cultures, two biologists were able to decide between these theories. They found no good correlation between the ability to drink milk and high latitudes, and no good correlation with arid landscapes. This weakens the second and third hypotheses. But they did find evidence that the people with the 194 G E N O M E
highest frequency of milk-digestion ability were ones with a history of pastoralism. The Tutsi of central Africa, the Fulani of western Africa, the Bedouin, Tuareg and Beja of the desert, the Irish, Czech and Spanish people — this list of people has almost nothing in common except that all have a history of herding sheep, goats or cattle. They are the champion milk digesters of the human race.4
The evidence suggests that such people took up a pastoral way of life first, and developed milk-digesting ability later in response to it. It was not the case that they took up a pastoral way of life because they found themselves genetically equipped for it. This is a significant discovery. It provides an example of a cultural change leading to an evolutionary, biological change. The genes can be induced to change by voluntary, free-willed, conscious action. By taking up the sensible lifestyle of dairy herdsmen, human beings created their own evolutionary pressures. It almost sounds like the great Lamarckian heresy that bedevilled the study of evolution for so long: the notion that a blacksmith, having acquired beefy arms in his lifetime, then had children with beefy arms. It is not that, but it is an example of how conscious, willed action can alter the evolutionary pressures on a species — on our species in particular.
C H R O M O S O M E 1 4
I m m o r t a l i t y
Heaven from all creatures hides the book of fate, All but the page prescribed, their present state.
Alexander Pope, An Essay on Man
Looking back from the present, the genome seems immortal. An unbroken chain of descent links the very first ur-gene with the genes active in your body now — an unbroken chain of perhaps fifty billion copyings over four billion years. There were no breaks or fatal mistakes along the way. But past immortality, a financial adviser might say, is no guarantee of future immortality. Becoming an ancestor is difficult — indeed, natural selection requires it to be difficult.
If it were easy, the competitive edge that causes adaptive evolution would be lost. Even if the human race survives another million years, many of those alive today will contribute no genes to those alive a million years hence: their particular descendants will peter out in childlessness. And if the human race does not survive (most species last only about ten million years and most leave no descendant species behind: we've done five million years and spawned no daughter species so far), none of us alive today will contribute 1 9 6 G E N O M E
anything genetic to the future. Yet so long as the earth exists in something like its present state, some creature somewhere will be an ancestor of future species and the immortal chain will continue.
If the genome is immortal, why does the body die? Four billion years of continuous photocopying has not dulled the message in your genes (partly because it is digital), yet the human skin gradually loses its elasticity as we age. It takes fewer than fifty cell doublings to make a body from a fertilised egg and only a few hundred more to keep the skin in good repair. There is an old story of a king who promised to reward a mathematician for some service with anything he wanted. The mathematician asked for a chessboard with one grain of rice on the first square, two on the second, four on the third, eight on the fourth and so on. By the sixty-fourth square, he would need nearly twenty million million million grains of rice, an impossibly vast number. Thus it is with the human body. The egg divides once, then each daughter cell divides again, and so on. In just forty-seven doublings, the resulting body has more than 100
trillion cells. Because some cells cease doubling early and others continue, many tissues are created by more than fifty doublings, and because some tissues continue repairing themselves throughout life, certain cell lines may have doubled several hundred times during a long life. That means their chromosomes have been 'photocopied'
several hundred times, enough to blur the message they contain.
Yet fifty billion copyings since the dawn of life did not blur the genes you inherited. What is the difference?
Part of the answer lies on chromosome 14, in the shape of a gene called TEP1. The product of TEP1 is a protein, which forms part of a most unusual little biochemical machine called telomerase. Lack of telomerase causes, to put it bluntly, senescence. Addition of telomerase turns certain cells immortal.
The story starts with a chance observation in 1972 by James Watson, D N A ' s co-discoverer. Watson noticed that the biochemical machines that copy D N A , called polymerases, cannot start at the very tip of a D N A strand. They need to start several 'words' into the text. Therefore the text gets a little shorter every time it is I M M O R T A L I T Y 1 9 7
duplicated. Imagine a photocopier that makes perfect copies of your text but always starts with the second line of each page and ends with the penultimate line. The way to cope with such a maddening machine would be to start and end each page with a line of repeated nonsense that you do not mind losing. This is exactly what chromosomes do. Each chromosome is just a giant, supercoiled, foot-long D N A molecule, so it can all be copied except the very tip of each end. And at the end of the chromosome there occurs a repeated stretch of meaningless 'text': the 'word' T T A G G G repeated again and again about two thousand times. This stretch of terminal tedium is known as a telomere. Its presence enables the DNA-copying devices to get started without cutting short any sense-containing
'text'. Like an aglet, the little plastic bit on the end of a shoelace, it stops the end of the chromosome from fraying.
But every time the chromosome is copied, a little bit of the telomere is left off. After a few hundred copyings, the chromosome is getting so short at the end that meaningful genes are in danger of being left off. In your body the telomeres are shortening at the rate of about thirty-one 'letters' a year - more in some tissues. That is why cells grow old and cease to thrive beyond a certain age. It may be why bodies, too, grow old — though there is fierce disagreement on this point. In an eighty-year-old person, telomeres are on average about five-eighths as long as they were at birth.1
The reason that genes do not get left off in egg cells and sperm cells, the direct ancestors of the next generation, is the presence of telomerase, whose job is to repair the frayed ends of chromosomes, re-lengthening the telomeres. Telomerase, discovered in 1984 by Carol Greider and Elizabeth Blackburn, is a curious beast. It contains R N A , which it uses as a template from which to rebuild telomeres, and its protein component bears a striking resemblance to reverse transcriptase, the enzyme that makes retroviruses and transposons multiply within the genome (see the chapter on chromosome 8).
Some think it is the ancestor of all retroviruses and transposons, the original inventor of R N A - t o - D N A transcription. Some think that because it uses R N A , it is a relic of the ancient R N A world.
1 9 8 G E N O M E
In this context, note that the 'phrase' T T A G G G , which is repeated a few thousand times in each telomere, is exactly the same in the telomeres of all mammals. Indeed, it is the same in most animals, and even in protozoans, such as the trypanosome that causes sleeping sickness, and in fungi such as Neurospora. In plants the phrase has an extra T at the beginning: T T T A G G G . The similarity is too close to be coincidental. Telomerase has been around since the dawn of life, it seems, and has used almost the same R N A template in all descendants. Curiously, however, the ciliate protozoans — busy microscopic creatures covered in self-propelling fur - stand out as having a somewhat different phrase repeated in their telomeres, usually T T T T G G G G o r T T G G G G . The ciliates, you may remember, are the organisms that most frequently diverge from the otherwise-universal genetic code. More and more evidence points to the conclusion that the ciliates are peculiar creatures that do not fit easily into the files of life. It is my personal gut feeling that we will one day conclude that they spring from the very root of the tree of life before even the bacteria evolved, that they are, in effect, living fossils of the daughters of Luca herself, the last universal common ancestor of all living things. But I admit this is a wild surmise - and a digression.3
Perhaps ironically, the complete telomerase machine has been isolated only in ciliates, not in human beings. We do not yet know for sure what proteins are brought together to make up human telomerase and it may prove very different from that in ciliates.
Some sceptics refer to telomerase as 'that mythical enzyme', because it is so hard to find in human cells. In ciliates, which keep their working genes in thousands of tiny chromosomes each capped with two telomeres, telomerase is much easier to find. But by searching a library of mouse D N A for sequences that resemble those used in the ciliate telomerase, a group of Canadian scientists found a mouse gene that resembled one of the ciliate genes; they then quickly found a human gene that matched the mouse gene. A team of Japanese scientists mapped the gene to chromosome 14; it produces a protein with the grand, if uncertain title of telomerase-associated I M M O R T A L I T Y 1 9 9
protein 1, or T E P 1 . But it looks as if this protein, although a vital ingredient of telomerase, is not the bit that does the actual reverse transcription to repair the ends of chromosomes. A better candidate for that function has since been found but, as of this writing, its genetic location is still uncertain.4
Between them, these telomerase genes are as close as we may get to finding the 'genes for youth'. Telomerase seems to behave like the elixir of eternal life for cells. Geron Corporation, a company devoted to telomerase research, was founded by the scientist who first showed that telomeres shrink in dividing cells, Cal Harley.
Geron hit the headlines in August 1997 for cloning part of telomerase. Its share price promptly doubled, not so much on the hope that it could give us eternal youth as on the prospect of making anti-cancer drugs: tumours require telomerase to keep them growing.
But Geron went on to immortalise cells with telomerase. In one experiment, Geron scientists took two cell types grown in the laboratory, both of which lacked natural telomerase, and equipped them with a gene for telomerase. The cells continued dividing, vigorous and youthful, far beyond the point where they would normally senesce and die. At the time the result was published the cells that had had the telomerase gene introduced had exceeded their expected lifespan by more than twenty doublings, and they showed no sign of slowing down.5
In normal human development, the genes that make telomerase are switched off in all but a few tissues of the developing embryo.
The effect of this switching off of telomerase has been likened to the setting of a stopwatch. From that moment the telomeres count the number of divisions in each cell line and at a certain point they reach their limit and call a halt. Germ cells never start the stopwatch
- they never switch off the telomerase genes. Malignant tumour cells switch the genes back on. Mouse cells in which one of the telomerase genes has been artificially 'knocked out' have progressively shorter telomeres.6
The lack of telomerase seems to be the principal reason that cells grow old and die, but is it the principal reason bodies grow old and 2 0 0 G E N O M E
die? There is some good evidence in favour: cells in the walls of arteries generally have shorter telomeres than cells in the walls of veins. This reflects the harder lives of arterial walls, which are subject to more stress and strain because arterial blood is under higher pressure. They have to expand and contract with every pulse beat, so they suffer more damage and need more repair. Repair involves cell copying, which uses up the ends of telomeres. The cells start to age, which is why we die from hardened arteries, not from hardened veins.7
The ageing of the brain cannot be explained so easily, because brain cells do not replace themselves during life. Yet this is not fatal to the telomere theory: the brain's support cells, called glial cells, do indeed duplicate themselves; their telomeres do, therefore, probably shrink. However, there are very few experts who now believe that ageing is, chiefly, the accumulation of senescent cells, cells with abridged telomeres. Most of the things we associate with ageing -
cancer, muscle weakness, tendon stiffness, hair greyness, changes in skin elasticity - have nothing to do with cells failing to duplicate themselves. In the case of cancer, the problem is that cells are copying themselves all too enthusiastically.
Moreover, there are huge differences between different species of animal in the rate at which they age. On the whole, bigger animals, such as elephants, live longer than smaller animals, which is at first sight puzzling given that it takes more cell doublings to make an elephant than a mouse — if cell doublings lead to senescent cells.
And lethargic, slow-lived animals such as tortoises and sloths are long-lived for their size. This led to a neat generalisation, which is so tidy it ought to be true and probably would be if physicists ran the world: every animal has roughly the same number of heartbeats per lifetime. An elephant lives longer than a mouse, but its pulse rate is so much slower that, measured in heartbeats, they both live lives of the same length.
The trouble is, there are damning exceptions to the rule: notably bats and birds. Tiny bats can live for at least thirty years, during almost all of which they eat, breathe and pump blood at a frantic I M M O R T A L I T Y 2 0 I
rate — and this applies even in species that do not hibernate. Birds —
whose blood is several degrees hotter, whose blood sugar is at least twice as concentrated and whose oxygen consumption is far faster than in most mammals - generally live long lives. There is a famous pair of photographs of the Scottish ornithologist George Dunnet holding the same wild fulmar petrel in 1950 and 1992. The fulmar looks exactly the same in the two pictures; Professor Dunnet doesn't.
Fortunately, where the biochemists and medics have failed to explain ageing patterns, the evolutionists have come to the rescue.
J. B. S. Haldane, Peter Medawar and George Williams separately put together the most satisfying account of the ageing process.
Each species, it seems, comes equipped with a program of planned obsolescence chosen to suit its expected life-span and the age at which it is likely to have finished breeding. 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.
Evidence for this theory comes from a natural experiment studied by Steven Austad on an island called Sapelo, which lies about five miles off the coast of Georgia in the United States. Sapelo contains a population of Virginia opossums that has been isolated for 10,000
years. Opossums, like many marsupials, age very rapidly. By the age of two years, opossums are generally dead from old age - the victims of cataracts, arthritis, bare skin and parasites. But that hardly matters because by two they have generally been hit by a truck, a coyote, 2 0 2 G E N O M E
an owl or some other natural enemy. On Sapelo, reasoned Austad, where many predators are absent, they would live longer and so —
exposed for the first time to selection for better health after two years of age - their bodies would deteriorate less rapidly. They would age more slowly. This proved an accurate prediction. On Sapelo, Austad found, the opossums not only lived much longer, but aged more slowly. They were healthy enough to breed successfully in their second year - rare on the mainland — and their tendons showed less stiffness than those in mainland opossums.8
The evolutionary theory of ageing explains all the cross-species trends in a satisfying way. It explains why slow-ageing species tend to be large (elephants), or well protected (tortoises, porcupines), or relatively free from natural predators (bats, seabirds). In each case, because the death rate from accidents or predation is low, so the selective pressure is high for versions of genes that prolong health into later life.
Human beings, of course, have for several million years been large, well protected by weaponry (even chimps can chase leopards off with sticks) and have few natural predators. So we age slowly -
and perhaps more slowly as the eras pass. Our infant mortality rate in a state of nature - of perhaps fifty per cent before the age of five — would be shockingly high by modern, western standards, but is actually low by the standards of other animals. Our Stone-Age ancestors began breeding at about twenty, continued until about thirty-five and looked after their children for about twenty years, so by about fifty-five they could die without damaging their reproductive success. Little wonder that at some time between fifty-five and seventy-five most of us gradually start to go grey, stiff, weak, creaky and deaf. All our systems begin to break down at once, as in the old story of the Detroit car maker who employed somebody to go around breakers' yards finding out which parts of cars did not break down, so that those bits could in future be made to a lower specification.
Natural selection has designed all parts of our bodies to last just long enough to see our children into independence, no more.
Natural selection has built our telomeres of such a length that I M M O R T A L I T Y 2 0 3
they can survive at most seventy-five to ninety years of wear, tear and repair. It is not yet known for certain, but it seems likely that natural selection may have given fulmars and tortoises somewhat longer telomeres, and Virginia opossums much shorter ones. Perhaps even the individual differences in longevity between one human being and another also indicate differences in telomere length. Certainly, there is great variety in telomere length between different people, from about 7,000 D N A 'letters' to about 10,000 per chromosome end. And telomere length is strongly inherited, as is longevity. People from long-lived families, in which members regularly reach ninety, may have longer telomeres, that take longer to fray, than the rest of us. Jeanne Calment, the French woman from Arles who in February 1995 became the first human being with a birth certificate to celebrate her 120th birthday, may have had many more repeats of the message T T A G G G . She eventually died at 122. Her brother lived to ninety-seven.9
In practice, though, it is more likely that Mme Calment could thank other genes for her longevity. Long telomeres are no good if the body decays rapidly; the telomeres will soon be shortened by the need for cell division to repair damaged tissues. In Werner's syndrome, an inherited misfortune characterised by premature and early ageing, the telomeres do indeed get shorter much more rapidly than in other people, but they start out the same size. The reason they get shorter is probably that the body lacks the capability to repair properly the corrosive damage done by so-called free radicals
- atoms with unpaired electrons created by oxygen reactions in the body. Free oxygen is dangerous stuff, as any rusty piece of iron can testify. Our bodies, too, are continually 'rusting' from the effects of oxygen. Most of the mutations that cause 'longevity', at least in flies and worms, turn out to be in genes that inhibit the production of free radicals - i.e., they prevent the damage being done in the first place, rather than prolong the replicating life of cells that repair the damage. One gene, in nematode worms, has enabled scientists to breed a strain that lives to such an exceptional age that they would be 350 years old if they were human beings. In fruit flies, Michael 2 0 4 G E N O M E
Rose has been selecting for longevity for twenty-two years: that is, in each generation he breeds from the flies that live the longest. His
'Methuselah' flies now live for 120 days, or twice as long as wild fruit flies, and start breeding at an age when wild fruit flies usually die. They show no sign of reaching a limit. A study of French centenarians quickly turned up three different versions of a gene on chromosome 6 that seemed to characterise long-lived people.
Intriguingly, one of them was common in long-lived men and another was common in long-lived women.10
Ageing is turning out to be one of those things that is under the control of many genes. One expert estimates that there are 7,000
age-influencing genes in the human genome, or ten per cent of the total. This makes it absurd to speak of any gene as 'an ageing gene'
let alone ''the ageing gene'. Ageing is the more or less simultaneous deterioration of many different bodily systems; genes that determine the function of any of these systems can cause ageing, and there is good evolutionary logic in it. Almost any human gene can accumulate with impunity mutations which cause deterioration after breeding age.n
It is no accident that the immortal cell lines used by scientists in the laboratory are derived from cancer patients. 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 Balti-more 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. They even somehow reached Russia in 1972 where they fooled scientists into thinking they had found new cancer viruses. HeLa cells were used for developing polio vaccines and have gone into space. Worldwide, they now weigh more than 400 times Henrietta's own body weight. They are spectacularly immortal. Yet nobody, at any time, thought to ask Henrietta Lacks's permission or that of her family - who were hurt when they learnt of her cellular immortality. In belated recognition of a 'scientific heroine', the city of Atlanta now recognises 11 October as Henrietta Lacks Day.
I M M O R T A L I T Y 2 0 5
HeLa cells plainly have excellent telomerase. If antisense R N A is added to HeLa cells - that is, R N A containing the exact opposite message to the R N A message in telomerase, so that it will stick to the telomerase R N A - then the effect is to block the telomerase and prevent it working. The HeLa cells are then no longer immortal.
They senesce and die after about twenty-five cell divisions.12
Cancer requires active telomerase. A tumour is invigorated with the biochemical elixir of youth and immortality. Yet cancer is the quintessential disease of ageing. Cancer rates rise steadily with age, more rapidly in some species than others, but still they rise: there is no creature on earth that is less likely to get cancer in old age than in youth. The prime risk factor for cancer is age. Environmental risk factors, such as cigarette smoking, work in part because they accelerate the ageing process: they damage the lungs, which require repair and repair uses up telomere length, thus making the cells
'older' in telomere terms than they would otherwise be. Tissues that are especially prone to cancer tend to be tissues that do a lot of cell division throughout life either for repair or for other reasons: skin, testis, breast, colon, stomach, white blood cells.
So we have a paradox. Shortened telomeres mean higher cancer risk, but telomerase, which keeps telomeres long, is necessary for a tumour. The resolution lies in the fact that the switching on of telomerase is one of the essential mutations that must occur if a cancer is to turn malignant. It is now fairly obvious why Geron's cloning of the telomerase gene caused its share price to rocket on the hopes of a general cure for cancer. Defeating telomerase would condemn tumours to suffer from the rapid advance of old age themselves.
C H R O M O S O M E 1 5
S e x
All women become like their mothers. That is their tragedy. No man does. That's his.
Oscar Wilde, The Importance of Being Earnest In the Prado Museum in Madrid hangs a pair of paintings by the seventeenth-century court painter Juan Carreno de Miranda, called
'La Monstrua vestida' and 'La Monstrua desnuda': the monster clothed and the monster naked. They show a grossly fat but very unmonstrous five-year-old girl called Eugenia Martinez Vallejo.
There is indeed clearly something wrong with her: she is obese, enormous for her age, has tiny hands and feet and strange-shaped eyes and mouth. She was probably exhibited as a freak at a circus.
With hindsight, it is plain that she shows all the classic signs of a rare inherited disease called Prader-Willi syndrome, in which children are born floppy and pale-skinned, refuse to suck at the breast but later eat till they almost burst, never apparently experiencing satiety, and so become obese. In one case, the parent of a Prader-Willi child found the child had consumed a pound of raw bacon in the back of a car while being driven back from the shop. People with this S E X 2 0 7
syndrome have small hands and feet, underdeveloped sex organs and they are also mildly mentally retarded. At times they throw spectacular temper tantrums, especially when refused food, but they also show what one doctor calls 'exceptional proficiency with jigsaw puzzles'.
Prader-Willi syndrome was first identified by Swiss doctors in 1956. It might have been just another rare genetic disease, of the kind I have repeatedly promised not to write about in this book because G E N E S A R E N O T T H E R E T O C A U S E D I S -
E A S E S . But there is something very odd about this particular gene.
In the 1980s doctors noticed that Prader-Willi syndrome sometimes occurs in the same families as a completely different, disease, a disease so different it might almost be called the opposite of Prader-Willi: Angelman's syndrome.
Harry Angelman was a doctor working in Warrington in Lanca-shire when he first realised that rare cases of what he called 'puppet children' were suffering from an inherited disease. In contrast to those with Prader-Willi syndrome, they are not floppy, but taut.
They are thin, hyperactive, insomniac, small-headed and long-jawed, and often stick out their large tongues. They move jerkily, like puppets, but have a happy disposition; they are perpetually smiling and are given to frequent paroxysms of laughter. But they never learn to speak and are severely mentally retarded. Angelman children are much rarer than Prader-Willi children, but they sometimes crop up in the same family tree.2
In both Prader-Willi and Angelman's syndrome it soon became clear that the same chunk of chromosome 15 was missing. The difference was that in Prader-Willi syndrome, the missing chunk was from the father's chromosome, whereas in Angelman's syndrome, the missing chunk was from the mother's chromosome.
Transmitted through a man, the disease manifests itself as Prader-Willi syndrome; transmitted through a woman it manifests itself as Angelman's syndrome.
These facts fly in the face of everything we have learnt about genes since Gregor Mendel. They seem to belie the digital nature 2 0 8 G E N O M E
of the genome and imply that a gene is not just a gene but carries with it some secret history of its origin. The gene 'remembers' which parent it came from because it is endowed at conception with a paternal or a maternal imprint — as if the gene from one parent were written in italic script. In every cell where the gene is active, the 'imprinted' version of the gene is switched on and the other version switched off. The body therefore expresses only the gene it inherited from the father (in the case of the Prader-Willi gene) or the mother (in the case of the Angelman gene). How this happens is still almost entirely obscure, though there is the beginning of an understanding. Why it happens is the subject of an extraordinary and daring evolutionary theory.
In the late 1980s, two groups of scientists, one in Philadelphia and one in Cambridge, made a surprising discovery. They tried to create a uniparental mouse — a mouse with only one parent. Since strict cloning from a body cell was then impossible in mice (post-Dolly, this is quickly changing), the Philadelphia team swapped the
'pronuclei' of two fertilised eggs. When an egg has been fertilised by a sperm, the sperm nucleus containing the chromosomes enters the egg but does not at first fuse with the egg nucleus: the two nuclei are known as 'pronuclei'. A clever scientist can sneak in with his pipette and suck out the sperm pronucleus, replacing it with the egg pronucleus from another egg — and vice versa. The result is two viable eggs, but one with, genetically speaking, two fathers and no mother and the other with two mothers and no father. The Cambridge team used a slightly different technique to reach the same result. But in both cases such embryos failed to develop properly and soon died in the womb.
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, S E X 2 0 9
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.
Why should this be? Five years later, David Haig, then at Oxford, thought he knew the answer. He had begun to reinterpret the mammalian placenta, not as a maternal organ designed to give sustenance to the foetus, but more as a foetal organ designed to parasitise the maternal blood supply and brook no opposition in the process. He noted that the placenta literally bores its way into the mother's vessels, forcing them to dilate, and then proceeds to produce hormones which raise the mother's blood pressure and blood sugar.
The mother responds by raising her insulin levels to combat this invasion. Yet, if for some reason the foetal hormone is missing, the mother does not need to raise her insulin levels and a normal pregnancy ensues. In other words, although mother and foetus have a common purpose, they argue fiercely about the details of how much of the mother's resources the foetus may have — exactly as they later will during weaning.
But the foetus is built parly with maternal genes, so it would not be surprising if these genes found themselves with, as it were, a conflict of interest. The father's genes in the foetus have no such worries. They do not have the mother's interest at heart, except insofar as she provides a home for them. To turn briefly anthropomorphic, the father's genes do not trust the mother's genes to make a sufficiently invasive placenta; so they do the job themselves. Hence the paternal imprinting of placental genes as discovered by the two-fathered embryos.
Haig's hypothesis made some predictions, many of which were soon borne out. In particular, it predicted that imprinting would not occur in animals that lay eggs, because a cell inside an egg has no means of influencing the investment made by the mother in yolk size: it is outside the body before it can manipulate her. Likewise, even marsupials such as kangaroos, with pouches in place of placentas, would not, on Haig's hypothesis, have imprinted genes. So far, it appears, Haig is right. Imprinting is a feature of placental mammals 2 1 0 G E N O M E
and of plants whose seeds gain sustenance from the parent plant.4
Moreover, Haig was soon triumphantly noting that a newly discovered pair of imprinted genes in mice had turned up exactly where he expected them: in the control of embryonic growth. I G F 2 is a miniature protein, made by a single gene, that resembles insulin. It is common in the developing foetus and switched off in the adult.
I G F 2 R is a protein to which I G F 2 attaches itself for a purpose that remains unclear. It is possible that I G F 2 R is there simply to get rid of I G F 2 . Lo and behold, both the IGF2 and the IGF2R
genes are imprinted: the first being expressed only from the paternal chromosome, the second from the maternal one. It looks very much like a little contest between the paternal genes trying to encourage the growth of the embryo and the maternal ones trying to moderate it.5
Haig's theory predicts that imprinted genes will generally be found in such antagonistic pairs. In some cases, even in human beings, this does seem to be the case. The human IGF2 gene on chromosome 11
is paternally imprinted and when, by accident, somebody inherits two paternal copies, they suffer from Beckwith-Wiedemann syndrome, in which the heart and liver grow too large, and tumours of embryonic tissues are common. Although in human beings IGF2R
is not imprinted, there does seem to be a maternally imprinted gene, H19, that opposes IGF2.
If imprinted genes exist only to combat each other, then you should be able to switch both off and it will have no effect at all on the development of the embryo. You can. Elimination of all imprinting leads to normal mice. We are back in the familiar territory of chromosome 8, where genes are selfish and do things for the benefit of themselves, not for the good of the whole organism. There is almost certainly nothing intrinsically purposeful about imprinting (though many scientists have speculated otherwise); it is another illustration of the theory of the selfish gene and of sexual antagonism in particular.
Once you start thinking in selfish-gene terms, some truly devious ideas pop into your head. Try this one. Embryos under the influence of paternal genes might behave differently if they share the womb S E X 2 1 1
with full siblings or if they share the womb with embryos that have different fathers. They might have more selfish paternal genes in the latter case. Having thought the thought, it was comparatively easy to do the deed and test this prediction with a natural experiment.
Not all mice are equal. In some species of mice, for example Peromyscus maniculatus, the females are promiscuous, and each litter generally contains babies fathered by several different males. In other species, for example Peromyscus polionatus, the females are strictly monogamous and each litter contains full siblings who share both father and mother.
So what happens when you cross a P. maniculatus mouse with a P. polionatus mouse? It depends on which species is the father and which is the mother. If the promiscuous P. maniculatus is the father, the babies are born giant-sized. If the monogamous P. polionatus is the father, the babies are born tiny. Do you see what is happening?
Paternal maniculatus genes, expecting to find themselves in a womb with competitors that are not even related, have been selected to fight for their share of the mother's resources at the expense of their co-foetuses. Maternal maniculatus genes, expecting to find embryos in their wombs that fight hard for her resources, have been selected to fight back. In the more neutral environment of polionatus wombs, the aggressive maniculatus genes from the father encounter only token opposition, so they win their particular battle: the baby is big if fathered by the promiscuous father and small if mothered by the promiscuous mother. It is a very neat demonstration of the imprinting theory.6
Neat as this tale is, it cannot be told without a caveat. Like many of the most appealing theories it may be too good to be true. In particular, it makes a prediction that is not borne out: that imprinted genes will be relatively rapidly evolving ones. This is because sexual antagonism would drive a molecular arms race in which each benefited from temporarily gaining the upper hand. A species-by-species comparison of imprinted genes does not bear this out. Rather, imprinted genes seem to evolve quite slowly. It looks increasingly as if the Haig theory explains some, but not all, cases of imprinting.
2 1 2 G E N O M E
Imprinting has a curious consequence. In a man, the maternal copy of chromosome 15 carries a mark that identifies it as coming from his mother, but when he passes it on to his son or daughter, it must somehow have acquired a mark that identifies it as coming from him: the father. It must switch from maternal to paternal and vice versa in the mother. That this switch does happen we know, because in a small proportion of people with Angelman syndrome there is nothing unusual about either chromosome except that both behave as if they were paternal. These are cases in which the switch failed to occur. They can be traced back to mutations in the previous generation, mutations that affect something called the imprinting centre, a small stretch of D N A close to both relevant genes, which somehow places the parental mark on the chromosome. The mark consists of one gene's methylation, of the kind encountered in chromosome 8.8
Methylation of the 'letter' C, you will recall, is the means by which genes are silenced, and it serves to keep selfish D N A under house arrest. But methylation is removed during the early development of the embryo - the creation of the so-called blastocyst — and then reimposed during the next stage of development, called gastrulation.
Somehow, imprinted genes escape this process. They resist the demethylation. There are intriguing hints about how this is achieved, but nothing definitive.9
That imprinted genes escape demethylation is, we now know, all that stood between science and the cloning of mammals for many years. Toads were fairly easily cloned by putting genes from a body cell into a fertilised egg, but it just didn't work with mammals, because the genome of a female's body cells had certain critical genes switched off by methylation and the genome of a male's body cells had other genes switched off - the imprinted genes. So, confidently, scientists followed the discovery of imprinting with the announcement that cloning a mammal was impossible. A cloned mammal would be born with all its imprinted genes either on or off on both chromosomes, upsetting the doses required by the cells of the animal and causing development to fail. 'A logical conse-S E X 2 1 3
quence', wrote the scientists who discovered imprinting,10 'is the unlikelihood of successful cloning of mammals using somatic cell nuclei.'
Then, suddenly, along came Dolly the cloned Scottish sheep in early 1997. Quite how she and those that came after evaded the imprinting problem remains a mystery, even to her creators, but it seems that a certain part of the treatment meted out to her cells during the procedure erased all genetic imprints.11
The imprinted region of chromosome 15 contains about eight genes. One of these is responsible, when broken, for Angelman syndrome: a gene called UBE3A. Immediately beside this gene are two genes that are candidates for causing Prader-Willi syndrome when broken, one called SNRPN and the other called IPW. There could be others, but let us assume for the moment that SNRPN
is the culprit.
The diseases, though, do not always result from a mutation in one of these genes but from an accident of a different kind. When an egg is formed inside a woman's ovary, it usually receives one copy of each chromosome, but in rare cases where a pair of parental chromosomes fails to separate, the egg ends up with two copies.
After fertilisation with a sperm, the embryo now has three copies of that chromosome, two from the mother and one from the father.
This is especially likely in elder mothers, and is generally fatal to the egg. The embryo can go on to develop into a viable foetus and survive more than a few days after birth only if the triplicate chromosome is number 21, the smallest of the chromosomes - the result being Down syndrome. In other cases the extra chromosome would so upset the biochemistry of the cells that development would fail.
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. It cannot be sure that it is deleting one of the two maternal chromosomes, or the single paternal one. Random deletion has a sixty-six per cent chance of getting one of the maternal ones, but accidents do happen. If, by mistake, it deletes the paternal 2 1 4 G E N O M E
one, then the embryo goes merrily on its way with two maternal chromosomes. In most cases this could not matter less, but if the tripled chromosome is number 15, you can see immediately what will ensue. Two copies of UBE3A, the maternally imprinted gene, are expressed, and no copies of SNRPN, the paternally imprinted gene. The result is Prader-Willi syndrome.12
Superficially, UBE3A does not look a very interesting gene. Its protein product is a type of 'E3 ubiquitin ligase', members of an obscure proteinaceous middle management within certain skin and lymph cells. Then in the middle of 1997, three different groups of scientists suddenly discovered that, in both mice and human beings, UBE3A is switched on in the brain. This is dynamite. The symptoms of both Prader-Willi and Angelman indicate something unusual about the brains of their victims. What is even more striking is that there is good evidence that other imprinted genes are active in the brain. In particular, it seems that in mice much of the forebrain is built by maternally imprinted genes, while much of the hypothalamus, at the base of the brain, is built by paternally imprinted genes.13
This imbalance was discovered by an ingenious piece of scientific work: the creation of mouse 'chimeras'. 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. Think of them as the opposite of identical twins: two different genomes in one body, instead of two different bodies with the same genome.
It is comparatively easy to make mouse chimeras in the laboratory by gently fusing the cells from two early embryos. But what the ingenious Cambridge team did in this case was to fuse a normal mouse embryo with an embryo that was made by 'fertilising' an egg with another egg's nucleus, so that it had purely maternal genes and no contribution from the father. The result was a mouse with an unusually large head. When these scientists made a chimera between a normal embryo and an embryo derived only from the father (i.e., S E X 2 1 5
grown from an egg whose nucleus had been replaced by two sperm nuclei), the result was the opposite: a mouse with a big body and a small head. By equipping the maternal cells with the biochemical equivalent of special radio transmitters to send out signals of their presence, they were able to make the remarkable discovery that most of the striatum, cortex and hippocampus of the mouse brain are consistently made by these maternal cells, but that such cells are excluded from the hypothalamus. The cortex is the place where sensory information is processed and behaviour is produced.
Paternal cells, by contrast, are comparatively scarce in the brain, but much commoner in the muscles. Where they do appear in the brain, however, they contribute to the development of the hypothalamus, amygdala and preoptic area. These areas comprise part of the 'limbic system' and are responsible for the control of emotions. In the opinion of one scientist, Robert Trivers, this difference reflects the fact that the cortex has the job of co-operating with maternal relatives while the hypothalamus is an egotistical organ.14
In other words, 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. If we are like mice, we may be walking around with our mothers' thinking and our fathers' moods (to the extent that thoughts and moods are inherited at all). In 1998 another imprinted gene came to light in mice, which had the remarkable property of determining a female mouse's maternal behaviour. Mice with this Mest gene intact are good, caring mothers to their pups. Female mice who lack a working copy of the gene are also normal except that they make terrible mothers. They fail to build decent nests, they fail to haul their pups back to the nest when they wander, they do not keep the pups clean and they generally seem not to care. Their pups usually die. Inexplicably, the gene is paternally inherited. Only the version inherited from the father functions; the mother's version remains silent.15
The Haig theory of conflict over embryonic growth does not easily explain these facts. But the Japanese biologist Yoh Iwasa has 2 l 6 G E N O M E
a theory that does. He argues that because the father's sex chromosome determines the sex of the offspring — if he passes on an X
rather than a Y chromosome, the offspring is female — so 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.16
The best vindication of this idea comes from an unusual natural experiment studied by David Skuse and his colleagues at the Institute of Child Health in London. Skuse located eighty women and girls aged between six and twenty-five who suffered from Turner's syndrome, a disorder caused by the absence of all or part of the X
chromosome. Men have only one X chromosome, and women keep one of their two X chromosomes switched off in all their cells, so Turner's syndrome should, in principle, make little difference to development. Indeed, Turner's girls are of normal intelligence and appearance. However, they often have trouble with 'social adjustment'. Skuse and his colleagues decided to compare two kinds of Turner's girls: those with the paternal X chromosome missing and those with the maternal X chromosome missing. 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. Skuse and his colleagues determined this by setting the children standard tests for cognition, and giving the parents questionnaires to assess social adjustment. The questionnaire asked the parents if the child lacked awareness of other people's feelings, did not realise when others were upset or angry, was oblivi-ous to the effect of her behaviour on other members of the family, was very demanding of people's time, was difficult to reason with when upset, unknowingly offended people with her behaviour, did not respond to commands, and other similar questions. The parents had to respond with 0 (for 'not at all true'), 1 for 'quite or sometimes S E X 2 1 7
true' and 2 for 'very or often true'. The total from all twelve questions was then totted up. All the Turner's girls had higher scores than normal girls and boys, but the ones who were lacking the paternal X chromosome had more than twice the score of the ones lacking the maternal X chromosome.
The inference is that there is an imprinted gene somewhere on the X chromosome, which is normally switched on only in the paternal copy and that this gene somehow enhances the development of social adjustment - the ability to understand other's feelings, for example. Skuse and his colleagues provided further evidence of this from children who were missing only part of one X chromosome.17
This study has two massive implications. First, it suggests an explanation for the fact that autism, dyslexia, language impairment and other social problems are much commoner in boys than girls.
A boy receives only one X chromosome, from his mother, so he presumably gets one with the maternal imprint and the gene in question switched off. As of this writing, the gene has not been located, but imprinted genes are known from the X chromosome.
But second, and more generally, we are beginning to glimpse an end to the somewhat ridiculous argument over gender differences that has continued throughout the late twentieth century and has pitted nature against nurture. Those in favour of nurture have tried to deny any role for nature, while those who favour nature have rarely denied a role for nurture. The question is not whether nurture has a role to play, because nobody of any sense has ever gone on record as denying that it does, but whether nature has a role to play at all. When my one-year-old daughter discovered a plastic baby in a toy pram one day while I was writing this chapter, she let out the kinds of delighted squeals that her brother had reserved at the same age for passing tractors. Like many parents, I found it hard to believe that this was purely because of some unconscious social conditioning that we had imposed. Boys and girls have systematically different interests from the very beginning of autonomous behaviour. Boys are more competitive, more interested in machines, weapons and deeds. Girls are more interested in people, clothes and words. To 2 l 8 G E N O M E
put it more boldly, it is no thanks only to upbringing that men like maps and women like novels.
In any case, the perfect, if unconscionably cruel, experiment has been done by the supporters of pure nurture. In the 1960s, in the United States, a botched circumcision left a boy with a badly damaged penis, which the doctor decided to amputate. It was decided to try to turn the boy into a girl by castration, surgery and hormonal treatment. John became Joan; she wore dresses and played with dolls. She grew up into a young woman. In 1973 John Money, a Freudian psychologist, claimed in a burst of publicity that Joan was a well adjusted adolescent, and her case thus put an end to all speculation: gender roles were socially constructed.
Not until 1997 did anybody check the facts. When Milton Diamond and Keith Sigmundson tracked down Joan, they found a man, happily married to a woman. His story was very different from that told by Money. He had always felt deeply unhappy about something as a child and had always wanted to wear trousers, mix with boys and urinate standing up. At the age of fourteen he was told by his parents what had happened, which brought great relief. He ceased hormonal treatment, changed his name back to John, resumed the life of a man, had his breasts removed and at the age of twenty-five married a woman and adopted her children. Held up as a proof of socially constructed gender roles, he proved the exact opposite: that nature does play a role in gender. The evidence from zoology has always pointed that way: male behaviour is systematically different from female behaviour in most species and the difference has an innate component. The brain is an organ with innate gender. The evidence from the genome, from imprinted genes and genes for sex-linked behaviours, now points to the same conclusion.18
C H R O M O S O M E 1 6
M e m o r y
Heredity provides for the modification of its own machinery. James Mark Baldwin, 1896
The human genome is a book. By reading it carefully from beginning to end, taking due account of anomalies like imprinting, a skilful technician could make a complete human body. Given the right mechanism for reading and interpreting the book, an accomplished modern Frankenstein could carry out the feat. But what then? He would have made a human body and imbued it with the elixir of life, but for it to be truly alive it would have to do more than exist.
It would have to adapt, to change and to respond. It would have to gain its autonomy. It would have to escape Frankenstein's control.
There is a sense in which the genes, like the hapless medical student in Mary Shelley's story, must lose control of their own creation.
They must set it free to find its own path through life. The genome does not tell the heart when to beat, nor the eye when to blink, nor the mind when to think. Even if the genes do set some of the parameters of personality, intelligence and human nature with surprising precision, they know when to delegate. Here on chromosome 2 2 0 G E N O M E
16 lie some of the great delegators: genes that allow learning and memory.
We human beings may be determined to a surprising extent by the dictates of our genes, but we are determined even more by what we have learnt in our lifetimes. The genome is an information-processing computer that extracts useful information from the world by natural selection and embodies that information in its designs.
Evolution is just terribly slow at processing the information, needing several generations for every change. Little wonder that the genome has found it helpful to invent a much faster machine, whose job is to extract information from the world in a matter of minutes or seconds and embody that information in behaviour - the brain.
Your genome supplies you with the nerves to tell when your hand is hot. Your brain supplies you with the action to remove your hand from the stove-top.
The subject of learning lies in the provinces of neurosciences and psychology. It is the opposite of instinct. Instinct is genetically-determined behaviour; learning is behaviour modified by experience.
The two have little in common, or so the behaviourist school of psychology would have had us all believe during much of the twentieth century. But why are some things learnt and others instinctive?
Why is language an instinct, while dialect and vocabulary are learnt?
James Mark Baldwin, the hero of this chapter, was an obscure American evolutionary theorist of the last century, who wrote an article in 1896 summarising a dense and philosophical argument that had little influence at the time, or indeed at any time during the subsequent ninety-one years. But by a stroke of good fortune, he was plucked from obscurity by a group of computer scientists in the late 1980s, who decided his argument was of great relevance to their problem of teaching computers how to learn.1
What Baldwin wrestled with was the question of why something is learnt by an individual in his lifetime rather than pre-programmed as an instinct. There is a commonly held belief that learning is good, instinct bad - or, rather, that learning is advanced and instinct primitive. It is therefore a mark of human rank that we need to M E M O R Y 2 2 1
learn all sorts of things that come naturally to animals. Artificial-Intelligence researchers, following this tradition, quickly placed learning on a pinnacle: their goal was the general-purpose learning machine. But this is just a factual mistake. Human beings achieve by instinct the same things that animals do. We crawl, stand, walk, cry and blink in just as instinctive a way as a chick. We employ learning only for the extra things we have grafted on to the animal instincts: things like reading, driving, banking and shopping. 'The main function of consciousness', wrote Baldwin, 'is to enable [the child] to learn things which natural heredity fails to transmit.'
And by forcing ourselves to learn something, we place ourselves in a selective environment that puts a premium on a future instinctive solution to the problem. Thus, learning gradually gives way to instinct. In just the same way, as I suggested in the chapter on chromosome 13, the invention of dairy farming presented the body with the problem of the indigestibility of lactose. The first solution was cultural - to make cheese — but later the body evolved an innate solution by retaining lactase production into adulthood. Perhaps even literacy would become innate eventually if illiterate people were at a reproductive disadvantage for long enough. In effect, since the process of natural selection is one of extracting useful information from the environment and encoding it in the genes, there is a sense in which you can look on the human genome as four billion years'
worth of accumulated learning.
However, there comes a limit to the advantages of making things innate. In the case of spoken language, where we have a strong instinct, but a flexible one, it would clearly be madness for natural selection to go the whole hog and make even the vocabulary of the language instinctive. That way language would have been far too inflexible a tool: lacking a word for computer, we would have to describe it as 'the thing that thinks when you communicate with it'.
Likewise, natural selection has taken care (forgive the teleological shorthand) to equip migratory birds with a star-navigation system that is not fully assembled. Because of the precession of the equi-noxes, which gradually changes the direction of North, it is vital 2 2 2 G E N O M E
that birds recalibrate their star compass in every generation through learning.
The Baldwin effect is about the delicate balance between cultural and genetic evolution. They are not opposites, but comrades, trading influence with each other to get best results. An eagle can afford to learn its trade from its parents the better to adapt to local conditions; a cuckoo, by contrast, must build everything into instinct because it will never meet its parents. It must expel its foster siblings from the nest within hours of hatching; migrate to the right part of Africa in its youth with no parents to guide it; discover how to find and eat caterpillars; return to its birthplace the following spring; acquire a mate; locate the nest of a suitable host bird - all by a series of instinctive behaviours with judicious bouts of learning from experience.
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. Bumble bees, for instance, have been shown to learn a great deal from experience about how to gather nectar from different types of flowers. Trained on one kind, they are incompetent at another until they have had practice; but once they know how to deal with, say, monkshood, they are also better at dealing with similar-shaped flowers such as lousewort - thus proving that they have done more than memorise individual flowers, but have generalised some abstract principles.
Another famous example of animal learning in an equally simple creature is the case of the sea slug. A more contemptibly basic animal is hard to imagine. It is slothful, small, simple and silent. It has a minute brain and it lives its life of eating and sex with an enviable lack of neurosis. It cannot migrate, communicate, fly or think. It just exists. Compared with, say, a cuckoo or even a bumble bee, its life is a cinch. If the idea that simple animals use instincts and complicated ones learn is right, then the sea slug has no need of learning.
Yet learn it can. If a jet of water is blown upon its gill, it withdraws the gill. But if the jet of water is repeatedly blown on the gill, the M E M O R Y 2 2 3
withdrawal gradually ceases. The sea slug stops responding to what it now recognises as a false alarm. It 'habituates'. This is hardly learning the differential calculus, but it is learning all the same.
Conversely, if given an electric shock once, before water is blown on the gill, the sea slug learns to withdraw its gill even further than usual - a phenomenon called sensitisation. It can also be 'classically conditioned', like Pavlov's famous dogs, to withdraw its gill when it receives only a very gentle puff of water if that gentle puff is paired with an electric shock: thereafter, the gentle puff alone, normally insufficient to make the sea slug withdraw its gill, results in a rapid gill withdrawal. Sea slugs, in other words, are capable of the same kinds of learning as dogs or people: habituation, sensitisation and associative learning. Yet they do not even use their brains. These reflexes and the learning that modifies them occur in the abdominal ganglion, a small nervous substation in the belly of the slimy creature.
The man behind these experiments, Eric Kandel, had a motive other than bothering slugs. He wanted to understand the basic mechanism by which learning occurred. What is learning? What changes occur to nerve cells when the brain (or the abdominal ganglion) acquires a new habit or a change in its behaviour? The central nervous system consists of lots of nerve cells, down each of which electrical signals travel; and synapses, which are junctions between nerve cells. When an electrical nerve signal reaches a synapse, it must transfer to a chemical signal, like a train passenger catching a ferry across a sea channel, before resuming its electrical journey. Kandel's attention quickly focused on these synapses between neurons. Learning seems to be a change in their properties.
Thus when a sea slug habituates to a false alarm, the synapse between the receiving, sensory neuron and the neuron that moves the gill is somehow weakened. Conversely, when the sea slug is sensitised to the stimulus, the synapse is strengthened. Gradually and ingeniously, Kandel and his colleagues homed in on a particular molecule in the sea-slug brain which lay at the heart of this weakening or strengthen-ing of the synapses. The molecule is called cyclic A M P .
Kandel and his colleagues discovered a cascade of chemical 2 2 4 G E N O M E
changes all centred around cyclic A M P . Ignoring their names, imagine a string of chemicals called A, B, C and so on: A makes B,
Which activates C,
Which opens a channel called D,
Thus allowing more of E into the cell,
Which prolongs the release of F,
Which is the neurotransmitter that ferries the signal across the synapse to the next neuron.
Now it so happens that C also activates a protein called C R E B
by changing its form. Animals that lack this activated form of C R E B
can still learn things, but cannot remember them for more than an hour or so. This is because C R E B , once activated, starts switching on genes and thus altering the very shape and function of the synapse. The genes thus alerted are called CRE genes, which stands for cyclic-AMP response elements. If I go into more detail I will drive you back to the nearest thriller, but bear with me, it is about to get simpler again.2
So simple, in fact, that it is time to meet dunce. Dunce is a mutant fruit fly incapable of learning that a certain smell is always followed by an electric shock. Discovered in the 1970s, it was the first of a string of 'learning mutants' to be discovered by giving irradiated flies simple tasks to learn and breeding from those that could not manage the tasks. Other mutants called cabbage, amnesiac, rutabaga, radish and turnip soon followed. (Once again, fruit-fly geneticists are allowed much more liberty with gene names than their human-genetics colleagues.) In all, seventeen learning mutations have now been found in flies. Alerted by the feats of Kandel's sea slugs, Tim Tully of Cold Spring Harbor Laboratory set out to find out exactly what was wrong with these mutant flies. To Tully's and Kandel's delight, the genes that were 'broken' in these mutants were all involved in making or responding to cyclic A M P . 3
Tully then reasoned that if he could knock out the flies' ability M E M O R Y 2 2 5
to learn, he could alter or enhance it as well. By removing the gene for the C R E B protein, he created a fly that could learn, but not remember that it had learnt - the lesson soon faded from its memory.
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. I am often struck by the fact that I easily 'remember' -
i.e., recognise — that I have read a particular piece of text before, or heard a particular radio programme, yet I could not have recited either: the memory is somehow hidden from my consciousness.
Presumably, it is not so hidden in mnemonists' minds.)4
Tully believes that C R E B lies at the heart of learning and memory mechanisms, a sort of master gene that switches on other genes. So the quest to understand learning becomes a genetic quest after all.
Far from escaping from the tyranny of genes by discovering how to learn instead of behave instinctively, we have merely found that the surest way to understand learning is to understand the genes and their products that enable learning to occur.
By now, it will come as no surprise to learn that C R E B is not confined to flies and slugs. Virtually the same gene is present in mice, as well, and mutant mice have already been created by knocking out the mouse CREB gene. As predicted they are incapable of simple learning tasks, such as remembering where the hidden under-water platform lies in a swimming bath (this is standard torture in mouse learning experiments) or remembering which foods were safe to eat. Mice can be made temporarily amnesiac by injecting the
'antisense', or opposite, of the CREB gene into their brains - this 2 2 6 G E N O M E
silences the gene for a while. Likewise, they are super-learners if their CREB gene is especially active.5
And from mice to men is but an evolutionary hair's breadth. We human beings have CREB genes, too. The human CREB gene itself is on chromosome 2, but its crucial ally, which helps CREB
to do its job, called CREBBP, is right here on chromosome 16.
Together with another learning' gene called alpha-integrin, also on chromosome 16, it provides me with a (somewhat weak) excuse for a chapter on learning.
In fruit flies the cyclic A M P system seems to be especially active in brain regions called mushroom bodies, toadstool-shaped extrusions of neurons in the fruit fly brain. If a fly has no mushroom bodies in its brain, then it is generally incapable of learning the association between a smell and an electric shock. C R E B and cyclic A M P seem to do their work in these mushroom bodies. Exactly how is only now becoming clear. By systematically searching for other mutant flies incapable of learning or memory, Ronald Davis, Michael Grotewiel and their colleagues in Houston came up with a different kind of mutant fly, which they called volado. ('Volado', they helpfully explain, is a Chilean colloquialism meaning something akin to 'absent-minded' or 'forgetful', and generally applied to professors.) Like dunce, cabbage and rutabaga, volado flies have a hard time learning.
But unlike those genes, volado seems to have nothing to do with C R E B or cyclic A M P . It is the recipe for a subunit of a protein called an alpha-integrin, which is expressed in mushroom bodies, and which seems to play a role in binding cells together.
To check that this was not a 'chopstick' gene (see the chapter on chromosome 11) that had lots of effects beside altering memory, the Houston scientists did something rather clever. They took some flies in which the volado gene had been knocked out, and inserted a fresh copy linked with a 'heat-shock' gene - a gene that becomes switched on when suddenly heated up. 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 M E M O R Y 2 2 7
learners. A few hours after that, as the heat shock faded into the past, they again lost the ability to learn. This means that volado is needed at the exact moment of learning; it is not just a gene required to build the structures that do the learning.6
The fact that the volado gene's job is to make a protein that binds cells together raises the intriguing hint that memory may consist, quite literally, of the tightening of the connections between neurons.
When you learn something, you alter the physical network of your brain so as to create new, tight connections where there were none or weaker ones before. I can just about accept that this is what learning and memory consist of, but I have a hard time imagining how my memory of the meaning of the word 'volado' consists of some strengthened synaptic connections between a few neurons. It is distinctly mind-boggling. Yet far from having removed the mystery from the problem by reducing it to the molecular level, I feel that scientists have opened before me a new and intriguing mystery, the mystery of trying to imagine how connections between nerve cells not only provide the mechanism of memory but are memory. It is every bit as thrilling a mystery as quantum physics, and a great deal more thrilling than Ouija boards and flying saucers.
Let us delve a little deeper into the mystery. The discovery of volado hints at the hypothesis that integrins are central to learning and memory, but there were already hints of this kind. By 1990 it was already known that a drug that inhibited integrins could affect memory. Specifically, such a drug interfered with a process called long-term potentiation ( L T P ) , which seems to be a key event in the creation of a memory. Deep in the base of the brain lies a structure called the hippocampus (Greek for sea-horse) and a part of the hippocampus is called the Ammon's horn (after the Egyptian god associated with the ram and later adopted as his 'father' by Alexander the Great after his mysterious visit to the Siwah oasis in Libya). In the Ammon's horn, in particular, there are a large number of 'pyramidal' neurons (note the continuing Egyptian theme) which gather together the inputs of other, sensory neurons. A pyramidal neuron is difficult to 'fire', but if two separate inputs arrive at once, 2 2 8 G E N O M E
their combined effect will fire it. Once fired, it is much easier to fire but only by one of the two inputs that originally fired it, and not by another input. Thus, the sight of a pyramid and the sound of the word 'Egypt' can combine to fire a pyramidal cell, creating an associative memory between the two, but the thought of a sea-horse, although perhaps connected to the same pyramidal cell, is not
'potentiated' in the same way because it did not coincide in time.
That is an example of long-term potentiation. If you think, too simplistically, of the pyramidal cell as the memory of Egypt, then it can now be fired by the word or the picture, but not by a sea-horse.
Long-term potentiation, like sea-slug learning, absolutely depends on a change in the properties of synapses, in this case the synapses between the inputting cells and the pyramidal cells. That change almost certainly involves integrins. Oddly, the inhibition of integrins does not interfere with the formation of long-term potentiation, but it does interfere with its maintenance. Integrins are probably needed for literally holding the synapse closely together.
I glibly implied a few moments ago that the pyramidal cell might actually be a memory. This is nonsense. The memories of your childhood do not even reside in the hippocampus, but in the neo-cortex. What resides in and near the hippocampus is the mechanism for creating a new long-term memory. Presumably, the pyramidal cells in some manner transmit that newly formed memory to where it will reside. We know this because of two remarkable and unfortunate young men, who suffered bizarre accidents in the 1950s. The first, known in the scientific literature by the initials H.M., had a chunk of his brain removed to prevent the epileptic seizures caused by a bicycle accident. The second, known as N.A., was a radar technician in the air force, who one day was sitting building a model when he happened to turn round. A colleague, who was playing with a miniature fencing foil, chose that moment to stab forward and the foil passed through N.A.'s nostril and into his brain.
Both men suffer to this day from terrible amnesia. They can remember events from their childhood quite clearly and from right up to a few years before their accidents. They can memorise current M E M O R Y 2 2 9
events briefly if not interrupted before being asked to recall them.
But they cannot form new long-term memories. They cannot recognise the face of somebody they see every day or learn their way home. In N.A.'s (milder) case, he cannot enjoy television because commercials cause him to forget what went before them.
H.M. can learn a new task quite well and retains the skill, but cannot recall that he has learnt it - which implies that procedural memories are formed somewhere different from 'declarative' memories for facts or events. This distinction is confirmed by a study of three young people with severe amnesia for facts and events, who were found to have gone through school, acquiring reading, writing and other skills with comparatively little difficulty. All three, on being scanned, proved to have unusually small hippocampuses.7
But we can get a little more specific than just saying that memories are made in hippocampuses. The damage that both H.M. and N.A.
suffered implies a connection between two other parts of the brain and memory formation: the medial temporal lobe, which H.M. lacks, and the diencephalon, which N.A. partly lacks. Prompted by this, neuroscientists have gradually narrowed down the search for the most vital of all memory organs to one principal structure, the perirhinal cortex. It is here that sensory information, sent from the visual, auditory, olfactory or other areas, is processed and made into memories, perhaps with the help of C R E B . The information is then passed to the hippocampus and thence to the diencephalon for temporary storage. If it is deemed worthy of permanent preservation it is sent back to the neo-cortex as a long-term memory: that strange moment when you suddenly don't need to keep looking up somebody's telephone number but can recall it. It seems probable that the transmission of memory from the medial temporal lobe to the neo-cortex happens at night during sleep: in rats' brains the cells of the lobe fire actively at night.
The human brain is a far more impressive machine than the genome. If you like quantitative measures, it has trillions of synapses instead of billions of bases and it weighs kilograms instead of micro-grams. If you prefer geometry, it is an analogue, three-dimensional 2 3 0 G E N O M E
machine, rather than a digital, one-dimensional one. If you like thermodynamics, it generates large quantities of heat as it works, like a steam engine. For biochemists, it requires many thousands of different proteins, neurotransmitters and other chemicals, not just the four nucleotides of D N A . For the impatient, it literally changes while you watch, as synapses are altered to create learned memories, whereas the genome changes more slowly than a glacier. For the lover of free will, the pruning of the neural networks in our brains, by the ruthless gardener called experience, is vital to the proper functioning of the organ, whereas genomes play out their messages in a predetermined way with comparatively little flexibility. 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.
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D e a t h
Dulce et decorum est pro patria mori
Horace
The old lie
Wilfred Owen
If learning is making new connections between brain cells, it is also about losing old connections. The brain is born with far too many connections between cells; many are lost as it develops. For example, at first each side of the visual cortex is connected to one half of the input from both eyes. Only by fairly drastic pruning does this change so that one slice of the brain receives input from the right eye and another slice receives input from the left eye. Experience causes the unnecessary connections to wither away and thereby turns the brain from a general to a specific device. Like a sculptor chipping away at a block of marble to find the human form within, so the environment strips away the surplus neurons to sharpen the skills of the brain. In a blind, or permanently blindfolded young mammal, this sorting out never happens.
But the withering means more than the loss of synaptic connections. It also means the death of whole cells. A mouse with a faulty version of a gene called ced-9 fails to develop properly because cells 2 3 2 G E N O M E
in its brain that are not needed fail to do their duty and die. The mouse ends up with a disorganised and overloaded brain that does not work. Folk wisdom loves to recite the grim (but meaningless) statistic that we lose a million brain cells a day. In our youth, and even in the womb, we do indeed lose brain cells at a rapid rate. If we did not, we would never be able to think at all.1
Prodded by genes like ced-9, the unneeded cells commit mass suicide (other ced genes cause suicide in other body tissues). The dying cells obediently follow a precise protocol. In microscopic nematode worms, the growing embryo eventually contains 1,090
cells, but precisely 131 of these kill themselves during development, leaving 959 cells in an adult worm. It is as if they sacrifice themselves for the greater good of the body. 'Dulce et decorum est pro corpore mori''
they cry and fade heroically away, like soldiers going over the top at Verdun, or worker bees suicidally stinging an intruder. The analogy is far from specious. The relationship between body cells is indeed very much like that between bees in a hive. The ancestors of your cells were once individual entities and their evolutionary 'decision'
to co-operate, some 600 million years ago, is almost exactly equivalent to the same decision, taken perhaps fifty million years ago by the social insects, to co-operate on the level of the body: 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.2
The analogy is so good that evolutionary biologists have begun to realise that the co-operative spirit goes only so far. Just as soldiers at Verdun were occasionally driven to mutiny against the greater good, so worker bees are capable of reproducing on their own if they get the chance; only the vigilance of other workers prevents them. The queen buys the loyalty of those other workers to herself rather than to their sister workers by mating with several males to ensure that most workers are only half-sisters of each other and therefore share little genetic common interest. And so it is with cells in the body. Mutiny is a perpetual problem. Cells are continually forgetting their patriotic duty, which is to serve the germ cells, and D E A T H 233
setting out to reproduce themselves. After all, each cell is descended from a long line of reproducing cells; it goes against the grain to cease dividing for a whole generation. And so, in every tissue every day, there is a cell that breaks ranks and starts to divide again, as if unable to resist the age-old call of the genes to reproduce themselves.
If the cell cannot be stopped, we call the result cancer.
But usually, it can be stopped. The problem of cancerous mutiny is so old that in all large bodied animals the cells are equipped with an elaborate series of switches designed to induce the cell to commit suicide if it should find itself turning cancerous. The most famous and important of these switches, in fact possibly the most talked about of all human genes since its discovery in 1979, is TP53, which lies on the short arm of chromosome 17. This chapter tells the remarkable story of cancer, through the eyes of a gene whose principal job is to prevent it.
When Richard Nixon declared war on cancer in 1971, scientists did not even know what the enemy was, beyond the obvious fact that it was an excessive growth of tissue. Most cancer was plainly neither infectious nor inherited. The conventional wisdom was that cancer was not a single form of disease at all, but a collection of diverse disorders induced by a multiplicity of causes, most of them external. Chimney sweeps 'caught' scrotal cancer from coal tar; X-ray technicians and Hiroshima survivors contracted leukaemia from radiation; smokers 'caught' lung cancer from cigarette smoke and shipyard workers 'caught' the same affliction from asbestos fibres.
There might be no common thread, but if there was it probably involved a failure of the immune system to suppress tumours. So went the conventional wisdom.
Two rival lines of research were, however, beginning to produce new insights that would lead to a revolution in the understanding of cancer. The first was the discovery in the 1960s by Bruce Ames in California that many chemicals and radiations that caused cancer, such as coal tar and X-rays, had one crucial thing in common: they were very good at damaging D N A . Ames glimpsed the possibility that cancer was a disease of the genes.
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The second breakthrough had begun much earlier. In 1909, Peyton Rous had proved that a chicken with a form of cancer called sarcoma could pass the disease to a healthy chicken. His work was largely ignored, since there seemed so little evidence that cancer was contagious. But in the 1960s, a whole string of animal cancer viruses, or oncoviruses, were discovered, beginning with the Rous sarcoma virus itself. Rous was eventually given the Nobel prize at the age of eighty-six in recognition of his prescience. Human oncoviruses soon followed and it became apparent that whole classes of cancer, such as cervical cancer, were indeed caused partly by viral infection.
Putting the Rous sarcoma virus through the gene-sequencer revealed that it carried a special cancer-causing gene, now known as src. Other such 'oncogenes' soon followed from other oncoviruses.
Like Ames, the virologists were beginning to realise that cancer was a disease of genes. In 1975 the world of cancer research was turned upside down by the discovery that src was not a viral gene at all. It was a gene that we all possessed, chicken, mouse and human, too. The Rous sarcoma virus had stolen its oncogene from one of its hosts.
More conventional scientists were reluctant to accept that cancer was a genetic disease: after all, except in rare cases, cancer was not inherited. What they were forgetting was that genes are not confined to the germline; they also function during an organism's lifetime in every other organ. A genetic disease within an organ of the body, but not in the reproductive cells, could still be a genetic disease. By 1979, D N A taken from three kinds of tumour had been used to induce cancerous growth in mouse cells, thus proving that genes alone could cause cancer.
It was obvious from the start what kinds of genes oncogenes would turn out to be - genes that encourage cells to grow. Our cells possess such genes so that we can grow in the womb and in childhood, and so that we can heal wounds in later life. But it is vital that they are switched off most of the time; if they are jammed on, the result can be disastrous. With 100 trillion body cells, and a fairly rapid turnover, there are plenty of opportunities for oncogenes to be jammed on during a lifetime, even without the encouragement D E A T H 2 3 5
of mutation-causing cigarette smoke or sunlight. Fortunately, however, the body possesses genes whose job is to detect excessive growth and shut it down. These genes, discovered first in the mid-1980s by Henry Harris at Oxford, are known as tumour-suppressor genes. Tumour suppressors are the opposite of oncogenes. Whereas oncogenes cause cancer if they are jammed on, tumour-suppressor genes cause cancer if they are jammed off.
They do their job by various means, the most prominent of which is to arrest a cell at a certain point in its cycle of growth and division, then release it from arrest only if it has all its papers in order, so to speak. To progress beyond this stage, therefore, a tumour must contain a cell that has both a jammed-on oncogene and a jammed-off tumour-suppressor gene. That is unlikely enough, but it is not the end of the matter. To escape and grow uncontrollably, the tumour must now pass by an even more determined checkpoint, manned by a gene that detects abnormal behaviour in a cell and issues an instruction to different genes to dismantle the cell from the inside: to commit suicide. This is TP53.
When TP53 was first discovered, by David Lane in Dundee in 1979, it was thought to be an oncogene, but it was later recognised to be a tumour suppressor. Lane and his colleague Peter Hall were discussing TP53 in a pub one day in 1992 when Hall offered his arm as a guinea pig for testing if TP53 was a tumour suppressor. Getting permission to perform an animal test would take months, but an experiment on a human volunteer could be done right away. Hall repeatedly scarred a small part of his arm with radiation and Lane took biopsies over the succeeding two weeks. They showed a dramatic rise in the level of p53, the protein manufactured from TP53, following the radiation damage, clear evidence that the gene responded to cancer-causing damage. Lane has gone on to develop p53 as a potential cancer cure in clinical trials; the first human volunteers will be taking the drug as this book is being published.
Indeed, so rapidly has cancer research in Dundee grown that p53
is now bidding to be the third most famous product of the small Scottish city on the Tay estuary, after jute and marmalade.
2 3 6 G E N O M E
Mutation in the TP53 gene is almost the defining feature of a lethal cancer; in fifty-five per cent of all human cancers, TP53 is broken. The proportion rises to over ninety per cent among lung cancers. People born with one faulty version of TP53 out of the two they inherit, have a ninety-five per cent chance of getting cancer, and usually at an early age. Take, as an example, colorectal cancer.
This cancer begins with a mutation that breaks a tumour-suppressor gene called APC. If the developing polyp then suffers a second mutation jamming on an oncogene called RAS, it develops into a so-called 'adenoma'. If it then suffers a third mutation breaking another, unidentified tumour-suppressor gene, the adenoma grows into a more serious tumour. And now comes the danger of a fourth mutation, in the TP53 gene, which turns the tumour into a full carcinoma. Similar multi-hit models apply to other kinds of cancer, with TP53 often coming last.
You can now see why detecting cancer early in the development of the tumour is so important. The larger a tumour becomes, the more likely it is to suffer the next mutation, both because of general probability and because the rapid proliferation of cells inside the tumour can easily lead to genetic mistakes, which can cause mutations. People who are especially susceptible to certain cancers often carry mutations in 'mutator' genes, which encourage mutation generally (the breast cancer genes BRCA1 and BRCA2, discussed in the chapter on chromosome 13, are probably breast-specific mutator genes), or because they already carry one faulty version of a tumour-suppressor gene. 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 environ-D E A T H 2 3 7
ment selects rabbits. It is not mysterious that mutations eventually show up in so many cases. Mutation is random, but selection is not.
Likewise, it is now clear why cancer is a disease that very roughly doubles in frequency every decade of our lives, being principally a disease of old age. In somewhere between a tenth and a half of us, depending on the country we live in, cancer will eventually get round the various tumour-suppressor genes, including TP53, and will inflict a terrible and possibly fatal disease upon us. That this is a sign of the success of preventative medicine, which has eliminated so many other causes of death at least in the industrialised world, is little consolation. The longer we live, the more mistakes we accumulate in our genes, and the greater the chance that an oncogene may be jammed on and three tumour-suppressor genes jammed off in the same cell. The chances of this occurring are almost unimaginably small, but then the number of cells we make in our lifetimes is almost unimaginably large. As Robert Weinberg has put it:5 'One fatal malignancy per one hundred million billion cell divisions does not seem so bad after all.'
Let us take a closer look at the TP53 gene. It is 1,179 'letters'
long, and encodes the recipe for a simple protein, p53, that is normally rapidly digested by other enzymes so that it has a half-life of only twenty minutes. In this state, p53 is inactive. But upon receipt of a signal, production of the protein increases rapidly and destruction of it almost ceases. Exactly what that signal is remains shrouded in mystery and confusion, but damage to D N A is part of it. Bits of broken D N A seem somehow to alert p53. Like a criminal task force or S W A T team, the molecule scrambles to action stations. What happens next is that p53 takes charge of the whole cell, like one of those characters played by Tommy Lee Jones or Harvey Keitel who arrives at the scene of an incident and says something like: ' F B I : we'll take over from here.' Mainly by switching on other genes, p53 tells the cell to do one of two things: either to halt proliferation, stop replicating its D N A and pause until repaired; or to kill itself.
Another sign of trouble that alerts p53 is if the cell starts to run 2 3 8 G E N O M E
short of oxygen, which is a diagnostic feature of tumour cells. Inside a growing ball of cancer cells, the blood supply can run short, so the cells begin to suffocate. Malignant cancers get over this problem by sending out a signal to the body to grow new arteries into the tumour - the characteristic, crab-claw-like arteries that first gave cancer its Greek name. Some of the most promising new cancer drugs block this process of 'angiogenesis', or blood-vessel formation.
But P53 sometimes realises what is happening and kills the tumour cells before the blood supply arrives. Cancers in tissues with poor blood supply, such as skin cancers, therefore must disable TP53 early in their development or fail to grow. That is why melanomas are so dangerous.
Little wonder that p53 has earned the nickname 'Guardian of the Genome', or even 'Guardian Angel of the Genome'. TP53 seems to encode the greater good, like a suicide pill in the mouth of a soldier that dissolves only when it detects evidence that he is about to mutiny. 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 pref-erentially killed dividing cells by damaging their D N A as it was being copied. But if that is the case, why do some tumours respond so poorly to treatment? There comes a point in the progression of fatal cancer when the treatment no longer works - the tumour no longer shrinks under chemical or radiation attack. Why should this be? If the treatment kills dividing cells, it should continue to work at all times.
Scott Lowe, working at Cold Spring Harbor Laboratory, has an ingenious answer. These treatments do indeed cause a little D N A damage, he says, but not enough to kill the cells. Instead, the D N A damage is just sufficient to alert p53, which tells the cells to commit suicide. So chemotherapy and radiation therapy are actually, like D E A T H 239
vaccination, treatments that work by helping the body to help itself.
The evidence for Lowe's theory is good. Radiation, or treatment with 5 -fluorouracil, etoposide or adriamycin - three chemical cancer treatments - all encourage apoptosis in laboratory cells infected with a viral oncogene. And when hitherto tractable tumours relapse and suddenly fail to respond to treatment, the change correlates closely with a mutation knocking out TP53. Likewise, 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.
These insights are of great importance to the treatment of cancer.
A major branch of medicine has been acting under a large misappre-hension. Instead of looking for agents that kill dividing cells, doctors should have been looking for agents that encourage cell suicide.
That does not mean chemotherapy has been wholly ineffective, but it has been effective only by accident. Now that medical research knows what it is doing, the results should be more promising. In the short term it promises a less painful death for many cancer patients. By testing to see if TP53 is already broken, doctors should soon be able to tell in advance if chemotherapy will work. If it will not, then the patient and his or her family can be spared the suffering and false hope that is now such a feature of the last months of life for such people.7
Oncogenes, in the unmutated state, are needed for cells to grow and proliferate normally throughout life: skin must be replaced, new blood cells generated, wounds repaired and so on. The mechanism for suppressing potential cancers must allow exceptions for normal growth and proliferation. Cells must frequently be given permission to divide, and must be equipped with genes that encourage division, so long as they stop at the right moment. How this feat is achieved is beginning to become clear. If we were looking at a man-made thing, we would conclude that a fiendishly ingenious mind must be behind it.
Once again, the key is apoptosis. Oncogenes are genes that cause division and growth but, surprisingly, several of them also trigger 2 4 0 G E N O M E
cell death. In the case of one such gene, known as MYC, both division and death are triggered by the gene, but its death signal is temporarily suppressed by external factors called survival signals.
When these survival signals run out, death takes over. It is as if the designer, aware of MYC's capacity to run amok, has automatically booby-trapped it so that any cell which gets carried away kills itself as soon as the supply of survival factors expires. The ingenious designer has gone a step further, by tying together three different oncogenes, MYC, BCL-2 and RAS, so that they control each other.
Normal cell growth can only occur if all three are working properly.
In the words of the scientists who discovered these connections:
'Without such support, booby traps spring and the affected cell is either killed or rendered moribund - either way, it is no longer a
[cancerous] threat.'
The story of p53 and the oncogenes, like much of my book, challenges the argument that genetic research is necessarily dangerous and should be curtailed. The story also strongly challenges the view that 'reductionist' science, which takes systems apart to understand them, is flawed and futile. Oncology, the medical study of whole cancers, diligent, brilliant and massively endowed though it was, achieved terribly little by comparison with what has already been achieved in a few years by a reductionist, genetic approach.
Indeed, one of the first calls for the complete sequencing of the human genome came from the Italian Nobel prize-winner Renato Dulbecco in 1986 because, he argued, it was the only way to win the war on cancer. There is now, for the first time in human history, a real prospect of a genuine cure for cancer, the cruellest and most common killer of all in the west, and it has come from reductionist, genetic research and the understanding that this brings. Those who would damn the whole science as dangerous should remember that.9
Natural selection, once she has selected a method of solving one problem, frequently uses it to solve another. Apoptosis has other functions than the elimination of cancer cells. It is also useful in the fight against ordinary infectious disease. If a cell detects that it has been infected with a virus, it can kill itself for the good of the D E A T H 2 4 1
body as a whole (ants and bees may do this as well, for the good of their colonies). There is good evidence that some cells do indeed do exactly this. There is also, inevitably, evidence that some viruses have evolved a way of preventing this from happening. Epstein¬
Barr virus, the cause of glandular fever or mononucleosis, contains a latent membrane protein whose job seems to be to head off any tendency the infected cell shows to commit suicide. Human papil-loma virus, cause of cervical cancer, has two genes aboard whose job is to switch off TP53 and another tumour-suppressor gene.
As I mentioned in the chapter on chromosome 4, Huntington's disease consists of unplanned and excessive apoptosis of brain cells which cannot then be replaced. Neurons cannot be regenerated in the adult brain - which is why some brain damage is irreversible.
This makes good evolutionary sense because unlike, say, skin cells, each neuron is an exquisitely shaped, trained and experienced opera-tor. To replace it with a naive and untrained randomly shaped neuron would be worse than useless. When a virus gets into a neuron, the neuron is not instructed to undergo apoptosis. Instead, for reasons that are not entirely clear, the virus itself sometimes induces apoptosis of the neuron. This is true in the case of fatal alphavirus encephalitis, for instance.10
Apoptosis can also be useful in preventing other kinds of mutiny than cancer, such as genetic distortion of the kind induced by selfish transposons. There is some good evidence that the germ cells in the ovary and testicle are under surveillance from follicular and Sertoli cells respectively, whose job is to detect any such selfishness and, if so, to induce apoptosis. In the ovary of a five-month-old human foetus, for example, there are nearly seven million germ cells.
By birth, there are only two million, and of those two million, just 400 or so will be ovulated during the coming lifetime. Most of the rest will be culled by apoptosis, which is ruthlessly eugenic, issuing strict orders to cells that are not perfect to commit suicide (the body is a totalitarian place).
The same principles may apply in the brain, where there is mass culling of cells during development by ced-9 and other genes. Again, 2 4 2 G E N O M E
any cell that does not work well is sacrificed for the good of the whole. So not only does the apoptotic cull of neurons enable learning to take place, it also improves the average quality of the cells that remain. Something similar probably happens in the immune cells, another subject to ruthless culling of cells by apoptosis.
Apoptosis is a decentralised business. There is no central planning, no bodily Politburo deciding who should die and who should live.
That is the beauty of it. Like the development of the embryo, it harnesses the self-knowledge of each cell. There is only one conceptual difficulty: how apoptosis could have evolved. In passing the test of killing itself if infected, cancerous or genetically mischievous, a cell by definition dies. It cannot therefore pass on its goodness to its daughters. Known as 'the kamikaze conundrum', this problem is solved by a form of group selection: whole bodies in which apoptosis works well do better than whole bodies in which it fails to work; the former therefore pass on the right traits to the cells of their offspring. But it does mean that the apoptotic system cannot improve during a person's lifetime, because it cannot evolve by natural selection within the body. We are stuck with the cell-suicide mechanism that we inherited.11
C H R O M O S O M E 1 8
C u r e s
Our doubts are traitors,
And make us lose the good we oft might win,
By fearing to attempt.
William Shakespeare, Measure for Measure As the third millennium dawns, we are for the first time in a position to edit the text of our genetic code. It is no longer a precious manuscript; it is on disc. We can cut bits out, add bits in, rearrange paragraphs or write over words. This chapter is about how we can do these things, whether we should, and why, on the brink of doing so, our courage seems to be failing us and we are strongly tempted to throw away the whole word processor and insist that the text remains sacrosanct. This chapter is about genetic manipulation.
For most laymen, the obvious destination towards which genetic research is headed, the ultimate prize if you like, is a genetically engineered human being. One day, centuries hence, that might mean a human being with newly invented genes. For the moment it means a human being with an existing gene borrowed from another human being, or from an animal or plant. Is such a thing possible? And, if it is possible, is it ethical?
2 4 4 G E N O M E
Consider a gene on chromosome 18 that suppresses colon cancer.
We have already met it briefly in the last chapter: a tumour suppressor whose location has not quite been determined for sure. It was thought to be a gene called DCC, but we now know that DCC
guides the growth of nerves in the spinal column and has nothing to do with tumour suppression. The tumour-suppressor gene is close to DCC, but it is still elusive. If you are born with an already faulty version of this gene you have a much increased risk of cancer. Could a future genetic engineer take it out, like a faulty spark plug from a car, and replace it? The answer, quite soon, will be yes.
I am just old enough to have begun my career in journalism cutting paper with real scissors and pasting with real glue. Nowadays, to move paragraphs around I use little software icons suitably decor-ated by the kind folk at Microsoft to indicate that they do the same job. (I have just moved this paragraph to here from the next page.) But the principle is the same: to move text, I cut it out and paste it back in somewhere else.
To do the same for the text of genes also requires scissors and glue. In both cases, fortunately nature had already invented them for her own purposes. The glue is an enzyme called ligase, which stitches together loose sentences of D N A whenever it comes across them. The scissors, called restriction enzymes, were discovered in bacteria in 1968. Their role in the bacterial cell is to defeat viruses by chopping up their genes. But it soon emerged that, unlike real scissors, a restriction enzyme is fussy: it only cuts a strand of D N A where it encounters a particular sequence of letters. We now know of 400 different kinds of restriction enzymes, each of which recognises a different sequence of D N A letters and cuts there, like a pair of scissors that cuts the paper only where it finds the word 'restriction'.
In 1972, Paul Berg of Stanford University used restriction enzymes in a test tube to chop two bits of viral D N A in half, then used ligases to stick them together again in new combinations. He thus produced the first man-made 'recombinant' D N A . Humanity could now do what retroviruses had long been doing: insert a gene into a C U R E S 245
chromosome. Within a year, the first genetically engineered bacterium existed: a gut bacterium infected with a gene taken out of a toad.
There was an immediate surge of public concern and it was not confined to lay people. Scientists themselves thought it right to pause before rushing to exploit the new technology. They called a moratorium on all genetic engineering in 1974, which only fanned the flames of public worry: if the scientists were worried enough to stop, then there really must be something to worry about. Nature placed bacterial genes in bacteria and toad genes in toads; who were we to swap them? Might the consequences not be terrible? A conference, held at Asilomar in 1975, thrashed out the safety arguments and led to a cautious resumption of genetic engineering in America under the supervision of a federal committee. Science was policing itself. The public anxiety seemed gradually to die down, though it was to revive quite suddenly in the mid-1990s, this time focusing not on safety but on ethics.
Biotechnology was born. First Genentech, then Cetus and Biogen, then other companies sprang up to exploit the new technique. A world of possibilities lay before the nascent businesses. Bacteria could now be induced to make human proteins for medicine, food or industrial use. Only gradually did disappointment dawn, when it emerged that bacteria were not very good at making most human proteins and that human proteins were too little known to be in great demand as medicines. Despite immense venture-capital investment, the only companies that made profits for their shareholders were the ones, such as Applied Biosystems, that made equipment for the others to use. Still, there were products. By the late 1980s, human growth hormone, made by bacteria, had replaced the expensive and dangerous equivalent extracted from the brains of cadavers.
The ethical and safety fears proved so far groundless: in thirty years of genetic engineering no environmental or public health accident big or small has resulted from a genetic engineering experiment. So far, so good.
Meanwhile, genetic engineering had a greater impact on science than it had on business. It was now possible to 'clone' genes (in 2 4 6 G E N O M E
this context the word has a different meaning from the popular one): to isolate a 'needle' of a human gene in the 'haystack' that is the genome, put it in a bacterium and grow millions of copies of it so that they can be purified and the sequence of letters in the gene read. By this means, vast libraries of human D N A have been created containing thousands of overlapping fragments of the human genome, each present in sufficient quantity to study.
It is from such libraries that the people behind the Human Genome Project are piecing together the complete text. The scale of their task is immense. Three billion letters of text would fill a stack of books 150 feet high. The Wellcome Trust's Sanger Centre near Cambridge, which leads the effort, is reading the genome at the rate of 100 million letters a year.
There are, of course, short cuts. One is to ignore the ninety-seven per cent of the text that is silent - the selfish D N A , the introns, repetitious minisatellites and rusting pseudogenes - and concentrate on the genes alone. The quickest way to find such genes is to clone a different sort of library, called a cDNA library. First, sieve out all fragments of R N A in the cell. Many of them will be messengers —
edited and abridged copies of genes in the process of being translated. Make D N A copies of those messengers and you will have, in theory, copies of the texts of the original genes with none of the junk D N A that lies in between. The main difficulty with this approach is that it gives no hint of the order or position of the genes on the chromosomes. By the late 1990s there was a marked difference of opinion between those who wanted to pursue this
'shotgun' method to the human genome with commercial patenting along the way, and those who wanted to be slow, thorough and public. On one side was a high-school drop-out, former professional surfer, Vietnam veteran and biotechnology millionaire named Craig Venter, backed by his own company Celera; on the other a studious, bearded, methodical Cambridge-educated scientist, John Sulston, backed by the medical charity Wellcome Trust. No prizes for guessing which camp is which.
But back to manipulation. Engineering a gene into a bacterium C U R E S 2 4 7
is one thing; inserting a gene into a human being is quite another.
Bacteria are happy to absorb little rings of D N A called plasmids and adopt them as their own. Moreover, each bacterium is a single cell. Human beings have 100 trillion cells. If your goal is to genetically manipulate a human being, you need to insert a gene into every relevant cell, or start with a single-celled embryo.
The discovery in 1970 that retroviruses could make D N A copies from R N A suddenly made 'gene therapy' seem, nonetheless, a feas-ible goal. A retrovirus contains a message written in R N A 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.
Throughout the early 1980s, scientists worried about the safety of such a procedure. The retrovirus might work too well and infect not just the ordinary cells of the body, but the reproductive cells, too. The retrovirus might reacquire its missing genes somehow and turn virulent; or it might destabilise the body's own genes and trigger cancer. Anything might happen. Fears about gene therapy were inflamed in 1980 when Martin Cline, a scientist studying blood disorders, broke a promise not to try inserting a harmless recombinant gene into an Israeli suffering from the genetic blood disorder thalassaemia (though not by retrovirus). Cline lost his job and his reputation; the result of his experiment was never published. Everybody agreed that human experiments were premature, to say the least.
But mouse experiments were proving both reassuring and disappointing. Far from being unsafe, gene therapy seemed more likely to be unworkable. Each retrovirus can only infect one kind of tissue; it needs careful packaging to get the genes into its envelope; it lands at random anywhere among the chromosomes and often fails to get switched on; and the body's immune system, primed by the crack troops of infectious disease, does not miss a clumsy, home-made 248 G E N O M E
retrovirus. Moreover, by the early 1980s so few human genes had been cloned that there was no obvious candidate gene to put in a retrovirus even if it could be got to work.
None the less, by 1989 several milestones had been passed. Retroviruses had carried rabbit genes into monkey cells; they had put cloned human genes into human cells; and they had put cloned human genes into mice. Three bold, ambitious men - French Anderson, Michael Blaese and Steven Rosenberg - decided the time was ripe for a human experiment. In a long and sometimes bitter battle with the American federal government's Recombinant D N A Advisory Committee, they sought permission for an experiment on terminal cancer patients. The argument brought out the different priorities of scientists and doctors. To the pure scientists, the experiment seemed hasty and premature. To the doctors, used to watching patients die of cancer, haste comes naturally. 'What's the rush?'
asked Anderson at one session. 'A patient dies of cancer every minute in this country. Since we began this discussion 146 minutes ago, 146 patients have died of cancer.' Eventually, on 20 May 1989, the committee granted permission and two days later Maurice Kuntz, a truck driver dying from melanoma, received the first deliberately introduced (and approved) new gene. It was not designed to cure him, nor even to remain in his body permanently. It was simply an adjunct to a new form of cancer treatment. A special kind of white blood cell, good at infiltrating tumours and eating them, had been cultivated outside his body. Before injecting them back in, the doctors infected them with retroviruses carrying a little bacterial gene, the only purpose of which was to enable them to track the cells inside his body and find out where they went. Kuntz died, and nothing very surprising emerged from the experiment. But gene therapy had begun.
By 1990, Anderson and Blaese were back before the committee with a more ambitious scheme. This time the gene would actually be a cure, rather than just an identification tag. The target was an extremely rare inherited disease called severe combined immune deficiency ( S C I D ) , which rendered children incapable of mounting C U R E S 2 4 9
an immune defence against infection; the cause was the rapid death of all white blood cells. Unless kept in a sterile bubble or given a complete bone marrow transplant from a fortuitously matched relative, such a child faces a short life of repeated infection and illness.
The disease is caused by a 'spelling' change in a single gene on chromosome 20, called the ADA gene.
Anderson and Blaese proposed to take some white blood cells from the blood of a S C I D child, infect them with a retrovirus armed with a new ADA gene, and transfuse them back into the child's body. Once again, the proposal ran into trouble, but this time the opposition came from a different direction. By 1990, there was a treatment for S C I D , called P E G - A D A , and it consisted of ingeniously delivering into the blood not the ADA gene, but A D A itself, the protein made by the equivalent gene in cattle. Like the cure for diabetes (injected insulin) or for haemophilia (injected clotting agents), S C I D had been all but cured by protein therapy (injected P E G - A D A ) . What need was there of gene therapy?
At their birth, new technologies often seem hopelessly uncompetitive. The first railways were far more expensive than the existing canals and far less reliable. Only gradually and with time does the new invention bring down its own costs or raise its efficacy to the point where it can match the old. So it was with gene therapy.
Protein therapy had won the race to cure S C I D , but it required painful monthly injections into the hip, it was expensive and it needed to continue for life. If gene therapy could be made to work, it would replace all that with a single treatment that re-equipped the body with the gene it should have had in the first place.
In September 1990, Anderson and Blaese got the go-ahead and treated Ashanthi DeSilva, a three-year-old girl, with genetically engineered ADA. It was an immediate success. Her white-cell count trebled, her immunoglobulin counts soared and she began making almost a quarter of the A D A that an average person makes. The gene therapy could not be said to have cured her, because she was already receiving and continued to receive P E G - A D A . But gene therapy had worked. Today more than one in four of all known 2 5 0 G E N O M E
S C I D children in the world have had gene therapy. None are definitively cured enough to be weaned off P E G - A D A , but the side-effects have been few.
Other conditions will soon join S C I D on the list of disorders that have been tackled by retroviral gene therapy, including familial hypercholesterolaemia, haemophilia and cystic fibrosis. But it is cancer that is undoubtedly the main target. In 1992 Kenneth Culver tried an audacious experiment that involved the first direct injection of gene-equipped retroviruses into the human body (as opposed to infection of cultured cells outside the body and transfusion of those cells back in). 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. But by then the cunning Dr Culver was treating the patient with drugs for herpes; the drugs attacked the tumours.
It seemed to work on the first patient, but on four of the next five it failed.
These are early days in gene therapy. Some think it will one day be as routine as heart transplants are today. But it is too early to tell if gene therapy will be the strategy that defeats cancer, or whether some treatment based on blocking angiogenesis, telomerase or p53 wins that particular race. Whichever, never in history has cancer treatment looked so hopeful - thanks almost entirely to the new genetics.1
Somatic gene therapy of this kind is no longer very controversial.
Concerns about safety still remain, of course, but almost nobody can think of an ethical objection. It is just another form of therapy and nobody who has watched a friend or relative go through chemotherapy or radiotherapy for cancer would begrudge them, on far-fetched safety grounds, the comparatively painless possibility of gene therapy instead. The added genes go nowhere near the germ cells that will form the next generation; that worry has been firmly laid to rest. Yet germline gene therapy - changing genes in places where they would be passed on to future generations, which remains C U R E S 2 5 1
a total taboo in human beings - would in one sense be much, much easier to do. It is germline gene therapy, in the form of genetically modified soya beans and mice, that has caused a resurgence of protest in the 1990s. This is, to borrow a term from its detractors, Frankenstein technology.
The genetic engineering of plants took off rapidly for several reasons. The first was commercial: farmers have for many years provided an eager market for new seed varieties. In ancient pre-history, conventional breeding had turned wheat, rice and maize from wild grasses to productive crops entirely by manipulating their genes, though these early farmers did not of course know that this is what they were doing. In modern times, the same techniques have trebled yields and increased per-capita food production by more than twenty per cent even as world population doubled between 1960 and 1990. The 'green revolution' in tropical agriculture was largely a genetic phenomenon. Yet all this had been done blindly: how much more could be achieved by targeted, careful gene manipulation? The second reason for the genetic engineering of plants is the ease with which plants can be cloned or propagated. You cannot take a cutting from a mouse and grow a new mouse as you can from many plants. But the third reason was a lucky accident. A bacterium called Agrobacterium had already been discovered, which had the unusual property of infecting plants with small loops of D N A called Ti plasmids that incorporated themselves into plant chromosomes. Agrobacterium was a ready-made vector: simply add some genes to the plasmid, rub it on a leaf, wait for the infection to take hold and grow a new plant from the leaf cells. The plant would now pass on the new gene in its seeds. So in 1983, first a tobacco plant, then a petunia and then a cotton plant were genetically modified in this way.
The cereals, which are resistant to Agrobacterium infection, had to wait until the invention of a rather more crude method: the genes are literally shot into the cell on board tiny particles of gold using gunpowder or particle accelerators. This technique has now become standard for all plant genetic engineering. It has led to the creation 2 5 2 G E N O M E
of tomatoes less likely to rot on the shelf, cotton resistant to boll weevils, potatoes resistant to Colorado beetles, maize resistant to corn borers and many other genetically modified plants.
The plants progressed from laboratory to field trial to commercial sale with relatively few hiccoughs. Sometimes the experiments did not work - boll weevils devastated the supposedly resistant cotton crop in 1996 - and sometimes they attracted protest from environmentalists. But there was never an 'accident'. When the genetically modified crops were brought across the Atlantic, they encountered stronger environmental resistance. In Britain in particular, where food safety regulators had lost public confidence after the 'mad-cow'
epidemic, genetically modified food was suddenly a big issue in 1999, three years after it had become routine in the United States.
Moreover, in Europe Monsanto made the mistake of starting with crops rendered resistant to its own indiscriminate herbicide, Roundup. This enabled the farmer to use Roundup to kill weeds.
Such a combination of manipulating nature, encouraging use of herbicides and making profits infuriated many environmentalists.
Eco-terrorists began tearing up experimental plots of genetically manipulated oilseed crop and paraded around in Frankenstein suits.
The issue became one of Greenpeace's top three concerns, a sure sign of populism.
The media, as usual, rapidly polarised the debate with shouting matches between extremists on late-night television and interviews that forced people into simplistic answers: are you for or against genetic engineering? The issue reached its nadir when a scientist was forced to take early retirement over claims made in a hysterical television programme that he had proved that potatoes into which lectin genes had been inserted were bad for rats; he was later 'vindicated' by a group of colleagues assembled by Friends of the Earth.
The result proved less about the safety of genetic engineering than it did about the safety of lectins - known animal poisons. The medium had become confused with the message. Putting arsenic in a cauldron makes the stew poisonous, but it does not mean all cooking is dangerous.
C U R E S 253
In the same way, genetic engineering is as safe and as dangerous as the genes that are engineered. Some are safe, some are dangerous.
Some are green, some are bad for the environment. Roundup-resistant rape may be eco-unfriendly to the extent that it encourages herbicide use or spreads its resistance to weeds. Insect-resistant potatoes are eco-friendly to the extent that they require fewer insecticide applications, less diesel for the tractors applying the insecticides, less road use by the trucks delivering the insecticides and so on.
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.
The politicisation of the issue has had absurd results. In 1992, Pioneer, the world's biggest seed company, introduced a gene from brazil nuts into soya beans. The purpose was to make soya beans more healthy for those for whom they are a staple food by correcting soya beans' natural deficiency in a chemical called methionine. However, it soon emerged that a very few people in the world develop an allergy to brazil nuts, so Pioneer tested its transgenic soya beans and they proved allergenic, too, to such people. At this point, Pioneer alerted the authorities, published the results and abandoned the project. This was despite the fact that calculations showed that the new soya-bean allergy would probably kill no more than two Americans a year and could save hundreds of thousands worldwide from malnutrition. Yet instead of becoming an example of extreme corporate caution, the story was repackaged by environmentalists 2 5 4 G E N O M E
and told as a tale of the dangers of genetic engineering and reckless corporate greed.
None the less, and even allowing for the cautious cancellation of many projects, it is a safe estimate that by the year 2000, fifty to sixty per cent of the crop seed sold in the United States will be genetically modified. For better or for worse, genetically modified crops are here to stay.
So are genetically modified animals. Putting a gene into an animal so that it and its offspring are permanently altered is now simple in animals as well as plants. You just stick it in. Suck your gene into the mouth of a very fine glass pipette, jab the tip of the pipette into a single-celled mouse embryo, extracted from a mouse twelve hours after mating, make sure the tip of the pipette is inside one of the cell's two nuclei, and press gently. The technique is far from perfect: only about five per cent of the resulting mice will have the desired gene switched on, and in other animals such as cows, success is even rarer. But in those five per cent the result is a 'transgenic'
mouse with the gene incorporated in a random position on one of its chromosomes.
Transgenic mice are scientific gold dust. They enable scientists to find out what genes are for and why. The inserted gene need not be derived from a mouse, but could be from a person: unlike in computers, virtually all biological bodies can run any kind of software. For instance, a mouse that is abnormally susceptible to cancer can be made normal again by the introduction of a human chromosome 18, which formed part of the early evidence for a tumour-suppressor gene on chromosome 18. But rather than inserting whole chromosomes, it is more usual to add a single gene.
Micro-injection is giving way to a subtler technique, which has one distinct advantage: it can enable the gene to be inserted in a precise location. At three days of age, the embryo of a mouse contains cells known as embryonic stem cells or ES cells. If one of these is extracted and injected with a gene, as Mario Capecchi was the first to discover in 1988, the cell will splice that gene in at precisely the point where the gene belongs, replacing the existing C U R E S 2 5 5
version of the gene. Capecchi took a cloned mouse oncogene called int-2, inserted it into a mouse cell by briefly opening the cell's pores in an electric field, and then observed as the new gene found the faulty gene and replaced it. This procedure, called 'homologous recombination', exploits the fact that the mechanism that repairs broken D N A often uses the spare gene on the counterpart chromosome as a template. It mistakes the new gene for the template and corrects its existing gene accordingly. Thus altered, an ES cell can then be placed back inside an embryo and grown into a 'chimeric'
mouse - a mouse in which some of the cells contain the new gene.3
Homologous recombination allows the genetic engineer not only to repair genes but to do the opposite: deliberately to break working genes, by inserting faulty versions in their place. The result is a so-called knockout mouse, reared with a single gene silenced, the better to reveal that gene's true purpose. The discovery of memory mechanisms (see the chapter on chromosome 16) owes much to knockout mice, as do other fields of modern biology.
Transgenic animals are useful not only to scientists. Transgenic sheep, cattle, pigs and chickens have commercial applications. Sheep have already been given the gene for a human clotting factor in the hope that it can be harvested from their milk and used to treat haemophiliacs. (Almost incidentally, the scientists who performed this procedure cloned the sheep Dolly and displayed her to an amazed world in early 1997.) A company in Quebec has taken the gene that enables spiders to make silk webs and inserted it into goats, hoping to extract raw silk protein from the goats' milk and spin it into silk. Another company is pinning its hope on hens' eggs, which it hopes to turn into factories for all sorts of valuable human products, from pharmaceuticals to food additives. But even if these semi-industrial applications fail, transgenic technology will transform animal breeding, as it is transforming plant breeding, generating beef cattle that put on more muscle, dairy cattle that give more milk or chickens that lay tastier eggs.4
It all sounds rather easy. The technical obstacles to breeding a transgenic or a knockout human being are becoming trivial for a 256 G E N O M E
good team at a well-equipped laboratory. In a few years from now you probably could, in principle, take a complete cell from your own body, insert a gene into a particular location on a particular chromosome, transfer the nucleus to an egg cell from which the nucleus had been removed, and grow a new human being from the embryo. The person would be a transgenic clone of yourself, identical in every way except, say, in having an altered version of the gene that made you go bald. You could alternatively use ES cells from such a clone to grow a spare liver to replace the one you sacrificed to the bottle. Or you could grow human neurons in the laboratory to test new drugs on, thus sparing the lives of laboratory animals.
Or, if you were barking mad, you could leave your property to your clone and commit suicide secure in the knowledge that something of you still existed, but slightly improved. Nobody need know that this person is your clone. If the increasing resemblance to you later became apparent as he grew older, the non-receding hairline would soon lay suspicions to rest.
None of this is yet possible - human ES cells have only just been found — but it is very unlikely to remain impossible for much longer. When human cloning is possible, will it be ethical? As a free individual, you own your own genome and no government can nationalise it, nor company purchase it, but does that give you the right to inflict it on another individual? (A clone is another individual.) Or to tamper with it? For the moment society seems keen to bind itself against such temptations, to place a moratorium on cloning or germline gene therapy and strict limits on embryonic research, to forego the medical possibilities in exchange for not risking the horrors of the unknown. We have drummed into our skulls with every science fiction film the Faustian sermon that to tamper with nature is to invite diabolic revenge. 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 C U R E S 257
to allow them; it just got used to the idea that those who desperately wanted such babies were able to have them.
Meanwhile, in one of those ironies which modern biology supplies in abundance, if you have a faulty tumour-suppressor gene on chromosome 18, forget gene therapy. A much simpler preventive treatment may be at hand. New research suggests that for those with genes that increase their susceptibility to bowel cancer, a diet rich in aspirin and unripe bananas offers the promise of protection against the cancer. The diagnosis is genetic, but the cure is not.
Genetic diagnosis followed by conventional cure is probably the genome's greatest boon to medicine.
C H R O M O S O M E 1 9
P r e v e n t i o n
Ninety-nine per cent of people don't have an inkling about how fast this revolution is coming.
Steve Fodor, president of Asymetrix
The improvement of any medical technology confronts our species with a moral dilemma. If the technology can save lives, then not to develop it and use it is morally culpable, even if there are attendant risks. In the Stone Age, we had no option but to watch our relatives die of smallpox. After Jenner had perfected vaccination we were derelict in our duty if we did so. In the nineteenth century, we had no alternative to watching our parents succumb to tuberculosis.
After Fleming found penicillin we were guilty of neglect if we failed to take a dying tubercular patient to the doctor. And what applies on the individual level applies with even greater force on the level of countries and peoples. Rich countries can no longer ignore the epidemics of diarrhoea that claim the lives of countless children in poor countries, because no longer can we argue that nothing medically can be done. Oral rehydration therapy has given us a conscience.
Because something can be done, so something must be done.
P R E V E N T I O N 2 5 9
This chapter is about the genetic diagnosis of two of the commonest diseases that afflict people, one a swift and merciless killer, the other a slow and relentless thief of memory: coronary heart disease and Alzheimer's disease. I believe we are in danger of being too squeamish and too cautious in using knowledge about the genes that influence both diseases, and we therefore stand at risk of committing the moral error of denying people access to life-saving research.
There is a family of genes called the apolipoprotein genes, or APO
genes. They come in four basic varieties, called A, B, C and - strangely
- E, though there are various different versions of each on different chromosomes. The one that interests us most is APOE, which happens to lie here on chromosome 19. To understand APOE's job requires a digression into the habits of cholesterol and triglyceride fats. 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 V L D L , for very-low-density lipoprotein. As it drops off some of its triglycerides, it becomes low-density lipoprotein, or L D L ('bad cholesterol').
Finally, after delivering its cholesterol, it becomes high-density lipoprotein, H D L ('good cholesterol') and returns to the liver for a new consignment.
The job of APOE's protein (called apo-epsilon) is to effect an introduction between V L D L and a receptor on a cell that needs some triglycerides; APOB's job (or rather apo-beta's) is to do the same for the cholesterol drop-off. It is easy to see therefore that APOE and APOB are prime candidates for involvement in heart disease. If they are not working, the cholesterol and fat stay in the bloodstream and can build up on the walls of arteries as atherosclerosis. Knockout mice with no APOE genes get atherosclerosis even 2 6 0 G E N O M E
on a normal mouse diet. The genes for the lipoproteins themselves and for the receptors on cells can also affect the way in which cholesterol and fat behave in the blood and thereby facilitate heart attacks. An inherited predisposition to heart disease, called familial hypercholesterolaemia, results from a rare 'spelling change' in the gene for cholesterol receptors.1
What marks APOE out as special is that it is so 'polymorphic'.
Instead of us all having one version of the gene, with rare exceptions, APOE is like eye colour: it comes in three common kinds, known as E2, E3 and E4. Because these three vary in their efficiency at removing triglycerides from the blood, they also vary in their susceptibility to heart disease. In Europe, E3 is both the 'best' and the commonest kind: more than eighty per cent of people have at least one copy of E3 and thirty-nine per cent have two copies. But the seven per cent of people who have two copies of E4 are at markedly high risk of early heart disease, and so, in a slightly different way, are the four per cent of people who have two copies of E2.2
But that is a Europe-wide average. Like many such polymorphisms, this one shows geographical trends. The further north in Europe you go, the commoner E4 becomes, at the expense of E3
(E2 remains roughly constant). In Sweden and Finland the frequency of E4 is nearly three times as high as in Italy. So, approximately, is the frequency of coronary heart disease.3 Further afield, there are even greater variations. Roughly thirty per cent of Europeans have at least one copy of E4; Orientals have the lowest frequency at roughly fifteen per cent; American blacks, Africans and Polynesians, over forty per cent; and New Guineans, more than fifty per cent.
This probably reflects in part the amount of fat and fatty meat in the diet during the last few millennia. It has been known for some while that New Guineans have little heart disease when they eat their traditional diet of sugar cane, taro and occasional meals of lean bush meat from possums and tree kangaroos. But as soon as they get jobs at strip mines and start eating western hamburgers and chips, their risk of early heart attacks shoots up - much more quickly than in most Europeans.4
P R E V E N T I O N 2 6 1
Heart disease is a preventable and treatable condition. Those with the E2 gene in particular are acutely sensitive to fatty and cholesterol-rich diets, or to put it another way, they are easily treated by being warned off such diets. This is extremely valuable genetic knowledge. How many lives could be saved, and early heart attacks averted, by simple genetic diagnosis to identify those at risk and target treatment at them?
Genetic screening does not automatically lead to such drastic solutions as abortion or gene therapy. Increasingly a bad genetic diagnosis can lead to less drastic remedies: to the margarine tub and the aerobics class. Instead of warning us all to steer clear of fatty foods, the medical profession must soon learn to seek out which of us could profit from such a warning and which of us can relax and hit the ice cream. This might go against the profession's puritanical instincts, but not against its Hippocratic oath.
However, I did not bring you to the APOE gene chiefly to write about heart disease, though I fear I am still breaking my rule by writing about another disease. The reason it is one of the most investigated genes of all is not because of its role in heart disease, but because of its pre-eminent role in a much more sinister and much less curable condition: Alzheimer's disease. The devastating loss of memory and of personality that accompanies old age in so many people — and that occurs in a few people when quite young
- has been attributed to all sorts of factors, environmental, pathological and accidental. The diagnostic symptom of Alzheimer's is the appearance in brain cells of 'plaques' of insoluble protein whose growth damages the cell. A viral infection was once suspected to be the cause, as was a history of frequent blows to the head. The presence of aluminium in the plaques threw suspicion on aluminium cooking pots for a while. The conventional wisdom was that genetics had little or nothing to do with the disease. 'It is not inherited,' said one textbook firmly.
But as Paul Berg, co-inventor of genetic engineering, has said, 'all disease is genetic' even when it is also something else. Pedigrees in which Alzheimer's disease appeared with high frequency were 2 0 2 G E N O M E
eventually discovered among the American descendants of some Volga Germans and by the early 1990s at least three genes had been associated with early-onset Alzheimer's disease, one on chromosome 21 and two on chromosome 14. But a far more significant discovery in 1993 was that a gene on chromosome 19 seemed to be associated with the disease in old people and that Alzheimer's in the elderly might also have a partial genetic basis. Quite soon the culprit gene was discovered to be none other than APOE itself.5
The association of a blood-lipid gene with a brain disease should not have come as such a surprise as it did. After all, it had been noticed for some time that Alzheimer's victims quite often had high cholesterol. None the less, the scale of the effect came as a shock. Once again, the 'bad' version of the gene is E4. In families that are especially prone to Alzheimer's disease, the chances of getting Alzheimer's are twenty per cent for those with no E4 gene and the mean age of onset is eighty-four. For those with one E4
gene, the probability rises to forty-seven per cent and the mean age of onset drops to seventy-five. For those with two E4 genes, the probability is ninety-one per cent and the mean age of onset sixty-eight years. In other words, if you carry two E4 genes (and seven per cent of Europeans do), your chances of eventually getting Alzheimer's disease are much greater than those of the population at large. There will still be some who escape either fate - indeed, one study found an eighty-six-year-old E4/E4 man with all his wits. In many people who show no symptoms of memory loss, the classic plaques of Alzheimer's are none the less present, and they are usually worse in E4 carriers than E3. Those with at least one E2 version of the gene are even less likely to get Alzheimer's than those with E3 genes, though the difference is small. This is no accidental side-effect or statistical coincidence: this looks like something central to the mechanism of the disease.6
Recall that E4 is rare among Oriental people, commoner among whites, commoner still among Africans and commonest in New Guinean Melanesians. It should follow that Alzheimer's obeys the same gradient, but it is not quite so simple. The relative risk of P R E V E N T I O N 263
getting Alzheimer's is much higher for white E4/E4S than for black or Hispanic E4/E4S - compared with the risk for E3/E3S. Presumably, susceptibility to Alzheimer's is affected by other genes, which vary between different races. Also, E4's effects seem to be more severe among women than men. Not only do more women than men get Alzheimer's, but females who are E 4 / E 3 ate just as much at risk as those who are E4/E4. Among men, having one E3 gene reduces risk.7
You may be wondering why E4 exists at all, let alone at such high frequencies. If it exacerbates both heart disease and Alzheimer's, it should surely have been driven extinct by the more benign E3 and E2 long ago. I'm tempted to answer the question by saying that high-fat diets were until recently so rare that the coronary side-effects were of little importance, while Alzheimer's disease is all but irrelevant to natural selection, since it not only happens to people who have long ago reared their own children to independence, but strikes at an age when most Stone-Age folk were long dead anyway. But I am not sure that is a good enough answer, because meaty and even cheesy diets have been around a long time in some parts of the world — long enough for natural selection to go to work. I suspect that E4 plays yet another role in the body, which we do not know about, and at which it is better than E3 . Remember: G E N E S A R E
N O T T H E R E T O C A U S E D I S E A S E S .
The difference between E4 and the commoner E3 is that the 334th 'letter' in the gene is G instead of A. The difference between E3 and E2 is that the 472nd 'letter' is a G instead of an A. The effect is to give E2's protein two extra cysteines and E4's two extra arginines compared with each other, E3 being intermediate. These tiny changes in a gene that is 897 'letters' long are sufficient to alter the way APOE's protein does its job. Quite what that job is remains obscure, but one theory is that it is to stabilise another protein called tau, which is supposed in turn to keep in shape the tubular 'skeleton'
of a neuron. Tau has an addiction to phosphate, which prevents it doing its j ob; APOE's job is to keep tau off the phosphate. Another theory is that APOE's job in the brain is not unlike its job in the 2 6 4 G E N O M E
blood. It carries cholesterol between and within brain cells so they can build and repair their fat-insulated cell membranes. A third and more direct theory is that, whatever APOE's job, the E4 version has a special affinity for something called amyloid beta peptide, which is the substance that builds up inside neurons of Alzheimer's sufferers. Somehow, it assists the growth of these destructive plaques.
The details will matter one day, but for now the important fact is that we are suddenly in possession of a means of making predictions. We can test the genes of individuals and make very good forecasts about whether they will get Alzheimer's disease. The geneticist Eric Lander recently raised an alarming possibility. We now know that Ronald Reagan has Alzheimer's, and it seems likely in retrospect that he had the early stages of the disease when he was in the White House. Suppose that some enterprising but biased journalist, anxious to find some way of discrediting Reagan as a presidential candidate in 1979, had snatched a napkin on which Reagan had wiped his mouth and tested the D N A on it (gloss over the fact that the test was not then invented). Suppose he had discovered that this second-oldest-ever presidential candidate was very likely to develop the disease in his term of office and had printed this finding in his newspaper.
The story illustrates the dangers for civil liberties that genetic testing brings with it. When asked if we should offer APOE tests to individuals curious to know if they will get Alzheimer's, most in the medical profession say no. After cogitating on the issue recently, the Nuffield Council on Bioethics, Britain's leading think-tank on such matters, reached the same conclusion. To test somebody for a disease that is incurable is dubious at best. It can buy reassurance for those who find themselves with no E4 gene, but at a terrible price: the almost-certain sentence to an incurable dementia for those with two E4 genes. If the diagnosis were absolutely certain, then (as Nancy Wexler argued in the case of Huntington's - see the chapter on chromosome 4), the test could be even more devastating.
On the other hand, it would at least not be misleading. But in cases P R E V E N T I O N 2 6 5
where there is less certainty, such as the APOE case, the test would be of still less value. You can still - if you are very lucky — have two E4 genes and live to an old age with no symptoms, just as you can still - if you are very unlucky - have no E4 genes and get Alzheimer's at sixty-five. Since a diagnosis of two E4 genes is neither sufficient nor necessary to predict Alzheimer's, and since there is no cure, you should not be offered the test unless you are already symptomatic.
At first I found all these arguments convincing, but now I am not so sure. After all, it has been considered ethical to offer people the test for the H I V virus if they want it, even though A I D S was (until recently) incurable. A I D S is not an inevitable outcome of H I V infection: some people survive indefinitely with H I V infection. True, there is in the case of A I D S the additional interest of society in preventing the spread of the infection, which does not apply to Alzheimer's disease, but it is the individual at risk we are considering here, not society at large. The Nuffield Council addresses this argument by implicitly making a distinction between genetic and other tests. To attribute a person's susceptibility to an illness to their genetic make-up distorts attitudes, argued the report's author, Dame Fiona Caldicott. It makes people believe wrongly that genetic influences are paramount and causes them to neglect social and other causes; that, in turn, increases the stigma attached to mental illness.8
This is a fair argument unfairly applied. The Nuffield Council is operating a double standard. 'Social' explanations of mental problems offered by psychoanalysts and psychiatrists are licensed to practise on the flimsiest of evidence, yet they are just as likely to stigmatise people as genetic ones. They continue to flourish while the great and the good of bioethics outlaw diagnoses that are supported by evidence merely because they are genetic explanations. In striving to find reasons to outlaw genetic explanations while allowing social ones to flourish, the Nuffield Council even resorted to calling the predictive power of the APOE4 test Very low' - bizarre word-ing for an eleven-fold difference in risk between the E4/E4S and 2 6 6 G E N O M E
the E3/E3s.9 As John Maddox has commented,10 citing APOE as a case in point, 'There are grounds for suspecting that physicians are not pursuing valuable opportunities out of diffidence at revealing unwelcome genetic information to their patients . . . but diffidence can be taken too far.'
Besides, although Alzheimer's disease is incurable, there are already drugs that alleviate some of the symptoms and there may be precautions of uncertain value that people can take to head it off. Is it not better to know if one should take every precaution?
If I had two E4 genes, I might well want to know so that I could volunteer for trials of experimental drugs. For those who indulge in activities that raise their risk of Alzheimer's disease, the test certainly makes sense. It is, for example, now apparent that professional boxers who have two E4 genes are at such risk of developing early Alzheimer's that boxers are indeed best advised to take a test and not box if they find themselves with two E4S. One in six boxers get Parkinson's disease or Alzheimer's — the microscopic symptoms are similar, though the genes involved are not - by the age of fifty, and many, including Mohammed Ali, suffer even younger. Among those boxers who do get Alzheimer's, the E4 gene is unusually common, as it is among people who suffer head injury and later turn out to have plaques in their neurons.
What is true for boxers may be true for other sports in which the head is struck. Alerted by anecdotal evidence that many great footballers sink into premature senility in old age — Danny Blanchflower, Joe Mercer and Bill Paisley being sad, recent examples from British clubs — neurologists have begun to study the prevalence of Alzheimer's disease in such sportsmen. Somebody has calculated that a soccer player on average heads the ball 800 times in a season; the wear and tear could be considerable. A Dutch study did indeed find worse memory loss in footballers than in other sportsmen and a Norwegian one found evidence of brain damage in soccer players.
Once more it is plausible that the E4/E4 homozygotes might benefit from at least knowing at the outset of their careers that they were specially at risk. As somebody who frequently hits his head on door P R E V E N T I O N 2 6 7
frames because architects have not made them big enough for tall people to walk through, I wonder myself what my APOE genes looks like. Maybe I should have them tested.
Testing could be valuable in other ways. At least three new Alzheimer's drugs are in development and testing. One that is already here, tacrine, is now known to work better in those with E3 and E2 genes than in E4 carriers. Again and again the genome drives home the lesson of our individuality. The diversity of humanity is its greatest message. Yet there is still a marked reluctance in the medical profession to treat the individual rather than the population.
A treatment that is suitable for one person may not suit another.
Dietary advice that could save one person's life might do no good at all to another. The day will come when a doctor will not prescribe you many kinds of medicine until he has checked which version of a gene or genes you have. The technology is already being developed, by a small Californian company called Affymetrix among others, to put a whole genome-full of genetic sequences on a single silicon chip. One day we might each carry with us exactly such a chip from which the doctor's computer can read any gene the better to tailor his prescription to us.11
Perhaps you have already sensed what the problem with this would be — and what is the real reason behind the experts' squeam¬
ishness about APOE tests. Suppose I do have E4/E4 and I am a professional boxer. I therefore stand a much higher than average chance of contracting angina and premature Alzheimer's disease.
Suppose that today, instead of going to see my doctor, I am going to see an insurance broker to arrange a new life-insurance policy to go with my mortgage, or to get health insurance to cover future illness. I am handed a form and asked to fill in questions about whether I smoke, how much I drink, whether I have A I D S and what I weigh. Do I have a family history of heart disease? - a genetic question. Each question is designed to narrow me down into a particular category of risk so that I can be quoted an appropriately profitable, but still competitive premium. It is only logical that the insurance company will soon ask to see my genes as well, to ask if 268 G E N O M E
I am E4/E4, or if I have a pair of E3s instead. Not only does it fear that I might be loading up on life insurance precisely because I know from a recent genetic test that I am doomed, thus ripping it off as surely as a man who insures a building he plans to burn down. It also sees that it can attract profitable business by offering discounts to people whose tests prove reassuring. This is known as cherry picking, and it is exactly why a young, slim, heterosexual non-smoker already finds he can get life insurance cheaper than an old, plump, homosexual smoker. Having two E4 genes is not so very different.
Little wonder that in America health-insurance companies are already showing interest in genetic tests for Alzheimer's, a disease that can be very costly for them (in Britain, where health cover is basically free, the main concern is life insurance). But mindful of the fury the industry unleashed when it began charging homosexual men higher premiums than heterosexuals to reflect the risk of A I D S , the industry is treading warily. 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. For the genetically unfortunate, it might prove unaffordable: they would become an insurance underclass. Sensitive to these issues, in 1997 the insurance industry association in Britain agreed that for two years it would not demand genetic tests as a condition of insurance and would not (for mortgages smaller than
£100,000) demand to know the results of genetic tests you may already have taken. Some companies went even further, saying that genetic tests were not part of their plans. But this shyness may not last.
Why do people feel so strongly about this issue, when it would in practice mean cheaper premiums for many? Indeed, unlike so many things in life, genetic good fortune is equitably distributed among the privileged as well as the less privileged - the rich cannot buy good genes and the rich spend more on insurance anyway. The answer, I think, goes to the heart of determinism. A person's decision P R E V E N T I O N 2 6 9
to smoke and drink, even the decision that led to his catching A I D S , was in some sense a voluntary one. His decision to have two E4
genes at the APOE gene was not a decision at all; it was determined for him by nature. Discriminating on the basis of APOE genes is like discriminating on the basis of skin colour or gender. A non-smoker might justifiably object to subsidising the premium of a smoker by being lumped with him in the same risk category, but if an E3/E3 objected to subsidising the premium of an E4/E4, he would be expressing bigotry and prejudice against somebody who was guilty of nothing but bad luck.12
The spectre of employers using genetic tests to screen potential staff is less fraught. Even when more tests are available, there will be few temptations for employers to use them. Indeed, once we get more used to the idea that genes lie behind susceptibilities to environmental risks, some tests might become good practice for employer and employee alike. In a job where there is some exposure to known carcinogens (such as bright sunlight - the job of lifeguard, say), the employer may in future be neglecting his duty of care to his workers if he employs people with faulty p53 genes. He might, on the other hand, be asking applicants to take a genetic test for more selfish motives: to select people with healthier dispositions or more outgoing personalities (exactly what job interviews are designed to do), but there are already laws against discrimination.
Meanwhile, there is a danger that the hobgoblin of genetic insurance tests and genetic employment tests will scare us away from using genetic tests in the interests of good medicine. There is, however, another hobgoblin that scares me more: the spectre of government telling me what I may do with my genes. I am keen not to share my genetic code with my insurer, I am keen that my doctor should know it and use it, but I am adamant to the point of fanaticism that it is my decision. My genome is my property and not the state's. It is not for the government to decide with whom I may share the contents of my genes. It is not for the government to decide whether I may have the test done. It is for me. There is a terrible, paternalist tendency to think that 'we' must have one 2 7 0 G E N O M E
policy on this matter, and that government must lay down rules about how much of your own genetic code you may see and whom you may show it to. It is yours, not the government's, and you should always remember that.
C H R O M O S O M E 2 0
P o l i t i c s
Oh! The roast beef of England,
And Old England's roast beef.
Henry Fielding,
The Grub Street Opera
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. Before the discovery of the genome, we did not know there was a document at the heart of every cell three billion letters long of whose content we knew nothing. Now, having read parts of that book, we are aware of myriad new mysteries.
The theme of this chapter is mystery. A true scientist is bored by knowledge; it is the assault on ignorance that motivates him -
the mysteries that previous discoveries have revealed. The forest is more interesting than the clearing. On chromosome 20 there lies as irritating and fascinating a copse of mystery as any. It has already yielded two Nobel prizes, merely for the revelation that it is there, 2 7 2 G E N O M E
but it stubbornly resists being felled to become knowledge. And, as if to remind us that esoteric knowledge has a habit of changing the world, it became one of the most incendiary political issues in science one day in 1996. It concerns a little gene called PRP.
The story starts with sheep. In eighteenth-century Britain, agriculture was revolutionised by a group of pioneering entrepreneurs, among them Robert Bakewell of Leicestershire. It was Bakewell's discovery that sheep and cattle could be rapidly improved by selectively breeding the best specimens with their own offspring to concentrate desirable features. Applied to sheep this inbreeding produced fast-growing, fat lambs with long wool. But it had an unexpected side-effect. Sheep of the Suffolk breed, in particular, began to exhibit symptoms of lunacy in later life. They scratched, stumbled, trotted with a peculiar gait, became anxious and seemed antisocial.
They soon died. This incurable disease, called scrapie, became a large problem, often killing one ewe in ten. The scrapie followed Suffolk sheep, and to a lesser extent other breeds, to other parts of the world. Its cause remained mysterious. The disease did not seem to be inherited, but it could not be traced to another origin. In the 1930s, a veterinary scientist, testing a new vaccine for a different disease, caused a massive epidemic of scrapie in Britain. The vaccine had been made partly from the brains of other sheep and although it had been thoroughly sterilised in formalin, it retained some infectious strength. From then on it became the orthodox, not to say blinkered, view of veterinary scientists that scrapie, being transmissible, must be caused by a microbe.
But what microbe? Formalin did not kill it. Nor did detergents, boiling or exposure to ultraviolet light. The agent passed through filters fine enough to catch the tiniest viruses. It raised no immune response in infected animals and there was sometimes a long delay between injection of the agent and disease — though the delay was much shorter if the agent was injected directly into the brain. Scrapie threw up a baffling wall of ignorance that defeated a generation of determined scientists. Even when similar symptoms appeared in American mink farms and in wild elk and mule deer inhabiting P O L I T I C S 2 7 3
particular national parks in the Rocky Mountains, the mystery only deepened. Mink proved resistant to sheep scrapie when experimentally injected. By 1962, one scientist had returned to the genetic hypothesis. Perhaps, he suggested, scrapie is an inherited but also transmissible disease, a hitherto unknown combination. There are plenty of inherited diseases, and contagious diseases in which inheritance determines susceptibility — cholera being a now classic case —
but the notion that an infectious particle could somehow travel through the germline seemed to break all the rules of biology. The scientist, James Parry, was firmly put in his place.
About this time an American scientist, Bill Hadlow saw pictures of the damaged brains of scrapie-riddled sheep in an exhibit in the Wellcome Museum of Medicine in London. He was struck by their similarity to pictures he had seen from a very different place. Scrapie was about to get a lot more relevant to people. The place was Papua New Guinea, where a terrible debilitating disease of the brain, known as kuru, had been striking down large numbers of people, especially women, in one tribe known as the Fore. First, their legs began to wobble, then their whole bodies started to shake, their speech became slurred and they burst into unexpected laughter. Within a year, as the brain progressively dissolved from within, the victim would be dead. By the late 1950s, kuru was the leading cause of death among Fore women, and it had killed so many that men outnumbered women by three to one. Children also caught the disease, but comparatively few adult men.
This proved a crucial clue. In 1957 Vincent Zigas and Carleton Gajdusek, two western doctors working in the area, soon realised what had been happening. When somebody died, the body was ceremonially dismembered by the women of the tribe as part of the funeral ritual and, according to anecdote, eaten. Funereal cannibalism was well on the way to being stamped out by the government, and it had acquired sufficient stigma that few people were prepared to talk openly about it. This has led some to question whether it ever happened. But Gajdusek and others gathered sufficient eye-witness accounts to leave little doubt that the Fore were not lying when 2 7 4 G E N O M E
they described pre-1960 funeral rituals in Pidgin as 'katim na kukim na kaikai' - or cut up, cook and eat. Generally, the women and children ate the organs and brains; the men ate the muscle. This immediately suggested an explanation for kuru's pattern of appearance. It was commonest among women and children; it appeared among relatives of victims - but among married relations as well as blood relatives; and after cannibalism became illegal, the age of its victims steadily increased. In particular, Robert Klitzman, a student of Gajdusek's, identified three clusters of deaths, each of which included only those who attended certain funerals of kuru victims in the 1940s and 1950s. For instance, at the funeral of a woman called Neno in 1954, twelve of fifteen relatives who attended later died of kuru. The three who did not comprised somebody who died young of another cause, somebody who was forbidden by tradition to take part in the eating because she was married to the same man as the dead woman, and somebody who later claimed to have eaten only a hand.
When Bill Hadlow saw the similarity between kuru-riddled human brains and scrapie-riddled sheep brains, he immediately wrote to Gajdusek in New Guinea. Gajdusek followed up the hint. If kuru was a form of scrapie, then it should be possible to transmit it from people to animals by direct injection into the brain. In 1962 his colleague, Joe Gibbs, began a long series of experiments to try to infect chimpanzees and monkeys with kuru from the brains of dead Fore people (whether such an experiment would now be regarded as ethical is outside the scope of this book). The first two chimpanzees sickened and died within two years of the injections. Their symptoms were like those of kuru victims.
Proving that kuru was a natural human form of scrapie did not help much, since scrapie studies were in such confusion over what could be the cause. Ever since 1900, a rare and fatal human brain disease had been teasing neurologists. The first case of what came to be known as Creutzfeldt-Jakob disease, or C J D , was diagnosed by Hans Creutzfeldt in Breslau in that year in an eleven-year-old girl who died slowly over the succeeding decade. Since C J D almost never strikes the very young and rarely takes so long to kill, this P O L I T I C S 2 7 5
was almost certainly a strange case of misdiagnosis at the outset leaving us with a paradox all too typical of this mysterious disease: the first C J D patient ever recognised did not have C J D . However, in the 1920s, Alfons Jakob did find cases of what probably was C J D and the name stuck.
Gibbs's chimpanzees and monkeys soon proved just as susceptible to C J D as they had been to kuru. In 1977, events took a more frightening turn. Two epileptics who had undergone exploratory brain surgery with electrodes at the same hospital suddenly developed C J D . The electrodes had been previously used in a C J D
patient, but they had been properly sterilised after use. Not only did the mysterious entity that caused the disease resist formalin, detergent, boiling and irradiation, it survived surgical sterilisation. The electrodes were flown to Bethesda to be used on chimps, who promptly got C J D , too. This proved the beginning of a new and yet more bizarre epidemic: iatrogenic ('doctor-caused') C J D . It has since killed nearly one hundred people who had been treated for small stature with human growth hormone prepared from the pituitary glands of cadavers. Because several thousand pituitaries contributed to each recipient of the hormone, the process amplified the very few natural cases of C J D into a real epidemic. But if you condemn science for a Faustian meddling with nature that backfired, give it the credit for solving this problem, too. Even before the extent of the growth-hormone C J D epidemic had been recognised in 1984, synthetic growth hormone, one of the first products to come from genetically engineered bacteria, was replacing the cadaver-derived hormone.
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 2 7 6 G E N O M E
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?
Almost forgotten in the excitement was the case of the Suffolk sheep and the hint that inbreeding had exacerbated scrapie at the outset. It was also gradually becoming clear that in a few human cases — though fewer than six per cent - there seemed to be a family connection that hinted at a genetic disease. The key to understanding scrapie lay not in the arsenal of the pathologist, but in that of the geneticist. Scrapie was in the genes. Nowhere was this more starkly underlined than in Israel. When Israeli scientists sought out C J D
in their own country in the mid-1970s, they noticed a remarkable thing. Fully fourteen of the cases, or thirty times more than expected by chance, were among the small number of Jews who had immigrated to Israel from Libya. Immediate suspicion fell upon their diet, which included a special predilection for sheep's brains. But no. The true explanation was genetic: all affected people were part of a single dispersed pedigree. They are now known to share a single mutation, one that is also found in a few families of Slovakians, Chileans and German-Americans.
The world of scrapie is eery and exotic yet also vaguely familiar.
At the same time that one group of scientists were being irresistably drawn to the conclusion that scrapie was in the genes, another had been entertaining a revolutionary, indeed heretical, idea that seemed at first to be heading in a contradictory direction. As early as 1967
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