Germs, Genes, & Civilization: How Epidemics Shaped Who We Are Today
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Viruses that live in the intestine follow much the same pattern. These viruses infect the cells of the gut lining and cause a small amount of damage. Most cause so little damage that they go virtually unnoticed. A few trigger outbreaks of diarrhea. Rotavirus is the most common virus that causes infant diarrhea. In third-world nations, it can be life-threatening, although in industrial nations it is rarely dangerous. Rotavirus has been with mankind long enough for special adaptations to evolve. The protein, lactadherin, is synthesized in the breast and found in human milk. Instead of being digested by babies, it remains in their intestines. Lactadherin mimics the receptor on intestinal cells to which rotavirus binds. When rotavirus binds to lactadherin, instead of attaching to the intestine, the virus remains floating in the gut and is flushed out. Infants whose mothers provide them with higher levels of lactadherin suffer much less from rotavirus-induced diarrhea.
Cholera comes from the Indian subcontinent
We can only speculate on the effects of infectious disease on the earliest civilizations. However, intestinal diseases were probably the first to topple whole human cultures. The first civilization whose collapse can be reasonably credited to infection is the Indus Valley culture, sited in what is now Pakistan and part of northern India. Good evidence indicates that cholera or a closely related waterborne infection might have been instrumental in its collapse. To understand this, we first need to consider the natural history of cholera itself.
Cholera is caused by the bacterium Vibrio cholerae. Its victims suffer severe diarrhea and can die of dehydration if not cared for. Cholera is thought to have origins in India and emerged onto the world stage only in the nineteenth century. Hindu physicians first described cholera around 400 B.C., but the disease was almost certainly endemic there much earlier. It has caused epidemics in India ever since, especially in the region of the Ganges delta. Hindus from all over India make pilgrimages to Benares, a holy city on the Ganges. Pilgrims in large numbers moving to and fro across India tend to spread waterborne disease between major population centers. This adds to the effect of the dense local populations in contaminating the Ganges River complex and the Bay of Bengal into which it empties.
Cholera stayed in India until the early 1800s. During the following century, half a dozen worldwide pandemics erupted. In 1817, cholera spread both westward to the Middle East and Southern Russia and eastward to Malaya, Thailand, and Japan. It reached England in 1831 and North America the next year. Another cholera pandemic was responsible for massive casualties during the Crimean War of 1854–1856. Of 250,000 troops engaged, the British and their allies lost approximately 20,000 to cholera.
But why did cholera not sweep through the unhygienic cities of Europe and Asia until the 1800s? European ships were in regular contact with India from the 1500s, and British troops and traders in India suffered substantial losses from cholera while in India. The answer is unknown, but a reasonably convincing suggestion is that cholera outbreaks burn themselves out in a few weeks, unless they can infect fresh victims. The slow-sailing ships of earlier times took a relatively long time to reach Europe, so cholera taken aboard in India could not survive the voyage. Faster steamships and the opening of the Suez Canal have since brought East and West into much speedier contact.
Cholera and the water supply
In 1832, John Snow investigated the cholera outbreak at Killingworth colliery near Newcastle in northern England. He concluded that cholera was not carried by bad air or passed directly from person to person. He blamed the constant diarrhea, unwashed hands, and shared food. The miners stayed in the pit for eight or nine hours, taking their food and drink with them. As one informant put it:
I fear that our colliers are no better than others as regards cleanliness. The pit is one huge privy, and of course the men always take their victuals with unwashed hands.
Snow continued his detective work in the London slums. The poor, crowded together in dirty conditions, were easy targets for cholera. But how did the rich contract the disease? Snow realized that the communal water supply could be contaminated by infected sewage. This explained why some communities were hard hit, whereas others, close by but supplied by a different water main or drawing water from a different well, remained unscathed. In the cholera epidemic of 1851, there were 4,093 deaths among the 266,000 people who drank water supplied by the Southark and Vauxhall water company that got water from the sewage-laden River Thames. In contrast, there were only 461 deaths among the 173,000 people whose water was supplied by the Lambeth water company, whose sources were uncontaminated.
Snow demonstrated that cholera is spread by contamination of water with the copious diarrhea its victims generated. England, followed by the other industrial nations, then took action to keep its water supplies clean. By the beginning of the twentieth century, most European and North American cities were as clean as the Romans had been in the first century. That’s progress! The last great cholera pandemic, which began in India in 1891, reached only as far as Russia. Western Europe went essentially unscathed.
The rise and fall of the Indus Valley civilization
The Indus Valley civilization flourished from about 3,000 B.C. to 2,000 B.C. and was centered around the Indus and Sarasvati Rivers in what is now part of northern India and Pakistan. By virtue of its location, the Indus Valley civilization was able to spread over a much larger area than the ancient civilizations of Egypt and the Middle East. Its two best-known cities were Harappa and Mohenjo-Daro, both now in southern Pakistan. Estimates of the population of Mohenjo-Daro range from around 30,000 to as high as 100,000. More relevant to infectious disease, several dozen towns of various sizes sprawled over the region, resulting in a large overall population, all in reasonable contact.
The Indus Valley towns were notable for being laid out in a well-designed grid. Streets were of fixed widths, 9m for main roads and 3m or 1.5m for lesser streets. Most houses were built to standardized designs with bricks of fixed sizes; the relative dimensions of virtually every brick used in the Indus Valley culture were 1 × 2 × 4. Perhaps the major achievement of the Indus Valley culture was its water supply and drainage system. All major centers had sophisticated communal plumbing, with water supply channels and drains. Almost every house in major centers such as Mohenjo-Daro had its own baths. Drains took the dirty water to a communal underground sewage system. The Great Bath of Mohenjo-Daro was the earliest public bath in the world. It measures 12m × 7m × 2.4m deep (approximately 40 ft. × 23 ft. × 8 ft.). Although no one really knows, most archeologists think that it served for religious purification, that it was a sort of baptism tank instead of a swimming pool. In any case, it was built of tightly fitting bricks that were plastered over and lined with a layer of bitumen, to make it waterproof.
Despite these initial technological advances, the Indus Valley culture remained stagnant, showing little progress beyond its initial achievements. Eventually, it collapsed, leaving no obvious successor culture. Around 1900 B.C., the Sarasvati River dried up, and its ancient course was rediscovered using satellite photos only in the 1990s. In contrast, several other minor rivers changed their courses to empty into the Indus River, which became overswollen and inundated its flood plain. By 1800 B.C., the Indus Valley culture had disappeared virtually without a trace, and urban civilization did not return to India for a millennium.
Were the changes in the rivers responsible? Some archeologists believe so. All the same, the cultures of Mesopotamia had to contend with floods, droughts, and the movement of the channels of the Tigris and Euphrates rivers. Although individual cities and regimes fell casualty, the culture as a whole did not collapse; the people relocated to other sites and continued evolving. The collapse of the Indus Valley culture has also been attributed to the arrival of the Indo-European (Aryan) invaders from the north. However, despite the usual exaggerated claims of antiquity typical for sacred writings, the Rig Veda, telling of the Aryan incursions, was assembled no earlier than 1,000 B.C. and was not written down for another
thousand years. Thus, the invaders arrived long after Harappa and Mohenjo-Daro were already abandoned mounds. Furthermore, life in the countryside appears to have carried on with relatively little discontinuity during the collapse of the Indus Valley cities. Some archeologists talk of a “systems collapse,” which means that they have no idea why it collapsed but find it embarrassing to admit this in front of laypeople.
Cities are vulnerable to waterborne diseases
After a millennium of highly organized urban life, cities scattered over hundreds of miles were all abandoned within a century or two. To explain the collapse of an entire civilization on such a scale, we need a reason why urban life became nonviable, yet rural life went on. The latest archeological levels of Harappa and Mohenjo-Daro revealed large numbers of unburied skeletons. Although this originally suggested invasion and conquest, closer examination of the skeletons has shown that they lack the characteristic marks typically left by swords, axes, and other weapons. This implies that the slaughter was not due to human agency. The only realistic alternative is an epidemic of some kind. The great strength of the Indus Valley civilization was also its Achilles’ heel (despite the fact that Achilles would not be born for another 500 years!). A water-distribution system can also distribute waterborne disease. This is well illustrated by the 550 outbreaks of waterborne disease documented in the United States between 1946 and 1977. Although few were serious, these numbers illustrate the constant vigilance necessary to ensure a safe water supply.
City-dwellers in Harappa and Mohenjo-Daro got water from public wells whose rims were usually within a few inches of the ground. The drainage system was underground, though buried only a foot or two below the surface. Whenever drains backed up due to blockages or local flooding, there would have been massive contamination of the water supply. In fact, the system is so susceptible to contamination that early archeologists did not believe that the drains could have been used for human excrement. However, later excavations revealed latrines connected directly to the drainage system and the presence of wooden mesh baffles for screening out solid waste. Refuse heaps left by maintenance workers who entered the drains by manholes in the streets demonstrate that blockages were not uncommon.
Today we might wonder how they got away with this for a thousand years. The answer seems to be that highly virulent waterborne diseases had not yet evolved when the Indus Valley cities were first built. As we have already discussed, most virulent epidemic infections have emerged only in the last few thousand years. Before dense populations that shared the same water supply and sewers arose, severe diarrheal diseases had no way to spread. During the period from 3,000 B.C. to 2,000 B.C., bacteria that had previously relied on occasional mild diarrhea to wander from intestine to intestine were presented with ideal conditions for evolving into virulent waterborne killers. To put it rather unkindly, the evolution of cholera could well be the legacy of the Indus Valley culture. Cholera is perhaps the most likely agent, especially because it was known in India from early times. But because more than a thousand years passed between the fall of the Indus Valley culture and the earliest convincing descriptions of cholera, other diarrheal diseases, caused by related enteric bacteria such as Shigella or Salmonella, might have been the cause.
When a virulent form of cholera had evolved, it would have rapidly spread from city to city throughout the Indus Valley region. The older and larger cities would have been most susceptible, whereas rural communities would have suffered far less. Before modern medicine, epidemics of cholera typically killed a high proportion of those infected within a few days. When an epidemic struck, many city-dwellers fled to the countryside, probably under the impression that they had offended the gods. If you doubt that disease could cause the abandonment of entire cities, remember that, in medieval Europe, the death rate in the cities was greater than the birth rate, and the city populations were maintained only by continued immigration from the countryside.
Why didn’t waterborne disease wipe out other urban cultures? Consider the Romans, who had an extensive system for water distribution. For one thing, the Roman sewer system was more effective in removing human waste. The Romans might have turned the River Tiber into a giant sewer, but the Romans did not generally use it for drinking water. Instead, aqueducts brought water supplies a considerable distance from elevated and sparsely populated regions. The aqueducts kept the water high off the ground, away from possible contamination. If anything, diseases that rely on contaminated water were kept at bay during the Roman period. Before moving on to consider what kind of diseases were the undoing of the world’s greatest empire, let’s reflect that the fall of Rome, and the collapse of its civil engineering system, provided the opportunity for diarrheal diseases to make a major comeback.
Cholera, typhoid, and cystic fibrosis
An interesting recent revelation is that cystic fibrosis is linked to cholera resistance. Cystic fibrosis is an inherited disease that affects about 1 in 2,000 white children but is rare in other races. You must inherit two defective copies of the gene, one from each parent, to suffer from the disease. Humans who have a single defective gene are carriers but do not show symptoms, because a single good copy of the gene is sufficient for normal health. The molecular basis of cystic fibrosis is a failure to secrete chloride ions across cell membranes. Water normally flows to follow the chloride ions. Deficient water flow means that the mucus that lines and protects the lungs is abnormally thick due to a lack of sufficient water diluting it. This not only obstructs the airways but also allows the growth of harmful bacteria. The bacteria are protected from the immune system by the mucus, which they also use as a source of nutrition. Cells lining the airways of the lungs are killed and replaced with fibrous scar tissue, hence the name of the disease. Eventually, the patient succumbs to respiratory failure.
In cholera, death results from dehydration. The mechanism involves the initial release of ions, including chloride, from intestinal cells. Water follows the ions, and diarrhea results. If one defective copy of the cystic fibrosis gene is present, chloride ions and water move more slowly, and this protects against water loss via diarrhea. Consequently, a single defective gene protects against cholera—or, for that matter, any other disease that causes diarrhea and dehydration—but does not inhibit water flow enough to cause cystic fibrosis.
About 4.3% of the white population carry one defective copy of the cystic fibrosis gene, and 0.05% have two defective copies. Until very recently, nobody who received two bad copies and, therefore, suffered from cystic fibrosis lived long enough to have children. This allows us to calculate the rate at which bad copies of the gene are eliminated from the gene pool. For the incidence of cystic fibrosis to stay constant, defective copies of the gene must be created by mutation at the same rate at which they are lost by selection. In practice, the required mutation rate turns out to be a hundred times higher than naturally occurring mutation rates. This tells us that the prevalence of cystic fibrosis cannot be due to the constant emergence of new mutations. On the contrary, the cystic fibrosis mutation, when present as a single copy, is somehow being favored and preferentially passed on. Deeper genetic analysis also shows linkage disequilibrium. This means that mutant versions of the cystic fibrosis gene are associated with particular versions of neighboring genes much more often than expected by chance. This confirms that the mutant version of the cystic fibrosis gene is being passed on in association with these nearby genes instead of being constantly re-created by new mutations appearing at random.
Many slightly different mutations at different sites within the cystic fibrosis gene can produce defects, and around 50 different defective versions of this gene have been detected. Nonetheless, 90% of defective cystic fibrosis genes found in Northern Europe have the same defect at the molecular level (the amino acid phenylalanine at position number 508 is missing). The other 10% include some 40 different defects. This indicates that the majority of defective genes have been inherited from a relatively small group of ancestors in
stead of appearing by random mutation. For the defective version of the cystic fibrosis gene to be maintained at its present level by inheritance, those who have a single bad copy can be calculated to have a preferential survival rate of 2.3% over those with two good copies.
But is this preferential survival really due to cholera resistance? If true, we would expect cystic fibrosis to be most common in Indians and other Asians, which is the opposite of what is found. As for the Europeans, if we assume a mutation rate of 1 in 100,000 per gene per generation, we would expect roughly 0.6% of the population to possess a single defective copy in the absence of any advantage. Cholera first appeared in Europe around 1820, approximately eight generations ago. An increase due to a selective advantage of 2.3% over eight generations would result in 0.72% having a single defective copy, a far cry from the 4.3% who actually have it. Assuming 20 years per generation, a selective advantage of 2.3% would need around 1,700 years to produce the level of 4.3% seen today.
The collapse of the Roman Empire and the ensuing decline in hygiene all over Europe fits the needed time scale rather well. This event would have resulted in the spread of many diseases, such as typhoid, bacterial dysentery, and rotavirus. Like cholera, these all share diarrhea as a symptom and are spread by contamination of water with human waste. Recently, the connection between typhoid and cystic fibrosis has been strengthened. It has been found that the typhoid bacterium uses the cystic fibrosis protein when it first enters cells of the gut lining on its way to invade the bloodstream. Thus, a defective cystic fibrosis protein specifically keeps typhoid at bay and generally reduces diarrhea. Typhoid, which has a fatality rate of 10% to 20%, was endemic throughout preindustrial Europe. Remember that infant mortality was well over 50% for much of this period, and perhaps half of these infant deaths were due to diseases causing dehydration via diarrhea. Survival of infants rather than adult casualties would have driven the selection for the cystic fibrosis mutation.