10% Human
How Your Body’s Microbes Hold the Key to Health and Happiness
ALANNA COLLEN

Copyright

William Collins

An imprint of HarperCollinsPublishers

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This eBook first published in Great Britain by William Collins in 2015

Copyright © Nycteris Ltd 2015

Line drawings by Mat Taylor

Cover illustration © Sorbetto/Getty Images

Alanna Collen asserts the moral right to be identified as the author of this work.

A catalogue record for this book is available from the British Library.

All rights reserved under International and Pan-American Copyright Conventions. By payment of the required fees, you have been granted the non-exclusive, non-transferable right to access and read the text of this e-book on-screen. No part of this text may be reproduced, transmitted, down-loaded, decompiled, reverse engineered, or stored in or introduced into any information storage and retrieval system, in any form or by any means, whether electronic or mechanical, now known or hereinafter invented, without the express written permission of HarperCollins.

Source ISBN: 9780007584055

Ebook Edition © April 2015 ISBN: 9780007584048

Version: 2016-03-05

Dedication

For Ben and his microbes. My favourite superorganism.

At the heart of science is an essential balance between two seemingly contradictory attitudes – an openness to new ideas, no matter how bizarre or counterintuitive they may be, and the most ruthless sceptical scrutiny of all ideas, old and new. This is how deep truths are winnowed from deep nonsense.

CARL SAGAN

CONTENTS

Cover

Title Page

Copyright

Dedication

Epigraph

Prologue: Being Cured

Introduction: The Other 90%

1. Twenty-First-Century Sickness

2. All Diseases Begin in the Gut

3. Mind Control

4. The Selfish Microbe

5. Germ Warfare

6. You Are What They Eat

7. From the Very First Breath

8. Microbial Restoration

Coda: Twenty-First-Century Health

Epilogue: 100% Human

Picture Section

References

List of Illustrations

Index

Acknowledgements

About the Publisher

PROLOGUE
Being Cured

As I walked back through the forest that night in the summer of 2005, with twenty bats in cotton bags hanging around my neck and all manner of insect life dashing for the light of my head torch, I realised my ankles were itching. I had my repellent-soaked trousers tucked into my leech socks, with another pair underneath for good measure. The humidity and drenching sweat, the muddy trails, my fear of tigers, and the mosquitoes were enough to contend with as I made my rounds, collecting bats out of traps in the darkness of the rainforest. But something had got through the barrier of fabric and chemicals protecting my skin. Something itchy.

At twenty-two, I spent what turned out to be a life-changing three months living in the heart of Krau Wildlife Reserve in peninsular Malaysia. During my biology degree, I had become fascinated by bats, and when the opportunity came up to work as a field assistant to a British bat scientist, I signed up immediately. Encounters with leaf monkeys, gibbons and an extraordinary diversity of bats made the challenges of sleeping in a hammock and washing in a river popu-lated by monitor lizards seem worthwhile. But, as I was to discover, the trials of life in a tropical forest can live on far beyond the experience itself.

Back at base camp, in a clearing next to the river, I peeled back the layers to reveal the source of my discomfort: not leeches, but ticks. Perhaps fifty or so, some embedded in my skin, others crawling up my legs. I brushed the loose ones off, and turned back to the bats, measuring and recording scientific data about them as quickly as I could. Later, with the bats released, and the forest pitch-black and buzzing with cicadas, I zipped myself into my cocoon-like hammock, and, with a pair of tweezers, under the light of my head torch, I removed every last tick.

A few months later, at home in London, the tropical infection introduced to me by the ticks took hold. My body seized up and my toe bone swelled. Weird symptoms came and went, as did various blood tests and hospital specialists. My life would be put on hold for weeks or months at a time as bouts of pain, fatigue and confusion gripped me without warning, then released me again as if nothing had happened. By the time I was diagnosed many years later, the infection was entrenched, and I was given a course of antibiotics long and intense enough to cure a herd of cattle. At last, I was going to be myself again.

But, unexpectedly, the story did not end there. I was cured, but not just of the tick-borne infection. Instead, it seemed I had been cured as if I were a piece of meat. The antibiotics had worked their magic, but I began to suffer new symptoms, as varied as before. My skin was raw, my digestive system was choosy, and I was prone to picking up every infection going. I had a suspicion that the antibiotics I had taken had not only eradicated the bacteria that plagued me, but also those that belonged in me. I felt like I had become inhospitable to microbes, and I learnt just how much I needed the 100 trillion friendly little creatures who had, until recently, called my body their home.

You are just 10 per cent human.

For every one of the cells that make up the vessel that you call your body, there are nine impostor cells hitching a ride. You are not just flesh and blood, muscle and bone, brain and skin, but also bacteria and fungi. You are more ‘them’ than you are ‘you’. Your gut alone hosts 100 trillion of them, like a coral reef growing on the rugged seabed that is your intestine. Around 4,000 different species carve out their own little niches, nestled among folds that give your 1.5-metres-long colon the surface area of a double bed. Over your lifetime, you will play host to bugs the equivalent weight of five African elephants. Your skin is crawling with them. There are more on your fingertip than there are people in Britain.

Disgusting, isn’t it? We are surely too sophisticated, too hygienic, too evolved to be colonised in this way. Shouldn’t we have shunned microbes, like we did fur and tails, when we left the forests? Doesn’t modern medicine have the tools to help us evict them so that we can live cleaner, more healthy, independent lives? Since the body’s microbial habitat was first discovered we have tolerated it, as it seemed to do us no harm. But unlike the coral reefs, or the rainforests, we have not thought to protect it, let alone to cherish it.

As an evolutionary biologist, I am trained to look for the advantage, the meaning, in the anatomy and behaviour of an organism. Usually, characteristics and interactions that are truly detrimental are either fought against, or lost in evolutionary time. That set me thinking: our 100 trillion microbes could not call us home if they brought nothing to the party. Our immune systems fight off germs and cure us of infections, so why would they tolerate being invaded in this way? Having subjected my own invaders, both good and bad, to months of chemical warfare, I wanted to know more about the collateral damage I had caused.

As it turned out, I was asking this question at exactly the right time. After decades of slow-paced scientific attempts at learning more about the body’s microbes by culturing them on Petri dishes, technology had finally caught up with our curiosity. Most of the microbes living inside us die when they are exposed to oxygen, because they are adapted to an oxygen-free existence deep in our guts. Growing them outside the body is difficult, and experimenting with them is even harder.

But, in the wake of the seminal Human Genome Project, in which every human gene was decoded, scientists are now capable of sequencing massive quantities of DNA extremely quickly and cheaply. Even our dead microbes, expelled from the body in the stool, could now be identified because their DNA remained intact. We had thought our microbes didn’t matter, but science is beginning to reveal a different story. A story in which our lives are intertwined with those of our hitchhikers, where our microbes run our bodies, and becoming a healthy human is impossible without them.

My own health troubles were the tip of the iceberg. I learnt of the emerging scientific evidence that disruptions to the body’s microbes were behind gastrointestinal disorders, allergies, autoimmune diseases, and even obesity. And it wasn’t just physical health that could be affected, but mental health as well, from anxiety and depression to obsessive–compulsive disorder (OCD) and autism. Many of the illnesses we accept as part of life were not, it seemed, down to flaws in our genes, or our bodies letting us down, but were instead newly emerging conditions brought on by our failure to cherish the long-held extension to our own human cells: our microbes.

Through my research, I hoped not only to discover what damage the antibiotics I had taken had done to my microbial colony, but how it had made me unwell, and what I could do to restore the balance of microbes I had harboured before the night of the tick bites, eight years earlier. To learn more, I signed up to take the ultimate step in self-discovery: DNA sequencing. But rather than sequence my own genes, I would have the genes of my personal colony of microbes – my microbiome – sequenced. By knowing which species and strains of bacteria I contained, I would have a starting point for self-improvement. Using the latest understanding of what should be living in me, I might be able to judge just how much damage I had done, and attempt to make amends. I used a citizen-science programme, the American Gut Project, based at the laboratory of Professor Rob Knight at the University of Colorado, Boulder. Available to anyone around the world for a donation, the AGP sequences samples of microbes from the human body to learn more about the species we harbour and their impact on our health. By sending a stool sample containing the microbes from my own gut, I received a snapshot of the ecosystem that called my body home.

After years of antibiotics, I was relieved to find I had any bacteria living in me at all. It was pleasing to see that the groups I harboured were at least broadly similar to those in other American Gut Project participants, and not the microbial equivalent of mutant creatures eking out a living on a toxic wasteland. But, perhaps predictably, the diversity of my bacteria seemed to have taken a beating. At the highest level of the taxonomic hierarchy, the diversity was relatively low, looking a bit bipartisan compared with the guts of other people. Over 97 per cent of my bacteria belonged to the two major bacterial groups, compared with around 90 per cent making up these two groups in the average participant. Perhaps the antibiotics I had taken had killed off some of the less abundant species, leaving me with only the hardy survivors. I was intrigued to know whether this loss might be related to any of my more recent health troubles.

But, just as comparing a tropical rainforest and an oak woodland by looking at the proportion of trees to shrubs, or birds to mammals, reveals little about how both ecosystems function, comparing my bacteria at such a broad scale may not tell me all that much about the health of my inner community. At the other end of the taxonomic hierarchy were the genera and species that I contained. What could the identities of the bacteria that had either clung on throughout my treatment, or returned since it ended, reveal about my current state of health? Or perhaps more pertinently, what did the absence of species that might have fallen victim to the chemical warfare I had unleashed on them, mean for me now?

As I embarked on learning more about us – myself and my microbes – I resolved to put what I learnt into practice. I wanted to get back on their good side, and I knew I needed to make changes to my life to restore a colony that would work in harmony with my human cells. If my most recent symptoms were stemming from the collateral damage I had inadvertently inflicted upon my microbiota, perhaps I could reverse it and rid myself of the allergies, the skin problems and the near-constant infections? My concern wasn’t just for myself, but for the children I hoped to have in the coming years. As I would pass on not only my genes, but also my microbes, I wanted to be sure I had something worth giving.

I resolved to put my microbes first, altering my diet to better suit their needs. I planned to have a second sample sequenced after my lifestyle changes had had a chance to take effect, in the hope that my efforts might be evident from the change in the diversity and balance of the species I play host to. Most of all, I hoped that my investment in them would pay dividends, by unlocking the door to better health and happiness.

INTRODUCTION
The Other 90%

In May 2000, just weeks before the announcement of the first draft of the human genome, a notebook began circulating among the scientists sitting at the bar in Cold Spring Harbor Laboratory in New York State. Excitement was building about the next phase of the Human Genome Project, in which the DNA sequence would be split into its functional parts – genes. The notebook contained a sweepstake: the guesses of the best-informed group of people on the planet concerning one intriguing question: How many genes does it take to build a human?

Senior research scientist Lee Rowen, who was leading a group working on decoding chromosomes 14 and 15, sipped her beer as she pondered the question. Genes make proteins, the building blocks of life, and the sheer complexity of humans made it seem probable that the number would be high. Higher than the mouse, surely, which was known to have 23,000 genes. Probably also higher than the wheat plant, with 26,000 genes. And, no doubt, far higher than ‘The Worm’, a favourite laboratory species of developmental biologists, with its 20,500 genes.

Despite guesses averaging over 55,000 genes, and topping 150,000, Rowen’s understanding of the field meant she was inclined to go low. She placed a bet of 41,440 that year, and followed it up a year later with a second bet of just 25,947 genes. In 2003, with the true gene number only just emerging from the nearly finished sequence, Rowen was awarded the prize. Her entry was the lowest of all 165 bets, and the latest gene count had just dropped even lower than any scientist had ever predicted.

With just shy of 21,000 genes, the human genome is hardly bigger than that of The Worm (C. elegans). It is half the size of the rice plant, and even the humble water flea outstrips it, with 31,000 genes. None of these species can talk, create, or think intelligent thoughts. You might think, as the scientists entering the Genesweep pool did, that humans would have a great many more genes than grasses and worms and fleas. After all, genes make proteins, and proteins make bodies. Surely a body as complex and sophisticated as a human’s would need more proteins, and therefore more genes, than a worm’s?

But these 21,000 genes are not the only genes that run your body. We do not live alone. Each of us is a superorganism; a collective of species, living side-by-side and cooperatively running the body that sustains us all. Our own cells, though far larger in volume and weight, are outnumbered ten to one by the cells of the microbes that live in and on us. These 100 trillion microbes – known as the microbiota – are mostly bacteria: microscopic beings made of just a single cell each. Alongside the bacteria are other microbes – viruses, fungi and archaea. Viruses are so small and simple that they challenge our ideas of what even constitutes ‘life’. They depend entirely on the cells of other creatures to replicate themselves. The fungi that live on us are often yeasts; more complex than bacteria, but still small, single-celled organisms. The archaea are a group that appear to be similar to bacteria, but they are as different evolutionarily as bacteria are from plants or animals. Together, the microbes living on the human body contain 4.4 million genes – this is the microbiome: the collective genomes of the microbiota. These genes collaborate in running our bodies alongside our 21,000 human genes. By that count, you are just half a per cent human.

A simplified tree of life, showing the three domains and four kingdoms of Domain Eukarya.

We now know that the human genome generates its complexity not only in the number of genes it contains, but also through the many combinations of proteins these genes are able to make. We, and other animals, are able to extract more functions from our genomes than they appear to encode at first glance. But the genes of our microbes add even more complexity to the mix, providing services to the human body that are more quickly evolved and more easily provided by these simple organisms.

Until recently, studying these microbes relied on being able to culture them on Petri dishes filled with broths of blood, bone marrow, or sugars, suspended in jelly. It’s a difficult task: most of the species living in the human gut die on exposure to oxygen – they simply haven’t evolved to tolerate it. What’s more, growing microbes on these plates means guessing what nutrients, temperature and gases they might need to survive, and failing to figure this out means failing to learn more about a species. Culturing microbes is the equivalent of checking who’s turned up for class by running down a register – if you don’t call someone’s name, you won’t know if they are there. Today’s technology – the DNA sequencing made so fast and cheap by the efforts of those working on the Human Genome Project – is more like requesting ID at the door; even those that you weren’t expecting can be accounted for.

As the Human Genome Project came to a close, expectations were high. It was seen as the key to our humanity, God’s greatest work, and a sacred library holding the secrets of disease. When the first draft was completed in June 2000, under budget at $2.7 billion and several years early, the US President, Bill Clinton, declared:

Today, we are learning the language in which God created life. We are gaining ever more awe for the complexity, the beauty, the wonder of God’s most divine and sacred gift. With this profound new knowledge, humankind is on the verge of gaining immense new power to heal. Genome science will have a real impact on all our lives – and even more, on the lives of our children. It will revolutionise the diagnosis, prevention and treatment of most, if not all, human diseases.

But in the years that followed, science journalists the world over began expressing their disappointment in the contribution that knowledge of our complete DNA sequence had made to medicine. Although decoding our own instruction book is an irrefutable achievement that has made a difference to treatments for several important illnesses, it has not revealed as much as we expected about the causes of many common diseases. Searching for genetic differences in common to people with a particular disease did not throw up straightforward links for as many conditions as had been expected. Often, conditions were weakly linked to tens or hundreds of gene variants, but rarely was it the case that possessing a given gene variant would lead directly to a given disease.

What we failed to appreciate at the turn of the century was that those 21,000 genes of ours are not the full story. The DNA-sequencing technology invented during the Human Genome Project enabled another major genome-sequencing programme, but one that received far less media attention: the Human Microbiome Project. Rather than looking at the genome of our own species, the HMP was set up to use the genomes of the microbes that live on the human body – the microbiome – to identify which species are present.

No longer would a reliance on Petri dishes and an over-abundance of oxygen hold back research into our cohabiters. With a budget of $170 million and a five-year programme of DNA sequencing, the HMP was to read thousands of times as much DNA as the HGP, from microbes living in eighteen different habitats on the human body. It was to be a far more comprehensive survey of the genes that make a person, both human and microbial. At the conclusion of the Human Microbiome Project’s first phase of research in 2012, not one world leader made a triumphant statement, and only a handful of newspapers featured the story. But the HMP would go on to reveal more about what it means to be human today than our own genome ever has.

Since life began, species have exploited one another, and microbes have proved themselves to be particularly efficient at making a living in the oddest of places. At their microscopic size, the body of another organism, particularly a macro-scale backboned creature like a human, represents not just a single niche, but an entire world of habitats, ecosystems and opportunities. As variable and dynamic as our spinning planet, the human body has a chemical climate that waxes and wanes with hormonal tides, and complex landscapes that shift with advancing age. For microbes, this is Eden.

We have been co-evolving side-by-side with microbes since long before we were humans. Before our ancestors were mammals even. Each animal body, from the tiniest fruit fly to the largest whale, is yet another world for microbes. Despite the negative billing many of them get as disease-causing germs, playing host to a population of these miniature life-forms can be extremely rewarding.

The Hawaiian bobtail squid – as big-eyed and colourful as any Pixar character – has diminished a major threat to its life by inviting just one species of bioluminescent bacterium to live in a special cavity in its underbelly. Here, in this light organ, the bacteria, known as Aliivibrio fischeri, convert food into light, so that viewed from below, the squid glows. This obscures its silhouette against the moonlit ocean surface, camouflaging it from predators approaching from beneath. The squid owes this protection to its bacterial inhabitants, and they owe the squid for their home.

While housing a microbial light source might seem a particularly inventive way to increase one’s life chances, squid are far from the only animal species who owe their lives to their body’s microbes. Strategies for living are many and varied, and cooperation with microbes has been a driving force of the evolutionary game since living beings with more than one cell first evolved, 1.2 billion years ago.

The more cells an organism is made of, the more microbes can live on it. Indeed, large animals such as cattle are well known for their bacterial hospitality. Cows eat grass, yet using their own genes they can extract very little nutrition from this fibrous diet. They would need specialist proteins, called enzymes, that can break down the tough molecules making the cell walls of the grass. Evolving the genes that make these enzymes could take millennia, as it relies on random mutations in the DNA code that can only happen with each passing generation of cows.

A quicker way to acquire the ability to get at the nutrients locked away in grass is to outsource the task to the specialists: microbes. The four chambers of the cow’s stomach house populations of plant-fibre-busting microbes numbering in their trillions, and the cud – a ball of solid plant fibre – travels back and forth between the mechanical grinding of the cow’s mouth and chemical breakdown by the enzymes produced by microbes living in the gut. Acquiring the genes to do this is quick and easy for microbes, as their generation times, and therefore opportunities for mutations and evolution, are often less than a day.

If bobtail squid and cows can both benefit from teaming up with microbes, is it possible that we humans do as well? We may not eat grass and have a four-chambered stomach, but we do have our own specialisations. Our stomachs are small and simple, there just to mix the food up, throw in some enzymes for digestion, and add a bit of acid to kill unwelcome bugs. But travel on, through the small intestine, where food is broken down by yet more enzymes and absorbed into the blood through the carpet of finger-like projections that give it the surface area of a tennis court, and you reach a cul-de-sac, more of a tennis ball than a tennis court, that marks the beginning of the large intestine. This pouch-like patch, at the lower right corner of your torso, is called the caecum, and it is the heart of the human body’s microbial community.

Dangling from the caecum is an organ that has a reputation for being there simply to cause pain and infection: the appendix. Its full title – the vermiform appendix – refers to its worm-like appearance, but it could equally be compared to a maggot or a snake. Appendices vary in length from a diminutive 2 cm to a distinctly stringy 25 cm, and, rarely, a person may even have two of them, or not one at all. If popular opinion is to be believed, we would be better off without one at all, since for over one hundred years they have been said to have no function whatsoever. In fact, the man who finally put the anatomy of animals into an elegant evolutionary framework is apparently responsible for this persistent myth. Charles Darwin, in The Descent of Man, a follow-up to On the Origin of Species, included the appendix in a discussion of ‘rudimentary’ organs. Having compared it with the larger appendices of many other animals, Darwin felt that the appendix was a vestige, steadily withering away as humans changed their diets.

With little to indicate otherwise, the vestigial status of the appendix was barely questioned for the next 100 years, and the perception of its uselessness is only enhanced by its tendency to cause a nuisance. So pointless has the medical establishment assumed it to be, that by the 1950s, removing it became one of the most common surgical procedures carried out in the developed world. An appendectomy was even often tacked on as a bonus during other abdominal surgery. At one point, a man stood a one in eight chance of having his appendix removed during his lifetime, and for a woman, the odds were one in four. About 5–10 per cent of people get appendicitis at some stage in their life, usually in the decades before they have children. Untreated, nearly half of these people would die.

This presents a conundrum. If appendicitis were a naturally occurring disease, frequently causing death at a young age, the appendix would be quickly eliminated by natural selection. Those with appendices large enough to become infected would die, most often before reproducing, and would therefore fail to pass on their appendix-forming genes. Over time, fewer and fewer people would have an appendix, and eventually it would be lost. Natural selection would have preferred those without one.

Darwin’s assumption that it was a relic of our pasts might have carried some weight, were it not for the often fatal consequences of possessing one. There are two explanations, therefore, for the persistence of the appendix, and they are not mutually exclusive. The first is that appendicitis is a modern phenomenon, brought on by some environmental change. Thus, even a pointless organ could have persisted in the past simply by keeping out of trouble. The other is that the appendix, far from being a malign vestige of our evolutionary past, actually has health benefits that outweigh its dark side, making its presence worthwhile despite the risk of appendicitis. That is, natural selection prefers those of us who possess one. The question is, why?

The answer lies in its contents. The appendix, which averages about 8 cm in length and a centimetre across, forms a tube, protected from the flow of mostly digested food passing its entrance. But rather than being a withered strand of flesh, it is packed full of specialised immune cells and molecules. They are not inert, but rather an integral part of the immune system, protecting, cultivating and communicating with a collective of microbes. Inside, these microbes form a ‘biofilm’ – a layer of individuals that support one another and exclude bacteria that might cause harm. The appendix, far from being functionless, appears to be a safe-house that the human body has provided for its microbial inhabitants.

Like a nest egg stashed away for a rainy day, this microbial stockpile comes in handy at times of strife. After an episode of food poisoning or a gastrointestinal infection, the gut can be repopulated with its normal inhabitants, which have been lurking in the appendix. It might seem like an excessive bodily insurance policy, but it is only in recent decades that gut infections such as dysentery, cholera and giardiasis have been all but eliminated in the Western world. Public sanitation measures, including sewerage systems and water-treatment plants, have prevented such illnesses in developed countries, but globally, one in five of all childhood deaths are still caused by infectious diarrhoea. For those who do not succumb, possession of an appendix likely hastens their recovery. It is only in a context of relatively good health that we have come to believe that the appendix has no function. Indeed, the negative consequences of undergoing an appendectomy have been masked by the modern, sanitised lifestyle.

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?

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