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The Language of the Genes
Steve Jones


Steve Jones’s highly acclaimed, double prize-winning, bestselling first book is now fully revised to cover all the new genetic breakthroughs from GM food to Dolly the sheep. ’An essential sightseer’s guide to our own genetic terrain.’

Peter Tallack, Sunday Telegraph



’Superb and stimulating…an exhilarating trip around the double spiral of DNA, a rush of gravity-defying concepts and wild swerves of the scientific imagination.’

J.G. Ballard, Daily Telegraph



’Not so much divination as demystification… An attempt to bring genetics and evolution more into the public domain. If, for instance, you ever wondered just what genetic engineering is about, here is as good a place as any to discover. Few have Jones’s ability to communicate a difficult idea with such humour, clarity, precision and ease.’

Laurence Hurst, Times Higher



‘Sensitive to the social issues raised by genetics… yet Jones’s interest reaches beyond contemporary social issues to the human past, to what genetics can and cannot tell us about our evolution and patterns of social development. He interleaves a broad knowledge of biology with considerations of cultural, demographic and – as his title indicates – linguistic history. At once instructive and captivating.’

Daniel J.Kevles, London Review of Books












STEVE JONES

The Language of the Genes


Biology, History and the Evolutionary Future

Revised Edition









DEDICATION (#ulink_2f182d8d-04a7-55b7-9ab6-5989145d9eac)


To my parents and my brotherwho share my genes and my affection




CONTENTS


Cover (#ud66de2e0-f9ce-52c2-a8b3-8bb33a5cb376)

Title Page (#u1dcd5fea-10a0-5b60-88b7-8515806e345d)

Dedication (#ub0e666d5-c965-5c75-ad54-94e613d9a2a2)

Preface: A Malacologist’s Apology (#u089786de-e669-5a66-9e8d-17428cfd755e)

Introduction: The Fingerprints of History (#uc426ca61-cd0b-548e-9856-d2072f47f2cb)

1 A Message from our Ancestors (#u7690fc2b-c58b-55a2-8e3c-0896de31d270)

2 The Rules of the Game (#ufef66067-6447-5308-ba3f-0e939f9c2ac0)

3 Herodotus Revised (#uf90d9a58-4548-5d11-b7df-ea1ab896be9b)

4 Change or Decay (#litres_trial_promo)

5 Caliban’s Revenge (#litres_trial_promo)

6 Behind the Screen (#litres_trial_promo)

7 The Battle of the Sexes (#litres_trial_promo)

8 Clocks, Fossils and Apes (#litres_trial_promo)

9 Time and Chance (#litres_trial_promo)

10 The Economics of Eden (#litres_trial_promo)

11 The Kingdoms of Cain (#litres_trial_promo)

12 Darwin’s Strategist (#litres_trial_promo)

13 The Deadly Fevers (#litres_trial_promo)

14 Cousins under the Skin (#litres_trial_promo)

15 Evolution Applied (#litres_trial_promo)

16 The Modern Prometheus (#litres_trial_promo)

17 The Evolution of Utopia (#litres_trial_promo)

Appendix: A Bibliographic Sketch (#litres_trial_promo)

Index (#litres_trial_promo)

Adout the Author (#litres_trial_promo)

Praise (#litres_trial_promo)

Copyright (#litres_trial_promo)

About the Publisher (#litres_trial_promo)




Preface A MALACOLOGIST’S APOLOGY (#ulink_1f3ce6a9-cf3b-503f-a8e7-95909c008894)


I have spent – some might say wasted – most of my scientific career working on snails. A malacologist may seem an unlikely author for a book about human genetics. However, my research, when I was still able to do it, was not driven by a deep interest in molluscs. Indeed, one of the few occasions when I thought of giving up biology as a career was when I first had to dissect one. Thirty years ago snails were among the few creatures whose genes could be used to study evolution. They carry a statement of ancestry on their shells in the form of inherited patterns of colour and banding. By counting genes in different places and trying to relate them to the environment one could get an idea of how and why snail populations diverged from each other: of why and how they evolved.

At the time, the idea that it might ever be possible to do the same with humans seemed absurd. Genetics textbooks of the 1960s were routine things. They dealt with the inheritance of pea shape, the sex lives of fungi and the new discoveries about the molecular biology of viruses and their bacterial hosts. Of ourselves, there was scarcely a mention – usually just a short chapter tagged on at the end which described pedigrees of abnormalities such as haemophilia or colour blindness.

Part of this reticence was due to ignorance but part came from the dismal history of the subject. In its early days, the study of human inheritance was the haunt of charlatans, most of whom had a political axe to grind. Absurd pedigrees purporting to show family lines of criminality or genius were the norm. Ignorance and confidence went together. Many biologists argued that it was possible to improve humankind by selective breeding or by the elimination of the unfit. The adulteration of the science reached its disastrous end in the Nazi experiment, and for many years it was seen as at best unfashionable to discuss the nature of inborn differences among people.

After the Second World War, the United Nations published a book – Statement on Race, by the American anthropologist Ashley Montagu – which tried to kill some of the genetical myths. I read this as a schoolboy and found it unpersuasive and hard to follow, although its liberal message was clear enough. Re-reading it a few years ago showed why: Ashley Montagu had tried, nobly, to make bricks without straw. The information needed to understand ourselves was simply not available and there seemed little prospect that it ever would be. Human genetics had moved from a series of malign to an equivalent set of pious opinions.

Now everything has been transformed. Homo sapiens is no longer the great unknown of the genetical world but has become its workhorse. More is known about the geographical patterns of genes in people than about those of any other animal (snails, incidentally, still come second). The three thousand million letters in the DNA alphabet have, at last, been read from end to end and, so it seems, the century of genetics that began with the rediscovery of Mendel’s laws has ended with a new and revolutionary insight into ourselves.

The completion of the DNA map marks the triumph of genetics as a science. Its success as a technology – or, at least, as a medical technology – has yet to be established. Everyone, in the end, dies; and genes are nearly always involved in that unpleasant process. Nobody escapes the fate coded into the double helix. Much of the damage arises anew, either in body cells or as a result of errors in parental sperm and egg. Indeed, most pregnancies end because of such errors. Science has given the hope of finding those at risk of inherited disease and, perhaps, of treating it. At last we understand what sex really means, why we age and die, and how nature and nurture combine to make us what we are.

Most of all, biology has altered our view of our place in the universe of life. For the first time, it is clear how humans are related to other animals and when they first appeared. The idea that Man did not evolve is open to scientific examination: and although creationism is supported by millions the test proves it wrong. Most people believe that they descend from simpler predecessors but would be hard put to say why. As Thomas Henry Huxley, Darwin’s great protagonist, said of the idea of evolution: ‘It is the customary fate of new truths to begin as heresies and to end as superstitions.’ Genetics has saved Darwinism from that fate. It has killed many old and disreputable superstitions. At last there is a real insight into race, and the ancient idea that the peoples of the world are divided into distinct units has gone for ever. Separatism has gained a new popularity among groups anxious to assert an identity of their own, but they cannot call on genes to support their views.

It is, though, the essence of scientific theories that they cannot resolve everything. Science cannot answer the questions that philosophers – or children – ask: why are we here, what is the point of being alive, how ought we to behave? Genetics has nothing to say about what makes people more than just machines driven by biology, about what makes us human. These questions may be interesting, but a scientist is no more qualified to comment on them than is anyone else. Human genetics has suffered from its high opinion of itself. For most of its history it failed to understand its own limits. Knowledge has brought humility to genetics, but its new awareness raises social and ethical problems that have as yet scarcely been addressed.

This book is about what genetics can – and cannot – tell us about ourselves. Its title, The Language of the Genes, points to the analogy upon which it turns, the parallels between biological evolution and the history of language.

Inheritance is a discourse through time, a set of instructions passed from generation to generation. It has a vocabulary – the genes themselves – a grammar, the way in which the information is arranged, and a literature, the thousands of instructions needed to make a human being. It is based on the DNA molecule, the famous double helix, the icon of the twentieth century. Johann Miescher, the Swiss discoverer of that marvellous substance, himself wrote in 1892 that its message might be transmitted ‘just as the words and concepts of all tongues can find expression in twenty-four to thirty letters of the alphabet.’ A century of science shows how right he was.

Both languages and genes evolve. Each generation makes errors in transmission and, sooner or later, enough differences accumulate to produce a new dialect – or a new form of life. Just as the living tongues of the world and their literary relics reveal their extinct ancestors, genes and fossils are an insight into the biological past. We have learned to read the language of the genes and it is saying remarkable things about our history, our present condition and even our future.

The first edition of this book emerged from my Reith Lectures, given on BBC Radio in the early 1990s. Those lectures began with the philosopher Bertrand Russell in 1948 (and, some argue, have gone downhill ever since). I would not dream of comparing myself with my illustrious predecessors but I hope that the series – and the book – can stand on the merits of their subject, the most fascinating in modern science. Perhaps my lectures in their small way helped to show that the BBC can still fulfil its obligations, set forth by its founder Lord Reith, to instruct, inform and entertain. The last might seem an unexpected word to use about science, but it is justified by the number of eccentrics and fools who have graced and disgraced the history of human genetics. They appear sporadically in these pages in the hope of enlivening an otherwise bald narrative.

Since that first edition, seven years ago, genetics – and public concern – have each exploded. What was then remote is here today. In spite of the complaints of Prince Charles, millions of acres of genetically modified crops have been planted; and Dolly the Cloned Sheep, with her penchant for standing on a trough and bullying her inferiors, has been joined by many other domestic animals born without benefit of sex. Some contain genes that make human proteins, as a statement of the new free trade in DNA which makes it possible to move genes from any part of the world of life to any other. We have, with the exception of a few footnotes, read the book of human inheritance. In 2000 it was announced that the order of the DNA bases for every one of the genes needed to make a human being had been established. The rest (small scraps of the ‘junk’ as it is optimistically called) will be read off within a year or so.

Nobody should disparage this work. The impossible has become commonplace. To decipher the DNA has been an enormous task. It was, briefly, the privilege of a professor (or his technicians). Then came the time of the postgraduates, with doctorate after doctorate awarded for one or other piece of the genetic jigsaw. Soon, the machines took over – cheaper, less subject to emotional upset, and far faster than even the most dedicated student. Brute force (helped by ingenuity) triumphed and the pace of discovery accelerated in a fashion more associated with computers than with biology. Part of the rush came from the excitement of a science armed with a goal and the technology to reach it, but part emerged from an attempt to make millions from patents and a competing effort to keep the information in the public domain.

The need for funds and the prospect of fortune has given birth to an era of exaggerated hopes and fears about inheritance. The public is obsessed with genes. In part that is because they come close to questions that lie outside science altogether; issues of sex, identity and fate that have occupied sages since the days of the Old Testament, the first genetics text of all. Genetics is more and more involved with social and political questions such as those of abortion, cloning, and human rights. It puts medical issues into sharp and sometimes uncomfortable focus, with much concern about problems of privacy, blame and the nature of disease. Many inherited illnesses are expensive to treat and hard to cure. They raise unwelcome questions about the balance of responsibility between individuals and populations.

Much has been spent in the past decade. Those who paid for the map of the genes are anxious for some return. It can be hard to translate theory into practice. Vesalius worked out the anatomy of the heart in 1543; but the first heart transplant was not until 1967. Although it will not take as long before gene transplants arrive, they are further away than most people realise, and one important task that genetics faces (and one of the aims of this book) is to tailor public demands to reality.

The new genetics sounds (and is) both beguiling and alarming. Some of those involved have been quick to take advantage of public naiveté and have maintained a stream of promises as to what they will soon achieve. Few have been fulfilled; and some will not be. The molecular biology business promotes its wares as well as any other, and the four letters of the genetic code might nowadays well be restated as H, Y, P and E. Even so, in genetics, more than most sciences, fantasy has a habit of turning into reality in unpredictable ways, even as much-heralded breakthroughs do not appear. At the time of my first edition, the idea that inherited disease would be cured with gene therapy was just around the corner, where it remains. At that time, though, the idea that animals – perhaps even humans – might routinely be cloned, or that lengths of DNA could be moved around at will seemed beyond belief. Now, genetic engineering is a business worth billions a year.

The biggest change in the past seven years has been in attitude. In the public mind, genetics is no longer a science but a faith; a curse or a salvation. It promises or threatens, according to taste. In fact, biology has told us little about human affairs that we did not know before. Both have had plenty of publicity. Dozens of works of exegesis now offer salvation in a molecular paradise or (choose your Church) eternal damnation to those who take the broad path down the double helix to Hell. Some are accounts of the latest advances, but too many are in that weary penumbra of science inhabited by sociologists, who wander like children in a toyshop, playing with devices they scarcely understand. Biochemistry has become a branch of the social sciences and, some say, life will be explained in genetic terms. Many welcome the idea, some are filled with horror, but few pause to consider what, if anything, it means.

The public needs a fairer statement of what science can and cannot do. Reality is harder to sell than hopes or fears; but DNA deserves more than the Frankensteins and designer babies that fill the press. The problem is, at all levels, one of unreasonable expectation, both positive and negative. In this revised version of The Language of the Genes I try to cover the many advances since its first version; in the map of human DNA, in the genetic manipulation of plants and animals, and in our new abilities to screen for inborn disease. I have tried to keep the book to size and have thrown out several sections to allow space for the developments of the past decade.

Since this work first appeared, my malacological career has taken second place to journalism. Perhaps, in time, human genetics will help to understand the world of snails, so that this episode of reporting, rather than doing, will not be wasted.



JSJ, June 2000.




Introduction THE FINGERPRINTS OF HISTORY (#ulink_fe35be09-6118-5861-8ac2-7a2ce8b17d6a)


In 1902, in Paris, a horrible murder was solved by the great French detective Alfonse Bertillon. He used a piece of new technology which struck fear into the heart of the criminal community. Eight decades later two young girls were killed near the Leicestershire village of Narborough. Again, the murderer was found through a technical advance, although the machinery involved would have been beyond the comprehension of Bertillon. These events link the birth and the coming-of-age of human genetics.

The Parisian killer was trapped because he left a fingerprint at the scene of the crime. For the first time, this was used in evidence as a statement of identity. The idea came from ancient Japan, where a finger pressed into a clay pot identified its maker. The Leicestershire murderer was caught in the same way. A new test looked for individual differences in genetic material. This ‘DNA fingerprint’ was as much a statement of personal uniqueness as Bertillon’s clue or the potter’s mark. As usual, life was more complex than science. The killer, a baker called Colin Pitchfork, was caught only after DNA fingerprints had eliminated a young man who had made a false confession and after Pitchfork had persuaded a friend to give a fraudulent blood sample under his name.

The idea that fingerprints could be used to trace criminals came from Charles Darwin’s cousin, Francis Galton. He founded the laboratory in which I work at University College London, the first human genetics institute in the world. Every day I walk past a collection of relics of his life. They include some rows of seeds that show similarities between parents and offspring, an old copy of The Times and a brass counting gadget that can be hidden in the palm of the hand. Each is a reminder of Galton. As well as his revolution in detective work Galton was the first person to publish a weather map and the only one to have made a beauty map of Britain, based on a secret ranking of the local women on a scale of one to five (the low point, incidentally, being in Aberdeen).

His biography reveals an unrelieved eccentricity, well illustrated by the titles of a dozen of his three hundred scientific papers: On spectacles for divers; Statistical inquiries into the efficacy of prayer; Nuts and men; The average flush of excitement; Visions of sane persons; Pedigree moths; Arithmetic by smell; Three generations of lunatic cats; Strawberry cure for gout; Cutting a round cake on scientific principles; Good and bad temper in English families; and The relative sensitivity of men and women at the nape of the neck. Galton travelled much in Africa, regarding the natives with some contempt and measuring the buttocks of the women using a sextant and the principles of surveying.

Galton’s work led, indirectly, to today’s explosion in human genetics. His particular interest was in the inheritance of genius (a class within which he placed himself). In his 1869 book Hereditary Genius, he investigated the ancestry of distinguished people and found a tendency for talent to crop up again and again in the same family. This, he suggested, showed that ability was inborn and not acquired. Hereditary Genius marked the first attempt to establish patterns of human inheritance with well-defined traits – such as becoming (or failing to become) a judge rather than with mere speculation about vague qualities such as fecklessness.

Galton and his followers would be astonished at what biology can now do. It still does not understand attributes such as genius (and reputable scientists hardly concern themselves with them), but DNA is much involved in mental and physical illness. Half a million DNA samples have been taken by police in Britain since the test was invented, and the government has a scheme to follow the genes – and the ailments – of the same number of its citizens over two decades in the hope of finding the biological errors responsible for killers like cancer and heart disease. New tests mean that parents can sometimes choose whether to risk the birth of a child with an inborn defect. Ten thousand such illnesses are known and if we include, as we should, all ailments with an inherited component, most people die because of the genes they carry.

Genetics does more than reveal fate. Humans share much of their heritage with other creatures. As Galton himself illustrated with the appropriate impression pasted near that made by Gladstone, the prime minister, chimpanzees have fingerprints. Now we know that much of their DNA is identical to our own (as indeed is that of bananas). All this suggests that humans and apes are close relatives.

Genetics is the key to the past. As every gene must have an ancestor, inherited diversity can be used to piece together a picture of history more complete than from any other source. Each segment of DNA is a message from our forebears and together they contain the whole story of human evolution. Everyone alive today is a living fossil and carries within themselves a record that revisits the birth of humankind. The Origin of Species expresses the hope that ‘light will be thrown on the origin of man and his history’. Darwin’s hint that humans share a common descent with all other creatures is now accepted by all scientists, because of the evidence of the genes.

Evolution, the appearance of new forms by the alteration of those already present, is no more than descent with modification. The same is true of language. As a boy, I was amused by the tale of the order going down the line of command to soldiers in the trenches. ‘Send reinforcements, we’re going to advance’ changed to ‘Send three and fourpence, we’re going to a dance’ as it passed from man to man. This simple tale illustrates how accidents, as an inherited message is copied, can lead to change. Because of mutation, life, too, is garbled during transmission.

This book is about inheritance: about the clues of our past, present and future that we all contain. The language of the genes has a simple alphabet, with not twenty-six letters, but four; the DNA bases – adenine, guanine, cytosine and thymine (A, G, C and T for short). They are arranged in words of three letters such as CGA or TGG. Most code for different amino acids, which are themselves joined together to make proteins, the building blocks of the body.

The economy of life’s language can be illustrated with an odd quotation from a book called Gadsby, written in 1939 by one Ernest Wright: ‘I am going to show you how a bunch of bright young folks did find a champion, a man with boys and girls of his own, a man of so dominating and happy individuality that youth was drawn to him as a fly to a sugar bowl.’ This sounds somewhat peculiar, as does the rest of the fifty-thousand word book, and it is. The quotation, and the whole work, lacks the letter ‘e’. An English sentence can be written with twenty-five letters instead of twenty-six, but only just. Biology manages with a mere four.

Although its vocabulary is simple the genetical message is very long. Each cell in the body contains about six feet of DNA. There are so many cells that if all the DNA in a single human body were stretched out it would reach to the moon and back eight thousand times. Twenty years ago, the Human Genome Project set out to read the whole of its three thousand million letters, and to publish perhaps the most dreary volume ever written, the equivalent of a dozen or so copies of the Encyclopaedia Britannica. The task is now more or less complete. The sequencers followed a grand scientific tradition: the Admiralty, after all, sent the Beagle to South America with Darwin on board not because they were interested in evolution but because they knew that if they were to understand (and, with luck, control) the world, the first step was to map it. The chart of the genes, like that of the Americas, has been expensive to make; but – like the theory of evolution itself – it may change our perception of ourselves.

Powerful ideas like inheritance and evolution soon attract myths. Impressed by his studies of genius, Galton founded the science (if that is the right word) of eugenics. Its main aim was ‘to check the birth rate of the Unfit and improve the race by furthering the productivity of the fit by early marriage of the best stock’. He led the new field of human genetics into a blind alley from which it did not emerge for half a century. At his death, he left £45,000 to found the Laboratory of National Eugenics at University College London and, in fine Victorian tradition, £200 to his servant who had worked for him for forty years. His research institute soon changed its name to the Galton Laboratory to escape from the eugenical taint. What became of his servant is not recorded.

Galton’s social ideas and Darwin’s evolutionary insights had a pervasive effect on the intellectual history of the twentieth century. They influenced left and right, liberal and reactionary, and continue – explicitly or otherwise – to do so. Many disparate figures trace their ideas to The Origin and to Hereditary Genius. All are united by one belief: in biology as destiny, in the power of genes over those who bear them.

The most famous monument in Highgate Cemetery in London, a couple of miles north of today’s Galton Laboratory, is that of Karl Marx. Its inscription is well known: ‘Philosophers have only interpreted the world. The point, however, is to change it.’ Darwinism was soon used in an attempt to live up to that demand. The philosopher Herbert Spencer, buried just across the path from Marx, founded what he called Social Darwinism; the notion that poverty and wealth are inevitable as they reflect the biological rules that govern society. In his day, Spencer was famous. His Times obituary claimed that ‘England has lost the most widely celebrated and influential of her sons.’ Now he is remembered only for that neatly circular phrase ‘the survival of the fittest’ and for inventing the word ‘evolution’.

He wrote with a true philosopher’s clarity: ‘Evolution is an integration of matter and concomitant dissipation of motion; during which matter passes from an indefinite, incoherent homogeneity, to a definite, coherent heterogeneity, through continuous differentiations and integrations’. Those lucid lines were parodied by a mathematical contemporary: ‘A change from a nohowish, untalkaboutable all-alikeness to a somehowish and in general talkaboutable not-all-alikeness by continuous somethingelsifications and sticktogetherations.’

Spencer used The Origin of Species as a rationale for the excesses of capitalism. The steel magnate Andrew Carnegie was one of many to be impressed by the idea that evolution excuses injustice. He invited Herbert Spencer to Pittsburgh. Unfortunately, the philosopher’s response to his trip to see his theories worked out in steel and concrete was that ‘Six months’ residence here would justify suicide.’

Galton, too, supported the idea of breeding from the best and sterilising those whose inheritance did not meet with his approval. The eugenics movement joined a gentle concern for the unborn with a brutal rejection of the rights of the living (a combination not unknown today). Galton’s main interest in genetics was as a means to forestall the imminent decline of the human race. He claimed that families of ‘genius’ had fewer children than most and was concerned about what this meant for the future. It was man’s duty to interfere with his own evolution. As he said: ‘What Nature does blindly and ruthlessly, man may do providently, quickly and kindly.’ Perhaps his own childless state helped to explain his anxiety.

Many of the eugenicists shared the highly heritable attributes of wealth, education and social position. Francis Galton gained his affluence from his family of Quaker gunmakers. Much of his agenda was the survival of the richest. Other eugenicists were on the left. They felt that if economies could be planned, so could genes. George Bernard Shaw, at a meeting attended by Galton in his last years, claimed that ‘Men and women select their wives and husbands far less carefully than they select their cashiers and cooks.’ Later, he wrote that ‘Extermination must be put on a scientific basis if it is ever to be carried out humanely and apologetically as well as thoroughly.’ Shaw was, no doubt, playing his role as Bad Boy to the Gentry, but subsequent events made his tomfoolery seem even less droll than it did at the time.

Sometimes, such notions were put into practice. Paraguay has an isolated village with an unusual name: Nueva Germania, New Germany. Many of its inhabitants have blonde hair and blue eyes. Their names are not Spanish, but are more likely to be Schutte or Neumann. They are the descendants of an experiment; an attempt to improve humankind. Their ancestors were chosen from the people of Saxony in 1886 by Elisabeth Nietzsche – sister of the philosopher, who himself uttered the immortal phrase ‘What in the world has caused more damage than the follies of the compassionate?’ – as particularly splendid specimens, selected for the purity of their blood. The idea was suggested by Wagner (who once planned to visit). The New Germans were expected to found a community so favoured in its genetic endowment that it would be the seed of a new race of supermen. Elisabeth Nietzsche died in 1935 and Hitler himself wept at her funeral. Today the people of Nueva Germania are poor, inbred and diseased. Their Utopia has failed.

The eugenics movement had an influence elsewhere in the New World. In 1898, Charles Davenport, then professor of evolutionary biology at Harvard, was appointed as Director of the Cold Spring Harbor Laboratory on Long Island Sound. Initially, the Laboratory concentrated on the study of ‘the normal variation of the animals in the harbor, lakes and woods, and the production of abnormalities’. It carried out some of the most important work in early twentieth-century biology.

Soon, Mrs E H Harriman, widow of the railway millionaire, decided to devote part of her fortune to the study of human improvement. The Eugenics Record Office was built next to the original laboratory. It employed two hundred field workers, who were sent out to collect pedigrees. Their 750,000 genetic records included studies of inherited disease and of colour blindness; but also recorded the inheritance of shyness, pauperism, nomadism, and moral control.

Davenport’s work had an important effect on American society. The first years of the twentieth century saw eugenical clubs with prizes for the fittest families and, for the first time, medicine became concerned about whether its duty to the future outweighed the interests of some of those alive today. In Galtonian style, Davenport claimed that: ‘Society must protect itself; as it claims the right to deprive the murderer of his life so also may it annihilate the hideous serpent of hopelessly vicious protoplasm.’ Twenty-five thousand Americans were sterilised because they might pass feeble-mindedness or criminality to future generations. One judge compared sterilisation with vaccination. The common good, he said, overrode individual rights.

Another political leader had similar views. ‘The unnatural and increasingly rapid growth of the feeble-minded and insane classes, coupled as it is with steady restriction among all the thrifty, energetic and superior stocks constitutes a national and race danger which it is impossible to exaggerate. I feel that the source from which the stream of madness is fed should be cut off and sealed off before another year has passed.’ Such were the words of Winston Churchill when Home Secretary in 1910. His beliefs were seen as so inflammatory by later British governments that they were not made public until 1992.

One of Galton’s followers was the German embryologist Ernst Haeckel. Haeckel was a keen supporter of evolution. He came up with the idea (which later influenced Freud) that every animal re-lived its evolutionary past during its embryonic development. His interest in Galton and Darwin and his belief in inheritance as fate led him to found the Monist League, which had thousands of members before the First World War. It argued for the application of biological rules to society and for the survival of some races – those with the finest heritage – at the expense of others. Haeckel claimed social rules were the natural laws of heredity and adaptation. The evolutionary destiny of the Germans was to overcome inferior peoples: ‘The Germans have deviated furthest from the common form of ape-like men … The lower races are psychologically nearer to the animals than to civilized Europeans. We must, therefore, assign a totally different value to their lives.’

In 1900 the arms manufacturer Krupp offered a large prize for the best essay on ‘What can the Theory of Evolution tell us about Domestic Political Development and the Legislation of the State?’ There were sixty entries. In spite of the interests of capital, the first German eugenic sterilisation was carried out by a socialist doctor (albeit one who claimed that trade union leaders were more likely to be blond than were their followers).

While imprisoned after the Beer Hall Putsch, Hitler read the standard German text on human genetics, The Principles of Human Heredity and Race Hygiene, by Eugene Fischer. Fischer was the director of the Berlin Institute for Anthropology, Human Heredity and Eugenics. One of his assistants, Joseph Mengele, later achieved a certain notoriety for his attempts to put Galtonian ideas into practice. Fischer’s book contained a chilling phrase: ‘The question of the quality of our hereditary endowment’ – it said – ‘is a hundred times more important than the dispute over capitalism or socialism.’

His thoughts were echoed in Mein Kampf: ‘Whoever is not bodily and spiritually healthy and worthy shall not have the right to pass on his suffering in the body of his children’. Hitler took this to its dreadful conclusion with the murder of those he saw as less favoured in order to breed from the best. The task was taken seriously, with four hundred thousand sterilisations of those deemed unworthy to pass on their genes, sometimes by the secret use of X-rays as the victims filled in forms. Those in charge of the programme in Hamburg estimated that one fifth of its people deserved to be treated in this way.

By 1936 the German Society for Race Hygiene had more than sixty branches and doctorates in racial science were offered at several German universities. Certain peoples were, they claimed, inferior because of inheritance. Half of those at the Wannsee Conference (which decided on the final solution of the Jewish problem) had doctorates and many justified their crimes on scientific grounds. The eugenics movement in Germany was opposed to abortion (except of the unfit) and imposed stiff penalties – up to ten years in prison – on any doctor rash enough to carry it out. The number of children born to women of approved stock went up by a fifth. The Hitlerian conjunction of extreme right wing views, an obsession with racial purity and a hatred of abortion has its echoes today.

Concern for the purity of German blood reached absurd lengths. One unfortunate member of the National Socialist Party received a transfusion from a Jew after he had been in a road accident. He was brought before a disciplinary court to see if he should he excluded from the Party. Fortunately, the donor had fought in the First World War, so that his Jewish red cells were – just about – acceptable.

The disaster of the Nazi experiment ended the eugenics movement, at least in its primitive form. Its blemished past means that human genetics is marked by the fingerprints of its own history. It sometimes seems to find them hard to wipe off. They should not be forgotten now that the subject is, for the first time, in a position to control the biological future.

Galton and his followers felt free to invent a science which accorded with their own prejudices. They believed that the duty to genes outweighs that to those who bear them. They were filled with extraordinary self-assurance and great weight was placed on their views although in retrospect it is obvious that they knew almost nothing.

Today’s new knowledge is as controversial as was the old ignorance. Even so, disputes among modern biologists are not about the vague general issues that obsessed their predecessors. Instead they concern themselves with the fate of individuals rather than of all humanity. Genetics has become a science and, as such, has narrowed its horizons.

Nevertheless, it raises ethical issues which will not go away. The newspapers are filled with debates about the morals of gene therapy or of human cloning, neither of which show any sign of becoming a reality. However, the diagnosis of defective genes before birth has already shifted the balance between birth and abortion to reduce the number of damaged children. This raises passions, from those who feel – in spite of the high natural wastage of fertilised eggs – that all foetuses are sacred, to others who consider that to pass on a faulty gene is equivalent to child abuse. Genetics presents a more universal difficulty – the problem of knowledge. Soon, it will tell many of us how and when we may die. Already, it is possible to diagnose at birth genes which will kill in childhood, youth or middle age. More will soon be found. Will people want to know that they are at risk of a disease which cannot be treated? Many genes show their effects in those who inherit damaged DNA from each parent. As everyone is likely to pass on a single copy of at least one such gene, will this help to choose a partner or to decide whether to have children?

Attitudes to inborn disease are flexible. In Ghana, babies are sometimes born with an extra finger or toe. Some tribal groups take no notice, others rejoice as it means that the new member of the family will become rich; but others, just a few miles away, regard such children with horror and they are drowned at birth. Even Christianity has seen the genetically unfortunate as less than human. Martin Luther himself declared that Siamese twins were monsters without a soul. Attitudes to genetics will always be influenced by those to abortion, which vary with time and place. St Augustine saw a foetus as part of its mother and not worthy of protection and in spite of its present views the Catholic Church did not condemn abortion until the thirteenth century. Ireland has a constitutional clause that establishes the right to life of the unborn child; while across the Irish Sea abortion until the third month is available almost on demand. Embryo research (which is becoming important with the discovery that embryonic cells can be used to treat adult disease) is forbidden in Germany but lightly controlled in Britain. All this shows how hard it is to set ethical limits to the new biology.

The problem can be illustrated with some old-fashioned biological discrimination. There has always been prejudice against certain genes, those carried on the chromosomes that determine sex. Women have two ‘X’ chromosomes, men a single X chromosome and a much smaller ‘Y’. All eggs have an X but that of sperm are of two kinds, X or Y. At fertilisation, both XY males and XX females are produced in equal number. Sex is as much a product of genes as are blood groups.

How the value of these genes is judged shows how biological choice can depend on circumstances. Sometimes, Y chromosomes seem to be worth less than Xs. When it comes to wars, murders and executions, males have always been more acceptable victims than females. But the balance can shift. Many parents express a preference for sons, especially as a first-born. Some even try to achieve them. The recipes vary from the heroic to the hopeful. In ancient Greece, to tie off the left testicle was said to do the job, while mediaeval husbands drank wine and lion’s blood before copulating under a full moon. Less drastic methods included sex in a north wind and hanging one’s underpants on the right side of the bed.

To sell gender is an easy way to make money. It has, after all, a guaranteed fifty per cent success rate. Today’s methods vary from the use of baking soda or vinegar at the appropriate moment (to take advantage of a supposed difference in the resistance of X and Y-bearing sperm to acids and alkalis) to sex at particular times of the female cycle. A diet high or low in salt is also said to help. Such recipes are useless and some of those who sell them have been prosecuted for fraud.

Now, fraud is out of date. Sex can be chosen in many ways. One is to separate X and Y sperm and to fertilise a woman with the appropriate type. The methods are not absolute, but shift the ratios by about two to one for males and four to one for females. Since Louise Brown in 1978, thousands of children have been born by in-vitro fertilisation, with sperm added to egg in a test-tube. A single cell can be taken from the embryo and its sex determined (and, indeed, as young male embryos grow faster, simply to choose the largest embryo biases the ratio of males). Only those of the desired gender are implanted into the mother. This technique has led to the birth of hundreds of babies.

Pregnancy termination is a less kind, but equally effective, way of choosing the sex of a child. Aristotle himself felt that a male foetus should be protected from abortion after forty days, but a female only after ninety. A recent survey of geneticists themselves showed that, in Holland, none would accept pregnancy termination just to choose the sex of a child, in Britain one in six, and in Russia nine out of ten. The Indian government was forced to shut down clinics which chose the sex of a baby with a test of the chromosomes of the foetus and aborted those with two Xs. More than two thousand pregnancies a year were ended for this reason in Bombay alone. The main reason was the need for large dowries when daughters were married off. The advertisements said ‘Spend six hundred rupees now, save fifty thousand later.’ The preference is an old one. A nineteenth-century visitor to Benares recorded that ‘Every female infant in the Rajah’s family born of a lawful wife, or Rani, was drowned as soon as it was born in a hole in the earth filled with milk.’ The rulers’ many wives were said to have produced no grown-up daughters for more than a century. The government nowadays pays a bonus for girl babies, but some states now have four females to five males and the country as a whole has a deficit of girls and women equivalent to the entire British female population.

All these methods interfere with genes. Their acceptability varies from the reasonably uncontentious choice of sperm to a crime where the murder of girl children is concerned. Where to draw the line depends on one’s own social, political or religious background; on how acceptable the notion might be that fate should depend on biological merit. All readers of this book would, I imagine, abhor infanticide, and most might feel that to terminate a pregnancy just because it is the wrong sex was also wrong. They might worry less about the choice of X or Y sperm.

The choice of a child’s sex can, however, involve more than parental self-indulgence. Sometimes it is a matter of life and death. Many inherited diseases are carried on the X chromosome. In most girls, an abnormal X is masked by a normal copy. Boys do not have this option, as they have but a single X. For this reason, sex-linked abnormalities, as they are known, are much more common in boys than in girls. They can be distressing. Duchenne muscular dystrophy is a wasting disease of the muscles. Symptoms can appear even in three year-olds and affected children have to wear leg braces by the age of seven, are often in a wheelchair by eleven and may die before the age of twenty-five. Parents who have seen one of their sons die of muscular dystrophy are in the agonising position of knowing that any later son has a one in two chance of having inherited it. A couple who have had a son with the illness can scarcely be blamed for a desire to ensure that no later child is affected. They hope to control the quality of their offspring and few will criticise them for doing so. Genetics has changed their ethical balance.

If a couple has a son with muscular dystrophy they know at once that the mother carries the gene. The chance of a second son with the disease is hence far greater than before. It is still just one in two, so that to terminate all male pregnancies means a real possibility of losing a normal boy. Even those who dislike the idea of choice of a child’s sex with X-bearing sperm might change their minds in these circumstances. Others would go further and accept the option of an externally fertilised embryo or the termination of all pregnancies which would produce a son.

Now, such choices have become more precise. The gene for muscular dystrophy has been found and changes in the DNA can show whether a foetus bears it. Hundreds of centres use the test. But the method is far from perfect. The gene can go wrong in many ways and not all of them show up. A foetus that appears normal may hence, in a proportion of cases, carry the gene. This complicates the parents’ decision as to whether to continue with a pregnancy. To sample foetal tissues also involves a certain hazard. This has become smaller as technology improves, with a check of foetal cells in the mother’s blood, but the risks of the test must themselves be weighed in the moral scales.

As more is found about the genes that cause death not at birth, or in the teens, but in middle or old age the dilemmas increase. Given the opportunity, some might avoid the birth of a baby doomed to dementia through Alzheimer’s disease in its forties. Others would argue that forty years of life are not to be dismissed; and that, in four decades of science, the cure may be found.

Decisions about the future of an unborn child will, as a result, more and more be influenced by estimates of risk and of quality: by whether the rights of a foetus depend on its genes. Such judgements are not just scientific decisions, but depend on the society and the people who make them. The debacle of the eugenics movement led to an understandable reluctance even to consider the idea of choices about rights based on inherited merit, but the new knowledge means that they are unavoidable.

Galton himself would have been delighted by the idea of preventing the birth of the damaged. The new eugenics can be overt. The Chinese People’s Daily is frank in its views. It reported a scheme to ban the marriage of those with mental disease unless they were sterilised with a robust simplification of Mendelism: ‘Idiots give birth to idiots!’ the eugenical message is often justified on financial grounds. At the Sesquicentennial Exhibition in Philadelphia in 1926 the American Eugenics Society had a board that counted up the $100 per second supposed to be spent on people with ‘bad heredity’. Sixty years later, one proponent of the plan to sequence the human genome claimed that the project would pay for itself by ‘curing’ schizophrenia – by which he meant the termination of pregnancies carrying the as yet hypothetical and undiscovered gene for the disease. The 1930s were a period of financial squeeze for health care. Seventy years on, the state is still anxious to limit the amount spent on medicine in the face of an inexorable rise in costs, with inborn diseases among the most expensive. There is a fresh danger that genetics will be used as an excuse to discriminate against the handicapped in order to save money.

Genetics – science as a whole – owes its success to the fact that it is reductionist: that to understand a problem, it helps to break it down into its component parts. The human genome project marks the extreme application of such a view. The approach works well in biology as far as it goes, but it only goes so far. Its limits are seen in a phrase once notorious in British politics, the late Prime Minister Mrs Thatcher’s statement that ‘There is no such thing as society, there are only individuals.’ The failures of her philosophy are all around us. To say, with Galton and his successors, ‘There are no people, there are only genes’ is to fall into the same trap.

In spite of the lessons of the past, there has been a resurgence of the dangerous and antique myth that biology can explain everything. Some have again begun to claim that we are controlled by our inheritance. They promote a kind of biological fatalism. Humanity, they say, is driven by its inheritance. The predicament of those who fail comes from their own weakness and has little to do with the rest of us. Such nouvelle Galtonism suggests that human existence is programmed and that, apart from a little selective pregnancy termination, there is no point in any attempt to change it – which is convenient for those who like things the way they are.

After the Second World War, genetics had – it seemed – at last begun to accept its own limits and to escape its confines as the haunt of the obsessed. Most of those in the field today are cautious about claims that the essence of humanity lies in DNA. Although it can say extraordinary things about ourselves, genetics is one of the few sciences that has reduced its expectations.

In mediaeval Japan, the science of dactylomancy – the interpretation of personality from fingerprints – had it that people with complex patterns were good craftsmen, those with many loops lacked perseverance, while those whose fingers carried an arched pattern were crude characters without mercy. Human genetics has escaped from its dactylomantic origins. The more we learn about inheritance the more it seems that there is to know. The shadow of eugenics has not yet disappeared but is fainter than it was. Now that genetics has matured as a subject it is beginning to reveal an extraordinary portrait of who we are, what we were, and what we may become. This book is about what that picture contains.




Chapter One A MESSAGE FROM OUR ANCESTORS (#ulink_ff865943-150b-5279-8800-1394de60c3d0)


The rich were the first geneticists. For them, vague statements of inherited importance were not enough. They needed – and awarded themselves – concrete symbols of wealth and consequence that could persist when those who invented them were long dead. The Lion of the Hebrew Tribe of Judah was, until a few years ago, the symbol of the Emperor of Ethiopia, while those of England descend from the lions awarded to Geoffroy Plantagenet in 1177. The fetish for ancestry means that royal families are important in genetics (Prince Charles, for example, has 262,142 ancestors recorded on his pedigree). The obsession persists against all attempts to deny it. Heraldry was cut off by the American Revolution, but George Washington himself attempted to make a connection with the Washingtons of Northamptonshire and used, illegally, their five-pointed stars as a book plate.

Heraldic symbols were invented because only when the past is preserved does it make sense. For much of history wealth was dissipated on funerary ornaments to remind the unborn from whence they sprang. University College London contains an eccentric object; the stuffed body of the philosopher Jeremy Bentham (who was associated with the College at its foundation). Bentham hoped to start a fashion for such ‘auto-icons’ in the hope of reducing the cost of monuments to the deceased. It did not catch on, although the popularity of his corpse with visitors suggests that it ought to have done.

Such pride in family would now be greeted, mainly, with derision. Harold Wilson, the British Prime Minister of the 1960s, did as much when he mocked his predecessor, Lord Home, for being the Seventeenth Earl of that name. Lord Home deflected the jest when he pointed out that his critic must be the seventeenth Mr Wilson. He made a valid claim: that while only a few preserve their heritage in an ostentatious way, every family, aristocratic or not, retains the record of their ancestors. Everyone, however deficient in history, can decipher their past in the narrative of the DNA.

Some can use inherited abnormalities. A form of juvenile blindness called hereditary glaucoma is found in France. Parish records show that most cases descend from a couple who lived in the village of Wierr-Effroy near Calais in the fifteenth century. Even today pilgrims pray in the village church of Sainte Godeleine, which contains a cistern whose waters are believed to cure blindness. Thirty thousand descendants have been traced and for many the diagnosis of the disease was their first clue about where their ancestors came from and who their relatives might be. The gene went with French emigrants to the New World.

Human genetics was, until recently, restricted to studying pedigrees that stood out because they contained an inborn disease. Its ability to trace descent was limited to those few kindreds who appear to deviate from some perfect form. Biology has now shown that perfection is a mirage and that, instead, variation rules. Thousands of characters – normal diversity, not diseases – distinguish each nation, each family and each person. Everyone alive today is different from everyone who ever has lived or ever will live. Such variation can be used to look at shared ancestry in any lineage, healthy or ill, aristocratic or plebeian. Every modern gene brings clues from parents and grandparents, from the earliest humans a hundred thousand years and more ago and from the origin of life four thousand million years before that.

Most of genetics is no more than a search for diversity. Some differences can be seen with the naked eye. Others need the most sophisticated methods of molecular biology. As a sample of how different each individual is we can glance beneath the way we look to ask about variation in how we sense the world and how the world perceives us.

Obviously, people do not much resemble each other. The inheritance of appearance is not simple. Eye colour depends first on whether any pigment is present. If none is made the eye is pale blue. Other tints vary in the amounts of the pigment made by several distinct genes, so that colour is not a dependable way of working out who fathered a particular child. The inheritance of hair type is also rather complex. Apart from very blonde or very red hair, the genetics of the rest of the range is confused and is further complicated by the effects of age and exposure to the sun.

Even a trivial test shows that individuals differ in other ways. Stick your tongue out. Can you roll it into a tube? About half those of European descent can and half cannot. Clasp your hands together. Which thumb is on top? Again, about half the population folds the left thumb above the right and about half do it the other way. These attributes run in families but their inheritance, like that of physical appearance, is uncertain.

People vary not just in the way the world sees them, but how they see it. A few are colour-blind. They lack a receptor for red, green or blue light. All three are needed to perceive the full range of colour. The absence of (or damage to) one (usually that for green, less often for red, almost never for blue) gives rise to a mild disability that may have made a difference when gathering food in ancient times. The three genes involved have now been tracked down. Those for red and green are similar and diverged not long ago, while the blue receptor has an identity of its own. John Dalton, best known for his atomic theory, was himself so colour-blind as to match red sealing-wax with a leaf (which must have made things difficult for a chemist). He believed that his own eyes were tinted with a blue filter and asked that they be examined after his death. They were, and no filter was found, but, a century and a half later, a check of the DNA in his pickled eyeballs showed him to have lacked the green-sensitive pigment.

Colour-blindness marks the extreme of a system of normal variation in perception. When asked to mix red and green light until they match a standard orange colour, people divide into two groups that differ in the hue of the red light chosen. There are two distinct receptors for red, differing in a single change in the DNA. About sixty per cent of Europeans have one form, forty per cent the other. Both groups are normal (in the sense that they are aware of no handicap) but one sees the world through rather more rose-tinted spectacles than the other. The contrast is small but noticeable. If two men with different red receptors were to choose jacket and trousers for Father Christmas there would be a perceptible clash between upper and lower halves.

In the 1930s, a manufacturer of ice trays was surprised to receive complaints that his trays made ice taste bitter. This baffled the entrepreneur as the ice tasted just like ice to him, but was a hint of inherited differences in the ability to taste. To some, a trace of a substance used in the manufacturing process is intolerable, while to others a concentration a thousand times greater has no taste at all. Much of the difference depends on just one gene which exists in two forms. That observation, the ability or otherwise to perceive a substance, now called PROP, was the key to a new universe of taste. Genetic ‘supertasters’ are very sensitive to the hops in beer, to pungent vegetables like broccoli, to sugar and to spices, while non-tasters scarcely notice them. Half the population of India cannot taste the chemical at all, but just one African in thirty is unable to perceive it. Students of my day thought it witty to make tea containing PROP to see the bafflement of those who could drink it and those who could not. Today’s undergraduates have more sense.

As truffle-hunters know, scent and taste are related. There is genetic variation in the ability to smell, among other things, sweat, musk, hydrogen cyanide and the odour of freesias. Many animals communicate with each other through the nose. Female mice can smell not only who a male is, but how close a relative he might be. Humans also have an odorous identity, as police dogs find it more difficult to separate the trails of identical twins (who have all their genes in common) than those of unrelated people. Man has more scent glands than does any other primate, perhaps as a remnant of some uniqueness in smell which has lost its importance in a world full of sight. The tie between sex and scent in ourselves is made by a rare inborn disease that both prevents the growth of the sex organs and abolishes the sense of smell, suggesting that the two systems share a common pathway of development in the early embryo.

Variation in the way we look, see, smell and taste is but a tiny part of the universe of difference. The genes that enable mice to recognise each other by scent are part of a larger system of identifying outsiders. The threat of infection means that every creature is always in conflict with the external world. The immune system determines what should be kept out. It differentiates ‘self’ from ‘not-self’ and makes protective antibodies that interact with antigens (chemical clues on a native or foreign molecule) to define whether any substance is acceptable. The millions of antibodies each recognises a single antigen. Cells bear antigens of their own that, with great precision, separate each individual from his fellows. Antigens are a hint of the mass of uniqueness beneath the bland surface of the human race.

When blood from two people is mixed, it may turn into a sticky mess. The process is controlled by a system of antigens called the blood groups. Only certain combinations can mix successfully. Some groups, ABO and Rhesus for example, are familiar, while others, such as Duffy and Kell, are less so. Because of their importance in transfusion, millions of people have been tested. A dozen systems are screened on a routine basis and each comes in a number of forms. This small sample of genes generates plenty of diversity. The chances of two Englishmen having the same combination of all twelve blood groups is only about one in three thousand. Of an Englishman and a Welshman it is even less and of an English person and an African less again.

Since the discovery of the blood groups and other cues on the surfaces of cells, there has been a technical revolution. Like the stone age revolution a thousand centuries ago, it depends on simple tools that can be used in many ways. The DNA of different people can now be compared letter by letter, to test how unique we are. The Human Genome Diversity Project is a spin-off from the main mapping effort which has tested thousands of people. On the average, and depending on what piece of the DNA is tested, two people differ in about one or two DNA letters per thousand; that is, in about three to six million places in the whole inherited message. Some of the differences involve changes in single bases (single nucleotide polymorphisms, or ‘snips’ as they are called), some in the number of short repeats of particular sequences (‘microsatellites’ and ‘minisatellites’) and some turn on the presence or absence of bits of mobile DNA that leapt into a particular place in the genome long ago. Blood groups show how improbable it is that two will be the same when a mere twelve variable systems are used. The chance that they both have the same sequence of letters in the whole genetic alphabet is one in hundreds of billions. Genetics has made individuals of us all. It disproves Plato’s myth of the absolute, that there exists one ideal form of human being, with rare flaws that lead to inborn disease.

Variation helps us to understand where we fit in our own family tree, in the pedigree of humankind, and in the world of life. Relatives are more likely to share genes because they have an ancestor in common. As all genes descend from a carrier long dead they can be used to test kinship, however distant that might be. The more variants two people share the more they are related. This logic can be used to sort out any pattern of affinity.

This detective work is easiest when close – or identical – relatives are involved. The US Army tests the fit of dead bodies to their previous owners by storing DNA samples from soldiers in the hope of identifying their corpses after death. DNA can also say a lot about the immediate family. Once, immigration officers faced with applicants for entry often refused to believe that a child was the offspring of the woman who claimed it. Comparison of the genes of mother and child almost always showed that the mother was telling the truth. Our society being what it is, the tests are now less used than they were. However, not all families are what they seem. Attempts to match the genes of parents and offspring in Britain or the United States reveal quite a high incidence of false paternity. Many children have a combination of genes which cannot be generated from those of their supposed parents. Often, they show that the biological father is not the male who is married to the biological mother. In middle class society about one birth in twenty is of this kind.

Such detective work can skip generations. During the Argentinian military dictatorship of the 1970s and 1980s thousands of people disappeared. Most were murdered. Some of the victims were pregnant women who were killed after they had given birth. Their children were stolen by military families. When civilian rule was restored, a group of mothers of the murdered women began to search for their grandchildren, whose DNA was compared with those who claimed to be their parents. The message passed in the genes enabled more than fifty children to be restored to their biological families, two generations on.

Other families have no hope of restoration. Bones dug up in a cellar in Ekaterinburg in 1991 were suspected to be those of the last Tsar and his family, shot in 1918. Checks of their DNA against modern relatives proves that the skeletons are, indeed, the remains of the Romanovs. Intriguingly enough, the skeleton of one young girl imprisoned with the group was missing. A woman known as Anna Anderson (who died in Virginia in 1984) claimed for many years to be the absent child, Anastasia, the daughter of the Tsar. Her assertion was rejected by a German court, but was accepted by thousands of émigré Russians. A check of the genes contained in a sample of her tissue found after her death showed her not to be related to the Romanovs, but instead to be (as many had suspected) a Pole, Franziska Schanzkowska, who had been rescued from a suicide attempt in a Berlin canal and ever after believed herself to be of noble blood.

Anna Anderson’s claim to the Russian Eagle was false; but everyone has been granted a genetic coat of arms to democratize the search for descent. Like that of the Romanovs, it records who the forebears were and from whence they came. When people move they take more than their escutcheons. The DNA goes too, so that maps of genes do more than just record ancestry. They recreate history.

History itself may suggest where to start. Alex Haley, in his book Roots, used documents on the slave trade to try to find his African ancestors. He found just one, Kunta Kinte, who had been taken as a slave from the Gambia in 1767; and later became suspicious of the tales told to him by a native story-teller upon which Roots was in part based. The genes of today’s Black Americans might have solved his problem.

The African slave trade began in the days of the Roman Empire. By AD 800 Arab traders had extended it to Europe, the Middle East and China. In the fifteenth century the Spanish and Portuguese started what became a mass migration, at first from the Guinea Coast, modern Mauritania. Mediaeval Venice had black gondoliers and by the sixteenth century one person in ten in Lisbon was of African origin. Soon, a bull of Pope Nicholas V instructed his followers to ‘attack, subject, and reduce to perpetual slavery the Saracens, Pagans and other enemies of Christ, southward from Cape Bojador and including all the coast of Guinea’.

The main trade was to the New World. About fifteen million Africans were shipped across the Atlantic. They came from all over West Africa and were dispersed over much of North and South America. The United States imported less than a twentieth of the total, but by the 1950s the USA had a third of all New World people of African descent, suggesting that slaves were treated less brutally there than in the Caribbean or Brazil. Slave-owners had their own preferences. In South Carolina slaves from the Gambia were favoured over those from Biafra as the latter were thought to be hard to control. In Virginia the preference was in the opposite direction.

Many Africans have an abnormal form of the red pigment of the blood, haemoglobin. One of the amino acids has suffered a genetic accident, a mutation. This ‘sickle-cell’ form protects against malaria. Its protective role has disappeared with the control of the disease in the United States, but many thousands of Black Americans still carry the gene as an unwelcome record of their past. Anyone, however light their skin, who has the sickle-cell variant must have had at least one African ancestor. The disease was first recognised in 1910, and was at once used as a statement of racial identity: anyone with the illness (whatever their colour) must, by definition, be a Negro. Indeed, its very presence was seen as proof of the degenerate nature of American Blacks. The related disorders in southern Europe also showed, in the words of one racial theorist, that such people were ‘not white clear through’ and that their immigration to the USA would ‘produce a hybrid race of people as worthless and futile as the good-for-nothing mongrels of Central America.’

The fact that many Black Americans have a copy of the gene for sickle-cell haemoglobin says little more than that they originated in West Africa, which we knew already. Molecular technology tells a tale of just who the ‘mongrels’ are. It uncovers a mass of variation around the haemoglobin genes and gives an insight into the ancestry of many Americans, black or not; including the great majority who do not carry a copy of sickle-cell at all.

The DNA in this part of the genome varies from place to place within Africa. The sickle-cell mutation itself is associated with different sets of DNA letters in Sierra Leone, Nigeria and Zaire, probably because it arose several times. The DNA around the normal version of the gene also varies and this, too, can be used to track down where in Africa the ancestors of today’s Americans came from.

That continent contains more diversity than anywhere else. Not only are its people more distinct one from the other, but different villages, tribes and nations have more individuality, because humans have been in Africa for longer than anywhere else. As a result, genes can track down the ancestry of Africans with some accuracy.

Black Americans from the north of the USA have a different set of variants from those in the south. The majority of northerners share a heritage with today’s Nigerians while their southern cousins have more affinities with peoples further west. The difference in the slave markets two hundred years ago has left evidence today. Alex Haley, by comparing his genes with those from Africa, would have learned much more about his forefathers than he could hope to uncover from the records. For any black American, a DNA test could be a first hint as to where to search for his slave ancestors – and, for a mere $250, one is now on sale (although the limited information yet available on the genes of West Africa mean that any hope of finding his native village – or even tribe – is largely vain).

Many of Alex Haley’s ancestors were probably not black at all. One particular variant in the Duffy blood group system is found only in West Africa. Europeans have a different version of this gene. Surveys of United States Blacks show that up to a quarter of their Duffy genes are of white origin, in many cases because of inter-racial matings during the days of slavery. Such liaisons were covert, but widespread. Even President Thomas Jefferson is said to have had several children by his slave mistress, Sally Hemings. The conjecture was proved by the discovery that one of her descendants carries DNA shared with that of the President’s family (a proof so firm that it has been accepted, grudgingly, by the association of Jeffersonian descendants).

A closer look at a set of DNA clues specific to Africa or to people of European origin says more about the history of slavery. In Jamaica (where whites were a small minority), just one black gene in sixteen is of European origin. In most American cities the figure is around one in six, but in New Orleans is higher, at between a fifth and a quarter. Until 1803, Louisiana was under French, rather than Anglo-Saxon, control. Gallic racial tolerance lives on in today’s genes. The differences in numbers of blacks and whites, and the small proportion of white families that have mated with blacks has transferred far fewer black genes into the American population that sees itself as white, with an overall proportion of about one gene in a hundred.

Race involves a lot more than DNA. As a result, the proportion of blacks in the United States is rising. In 1997, about thirteen per cent of Americans perceived themselves as black and, over the past two decades the country’s black population has increased at twice the rate of the white. Most of this has nothing to do with genes, but is a matter of identity. Thirty years ago anyone of mixed ancestry would do their best to classify themselves as white. Now, with the rise of black self-esteem, many find themselves more at home as blacks. As a result, any genetic measure of admixture then and now will give different results, as a reminder that race is constructed by society as much as by DNA.

Seventeenth- and eighteenth-century England, too, had a substantial black population. It disappeared; not because it died out, but because it was assimilated. Part of its heritage is, without doubt, still around in the streets of modern Britain. Dr Johnson himself had a black servant, Francis Barber, to whom he left enough money to set up in trade. Many people around Lichfield are proud to trace their descent from him, although their skins are as fair as those of their neighbours. White Britons contain other exotic genes as well. After all, the first slaves to cross the Atlantic were the Caribbean Indians sent to Spain by Columbus in 1495 and there was a sixteenth-century fashion for bringing newly discovered peoples back to Europe. The English explorer Frobisher brought back some Eskimos in 1577 and more than a thousand American Indians (including a Brazilian king) were transported to Europe. Many of the unwilling migrants died, but some brought up families. Their legacy persists, no doubt, today; but they have been absorbed so fully into the local population that only a genetic test – or provision of a dependable pedigree – can say who bears it.

Genes have taken us back for hundred of years – for fifteen generations or so where black Americans are concerned. But they bear messages from earlier in history. Sometimes, the evidence is direct, more often indirect: but in every case it links the present with the past.

For good historical reasons, a great deal is known about the genetics of Hiroshima and Nagasaki. The Americans spent many years on a survey of whether the atom bombs had increased the mutation rate. No effect was found, but a mass of information on the genes of the two cities was gathered. Each has a cluster of rare variants not present in the other. They are relics of an ancient history. Hiroshima and Nagasaki were each founded by the amalgamation of different warring clans that lived in the region eight thousand years ago. Like tribal peoples today, they had diverged in their DNAs. The slight differences between the ancient tribes persist in the modern towns. Nagasaki was one of the few ports open to the outside world during Japan’s self-imposed isolation, but has no more sign of an influx of a foreign heritage than does Hiroshima. The voices of remote ancestors echo more loudly through the two cities than do those of more recent invaders.

Because genes copy themselves, there is no need to go back to the source to find an ancestor; but, sometimes, the source has been preserved. The Egyptian pharaoh Tutankhamun was buried at about the same time as another mummy, Smenkhare. Their blood groups can still be identified and show them to have been brothers. The first piece of human fossil DNA was found in the dried corpse of an Egyptian child, buried in the sands. It had survived for two and a half thousand years. Since then, many pieces of ancient DNA have turned up (although their analysis is confused by a tendency for contamination with modern material).

It has, nevertheless, become possible to read ancestral genes directly. Some ancient DNA, like that of the Easter Islanders, whose civilization was destroyed by constant warfare and ecological vandalism, has no equivalent in the modern world and remains, like their enigmatic statues, as the sole evidence of a people who left no posterity. Sometimes, it adds to the clues of the present. Agriculture began in Japan with the Jomon people, about ten thousand years ago, but they also spent much of their time as hunters. Farming did not take off as a way of life, with rice as a staple diet, until the Yayoi tribes who followed them, thousands of years later. Rice was brought by the Chinese, and the Japanese argue about how many of their genes entered the country with the crop. Many believe that the immigrants drove out most of the natives; that people moved, rather than ideas. However, DNA extracted from a two-thousand-year-old Chinese burial site links its inhabitants with modern Chinese, but not with the fossil DNA of the extinct Japanese. It proves that few mainlanders made the journey. Instead, the locals of two millennia ago, much like their modern descendants, picked up and used a new technology invented in a foreign land. Modern Japan, on the other hand, does have biological links with the Chinese, so that a movement from the mainland had an impact much later.

Some ancestral voices are particularly fluent in telling the story of the past. Mitochondria are small energy-producing structures in the cell. Each has its own piece of DNA, a closed circle of about sixteen thousand DNA bases, quite distinct from that in the cell nucleus. Eggs are full of mitochondria but those in sperm are killed off as they enter the egg. As a result, such genes are inherited almost exclusively through females. Like Jewishness, they pass from mothers to daughters and sons, but daughters alone pass them on to the next generation.

Every family, every nation and every continent can trace descent from its mitochondrial Eve, a woman (needless to say, one of many alive at the same time) upon whom all their female lineages converge. Sometimes she lived not long ago: in New Zealand, for instance, nearly all Maoris share the same mitochondrial identity, hinting that just a few women founded their nation a thousand years ago. A world family tree based on mitochondria finds its roots in Africa, with more diversity in that continent than anywhere else. To track more recent paths of migration shows that mitochondria are an accurate record of history: thus, in the New World, native mitochondria have a tie with those of Siberia, confirming an ancient pattern of migration.

Shared genes link New Zealand, Siberia and the rest of the world to an African ancestor. The first modern human appeared in Africa over a hundred thousand years ago, in the continent that gave rise to most of our pre-human kin and of the apes to whom we claim affinity. A few of these African relatives from a deeper branch of the tree are alive today. One, the chimpanzee, has always seemed a near neighbour; and Koko (an inhabitant of the Gombe Stream Reserve) was the first animal to have an obituary in The Times.

As any literate teenager knows, Tarzan of the Apes was proved to be the son of Lord Greystoke by virtue of the inky fingermarks in a childhood notebook. Galton had shown that chimpanzees have fingerprints that look much like those of a human being. Chimps and men, they prove, share genes. A joint heritage goes beyond the fingertips. A distinguished geneticist of the 1940s once tested whether chimps share our variation in the ability to taste the bitter chemical PROP by feeding it to three of the inhabitants of London Zoo. Two swallowed the drink with every sign of delight, but the third spat the liquid all over the famous professor as further evidence of common ancestry.

The biological affinity goes much further. Apes have blood groups like our own, their chromosomes are almost identical, and a test of the overall similarity of DNA shows that humans share ninety-eight per cent of their genetic material with chimpanzees. We trace relatedness to the rest of the animal kingdom as well, with about a quarter of our genes similar to others in remote places among the insects or the jellyfish. Mice and men have much more in common, including dozens of inherited diseases. We share even more genes with rabbits and plenty with remote branches of existence, from bacteria to yeasts to bananas. All living creatures seem to need a set of ‘housekeeping genes’ that do the basic work of the cell, and many of the seven hundred such structures are shared. Most have changed little since they began. An unkind experiment in which more and more of the five hundred genes in a simple bacterium were destroyed showed that it needs, at an absolute minimum, three hundred or so; nearly all of which have parallels in our own DNA. This common core shows that the most unlikely beings speak the same genetic language.

Pharaoh Psamtik the First, who flourished in the seventh century before Christ, searched for the first word of all. He put a baby in the care of a dumb nurse and noted the sounds it made. One word was (or seemed to be) ‘becos’, the Phrygian for bread, suggesting to Psamtik that the Phrygians (who lived in what is modern Turkey) were the first people of all. A computer search through the millions of DNA letters now sequenced from dozens of organisms also hints at a shared structure from bacteria to humans; the father (or mother) of all genes, that might have persisted since life began. The scientist who published the ur-sequence has turned the information to a useful end. Assigning musical notes to each DNA letter he used them as a theme for a ‘symphony of life’.

Gene sharing, from bacteria to humans, proves the unity of existence. It also defines the limits of what biology can say. A chimp may share ninety-eight per cent of its DNA with ourselves but it is not ninety-eight per cent human: it is not human at all – it is a chimp. And does the fact that we have genes in common with a mouse, or a banana, say anything about human nature? Some claim that genes will tell us what we really are. The idea is absurd.

One gene is found in a certain form in men, but a different one in all other apes. It codes for a molecule on the cell surface much involved in communication between cells, brain cells more than most. Perhaps this is the gene – or one of the genes – that makes us human. Its message spelt out in the four DNA letters, A, G, C and T starts like this: AACCGGCAGACAT … Altogether, it has three thousand letters. Together they contain an important part of the tedious biological story of being a man or woman rather than a chimpanzee or gorilla. Needless to say, that ancestral bulletin does nothing to tell us – or apes – what it means to be part of humankind. That calls for a lot more than a sequence of DNA bases and lies outside the realm of science altogether.

St Bede – whose writings are the best source of information about England before the eighth century – had a powerful metaphor for existence. To him human existence was ‘As if when on a winter’s night you sit feasting with your ealdormen and thegns, a single sparrow should fly swiftly into the hall, and coming in at one door instantly fly out through another. In that time in which it is indoors it is indeed not touched by the fury of the winter, but yet, this smallest space of calmness being passed almost in a flash, from winter going into winter again, it is lost to your eyes. Somewhat like this appears the life of man; but of what follows or what went before, we are utterly ignorant.’

His allegory was a religious one but has a biological parallel. Genes have a memory of their own. To read it gives new hope of looking beyond the hall into which our own brief existence is confined. It allows us to learn what went before in the life of our own species; to guess at what happened much earlier, and even to speculate about what fate may hold for generations yet to come.




Chapter Two THE RULES OF THE GAME (#ulink_559629fe-b0bd-5b16-8ab4-ef521f9f6c32)


It is always painful to watch an unfamiliar game and to try to work out what is going on. Although I lived in the United States for several years, and although the sport is now shown on British television, I have almost no idea how American football works. There is a clear general desire to score, but how play stops and starts and why the spectators cheer at odd moments remains a closed book. A deep lack of interest in ball games helps in my case, but cricket is equally dull to sporting enthusiasts from other countries. They just do not understand the rules.

The rules of the game known as sexual reproduction are not obvious from its results. As a consequence, how inheritance works was a closed book until quite recently. Part of the problem is that the way sex works is so different from how it seems that it ought to. It seems obvious that a character acquired by a parent must be passed on to the next generation. After all, blacksmiths’ children tend to be muscular and those of criminals less than honest. In the Bible, Jacob, when allowed to choose striped kids from Laban’s herd of goats, put striped sticks near the parents as they mated in the hope of increasing the number available. Later, pregnant women looked on pictures of saints and avoided people with deformities. It took a series of painful trials in which generations of mice were deprived of their tails to show that acquired characters were not in fact inherited. Of course, Jews had been doing the same experiment for thousands of years.

Another potent myth about inheritance is that the characters of a mother and a father pass to their blood, which is mixed in their offspring. Children are, as a result, a blend of the attributes of their parents. This idea – a sort of genetics of the average – copes quite well with traits such as height or weight but fails to explain why a child may look like a distant relative rather than its father or mother. The idea lasted until just a few years ago. The stud book is the record kept by racehorse breeders. A mare who had borne a foal by mating with a non-stud stallion was struck off as her blood was deemed to be polluted. Indeed, a survey of elderly women in Bristol showed that half believed in the chance of a woman having a black baby if she had sex with a black man many years before. The crones of the west country, like the breeders of horses, had never managed to work out the instructions for the reproductive game.

The only section of The Origin of Species which does not make good reading today is Chapter Five, ‘Laws of Variation’. Darwin got it wrong and, after much agonising, suggested that the organs of parents passed material to the blood and then to sperm and egg. Children were, he thought, intermediate between those who produced them. Such a mode of inheritance would be fatal to the idea of evolution. The problem was pointed out by Fleeming Jenkin, the first Professor of Engineering at the University of Edinburgh. Writing in 1867 – and with a sturdy disregard of today’s proprieties – Jenkin imagined ‘a white man wrecked on an island inhabited by negroes. Suppose him to possess the physical strength, energy and ability of a dominant white race. There does not follow the conclusion that after a … number of generations the inhabitants of the island will be white. Our shipwrecked hero would probably become king; … he would have a great many wives, and children … much superior in average intelligence to the negroes, but can anyone believe that the whole island will gradually acquire a white or even a yellow population? A highly favoured white cannot blanch a nation of negroes.’

Jenkin saw that the attributes of a distant ancestor, valuable as they might be, are of little help to later generations if bloods mix. Characters would then blend over the years until their effects disappear. However useful an ink drop in a gallon of water might be at some time in the future it is impossible to get it back from a single mixed drop. Genetics by blending means that any advantageous character would be diluted out in the next generation. Fortunately, the blood myth is wrong.

It was shot down by Galton himself. He transfused blood from a black rabbit to a white to see if the latter had black offspring. It did not. Inheritance by dilution had been disproved, but Galton had nothing to put in its place.

Unknown to either Darwin or to his cousin the rules of genetics had already been worked out by another biological genius. Gregor Mendel lived in Bohemia and published in a rather obscure scientific journal, the Transactions of the Brunn Natural History Society. His breakthrough was overlooked for thirty-five years after it was published in 1866. Mendel, an Augustinian monk, attempted a science degree but failed to complete it. Like Darwin and Galton he suffered from bouts of depression which prevented him from working for months at a time. Nevertheless, he persisted with his experiments. He found that the inherited message is transmitted according to a simple set of regulations – the grammar of the genes. Later in his career (and setting a precedent for the present age) he was unable to continue with research because of the pressures of administration. The study of inheritance came to a halt for almost half a century.

Grammar is always more tedious than vocabulary, but cannot be avoided. The rest of this chapter explores the basic rules of genetics. Those who teach the subject still have an obsession with Mendel and his peas and I make no excuse for having them as a first course.

Mendel made a conceptual breakthrough. Instead of (like his predecessors) working on traits such as height or weight (which could only be measured) Mendel was more or less the first biologist to count anything. This put him on the road to his great discovery.

Peas, like many garden plants, exist in true-breeding lines within which all individuals look the same. Different lines are distinct in characters such as seed shape (which can be round or wrinkled) and seed colour, which may be yellow or green. Peas also have the advantage that each plant carries both male and female organs. Using a small brush it is possible to fertilise any female flower with pollen from any male. Even a male flower from the same plant can be used. The process, a kind of botanical incest, is called self-fertilisation.

Mendel added pollen (male germ cells) from a line with yellow peas to the female part of a flower from a green pea line. In the next generation he got an unexpected result. Instead of all the offspring being intermediate, all the plants in the new generation looked like one of the parents and not the other. They all had yellow peas. This is not at all what would be expected if the ‘blood’ of the two lines was blended into a yellowish-green mixture.

The next step was to self-fertilise these first-generation yellow plants; in other words to expose their eggs to pollen from the same individual. That gave another unforeseen outcome. Both the original colours, yellow and green, reappeared in the next generation. Whatever it was that produced green could still do so, even though it had spent time within a plant with yellow peas. This did not fit at all with the idea that the different properties of each parent were blended together. Inheritance was, his experiment showed, based on particles rather than fluids.

Mendel did more. He added up the numbers of yellow and green peas in each generation. In the first generation (the offspring of the crossed pure lines) all the plants had yellow peas. In the second, obtained by self-fertilising the yellow plants from the first generation, there were always, on the average, three yellows to one green. From this simple result, Mendel deduced the fundamental rule of genetics.

Pea colour was, he thought, controlled by pairs of factors (or genes, as they became known). Each adult plant had two factors for pea colour, but pollen or egg received only one. On fertilisation – when pollen met egg – a new plant with two factors (or genes) was reborn. The colour of the peas was determined by what the plant inherited. In the original pure lines all individuals carried either two ‘yellow’ or two ‘green’ versions of the seed colour gene. As a result, crosses within a pure line gave a new family of plants identical to their parents.

When pollen from one pure line fertilised eggs from a different line new plants were produced with two different factors, one from each parent. In Mendel’s experiment these plants looked yellow although each carried a hidden set of instructions for making green peas. In other words, the effects of the yellow version were concealing those of the green. The factor for yellow is, we say, dominant to that for green, which is recessive.

Plants with both variants make two kinds of pollen or egg. Half carry the instructions for making green peas and half for yellow. There are hence four ways in which pollen and egg can be brought together when two plants of this kind are mated, or a single one self-fertilised. One quarter of fertilisations involve yellow with yellow, one quarter green with green; and two quarters – one half – yellow with green.

Mendel had already shown that yellow with green produces an individual with yellow peas. Yellow with yellow, needless to say, produces plants with yellow peas, and in a plant with two green factors the pea is green. The ratio of colours in this second generation is therefore three yellow to one green. Mendel worked backwards from this ratio to define his basic rule of inheritance.

Mendel made crosses using many different characters – flower colour, plant height and pea shape – and found that the same ratios applied to each. He also tested the inheritance of pairs of characters considered together. For example, plants with yellow and smooth peas were crossed with others with green and wrinkled peas. His law applied again. Patterns of inheritance of colour were not influenced by those for shape. From this he deduced that separate genes (rather than alternative forms of the same one) must be involved for each attribute. Both for distinct forms of the same trait (yellow or green colour, for example) and for quite different ones (such as colour and shape) inheritance was based on the segregation of physical units. Mendel was the first to prove that offspring are not the average of their parents and that genetics is based on differences rather than similarities.

Biologists since his day have delighted in picking over his results (and accusing him of fraud because they may fit his theories too well). They argue about what he thought his factors were, and speculate about why his work was ignored. Whatever lies behind its long obscurity, Mendel’s result was rediscovered by plant breeders in the first year of the twentieth century and was soon found to apply to hundreds of characters in both animals and plants. Mendel had the good luck, or the genius, needed to be right where all his predecessors had been wrong. No science traces its origin to a single individual more directly than does genetics, and Mendel’s work is still the foundation of the whole enormous subject which it has become.

Mendel rescued Darwin from his dilemma. A gene for green pea colour or for white skin, rare though it may be, is not diluted by the presence of many copies of genes for other colours. Instead, it can persist unchanged over the generations and will become more common should it gain an advantage.

Soon after the crucial rules were rediscovered they were used to interpret patterns of human inheritance. It is not possible to carry out breeding experiments on our fellow citizens. They would take too long, for one thing. Instead, biologists must rely on the experiments which are done as humans go about their sexual business. They use family trees or pedigrees – from the French pied de grue, crane’s foot, after a supposed resemblance of the earliest aristocratic pedigrees (which were arranged in concentric circles) to a bird’s toes. Some are fanciful, going back to Adam himself, but geneticists usually have fewer generations to play with, although one or two pedigrees do trace back for hundreds of years.

The first was published in 1903. It showed the inheritance of shortened hands and fingers in a Norwegian village. Such fingers ran in families and showed a clear pattern. The trait never skipped a generation. Anyone with short fingers had a parent, a grandparent and so on with the same thing. If an affected person married someone without the abnormality (as most did), about half their children were affected. If any of their normal children married another person with normal hands the character disappeared from that branch of the family.

The pattern is just what we expect for a dominant character. Only one copy of the damaged DNA (as in the case of yellow pea colour) is needed to show its effects. Most sufferers, coming as they do from a marriage between a normal and an affected parent, have a single copy of the normal and a single copy of the abnormal form, one from either parent. As a result, their own sperm – or eggs – are of two types, half carrying the normal and half the abnormal variant. When they marry, half their children carry a copy of the damaged gene. The chance of any child of a normal and an affected person having short fingers is hence one in two. An unaffected couple never has a child showing the abnormality as neither of them possesses the flawed instruction that makes it.

Other inherited traits do not behave in this simple way. They are recessives. To show the effect, two copies of the inherited factor, one from each parent, are needed. The parents themselves usually each have a single copy and appear quite normal. Most do not know that they are at risk of having an affected child. Sometimes, though, their offspring looks more like a distant relative or an ancestor than it does either parent. Before Mendel, that pattern was inexplicable. Such children were sometimes called ‘throwbacks’. Now we know that they are obeying Mendel’s laws. They have, by chance, inherited two copies of a recessive abnormality while their mother and father each have just one.

In Britain, one child in several thousand is an albino, lacking any pigment in eyes, hair or skin. Elsewhere, the anomaly is more common. In some North American Indians, about one person in a hundred and fifty is an albino. According to the Book of Enoch (one of the apocryphal books of the Bible), Noah himself suffered from the condition. If he did, there is not much sign of the gene in his descendants.

The great majority of albino children are born to parents of normal skin colour. They must each have a single copy of the albino factor matched with another copy of that for full pigmentation. Half the father’s sperm carry the altered gene. Should one of these fertilise one of that half of his partner’s eggs which carry the same thing, then the child will have two copies of the recessive form and will lack pigment. In a marriage such as this, the chance of any child being an albino is a half times a half. This one in four probability is the same for all the children. It is not the case, as some parents think, that having had one albino child means that the next three are bound to be normal.

Patterns of inheritance in humans can, then, follow the same rules as those found in peas. However, biology is rarely pure and never simple. Much of the history of human genetics has been a tale of exceptions to Mendel’s laws.

For example, variants do not have to be dominant or recessive. In some blood groups, both show their effects. Someone with a factor for group A and group B has AB blood, which shares the properties of both. At the DNA level, the whole concept of dominance or recessivity goes away. A change in the order of bases can be identified with no difficulty, whether one or two copies are present. Molecular biology makes it possible to see genes directly, rather than having to infer what is going on, as Mendel did, from looking at what they make.

Another result which would have surprised Mendel is that one gene may control many characters. Thus, sickle-cell haemoglobin has all kinds of side-effects. People with two copies may suffer from brain damage, heart failure and skeletal abnormalities (all of which arise from anaemia and from the blockage of blood vessels). In contrast, some characters (such as height or weight) are controlled by many genes. What is more, Mendelian ratios sometimes change because one or other type is lethal, or bears some advantage.

All this (and much more) means that the study of inheritance has become more complicated in the past century and a half. Nevertheless, Mendel’s laws apply to humans as much as to any other creature.

They are beguilingly simple and have been invoked to explain all conceivable – and some inconceivable – patterns of resemblance. In the early days, long pedigrees claimed to show that outbursts of bad temper were due to a dominant gene and that there were genes for going to sea or for ‘drapetomania’ – pathological running away among slaves. This urge for simple explanations persists today, but mainly among non-scientists. Geneticists have had their fingers burned by simplicity too often to believe that Mendelism explains everything.

Mendel had no interest in what his inherited particles were made of or where they might be found. Others began to wonder what they were. In 1909 the American geneticist Thomas Hunt Morgan, looking for a candidate for breeding experiments hit upon the fruit fly. It was an inspired choice and his work, with Drosophila melanogaster (the black-bellied dew lover, to translate its name) was the first step towards making the human gene map.

Many fruit fly traits were inherited in a simple Mendelian way, but some showed odd patterns of inheritance. When peas were crossed it made no difference which parent carried green or yellow seeds. The results were the same whether the male was green and the female yellow, or vice versa. Some traits in flies gave a different result. For certain genes – such as that controlling the colour of the eye, which may be red or white – it mattered whether the mother or the father had white eyes. When white-eyed fathers were crossed with red-eyed mothers all the offspring had red eyes but when the cross was the other way round (with white-eyed mothers and red-eyed fathers) the result was different. All the sons had white eyes and the daughters red. To Morgan’s surprise, the sex of the parent that bore a certain variant had an effect on the appearance of the offspring.

Morgan knew that male and female fruit flies differ in another way. Chromosomes are paired bodies in the cell which appear as dark strands. Most of the chromosomes of the two sexes look similar but one pair – the sex chromosomes – are different. Females have two large X chromosomes; males a single X and a much smaller Y.

Morgan noticed that the pattern of inheritance of eye colour followed that of the X chromosome. Males, with just a single copy of the X (which comes from their mother, the father providing the Y) always looked like their mother. In females, the copy of the X chromosome from the mother was accompanied by a matching X from the father. In a cross between white-eyed mothers and red-eyed fathers, the female offspring have one X chromosome bearing ‘white’ and another bearing ‘red’. Just as Mendel would have expected, they have eyes like only one of the parents, in this case the one with red eyes.

The eye colour gene and the X chromosome hence show the same pattern of inheritance. Morgan suggested that this meant that the gene for eye colour was actually on the X chromosome. He called this pattern ‘sex-linkage’. Chromosomes were already candidates as the bearers of genes as, like Mendel’s hypothetical particles, their number is halved in sperm and egg compared to body cells.

Everyone has forty-six chromosomes in each body cell. Twenty-two of these are paired, but the sex chromosomes, X and Y, are distinct. Because the Y carries few genes, in males the ordinary rules of Mendelian dominance and recessivity do not apply. Any gene on the single X will show its effects in a male, whether or not it is recessive in females.

The inheritance of human colour blindness is just like that of Drosophila eye colour. When a colour-blind man marries a normal woman none of his children is affected, but a colour-blind woman whose husband has normal vision passes on the condition to all her sons but none of her daughters. Because all males with the abnormal X show its effects (while in most females the gene is hidden by one for normal vision) the trait is commoner in boys than in girls. Many other abnormalities show the same pattern.

Sex-linkage leads to interesting differences between the sexes. For the X chromosome, females carry two copies of each gene, but males only one. As a result, women contain more genetic information than do men. Because of the two different sensors for the perception of red controlled by a gene on the X chromosome, many women must carry both red receptors, each sensitive to a slightly different point in the spectrum. Males are limited to just one. As a result, some women have a wider range of sensual experience for colour at least – than is available to any man.

Whatever the merits of seeing the world in a different way, women have a potential problem with sex-linkage. Any excess of a chromosome as large as the X is normally fatal. How do females cope with two, when just one contains all the information needed to make a normal human being (or a male)? The answer is unexpected. In almost every cell in a woman’s body one or other of her two X chromosomes is switched off.

Tortoiseshell cats have a mottled appearance, which comes from small groups of yellow and black hairs mixed together. All tortoiseshells are females and are the offspring of a cross in which one parent passes on a gene for black and the other transmits one for yellow hair. Because the coat-colour gene is sex-linked about half the skin cells of the kitten switch off the X carrying the black variant and the remainder that for yellow. The coat is a mix of the two types of hair, the size of the patches varying from cat to cat.

The same happens in humans. If a woman has a colour-blind son, she must herself have one normal and one abnormal colour receptor. When a tiny beam of red or green light is scanned across her retina her ability to tell the colour of the light changes as it passes from one group of cells to the next. About half the time, she makes a perfect match but for the rest she is no better at telling red and green apart than is her colour-blind son. Different X chromosomes have been switched off in each colour-sensitive cell, either the normal one or that bearing the instruction for colour blindness.

The inheritance of mitochondrial genes also shows sexual differences. When an egg is fertilised, much of its contents, including those crucial structures, is passed on to the developing embryo. Mitochondria have a pattern of inheritance quite different from those in the nucleus. They do not bother with sex, but instead are passed down the female line. Sperm are busy little things, with a long journey to make, and are powered by many mitochondria. On fertilisation these are degraded, so that only the mother’s genes are passed on. In the body, too, mitochondria are transmitted quite passively, each cell dividing its population among its descendants. Their DNA contains the history of the world’s women, with almost no male interference. Queen Elizabeth the Second’s mitochondrial DNA descends, not from Queen Victoria (her ancestor through the male line) but from Victoria’s less eminent contemporary Anne Caroline, who died in 1881.

Mitochondria, small as they are, are the site of an impressive variety of diseases. Their sixteen and a half thousand DNA bases – less than a hundredth of the whole sequence – were, a century after the death of Anne Caroline, the first to be read off. Every cell contains a thousand or so of the structures. They are the great factories of metabolism; places where food – the fuel of life – is burned. Mitochondrial genes code for just thirteen proteins, and about twice that number of the molecules that transfer information from the DNA to where proteins are made.

They are more liable to error than are others. Some of the mistakes pass between generations, while others build up in the body itself as it ages. Some of the two hundred known faults involve single changes in the DNA, others the destruction of whole lengths of genetic material. Some are frequent: thus, a certain change in one mitochondrial gene is present in about one in seven thousand births.

Mitochondrial disease involves many symptoms: deafness, blindness, or damage to muscles or the brain. Certain forms of diabetes are due to mitochondrial errors, as is an inherited muscle weakness and drooping of the eyelids. Different patients in the same family may have distinct problems; perhaps deafness in one child and brain damage in another. All this comes from the role of mitochondria in burning energy and from their random shuffling as cells divide. An egg may carry both normal and abnormal mitochondria. If, in an embryo, those with an error become by chance common in the cell lines that make brain tissue, that organ suffers; if in cells that code for insulin, then diabetes is the result. Mothers pass such genes to sons and daughters, but only daughters pass it to the next generation; a pattern quite different from sex-linked inheritance.

These, then, are the rules of the genetical game. From here on, the rest is molecular biology: mechanics rather than physics. The notion that life is chemistry came first from humans. In 1902, just two years after the rediscovery of Mendelism, the English physician Sir Archibald Garrod noticed that a disease called alkaptonuria – at the time thought to be due to an intestinal worm – was more frequent in the children of parents who shared a recent ancestor than in those of unrelated people. Its symptoms, a darkening of the urine and the earwax, together with arthritis, followed that of a recessive. The disease was, he thought, due to an inherited failure in one of the pathways of metabolism, what he called a “chemical sport’ (Darwin’s own word for a deviation from the norm). It was the first of many inborn errors of metabolism. The actual gene itself was found just four years before the century ended. The key to its discovery showed how wide the genetical net must spread. An identical was found in a fungus, and that piece of damaged DNA used to search out its human equivalent.

What genes are made of came from the discovery it was possible to change the shape of bacterial colonies by inserting a ‘transforming principle’ extracted from a relative with different shaped colonies. That substance was DNA, discovered many years before in some rather disgusting experiments using pus-soaked bandages. It was the most important molecule in biology.

The story of how the structure of DNA, the double helix, was established is too well known to need repeating. The molecule consists of two intertwined strands, each made up of a chain of chemical bases – adenine, guanine, cytosine and thymine – together with sugars and other material. The bases pair with each other, adenine with thymine and guanine with cytosine. Each strand is a complement of the other. When they separate, one acts as the template to make a matching strand. The order of the bases along the DNA contains the information needed to produce proteins. Every protein is made up of a series of different blocks, the amino acids. The instructions to make each amino acid are encoded in a three-letter sequence of the DNA alphabet.

The inherited message contained within the DNA is passed to the cytoplasm of the cell (which is where proteins are made) through an intermediary, RNA. This ribose-nucleic acid comes in several distinct forms, each involved in passing genetic information to where it is used.

The DNA molecule – the agent of continuity between generations – has become part of our cultural inheritance. The new ability to read (and to interfere with) its message has transformed our vision of our place in nature and our dominion over its inhabitants. It is, nevertheless, worth remembering that the laws of genetics were worked out with no knowledge of where or what the inherited units might be. Like Newton, Mendel had no interest in the details. He was happy with a universe of interacting and independent particles which behaved according to simple rules. These rules worked well for him, and often work just as well today.

Again like Newton, Mendel was triumphantly right, but only up to a point. Molecular biology has turned a beautiful story based on peas into a much murkier tale which looks more like pea soup. The new genetical fog is described in the next chapter.




Chapter Three HERODOTUS REVISED (#ulink_96d53917-6372-585d-9921-782c1044ef2e)


The Greek traveller Herodotus felt that he knew the world well. He voyaged around the Mediterranean and heard much of the Phoenicians’ journeys into Africa. By putting what he knew of the globe’s landmarks together he came to the conclusion that ‘Europe is as long as Africa and Asia put together, and for breadth is not, in my opinion, even to be compared with them.’ Herodotus had things in about the right places in relation to each other but the physical distances between them were hopelessly wrong.

For two thousand years maps could only be made in the Greek way. They were relative things, made by trying to fit landmarks together, with no measure of the absolute distances involved. Familiar bits of the countryside loomed far larger than they deserved. Mediaeval charts were not much better. Although the shape of Africa is recognisable it is much distorted. The cartographers’ perception of remoteness was determined by how long it took to travel between two points rather than how far apart they really were.

Genetics, like geography, is about maps; in this case the inherited map of ourselves. Not until the invention of accurate clocks and compasses two thousand years after Herodotus was it possible to measure real distances on the earth’s surface. Once these had been perfected, good maps soon appeared and Herodotus was made to look somewhat foolish. Now the same thing is happening in biology. Geneticists, it appears, were until not long ago making the same mistakes as the ancient Greeks.

Just as in mapping the world, progress in charting genes had to wait for technology. Now that it has arrived the shape of the biological atlas has been revolutionised, with a change in world-view far greater than that which separates the geography of the Athenians from that of today. What, even three decades ago, seemed a simple and reliable chart of the genome (based, as it was, on landmarks such as the colour of peas or of inborn disease) now looks very deformed.

The great age of cartography was driven, in the end, by economics: by the desire to find new materials and new markets. The mappers’ Columbian ambitions needed a Ferdinand and Isabella. Even fifty years ago, to those in the know, there seemed to be money in DNA, and many great foundations gave cash to the subject. Not until the 1980s did it seem feasible to chart the whole lot and, even then, it seemed that the task would take decades. Such is the rate of progress that the job is now, just after the millennium, in effect complete. The politician’s ear and the scientist’s ego shifted cash into Programs, Institutes and Centres as the free market in science was abandoned in favour of the planned economy; but, in the end, the Human Genome Project worked and at last we have the map of ourselves. Taxpayers (most of them American) played an important part, but in its latter days the job was split, with some acrimony, between governments in consort with charities (such as the Wellcome Foundation at its campus near Cambridge) and private institutions, the biggest run by a defector from an American government laboratory. There was a mad rush to patent genes. Large sums changed hands. The rights to one technology were sold to a Swiss company for three hundred million dollars. At the end of the DNA bonanza the altruists were ahead and large parts of the information were fed onto the internet, where it is available to all.

The idea of a gene map came first not from technology but from deviations from Mendel’s laws. Morgan, with his flies, found lots of inherited attributes that followed the rules. Their lines of transmission down the generations were not connected to each other; like pea colour and shape the traits were independently inherited. There was one big exception. Certain combinations of characters, those on the sex chromosomes, did not behave in this way. Soon, they were joined by others.

Mendel found that the inherited ratios for the colour of peas were not affected by whether the peas were round or wrinkled. Morgan, in contrast, discovered that, quite often, pairs of characteristics (such as eye colour and sex) travelled down the generations together. Soon, many different genes (such as those for eye colour, reduced wings and forked body hairs) in flies were found to share a pattern of inheritance with sex and, as a result, with the X chromosome. They were, in flagrant disregard of Mendel’s rules, not independent. To use Morgan’s term, they were linked.

Within a few years, many other traits turned out to be transmitted together. Experiments with millions of flies showed that all Drosophila genes could be arranged into groups on the basis of whether or not their patterns of inheritance were independent. Some combinations behaved as Mendel expected. For others, pairs of traits from one parent tended to stay together in later generations. The genes involved were, as Morgan put it, in the same linkage group. The number of groups was the same as the number of chromosomes. This discovery began the ‘linkage map’ of Drosophila and became the connection between Mendelism and molecular biology.

Linkage is the tendency of groups of genes to travel together down the generations. It is not absolute. Genes may be closely associated or may show only a feeble preference for each other’s company. Such incompleteness is explained by some odd events when sperm and egg are formed. Every cell contains two copies of each of the chromosomes. The number is halved during a special kind of cell division in testis or ovary. The chromosomes lie together in their pairs and exchange parts of their structure. Sperm or egg cells hence contain combinations of chromosomal material that differ from those in the cells of the parents who made them.

That is why, within a linkage group, certain genes are inherited in close consort while others have a less intimate association. If genes are near each other they are less likely to be parted when chromosomes exchange material. If they are a long way apart, they split more often. Pairs of genes that each follow Mendel are on different chromosomes. Recombination, as the process is called, is like shuffling a red and a black hand of cards together. Two red cards a long way apart in the hand are more likely to find themselves split from each other when the new deck is divided than are two such cards close together. Such rearrangements mean that each chromosome in the next generation is a new mixture of the genetic material made up of reordered pieces of the chromosome pairs of each parent.

Recombination helped make the first genetic maps. Like the cards in a hand held by a skilled player, genes are arranged in a sequence. Their original position can be determined by how much this is disturbed each generation as the inherited cards are shuffled. By studying the inheritance of groups of genes Morgan worked out their order and their relative distance apart. Combining the information from small sets of inherited characters allowed what he called a ‘linkage map’ to be made.

Linkage maps, based as they are on exceptions to Mendelism, are very useful. They have been made for bacteria, tomatoes, mice and many other beings. Thousands of genes have been mapped in this way. In Drosophila almost all have been arranged in order along the chromosomes and in mice almost as many.

Because this work needs breeding experiments, the human linkage map remained for many years almost a perfect and absolute blank. Most families are too small to look for deviations from Mendel’s rules and too few variants were known to look for them. There seemed little hope that a genetic chart of humankind could be made.

The one exception to this terra incognita was sex linkage. If genes are linked to the X chromosome, they must be linked to each other. It did not take long for dozens of traits to be mapped there. To draw the linkage map for other chromosomes was a painfully slow business. The gene for colour-blindness was mapped to the X in 1911, but the first linkage on other chromosomes did not emerge until 1955, when the gene for the ABO blood groups was found to be close to that for an abnormality of the skeleton. The actual number of human chromosomes was established in the following year and the first non-sex linked gene mapped onto a specific chromosome in 1968.

Now, genetics has been transformed. The technology involved is as to linkage mapping as satellites are to sextants. It does not depend on crosses and comes up with much more than a biological chart based on patterns of inheritance. Geneticists have now made a more conventional (but much more detailed) kind of chart, a physical map of the actual order of all the bases along the DNA. The new atlas of ourselves has changed our views of what genes are.

In the infancy of human genetics, thirty years ago, biologists had a childish view of what the world looks like. As in the mental map of an eleven year-old (or of Herodotus) linkage was based on a few familiar landmarks placed in relation with each other. The tedious but objective use of a measure of distance changed all that. Thirty years ago, molecular biologists were full of hubris. They had, they thought, solved the problems of inheritance. The new ability to read the DNA message would do the job that family studies and linkage mapping had failed to complete; it would show where all our genes were in relation to each other. The edifice whose foundations were laid by Mendel would then be complete. Optimism was, at the time, reasonable. It seemed a fair guess that the physical map of the genes would look much like a biological map based on patterns of inheritance and might in time replace it.

Such optimism was soon modified. The first explorations of the unknown territory which lay along the DNA chain showed that the physical map was quite different from the linkage map as inferred from peas or fruit-flies. The genes themselves are not beads lined up on a chromosomal string, but have a complicated and unexpected structure.

The successes of the molecular explorers depended, like those of their geographical predecessors, on new surveying instruments which made the world a bigger and more complicated place. The tools used in molecular geography deserve a mention.

The first device is electrophoresis, the separation of molecules in an electric field. Many biological substances, DNA included, carry an electrical charge. When placed between a positive and a negative terminal they move towards one or the other. A gel (which acts as a sieve) is used to improve the separation. Gels were once made of potato starch, while modern ones are made of chemical polymers. I have tried strawberry jelly, which works quite well. The gel separates molecules by size and shape. Large molecules move more slowly as they are pulled through the sieve while smaller ones pass with less difficulty. Various tricks improve the process. Thus, a reversal of the current every few seconds means that longer pieces of DNA can be electrophoresed, as they wind and unwind each time the power is interrupted. The latest technology uses arrays of fine glass tubes filled with gel, into each of which a sample is loaded. With various tricks the whole process becomes a production line and tens of thousands of samples can be analysed each day.

The computer on which I wrote this book has some fairly useless talents. It can – if asked – sort all sentences by length. This sentence, with its twenty words, would line up with many otherwise unrelated sentences from the rest of the book. Electrophoresis does this with molecules. The length of each DNA piece can be measured by how far it has moved into the gel. Its position is defined with ultraviolet light (absorbed by DNA), with chemical stains, fluorescent dyes that light up when a laser of the correct wavelength is shone on them, or with radioactive labels. Each piece lines up with all the others which contain the same number of DNA letters.

Another tool uses enzymes extracted from bacteria to divide the landscape into manageable pieces. Bacteria are attacked by viruses which insert themselves into their genetic message and force the host to copy the invader. They have a defence: enzymes which cut foreign DNA in specific places. These ‘restriction enzymes’ can be used to slice human genes into pieces. Dozens are available, each able to cut a particular group of DNA letters. The length of the pieces that emerge depends on how often the cutting-site is repeated. If each sentence in this volume was severed whenever the word ‘and’ appeared, there would be thousands of short fragments. If the enzyme recognised the word ‘but’, there would be fewer, longer sections; and an enzyme that sliced through the much less frequent word ‘banana’ (which, I assure you, does appear now and again) would produce just a few fragments thousands of letters long.

The positions of the cuts (like those of the words and, but and banana) provide a set of landmarks along the DNA. To track them down is a first step to reconstituting the book itself. The process is close to that carried out by the students who stormed the American Embassy in Tehran after the fall of the Shah. With extraordinary labour they pieced together secret documents which had been put through a shredder. By putting the fragments together the students reconstituted a long, complicated and compromising message.

Molecular biology does much the same. First, it needs to multiply the number of copies of the message to allow each short piece to be surveyed in detail as a preliminary to the complete map. Various tricks allow cut pieces of DNA to be inserted into that of a bacterium or yeast. The DNA has been cloned. Whenever the host divides, it multiplies not only its own genetic message but the foreign gene. As a result, millions of copies of an original are ready for study in the exquisite detail needed for genetic geography.

Cloning has been supplemented by another contrivance, the polymerase chain reaction. This takes advantage of an enzyme used in the natural replication of DNA to make replicas of the molecule in the laboratory. To pursue our rather tortured literary analogy, the method is a biological photocopier which can produce many duplicates of each page in the genetic manual. The photocopying enzyme comes from a bacterium which lives in hot springs. The reaction is started with a pair of short artificial DNA sequences which bind to the natural DNA on either side of the length to be amplified. By heating and cooling the reaction mixture and feeding it with a supply of the four bases, the targeted strands of DNA unwind, copy themselves with the help of the enzyme, and re-form. Each time the cycle is repeated, the number of copies doubles and millions of replicas of the original piece of DNA are soon generated.

Another piece of trickery exploits DNA’s ability to bind to a mirror image of itself. DNA bases form two matched pairs; A with T and G with C. To find a gene, a complementary copy is made in the laboratory. When added to a cell this seeks out and binds to its equivalent on the chromosome. My computer can do the same. On a simple command, it will search for any word I choose and highlight it in an attractive purple. It does the job best with rare words (like ‘banana’). A DNA probe labelled with a fluorescent dye shows up genes in the same way. The method is known as FISHing (for Fluorescent In-Situ Hybridisation) for genes. A modified kind of FISH involves unwinding the DNA before it is stained. This makes the method more sensitive.

All this and much more has revolutionised the mapping of human DNA. First, it has improved the linkage map. Patterns of inheritance of short sequences of DNA can be tracked through the generations just as well as can those of colour-blindness or stubby fingers. There are millions of sites which vary from person to person. All can be used in pedigree studies. Another scheme is to use the polymerase chain reaction to multiply copies of DNA from single sperm cells. The linkage map is made from a comparison of the reordered chromosomes in the sperm with that in the man who made them. This avoids the problem of family size altogether.

Linkage mapping in humans took a long time to get started and still has some way to go. Before the days of high technology the great problem was a shortage of differences; of variable genes, or segments of genetic material, whose joint patterns of inheritance could be studied. That problem has been solved. Our DNA is now known to be saturated with hundreds of thousands of variable sites, many based on individual variation in the numbers and positions of repeats of the two letters C and A. As a result, a whole new industry based on the most traditional kind of genetics has burst into existence.

It needs, like any industry, raw material. The French, together with the Americans, have identified sixty or so large families with long and complicated pedigrees, well suited for gene mapping. They come from various parts of the world, from Venezuela to Bangladesh. From each individual, lines of cells are kept alive in the laboratory and thousands of variants have been identified, tightly packed along the entire length of the chromosomes. Patients with, say, heart disease can be screened to see whether they also tend to carry other inherited variants. If they do, there is a good chance that the actual gene involved is nearby, and is dragging its anonymous fellows along with it. To find such a milestone may be the first step to the gene itself.

The descendants of Morgan have at last managed to do for humans what was long ago achieved for the fruit fly, and a linkage map of man is close at hand. That of woman, it transpires, is rather longer. Such maps depend on the sexual reshuffling of genes. This takes place, for some reason, more in females than in males and, as a result, their chart works to a different scale.

The human linkage map is useful, but biologists have always wanted to make a different kind of chart, one rather like that used by geographers, based on a straightforward description of the genetic material. Now, it is here. The approach was brutal: to assault the genome with time, money and tedium until the whole lot was read from one end to the other.

The first move in tying the linkage map to one based on the physical structure of DNA depended on a stroke of luck. Morgan noticed that in one of his fly stocks a gene which was usually sex-linked started behaving as if it was not on the X chromosome at all. A glance down the microscope showed why. The X was stuck to one of the other chromosomes and was inherited with it. A change in the linkage relationships of the gene was due to a shift in its physical position.

Such chromosomal accidents were used to begin the human physical map. Sometimes, because of a mistake in the formation of sperm or egg, part of a chromosome shifts to a new home. Any parallel change in the pattern of inheritance of a particular gene shows where it must be. Now and again a tiny segment of chromosome is absent. That can lead to several inborn diseases at once. One unfortunate American boy had a deficiency of the immune system, a form of inherited blindness, and muscular dystrophy. A minute section of his X chromosome had been deleted. It must have included the length of DNA which carried these genes. He gave a vital hint as to just where the gene for muscular dystrophy – one of the most frequent and most distressing of all inherited diseases – was located. The absent segment was a landmark upon which a physical map of the area around this gene could be anchored.

To map genes with changes in chromosomes need not wait for natural accidents. Human cells, or those of mice or hamsters, can be cultured in the laboratory. When mixtures of mouse and human cells are grown together, the cells may fuse to give a hybrid with chromosomes from both species. As the hybrids divide, they lose the chromosomes (and the genes) from one species or the other. Some specifically human genes are lost each time a human chromosome is ejected. To match the loss of particular genes with that of chromosomes (or of their short segments) shows where they must be.

All these methods hint at a gene’s position rather than giving its precise coordinates. Small-scale cartography (or mindless sequencing, as it is affectionately known) involves various clever ruses. One depends on the ability of DNA to copy itself when a special enzyme is provided and the mixture fed with the A, G, C and T bases. It is possible to gradually lengthen pieces of a DNA strand from one end to the other, in four separate experiments (each using a different base). By chemical trickery, some of the growing strands are stopped each time a base is added. This produces a set of DNA pieces of different length, each stopped at an A, a G, a C or a T. Electrophoresis of the mixtures on the same gel gives four parallel lines of DNA fragments arranged by length. A scan across and down the gel gives the order of the bases. This is a most tedious task. It has been supplanted by machines that do the job in other ways. The most important change in genetics is a conceptual one. Because the three-letter code for each amino acid is known, it is possible to deduce the order of the amino acids made by a piece of the DNA once its sequence of bases has been established. What any gene does can be inferred by comparing that sequence with the computer database of others whose job is known. The fit need not be precise; after all, a French dictionary contains thousands of words similar enough to those in English to allow its meaning to be guessed at. It is also sometimes possible to work out the three-dimensional structure of the protein from its amino acid sequence and to deduce what its function might be.

There are some remarkable similarities among inherited vocabularies. The genes that control development are similar in humans and fruit flies, as are those that make their brains. Genes that, when they go wrong, damage the nervous system have close analogues in yeast (which do not have nerves at all) and one of our own genes is almost identical to another that alters the pattern of veins on an insect wing. Such conservatism has had a radical influence on human genetics.

The parts catalogue for a Mercedes C-class car contains four and a half thousand named items, from accelerator pedal to wing mirror to wheel nuts. Some (like individual bolts or washers) may be repeated dozens of times; but the factory has to make fewer than five thousand pieces to feed its assembly line and, in the end, to make its contribution to the European traffic jam. To make a human takes ten times as many – an executive jet’s worth – and the task of seeing how that vast number of pieces is bolted together might seem almost impossible. Even the yeast cell (scarcely the Mercedes of the living world) needs more than the car, with six thousand proteins.

The yeast gene sequence itself, like any other, is no more than a factory manual, containing information on castings, mouldings and blanks but also on various extraneous bits which are removed before the assembly line gets them. Then, as in the Mercedes factory, the parts have to be put together to make a functional piece of machinery. Even that is of no use to someone who cannot drive, and even a skilled driver is no help when dumped in a strange city without a road map. To understand the workings of the cell demands even more.

DNA dismantlers, like car wreckers, generate only a box of bits and pieces; the biological equivalents of the nuts, bolts, relays, springs, struts, wires and all the other things needed to make an automobile. The shape of a human protein can be inferred from a DNA sequence, but even usually gives no hint as to how it fits into the cellular machinery. Yeasts are simpler, and rather more is known about their mechanics. Life’s unwillingness to change allows the yeast machine to be used to explore our own cells. One approach in the human gene hunt is rather like fishing. Take a protein whose job is known, and attach a molecular hook and a separate float to it. Insert it into a male (or a cell showing what passes for maleness in yeasts). Then, mate that alluring individual to a female and drift his gene past all her thousands of cell parts until one takes the bait by slotting into it. The float causes the female cell to light up and the match is made.

A fishing expedition with two hundred or so bait proteins from yeast captured more than a thousand genes in human cells. One whole set of yeast proteins attached themselves to a single human protein that tells the cell when to start dividing and when to stop. The yeast bait is similar to one that, when it goes wrong, causes human cancer: and a quick test proved that the newly hooked human equivalents represented crucial parts of our own cells’ brake and accelerator systems. Such a discovery is of great interest to medicine, and marked the first step in what may become an era of hunting for genes in complex creatures with a lure based on more humble beings.

The genetic languages spoken by different organisms are close indeed; close enough, in fact, to give an even chance that a newly-discovered human gene sequence will be related to something else, either another of our genes or one from a creature remote from ourselves. Human genetics has been transformed. No longer does it start with an inherited change (such as a genetic disease) and search for its location. Instead, it uses the opposite strategy, with a logic precisely opposite that of Mendel: from inherited particle to function, rather than the other way around. Genetics is the first science to have accelerated by going into reverse.

The first breakthrough of this new approach was the successful hunt for the cystic fibrosis gene in 1990. It gave a hint as to what was possible and was the introduction to the advances that led to the complete map a mere decade or so later. The job cost one hundred and fifty million dollars, but the costs per gene have now dropped by hundreds of times.

Cystic fibrosis is the most common inherited abnormality among white-skinned people. In Europe, it affects about one child in two thousand five hundred. Until a few years ago those with the disease died young. Their lungs filled with mucus and became infected. Those with the illness find it hard to digest food as they cannot produce enough gut enzymes. Its dangers have long been recognised. Swiss children sing a song that says ‘The child will die whose brow tastes salty when kissed.’ These symptoms seem at first sight unrelated, but all are due to a failure to pump salt across the membranes which surround cells. Medicine has improved the lives of those affected, but few survive beyond their mid-thirties.

Family studies showed long ago that the disease is due to a recessive gene that is not carried on the sex chromosomes. In 1985, pedigrees revealed that it was linked to another DNA sequence which controls a liver enzyme, although it was not then known upon which chromosome that was. Within a year or so, a kindred was discovered in which this pair of genes was linked to a DNA variant that had already been mapped to chromosome seven. The relevant segment of that chromosome was inserted into a mouse cell line, cut into short lengths and the painful task of sequencing begun. By 1988 the crucial region had been tracked down to a segment of DNA one and a half million base-pairs long. Fragments were tested to see if (like the yeast and human sequences later found to control cell division) they had sequences in common with the DNA of other animals as, if they did, the order of letters must have been retained through evolution because they did some unknown but useful job. Several such sections were uncovered. One had an order of DNA letters similar to that of other proteins involved in transport across membranes. It followed the pattern of inheritance of cystic fibrosis. The gene had been tracked down.

The cystic fibrosis gene is a quarter of a million DNA bases long, although the protein has only about one and a half thousand amino acids. Computer models of its shape show that it spans the cell membrane several times, just as expected for a molecule whose job is to act as a pump. Many families with the disease have just one change in the protein: a single amino acid is missing. That changes its shape and stops the new protein from going to the right place in the cell. Instead it is picked up and destroyed by the internal quality-control network.

The discovery of the gene allowed carriers (together with foetuses bearing two copies) to be identified. Unfortunately, cystic fibrosis which once seemed a simple disorder, can, we now know, be caused by many different DNA changes that vary from place to place and from family to family. The illness gave the first hint about the unexpected and unwelcome complexity that the full map was to reveal.

Mapping exploded after that first discovery. At first, the mappers behaved like any explorer in a new territory. A cartographer does not start with a plan of the beach which is then extended in excruciating detail until the whole country is covered. Instead he picks out the major landmarks and leaves the details until later, when he knows what is likely to be interesting. Before today’s triumph of technology, most mappers were concerned with a small proportion of the genes, those that lead to inherited disease.

All the most important single-gene inherited illnesses were tracked down within a few years. Huntington’s Disease leads to a degeneration of the nervous system and death in middle age. It was once called Huntington’s Chorea (a word with the same root as choreography) after the involuntary dancing movements of those afflicted. An eighteenth-century Harvard professor claimed that those with the disease were blasphemers as their gestures were imitations of the movements of Christ on the Cross and some sufferers were burned. It is a dominant, but with a nasty twist: because of the late onset of symptoms, those at risk are left in uncertainty about their predicament. In 1983 came a breakthrough helped by great good luck. Soon after the search started, the approximate site of the Huntington’s gene was found by following its association with a linked DNA variant some distance away on the same chromosome. Then, luck ran out, and it took ten years to find the gene. It has now been tracked to the tip of chromosome 4. The shape of the protein which has gone wrong – huntingtin, as it is with some lack of imagination called – has been worked out to give, for the first time, some insight into the nature of the disease, which involves nerve cells in effect committing suicide when the aberrant protein (which looks like nothing else in the cell) instructs them to do so. Many more damaged genes soon fell victim to the genetic explorers and were pinned onto the map.

Type in the four letters OLIM – On Line Inheritance In Man – into any search engine and a list of ten thousand inherited diseases at once appears; symptoms, inheritance patterns, and, for nearly all, chromosomal grid reference. From the hunt for inherited illness, the search shifted to a wider set of genes. No longer were diseases needed as a first clue. To look for genes only when they go wrong is like trying to work out the principles of the internal combustion engine from car breakdowns. Now, the machine itself can be dismantled and its mechanism inferred directly.

When a gene makes something, it generates a complementary molecule – a messenger, as it is known – which transfers information from DNA to the main part of the cell. Because it produces nothing, most DNA generates no messengers at all. To find such molecules is hence an excellent way to search out working genes. There are tens of thousands of distinct messengers. What most do is quite unknown. In most cells, most are switched off but in the brain a large proportion are at work at any time. The brain is more active than is any other tissue (which may help to explain why more than a quarter of all inherited diseases lead to mental illness).

The hunt for genes is more like that for Timbuctu than for El Dorado. The mappers soon found that genes are oases of sense in a desert of nonsense. At one time, it seemed scarcely worth sifting the sands between the genetic cities, but, in the end, the complete map was made mainly on the grounds that it was worth while as one never knows what might turn up. It reaffirmed one of the most misunderstood facts in science; that it is possible to solve most problems by throwing money at them.

The assault on the physical map is best compared to surveying a country with a six-inch ruler, starting at one end and driving on to the opposite frontier. Twenty and more years ago, when the job began, one person could do about five thousand DNA bases a year. Now, it is routine to do thousands of times as many. Much of the intellectual effort of the job has moved from the simple accumulation of information to understanding it. Computer wizardry has played as important a part in the gene map as has biochemical machinery.

Once a segment of DNA has been sequenced, the local maps – the town plans – must be put in the right order. One way to build up a larger chart is to make a series of overlapping sequences of short pieces of DNA. The approach is a little like putting pages ripped out of a street guide back together by looking at the overlaps at the edge of each page in an attempt to find streets which run into each other. Sophisticated programs look for superimposed segments, long or short, and reassemble the torn fragments of DNA. That is much harder than it seems. An alphabet of just four letters and – like the map of an American city – many repeats of the same pattern of streets, gives plenty of chances for confusion. There are some short cuts. One trick, useful in the early days, was to jump several pages in the guide in the hope of missing out particularly tedious parts of the neighbourhood but for completion even the dullest parts of town must be charted.

New and powerful computers have made it possible, in principle at least, to make a whole genetic atlas at once, rather than piecing it together page by page. The ‘random shotgun’ approach lives up to its name. It blasts copies of the genome into thousands of segments, again and again, and, like a taxidermist rebuilding a single pheasant from the casual slaughter of many by a blind man with a twelve-bore, reconstitutes the whole thing from scratch. A giant program puts all the shattered pieces together, until at last they look like a map (or a game-bird). That approach worked well in fruit-flies, whose genome was sequenced before that of our own, but flies have a tenth as many DNA letters and far less repetition of easily-confused short sequences than we do. The less audacious ‘clone by clone’ approach takes tiny fragments (each about a twenty-thousandth of the whole of human DNA) and sequences them one by one. Then, it reassembles short segments of genes and, in time, re-forms the whole atlas. The approach, plodding as it may be, has worked well with humans and was used by the publicly-funded mappers to publish each clone as it appeared and to help thwart the privatised plan to sequence (and patent) the whole of our DNA at one fell swoop.

The physical map does not look at all like the linkage maps which emerged from family studies. The central difficulty is one of scale. A few tens of thousands of functional genes fit into three thousand million DNA letters. As most genes use only the information coded into several thousand bases there seems to be far more DNA than is needed. Mapping shows that just one part in twenty represents part of a gene. Our genome has an extraordinary and quite unexpected structure.

A geographical analogy may help. Imagine the journey along the whole of your own DNA as a trip from Land’s End to John o’Groat’s via London; about a thousand miles altogether. To fit in all the DNA letters into a road map on this scale, there have to be fifty DNA bases per inch, or about three million per mile. The journey passes through twenty-three counties of different sizes. These administrative divisions, conveniently enough, are the same in number as the twenty-three chromosomes into which human DNA is packaged. With the exception of some short segments a few hundred yards long which, for various technical reasons, have proved recalcitrant, the whole lot has been mapped out with an accuracy of one part in fifty thousand – an inch in a mile (which is as good or better than the maps sold by the Ordnance Survey).

The scenery for most of the trip is tedious. Like much of modern Britain it seems to be unproductive. About a third of the whole distance is covered by repeats of the same message. Fifty miles, more or less, is filled with words of five, six or more letters, repeated next to each other. Many are palindromes. They read the same backwards as forwards, like the obituary of Ferdinand de Lesseps – ‘A man, a plan, a canal: Panama!’ Some of these ‘tandem repeats’ are scattered in blocks all over the genome. The position and length of each block varies from person to person. The famous ‘genetic fingerprints’, the unique inherited signature used in forensic work, depend on variation in the number and position of such segments. Other repeated sequences involve just the two letters, C and A, multiplied thousands of times while yet more are remnants of ancient viruses. Large sections of the genome are given over to long and complicated messages that seem to say nothing.

It is dangerous to dismiss all this DNA as useless because we do not understand what it says. The Chinese term ‘Shi’ can – apparently – have seventy-three different meanings depending on how it is pronounced. It is possible to construct a sentence such as ‘The master is fond of licking lion spittle’ just by using ‘Shi’ again and again. This would seem like empty repetition to those who cannot speak Chinese.

Much of the inherited landscape is littered with the corpses of abandoned genes, sometimes the same one again and again. The DNA sequences of these ‘pseudogenes’ look rather like that of their functional relatives, but are riddled with decay and no longer make anything. At some time in their history a crucial part of the machinery was damaged. Since then they have been rusting. Oddly enough, the same pseudogenes may turn up at several points along the journey.

After many miles of dull and repetitive DNA terrain, we begin to see places where some product is made. These are the functional genes. They, too, have some surprises in their structure. Each can be recognised by the order of the letters in the DNA alphabet, which start to read in words of three letters written in the genetic code, as a hint that it could produce a protein. In most cases there are few clues about what its product does, although its structure can be deduced (and its shape inferred) from the order of its DNA letters.

Most genes are arranged in groups that make related products, with about a thousand of these ‘gene families’ altogether. One is involved in the manufacture of the red pigment of the blood. Most of the DNA in the bone-marrow cells which produce the red cells of the blood is switched off. One small group of genes is hard at work. As a result they are better known than any other. Much of human molecular biology grew from research on this particular genetic industrial centre, the globin genes.

They have two factories. One is halfway along the genetic road to John o’Groat’s – in Leeds. It makes one part of the protein involved in carrying oxygen. The beta-globin industrial estate contains about half a dozen sections of DNA that code for related things. That responsible for part of adult haemoglobin (and involved, when it goes wrong, in sickle-cell disease) is quite small: about three feet long on this map’s scale. A few feet away is another one which makes a globin found in the embryo. Close to that is the decayed hulk of some equipment which stopped working years ago. The beta-globin factory covers about a hundred feet altogether, most of which seems to he unused space between functional genes. It co-operates with a sister estate, the alpha-globin unit, a long way away, (near London, on this mythical map) which produces a related protein. When joined together, the two products make the red blood pigment itself. Most genes are arranged in families, either close together or scattered all over the genome.

The map of ourselves shows that genes are of very different size, from about five hundred letters long to more than two million. One makes the largest known protein, titin, a molecular shock-absorber; a long, pleated structure found in muscles, in blood cells and in chromosomes. Whatever the size of its product, titin is by no means the largest gene. Most human genes have their functional segments interrupted by lengths of non-coding DNA – in Huntington’s disease, for example, by nearly seventy In many genes (such as the one which goes wrong in muscular dystrophy) the great majority of the DNA codes for nothing. The non-coding material, whose importance varies greatly from gene to gene, participates in the first part of the production process, but this segment of the genetic alphabet is snipped out of the message before the protein is assembled. This seems an odd way to go about things, but it is the one which evolution has come up with.

The general picture began to emerge as soon as the mappers began work. In the year 2000 – almost exactly a century after the rediscovery of Mendel’s rules – their labours were, in effect, complete and the whole human gene sequence was laid out in all its tedium before a less than startled world. Three thousand million letters (or, as now it appears, slightly more) is a lot. For accuracy, each section had to be sequenced ten times or more and even at a thousand DNA bases a second (which is what the machinery pumps out) that was not easy. Sixteen centres, in France, Japan, Germany, China, Britain and the United States combined to do the job. Most were funded by governments or charities, with the notorious exception of the Celera Genomics company (their motto: ‘Discovery Can’t Wait!’), whose head defected from a government programme. Advances in technology reduced the original estimate of three billion dollars by ten times which, for a project – described by President Clinton as the most wondrous map ever produced – with far more scientific weight than the Moon landings, was a remarkable bargain. For much of the time, the private and public sectors were at daggers drawn (vividly illustrated by Celera’s description of the director of one public laboratory behaving as if he had been bitten by a rabid dog).




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