The Language of the Genes

by Steve Jones

  Patterns of infection depend on the number of potential victims. As a result, the importance of disease has changed throughout history. The longer an illness has a hold and the more efficiently it is transmitted, the smaller the population needed to allow it to persist. Immunity also plays a part. Some sicknesses must have started long before others. Signs of tuberculosis, which can drag on for decades, can be seen in the bones of those who died tens of thousands of years ago. In contrast, measles is new. It does not last long and is not very infectious. Those who have been infected become immune and cannot be attacked again so that a large population is needed to keep it going. The history of measles is close to those of the many novel ills that have inflicted themselves upon the human species since it began.

  In a population which has never been exposed and which has no immunity, measles can have terrible effects. When it came to Fiji in 1875 (the result of a visit by the King to Sydney) it killed a third of his hundred and fifty thousand subjects. It soon disappeared from the island as it needs a community of at least half a million to persist. Measles may arrive in a place with fewer inhabitants, but cannot maintain itself. In Iceland before the Second World War there were gaps of up to seven years between epidemics. Only after 1945 (when constant movement meant that the Icelanders became part of the European population as a whole) did measles become a continuous problem. Humans have lived in groups of half a million or more for a mere two or three thousand years, so that measles must be a fairly new disease. Its initial impact was much worse than was its effect on populations who had lived with ii lor many generations.

  The constant change in the pattern of infection means that evolution can never rest: far from perfecting us, it is constantly faced with new challenges. Ten thousand years ago, when humans lived in small bands, contagious disease may scarcely have existed. No doubt there were plenty of lice and tapeworms around as their long lives and ability to reinfect their own hosts mean that they do not need many people to keep going. In general the ancient world was a healthy one. People starved, froze or were eaten by tigers instead. Even when an epidemic struck, it was a local matter. The few hunter-gatherers who remain show remnants of this pattern. In the 1950s, tribal groups of Yanomamo differed greatly in the antibodies that they possessed. In some villages, everyone had antibodies to (and must have been infected with) chickenpox. In others, that disease had never arrived but the whole population had once had influenza. The pattern of disease reflected a balance between a chance arrival of a new pathogen and a local epidemic which ended as soon as everyone was immune or dead. The same pattern exists in chimpanzees today. Now, the Yanomamo have joined the rest of humanity and its diseases and have suffered as a result.

  With farming, the human population shot up and began to coalesce into one continental mass. A whole new set of disorders appeared. Irrigation helped with the appearance of water-borne parasites such as schistosomes, which are carried by snails. Their eggs have been found in mummies from 1200 BC. Schistosomiasis is still common in Egypt. Many of the biblical plagues were new diseases that took hold as the population of Egypt grew large enough to sustain them.

  Some contagions came from animals. The closest relative of measles is the cattle disease rinderpest and measles itself may have evolved from this. A relation of smallpox is found in cows and of sleeping sickness in wild game. Only a small genetic change in the parasites was required to allow them to attack a new host. Homo sapiens.

  Some maladies came and went and have never been identified. The towns of mediaeval Europe suffered from outbreaks of dancing mania in which thousands took part. Some may have been due to mass hysteria, but the swellings and pain suggest an organic cause. In Italy the affliction was called tarantism and ascribed (wrongly) to the bite of spiders. St Vitus' Dance, with its visions of God, may have been the same illness. The epidemics began in eleventh-century Germany and had disappeared by the seventeenth century. England had its own mysterious and transient illness, the English Sweat, which came and went several times between 1480 and 1550.

  The effects were terrifying. It was brought into London by soldiers fleeing the Battle of Bosworth and a month later was at its peak. It killed its victims within a day. The University of Oxford was closed for six weeks. The disease returned several times over the next fifty years and in parts of Europe the mortality was so high that eight corpses were put into each grave. The last epidemic started in Shrewsbury in 1551, killing thousands. Since then the disease has gone. What it was, nobody knows.

  Hippocrates, in the fourth century before Christ, was the first to describe symptoms well enough to allow diseases to be diagnosed with any confidence. Ancient Greece had diphtheria, tuberculosis and influenza, but none of his records suggest the presence of smallpox, bubonic plague or measles. Travel soon led to a new set of pestilences. Smallpox was in India a thousand years before Christ, but its'short incubation period meant that it killed its carriersquickly and did not travel well by land. It reached Europe by sea, with the first epidemic in Rome in 165 BC. Perhaps the disease helped in the spread of Christianity, as even to give a sufferer a glass of water can relieve some of the symptoms. Anglo-Saxon records mention nearly fifty epidemics between 516 and 1087.

  Life got even worse in the first large towns. Big cities are recent things. Before 1800 just one European in fifty lived in a settlement of more than a hundred thousand people. There has been movement from the countryside for a thousand years, but epidemics meant that no city could sustain its own numbers until the nineteenth century. London at the time of Pepys had a population of a hundred thousand, but it needed five thousand immigrants a year to maintain its population in the face of pestilence.

  Plague had killed millions in the centuries before his day, but its last and worst epidemic was during Pepys' own lifetime. In December 1664, two Frenchmen died in Drury Lane. In the following June, Pepys wrote in his diary: 'This day, much against my will, I did in Drury Lane see two or three houses marked with a red cross upon the door, and the "Lord have Mercy upon Us" writ there: which was a sad sight to me, being the first of the kind that, to my remembrance, I ever saw. It put me into an ill conception of myself and my smell, so that I was forced to buy some roll-tobacco to smell and to chew, which took away my apprehension/ By the summer of that year, two thirds of the population of London had fled and the disease raged throughout England. The cycle of epidemics which tormented the capital and reached its peak in the Plague Year of 1665 ended with the replacement of thatched roofs (and their resident rats) by slates after the Great Fire in 1666. The last European plague was a century later, in the Balkans. The disease has often been introduced since then, but has never spread. Three hundred years ago, England had great cycles of death. Life expectancy fell from forty-two years in the late sixteenth century to thirty years in the seventeenth, returning to the earlier level only in Victorian times. The greatest mortality was in low-lying villages. 'Fevers* were usually blamed. City conscripts impressed into the army did better than the healthier youth from the countryside. The urban soldiery were pinched and weak, bur had been exposed to infection so often that they were immune to the diseases which slaughtered their country cousins when forced into crowded barracks.

  New contagions continue to appear. As well as AIDS, Africa had another mysterious epidemic in the 1970s, when outbreaks of the deadly (and until then unknown) Ebola fever killed half those infected. Even a trivial change can spark off new illnesses. In the past thirty years, Lyme Disease (named after the village of Lyme, in Connecticut, where it first appeared) has become the most widespread pest-borne disease in the United States, with more than ten thousand cases a year. It causes arthritis and a variety of painful nervous symptoms. The malady is due to a microorganism which spends part of its time in a tick found on white-tailed deer. A few cases were known a century ago but it did not become common until people moved to the suburbs and were exposed to the deer that flourish there. Nineteenth-century sanitation meant that cities became safer places. But it
had a cost. Before sewers, every infant was exposed to a constant small dose of polio virus. Their immune system works well and most became resistant. Once the water had been cleaned up only those few children unlucky enough to come into contact with a sudden dose of the virus got the disease. If the World Health Organisation succeeds (as it hopes to) in eliminating it altogether, any accidental escape might cause a disaster.

  For most of the world infection is still a scourge. Ten million lives a year are lost to measles, and five million to diarrhoea, diseases that could, given the political will, be controlled by vaccines and by clean water. Schistosomes, another parasite that should be simple to contain, attack two hundred million people. Faced with this onslaught by a series of changing enemies, natural selection can never relax. As more is discovered about ourselves, the importance of disease, extant or extinct, looms larger. It may be that much of the mass of human variation is a remnant of past battles against infection and that many of the genetic trends across the globe result from selection by disease today or in earlier times.

  Disease itself also evolves. If it did not, its agents would soon be extinct. It once appeared that evolution would inevitably lead to a truce with those infected and that the best strategy for a pathogen would be to keep its host — its homeland — alive. Sometimes, no doubt, this is true. However, the genes that drive a disease alter in their own interest alone. If the most efficient way to increase in number is to kill the patient, then natural selection will provide the means to do so.

  Before flush toilets (which, in their early days, fed directly into rivers) cholera was less dangerous. It had to keep its prey healthy for long enough for them to move to another village and to pollute its wells with the bacillus. As soon as one patient could infect hundreds more as his waste poured into a river cholera turned vicious: the victim needed to survive only to reach a water closet. If he died from fluid loss while pumping out millions of bacteria, that mattered not at all.

  The evolutionary struggle against malaria is the best illustration of the power of disease in evolution. Three hundred million people are infected and the disease kills two million a year — half of them African children. Almost half the world's population lives in malarious regions and, given the rate of growth in the tropics, the death rate may double within the next thirty years. Increased travel means that the disease can spread at a great rate. More than two thousand cases are imported to Britain each year and, now and again, malaria is transmitted within southern England by a native mosquito. In the United States, with its delta cities, the risk of a return of endemic malaria is real (particularly as mosquitoes have found new places to breed such as in the vast dumps of tyres fitted with stagnant water that defile the landscape).

  The malady is caused by a single-celled parasite, one of several species of Plasmodium, which is transmitted by mosquitoes. Females mosquitoes are deadlier than males, as they drink blood (which they need to make eggs). The parasites are injected from the salivary glands and pass to the recipient's liver. Here, they multiply. One infective cell can produce a thousand descendants. These enter the blood, break into red cells and divide again, digesting the haemoglobin as they do. The Plasmodium cells need iron, which they take from the blood. To give under-nourished African children iron supplements can as a result lead to a new eruption of malaria, which had been lying low.

  Bouts of fever take place as new waves of cells emerge from the reservoir in the liver. Many of the disease's symptoms are due to the release of iron and other toxic breakdown products as the blood is digested. If the parasites enter the brain there may be a fatal cerebral malaria.

  Once the sufferer has been bitten by a mosquito, parasites go into their next phase. Within a man or woman Plasmodium has a life of blameless rectitude as it does little but make thousands of identical copies of itself. In the mosquito it has sex. Males and females mature and mate to give new combinations of genes among their offspring. The next generation migrates to the salivary glands, where they are ready to be injected into a human to start the cycle again.

  The several species of malaria parasite have an unexpected evolutionary history. Some of their genes are similar to those found in green plants, so that, perhaps, in the distant past, their ancestors were related to single-celled plants (perhaps those whose modern equivalents cause the 'red tides' that kill fish). The DNA of the most virulent form, Plasmodium falciparum, is similar to that of one which infects birds. Other malaria parasites are closer to those that attack apes. They may owe their relative mildness to a long history within our relatives.

  Falciparum malaria needs a dense population to maintain itself. It probably began ten thousand years ago, when Africans shifted from the savannah to farming on the edges of the forests. The symptoms can be recognised in documents from ancient Egypt and China. Hippocrates was the first to point to its association with wet places. The swampy area around Rome — the Campagna — was uninhabited for most of its history because of endemic malaria and the disease destroyed the prosperity of the coastal cities of Greater Greece, such as Sybans and Syracuse. As a result of malaria the fertile Yangtse basin was abandoned for a thousand years. The disease spread over the whole world with the advance of exploration. It was once common in East Anglia, whose local population were once called 'yellowbellies1 after the jaundice caused by chronic infection. It killed King James the First and Oliver Cromwell; and Sir Walter Raleigh on the scaffold was concerned that his trembling might be interpreted as fear rather than what was, ague (or malarial fever).

  Hundreds of millions are infected and millions die. Even so, there seems to be an uneasy coexistence between the parasite and its host. Evolution has provided dozens of ways to foil its activities. How humanity copes with the disease demonstrates the strengths and weaknesses of natural selection. All kinds of defences have appeared. Some are effective, some less so; and some impose a terrible cost on those who use them.

  One of the great puzzles of biology is the mass of inherited variation on the cell surface. It is important, as it prevents people from accepting tissues from each other. But it did not evolve to make kidney transplants difficult. Perhaps such diversity is a relic ot a history of natural selection by disease, with particular antigens favoured because they protect against specific infections. For malaria, selection must have been strong as half of the population of West Africa have protective antigens although the most severe form of the illness has been around for a mere five hundred human generations.

  Once the Plasmodium gets into the red cells there are other defences. Peoples of the Mediterranean and the Middle East bear a mutation which reduces the activity of an enzyme. This makes it hard for the parasite to feed itself, and the cells die, as do their invaders.

  Evolution has come up with hundreds more tricks involving the red blood pigment, haemoglobin. In some places in West Africa, up to a third of children carry one or two copies of a mutated haemoglobin known as sickle cell. They have a single alteration in the DNA. This in turn leads to a change in one of the amino acids, the building blocks of the red pigment. When a cell from a carrier of sickle eel! is attacked, the haemoglobin forms fibres and the cell collapses, slowing the invader's growth. This is very effective. A child with a copy of the gene has a ninety per cent protection against the disease.

  India and the Middle East have mutations of other amino acids which acr in much the same way, while Italians, Cypriots and others have evolved more drastic defences. Whole sections of the haemoglobin molecule are deleted. Once again, this slows the growth of the Plasmodium. The name of these diseases, the thaiassaemias, reflects their distribution, meaning, as it does, the anaemias of the sea (in this case the Mediterranean). The response to malaria can also involve the persistence into adulthood of a haemoglobin normally found in the foetus.

  The picture looks pretty confused already. Now that it is possible to use DNA to examine it in more detail, things have got even more complicated. What seemed to be the same defence mechanism in separate places
turn out to be genetically quite different. Scores of distinct deletions of bits of the haemoglobin chain are found, as are many different protective cell-surface cues. Altogether, hundreds of mutations have been pressed into service in the struggle. What is more, the same mechanism (sickle cell, for example) has turned up independently in populations a long way apart. Several distinct foci of the sickle gene, each associated with a different set of variants in the adjacent DNA, are known from Africa, with another from India.

  A few patches of sickle-cell haemoglobin are found in Europe, where in some places the mutation is carried by people with white skins. One is in the town of Coruche, in central Portugal, where malaria was once common. Most of its inhabitants1 DNA resembles that of other Europeans, but the DNA around their sickle-cell gene is of a type only found in West Africa. The Portuguese brought home the first slaves in 1444 and, a century later, the Algarve was filled with Africans and rheir children, a high proportion of whom had a white parent. Many of these children must have carried sickle cell. This protected them against the local disease so that the African gene flourished and spread although those for black skin were absorbed into the local population and, after hundreds of years, lost from sight.

  The malaria story has many lessons for evolution. In any revolution, the mob grabs whatever is at hand to make a rough and ready barrier which, even if it does not stop the forces of repression, slows them down. Natural selection has responded to disease in the same way. Whenever a mutation which might be useful turns up it is used to try and halt the invader. In different places, different genes become available, and the first at hand is used even if it was not the best. The solution which emerges may be wasteful and inefficient, but an ability in 'make do and mend' is characteristic of evolution. It explains why no creature is a beautiful solution to the problems of its own history and why life is, basically, such a mess.