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As it turns out, appendicitis is a modern phenomenon. In Darwin’s day, it was extremely rare, causing very few deaths, so we can perhaps forgive him for thinking the appendix was merely one of evolution’s leftovers, neither harming nor helping us. Appendicitis became common in the late nineteenth century, with cases in one British hospital shooting up from a stable rate of three or four people per year prior to 1890, to 113 cases per year by 1918; a rise mirrored throughout the industrialised world. Diagnosis had never been a problem – the cramping pain followed by a quick autopsy if the patient didn’t make it revealed the cause of death even before appendicitis became as common as it is now.

Many explanations were put forward to explain it, from increased meat, butter and sugar consumption, to blocked sinuses and rotting teeth. At that time, consensus opinion alighted on a reduction in fibre in our diets as the ultimate cause, but hypotheses still abound, including one that blames the rise on improved water sanitation and the hygienic conditions it brings – the very development that appeared to render the appendix almost impotent. Whatever the ultimate cause, by the Second World War our collective memory had been purged of the rise in appendicitis cases, leaving us with the impression that it is an expected, though unwelcome, feature of normal life.

In fact, even in the modern, developed world, keeping hold of the appendix at least until adulthood can prove to be beneficial, protecting us from recurring gastrointestinal infections, immune dysfunction, blood cancer, some autoimmune diseases and even heart attacks. Somehow, its role as a sanctuary of microbial life brings these benefits.

That the appendix is far from pointless tells us something bigger: our microbes matter to our bodies. It seems they are not just hitching a ride, but providing a service important enough that our guts have evolved an asylum just to keep them safe. The question is, who is there, and what exactly do they do for us?

Although we have known for several decades that our bodies’ microbes offer us a few perks, like synthesising some essential vitamins, and breaking down tough plant fibres, the degree of interaction between our cells and theirs wasn’t realised until relatively recently. In the late 1990s, using the tools of molecular biology, microbiologists took a great leap into discovering more about our strange relationship with our microbiotas.

New DNA-sequencing technology can tell us which microbes are present, and allows us to place them within the tree of life. With each step down this hierarchy, from domain to kingdom then phylum through class, order and family, and on to genus, species and strain, individuals are more and more closely related to one another. Working from the bottom up, we humans (genus Homo and species sapiens) are great apes (family Hominidae), which sit alongside monkeys and others within the primates (order Primates). All of us primates belong with our fellow furry milk-drinkers, as a member of the mammals (class Mammalia), who then fit within a group containing animals with a spinal cord (phylum Chordata), and finally, amongst all animals, spinal cord or otherwise (think of our squid, for example), in kingdom Animalia, and domain Eukarya. Bacteria and other microbes (except the category-defying viruses) find their place on the other great branches of the tree of life, belonging not to kingdom Animalia, but to their own unique kingdoms in separate domains.

Sequencing allows different species to be identified and placed within the hierarchy of the tree of life. One particularly useful segment of DNA, the 16S rRNA gene, acts as a kind of barcode for bacteria, providing a quick ID without the need to sequence an entire bacterial genome. The more similar the codes of the 16S rRNA genes, the more closely related the species, and the more twigs and branches of the tree of life they share.

DNA sequencing, though, is not the only tool at our disposal when it comes to answering questions about our microbes, especially regarding what they do. For these mysteries, we often turn to mice. In particular, ‘germ-free’ mice. The first generations of these laboratory staples were born by Caesarean section and kept in isolation chambers, preventing them from ever becoming colonised with microbes, either beneficial or harmful ones. From then on, most germ-free mice are simply born in isolation to germ-free mothers, sustaining a sterile line of rodents untouched by microbes. Even their food and bedding is irradiated and packed in sterile containers to prevent any contamination of the mice. Transferring mice between their bubble-like cages is quite an operation, involving vacuums and antimicrobial chemicals.

By comparing germ-free mice with ‘conventional’ mice, which have their full complement of microbes, researchers are able to test the exact effects of having a microbiota. They can even colonise germ-free mice with a single species of bacterium, or a small set of species, to see precisely how each strain contributes to the biology of a mouse. From studying these ‘gnotobiotic’ (‘known life’) mice, we get an inkling of what microbes do in us as well. Of course, they are not the same as humans, and sometimes results of experiments in mice are wildly different from results in humans, but they are a fantastically useful research tool and very often provide crucial leads. Without rodent models, medical science would progress at a millionth of the speed.

It was by using germ-free mice that the commander-in-chief of microbiome science, Professor Jeffrey Gordon from the University of Washington in St Louis, Missouri, discovered a remarkable indication of just how fundamental the microbiota are to the running of a healthy body. He compared the guts of germ-free mice with those of conventional mice, and he learnt that under the direction of bacteria the mouse cells lining the gut wall were releasing a molecule that ‘fed’ the microbes, encouraging them to take up residence. The presence of a microbiota not only changes the chemistry of the gut, but also its morphology. The finger-like projections grow longer at the insistence of microbes, making the surface area large enough to capture the energy it needs from food. It’s been estimated that rats would need about 30 per cent more to eat if it weren’t for their microbes.

It is not only microbes that are benefiting from sharing our bodies, but us too. Our relationship with them is not just one of tolerance, but encouragement. This realisation, combined with the technical power of DNA sequencing and germ-free mouse studies, began a revolution in science. The Human Microbiome Project, run by the United States’ National Institutes for Health, alongside many other studies in laboratories around the world, has revealed that we utterly depend on our microbes for health and happiness.

The human body, both inside and out, forms a landscape of habitats as diverse as any on Earth. Just as our planet’s ecosystems are populated by different species of plants and animals, so the habitats of the human body host different communities of microbes. We are, like all animals, an elaborate tube. Food goes in at one end of the tube and comes out the other. We see our skin as covering our ‘outside’ surface, but the inner surface of our tube is also ‘outside’ – exposed to the environment in a similar way. Whilst the layers of our skin protect us from the elements, invading microbes and harmful substances, the cells of the digestive tract that runs right through us must also keep us safe. Our true ‘inside’ is not this digestive tract, but the tissues and organs, muscles and bones that are packed away between the inside and the outside of our tubular selves.

The surface of a human being, then, is not just their skin, but the twists and turns, furrows and folds of their inner tube as well. Even the lungs, the vagina and the urinary tract count as being on the outside – as part of the surface – when you view the body in this way. No matter if it’s inner or outer, all of this surface is potential real estate for microbes. Sites vary in their value, with dense city-like communities building up in resource-rich prime locations like the intestines, while sparser collections of species occupy more ‘rural’ or hostile locations such as the lungs and the stomach. The Human Microbiome Project set out to characterise these communities, by sampling microbes from eighteen sites across the inner and outer surfaces of the human body, in each of hundreds of volunteers.

Over the first five years of the HMP, molecular microbiologists oversaw a biotechnological echo of the golden age of species discovery; one that saw formaldehyde-infused collecting cabinets stuffed with the haul of birds and mammals discovered and named by explorer– biologists in the eighteenth and nineteenth centuries. The human body is, as it turns out, a treasure trove of strains and species new to science, many of them present on only one or two of the volunteers participating in the study. Far from each person harbouring a replicate set of microbes, very few strains of bacteria are common to everyone. Each of us contains communities of microbes as unique as our fingerprints.

Though the finer details of our inhabitants are specific to each of us, we all play host to similar microbes at the highest hierarchical levels. The bacteria living in your gut, for example, are more similar to the bacteria in the gut of the person sitting next to you, than they are to the bacteria on your knuckles. What’s more, despite our distinctive communities, the functions they perform are usually indistinguishable. What bacterium A does for you, bacterium B might do for your best friend.

From the arid, cool plains of the skin on the forearms to the warm, humid forests of the groin and the acidic, low-oxygen environment of the stomach, each part of the body offers a home to those microbes that can evolve to exploit it. Even within a habitat, distinct niches host different collections of species. The skin, all two square metres of it, contains as many ecosystems as the landscapes of the Americas, but in miniature. The occupants of the sebum-rich skin of the face and back are as different from those of the dry, exposed elbows as the tropical forests of Panama are from the rocks of the Grand Canyon. Where the face and back are dominated by species belonging to the genus Propionibacterium, which feed off the fats released by the densely packed pores in these areas, the elbows and forearms host a far more diverse community. Moist areas, including the navel, the underarms and the groin, are home to Corynebacterium and Staphylococcus species, which love the high humidity, and feed off the nitrogen in the sweat.

This microbial second skin provides a double layer of protection to the body’s true interior, reinforcing the sanctity of the barrier formed by the skin cells. Invading bacteria with malicious intentions struggle to get a foothold in these closely guarded bodily border towns, and face an onslaught of chemical weapons when they try. Perhaps even more vulnerable to invasion are the soft tissues of the mouth, which must resist colonisation by a flood of intruders smuggled on food and floating in the air.

From the mouths of their volunteers, researchers working on the Human Microbiome Project took not just one sample, but nine, each from a slightly different location. These nine sites turned out to have discernibly different communities, within mere centimetres of one another, made up of around 800 species of bacteria dominated by Streptococcus species and a handful of other groups. Streptococcus gets bad press, on account of the many species that cause diseases, from ‘strep throat’ to the flesh-eating infection necrotising fasciitis. But many other species in this genus behave themselves impeccably, crowding out nasty challengers in this vulnerable entrance to the body. Of course these tiny distances between sampling locations within the mouth may seem insignificant to us, but to microbes they are like vast plains and mountain ranges with climates as different as northern Scotland and the south of France.

Imagine, then, the climatic leap from the mouth to the nostrils. The viscous pool of saliva on a rugged bedrock replaced by a hairy forest of mucus and dust. The nostrils, as you might expect from their gatekeeper status at the entrance to the lungs, harbour a great range of bacterial groups, numbering around 900 species, including large colonies of Propionibacterium, Corynebacterium, Staphylococcus and Moraxella.

Heading down the throat towards the stomach sees the enormous diversity of species found in the mouth drop dramatically. The highly acidic stomach kills many of the microbes that enter with food, and just one species is known for certain to reside there permanently in some people – Helicobacter pylori, whose presence may be both a blessing and a curse. From this point on, the journey through the digestive tract reveals an ever-greater density – and diversity – of microbes. The stomach opens into the small intestine, where food is rapidly digested by our very own enzymes and absorbed into the bloodstream. There are still microbes here though; around ten thousand individuals in every millilitre of gut contents at the start of this 7-m-long tube, rising to an incredible ten million per millilitre at the end, where the small intestine meets the large intestine’s starting point.

Just outside the safe-house created by the appendix is a teeming metropolis of microbes, in the heart of the microbial landscape of the human body – the tennis-ball-like caecum, to which the appendix is attached. This is the epicentre of microbial life, where trillions of individual microbes of at least 4,000 species make the most of the partially digested food that has passed through round one of the nutrient-extraction process in the small intestine. The tough bits – plant fibres – are left over for the microbes to tackle in round two.

The colon, which forms most of the length of the large intestine, running up the right-hand side of your torso, across your body under your rib cage, and back down the left-hand side, provides homes for microbes, numbering one trillion (1,000,000,000,000) individuals per millilitre by now, in the folds and pits of its walls. Here, they pick up the scraps of our food and convert them into energy, leaving their waste products to be absorbed into the cells of the colon’s walls. Without the gut’s microbes, these colonic cells would wither and die – whilst most of the body’s cells are fed by sugar transported in the blood, the colonic cells’ main energy source is the waste products of the microbiota. The colon’s moist, warm, swamp-like environment, in parts completely devoid of oxygen, provides not only a source of incoming food for its inhabitants, but a nutrient-rich mucus layer, which can sustain the microbes in times of famine.

The human gut.

Because HMP researchers would have to cut open their volunteers to sample the different habitats of the gut, a far more practical way of collecting information about the gut’s inhabitants was to sequence the DNA of microbes found in the stool. On its passage through the gut, the food we eat is mostly digested and absorbed, both by us and our microbes, leaving only a small amount to come out the other end. Stool, far from being the remains of our food, is mostly bacteria, some dead, some alive. Around 75 per cent of the wet weight of faeces is bacteria; plant fibre makes up about 17 per cent.

At any one time, your gut contains about 1.5 kg of bacteria – that’s about the same weight as the liver – and the lifespans of individuals are a matter of just days or weeks. The 4,000 species of bacteria found in the stool tell us more about the human body than all the other sites put together. These bacteria become a signature of our health and dietary status, not only as a species, but as a society, and personally. By far the most common group of bacteria in the stool are the Bacteroides, but because our gut bacteria eat what we eat, bacterial communities in the gut vary from person to person.

The gut microbes aren’t just scavengers, though, taking advantage of our leftovers. We have exploited them too, especially when it comes to outsourcing functions that would take us time to evolve for ourselves. After all, why bother having a gene for a protein that makes Vitamin B12, which is essential for our brain function, when Klebsiella will do it for you? And who needs genes to shape the intestine’s walls, when Bacteroides have them? It’s much cheaper and easier than evolving them afresh. But, as we will discover, the role of the microbes living in the gut goes far beyond synthesising a few vitamins.

The Human Microbiome Project began by looking only at the microbiotas of healthy people. With this benchmark set down, the HMP went on to ask how they differ in poor health, whether our modern illnesses could be a consequence of those differences, and if so, what was causing the damage? Could skin conditions like acne, psoriasis and dermatitis signal disruption to the skin’s normal balance of microbes? Might inflammatory bowel disease, cancers of the digestive tract and even obesity be due to shifts in the communities of microbes living in the gut? And, most extraordinarily, could conditions that were apparently far removed from microbial epicentres, such as allergies, autoimmune diseases and even mental health conditions, be brought on by a damaged microbiota?

Lee Rowen’s educated guess in the sweepstake at Cold Spring Harbor hinted at a much deeper discovery. We are not alone, and our microbial passengers have played a far greater role in our humanity than we ever expected. As Professor Jeffrey Gordon puts it:

This perception of the microbial side of ourselves is giving us a new view of our individuality. A new sense of our connection to the microbial world. A sense of the legacy of our personal interactions with our family and environment early in life. It’s causing us to pause and consider that there might be another dimension to our human evolution.

We have come to depend on our microbes, and without them, we would be a mere fraction of our true selves. So what does it mean to be just 10 per cent human?

ONE
Twenty-First-Century Sickness

In September 1978, Janet Parker became the last person on Earth to die of smallpox. Just 70 miles from the place where Edward Jenner had first vaccinated a young boy against the disease with cowpox pus from a milkmaid, 180 years earlier, Parker’s body played host to the virus in its final outing in human flesh. Her job as a medical photographer at the University of Birmingham in the UK would not have put her in direct jeopardy were it not for the proximity of her dark room to the laboratory beneath. As she sat ordering photographic equipment over the telephone one afternoon that August, smallpox viruses travelled up the air ducts from the Medical School’s ‘pox’ room on the floor below, and brought on her fatal infection.

The World Health Organisation (WHO) had spent a decade vaccinating against smallpox around the world, and that summer they were on the brink of announcing its complete eradication. It had been nearly a year since the final naturally occurring case of the disease had been recorded. A young hospital cook had recovered from a mild form of the virus in its final stronghold of Somalia. Such a victory over disease was unprecedented. Vaccination had backed smallpox into a corner, ultimately leaving it with no vulnerable humans to infect, and nowhere to go.

But the virus did have one tiny pocket to retreat to – the Petri dishes filled with human cells that researchers used to grow and study the disease. The Medical School of Birmingham University was one such viral sanctuary, where one Professor Henry Bedson and his team were hoping to develop the means to quickly identify any pox viruses that might emerge from animal populations now that smallpox was gone from humans. It was a noble aim, and they had the blessing of the WHO, despite inspectors’ concerns about the pox room’s safety protocols. With just a few months left before Birmingham’s lab was due to close anyway, the inspectors’ worries did not justify an early closure, or an expensive refit of the facilities.

Janet Parker’s illness, at first dismissed as a mild bug, caught the attention of infectious disease doctors a fortnight after it had begun. By now she was covered in pustules, and the possible diagnosis turned to smallpox. Parker was moved into isolation, and samples of fluid were extracted for analysis. In an irony not lost on Professor Bedson, his team’s expertise in identifying pox viruses was called upon for verification of the diagnosis. Bedson’s fears were confirmed, and Parker was moved to a specialist isolation hospital nearby. Two weeks later on 6 September, with Parker still critically ill in hospital, Professor Bedson was found dead at his home by his wife, having slit his own throat. On 11 September 1978, Janet Parker died of her disease.

Janet Parker’s fate was that of many hundreds of millions before her. She had been infected by a strain of smallpox known as ‘Abid’, named after a three-year-old Pakistani boy who had succumbed to the disease eight years previously, shortly after the WHO’s intensive smallpox eradication campaign had got under way in Pakistan. Smallpox had become a significant killer across most of the world by the sixteenth century, in large part due to the tendency of Europeans to explore and colonise other regions of the world. In the eighteenth century, as human populations grew and became increasingly mobile, smallpox spread to become one of the major causes of death around the world, killing as many as 400,000 Europeans each year, including roughly one in ten infants. With the uptake of variolation – a crude and risky predecessor of vaccination, involving intentional infection of the healthy with the smallpox fluids of sufferers – the death toll was reduced in the latter half of the eighteenth century. Jenner’s discovery of vaccination using cowpox in 1796 brought further relief. By the 1950s, smallpox had been all but eliminated from industrialised countries, but there were still 50 million cases annually worldwide resulting in over 2 million deaths each year.

Though smallpox had released its grip on countries in the industrialised world, the tyrannical reign of many other microbes continued in the opening decade of the twentieth century. Infectious disease was by far the dominant form of illness, its spread aided by our human habits of socialising and exploring. The exponentially rising human population, and with that, ever-greater population densities, only eased the person-to-person leap that microbes needed to make in order to continue their life cycle. In the United States, the top three causes of death in 1900 were not heart disease, cancer and stroke, as they are today, but infectious diseases, caused by microbes passed between people. Between them, pneumonia, tuberculosis and infectious diarrhoea ended the lives of one-third of people.

Once regarded as ‘the captain of the men of death’, pneumonia begins as a cough. It creeps down into the lungs, stifling breathing and bringing on a fever. More a description of symptoms than a disease with a sole cause, pneumonia owes its existence to the full spectrum of microbes, from tiny viruses, through bacteria and fungi, to protozoan (‘earliest-animal’) parasites. Infectious diarrhoea, too, can be blamed on each variety of microbe. Its incarnations include the ‘blue death’ – cholera – which is caused by a bacterium; the ‘bloody flux’ – dysentery – which is usually thanks to parasitic amoebae; and ‘beaver fever’ – giardiasis, again from a parasite. The third great killer, tuberculosis, affects the lungs like pneumonia, but its source is more specific: an infection by a small selection of bacteria belonging to the genus Mycobacterium.

A whole host of other infectious diseases have also left their mark, both literally and figuratively, on our species: polio, typhoid, measles, syphilis, diphtheria, scarlet fever, whooping cough and various forms of flu, among many others. Polio, caused by a virus that can infect the central nervous system and destroy nerves controlling movements, paralysed hundreds of thousands of children each year in industrialised countries at the beginning of the twentieth century. Syphilis – the sexually transmitted bacterial disease – is said to have affected 15 per cent of the population of Europe at some point in their lifetime. Measles killed around a million people a year. Diphtheria – who remembers this heart-breaker? – used to kill 15,000 children each year in the United States alone. The flu killed between five and ten times as many people in the two years following the First World War than were killed fighting in the war itself.

Not surprisingly these scourges had a major influence on human life expectancy. Back then, in 1900, the average life expectancy across the whole planet was just thirty-one years. Living in a developed country improved the outlook, but only to just shy of fifty years. For most of our evolutionary history, we humans have managed to live to only twenty or thirty years old, though the average life expectancy would have been much lower. In one single century, and in no small part because of developments in one single decade – the antibiotic revolution of the 1940s – our average time on Earth was doubled. In 2005, the average human could expect to live to sixty-six, with those in the richest countries reaching, again on average, the grand old age of eighty.

These figures are highly influenced by the chances of surviving infancy. In 1900, when up to three in ten children died before the age of five, average life expectancy was dramatically lower. If, at the turn of the next century, rates of infant mortality had remained at the level they were in 1900, over half a million children would have died before their first birthday in the United States each year. Instead, around 28,000 did. Getting the vast majority of children through their first five years unscathed allows most of them to go on and live to ‘old age’ and brings the average life expectancy up accordingly.

Though the effects are far from fully felt in much of the developing world, we have, as a species, gone a long way towards conquering our oldest and greatest enemy: the pathogen. Pathogens – disease-causing microbes – thrive in the unsanitary conditions created by humans living en masse. The more of us we cram onto our planet, the easier it becomes for pathogens to make a living. By migrating, we give them access to yet more humans, and in turn, more opportunity to breed, mutate and evolve. Many of the infectious diseases we have contended with in the last few centuries originated in the period after early humans had left Africa and set up home across the rest of the world. Pathogens’ world domination mirrored our own; few species have as loyal a pathogenic following as us.

For many of us living in more developed countries, the reign of infectious diseases is confined to the past. Just about all that remain of thousands of years of mortal combat with microbes are memories of the sharp prick of our childhood immunisations followed by the ’reward’ of a polio-vaccine-infused sugar lump, and perhaps more clearly, the melodramatic queues outside the dinner hall as we waited with our school friends for a teenage booster shot. For many children and teenagers growing up now, the burden of history is even lighter, as not only the diseases themselves, but once-routine vaccinations, such as the dreaded ‘BCG’ for tuberculosis, are no longer necessary.

Medical innovations and public health measures – largely those of the late nineteenth and early twentieth centuries – have made a profound difference to life as a human. Four developments in particular have taken us from a two-generation society to a four-, or even five-generation society in just one, long, lifetime. The first and earliest of these, courtesy of Edward Jenner and a cow named Blossom, is, of course, vaccination. Jenner knew that milkmaids were protected from developing smallpox by virtue of having been infected by the much milder cowpox. He thought it possible that the pus from a milkmaid’s pustules might, if injected into another person, transfer that protection. His first guinea pig was an eight-year-old boy named James Phipps – the son of Jenner’s gardener. Having inoculated Phipps, Jenner went on to attempt to infect the brave lad, twice injecting pus from a true smallpox infection. The young boy was utterly immune.

Beginning with smallpox in 1796, and progressing to rabies, typhoid, cholera and plague in the nineteenth century, and dozens of other infectious diseases since 1900, vaccination has not only protected millions from suffering and death, but has even led to countrywide elimination or complete global eradication of some pathogens. Thanks to vaccination, we no longer have to rely solely on our immune systems’ experiences of full-blown disease to defend us against pathogens. Instead of acquiring natural defences against diseases, we have circumvented this process using our intellect to provide the immune system with forewarning of what it might encounter.

Without vaccination, the invasion of a new pathogen prompts sickness and possibly death. The immune system, as well as tackling the invading microbe, produces molecules called antibodies. If the person survives, these antibodies form a specialist team of spies that patrol the body looking out specifically for that microbe. They linger long after the disease has been conquered, primed to let the immune system know the moment there is a reinvasion of the same pathogen. The next time it is encountered, the immune system is ready, and the disease can be prevented from taking hold.