I, Superorganism E-Book

Jon Turney

• Herausgeber: Icon Books
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 457

Veröffentlichungsjahr: 2015

Beschreibung

Every human body carries a secret cargo: a huge population of microorganisms living in the mouth, on the skin, in the gut. They help digest our food. They make essential vitamins. They break down toxins and metabolise drugs. They exert an invisible influence on our hormones, our immune systems, perhaps even our brains. This is the human microbiome – a living, shifting system of previously unimagined importance and complexity. In this first book-length account of this new realm of human biology, award-winning science writer Jon Turney explores the microbiome in detail, charting its birth and development, investigating how it works, and assessing its many implications for our health, including its potential to shed new light on conditions such as bowel diseases, cancer, allergies and asthma. He considers the potential impacts of our modern disinfectant and antibiotic obsessions, and ponders a future of designer microbiomes and mood-altering probiotics. This book will make you think again about your relationship with your body, your habits – even your sense of who and what you are – as it reveals what it means to be a 21st century superorganism.

Leseprobe

I, SUPERORGANISM

LEARNING TO LOVE YOUR INNER ECOSYSTEM

JON TURNEY

Published in the UK in 2015 by Icon Books Ltd, Omnibus Business Centre, 39–41 North Road, London N7 9DP email: [email protected]

Sold in the UK, Europe and Asia by Faber & Faber Ltd, Bloomsbury House, 74–77 Great Russell Street, London WC1B 3DA or their agents

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ISBN: 978-184831-822-9

Text copyright © 2015 Jon Turney

The author has asserted his moral rights.

No part of this book may be reproduced in any form, or by any means, without prior permission in writing from the publisher.

Typeset in Garamond by Marie Doherty

Printed and bound in the UK by Clays Ltd, St Ives plc

The contents of this book are based on the best information available to the author at the time of writing. The book does not constitute medical or professional advice – always consult a doctor or appropriate professional where necessary. Neither the author nor the publisher shall be liable or responsible for any loss or damage allegedly arising from any information or suggestion in this book.

Contents

Introduction: Organism, meet superorganism

Chapter 1Strange new world

Chapter 2Microbes aren’t us – or are they?

Chapter 3Invisible lives

Chapter 4Microbes, microbes, everywhere

Chapter 5The big one

Chapter 6A microbiome is born

Chapter 7Working together

Chapter 8There goes the neighbourhood

Chapter 9Gut feelings

Chapter 10Viruses are us, too

Chapter 11Civilising the microbiome

Chapter 12I, superorganism?

Acknowledgements

Notes

Bibliography

Further reading

Index

‘with increasing knowledge, revulsion sometimes yields to fascination’ —Theodor Rosebury, Life on Man

Introduction Organism, meet superorganism

Who am I? The mirror reminds me. Here I stand, unclothed (don’t worry, I’ll look so you don’t have to). I see a pale, upright biped. White, middle-aged, male. Tall for a human, with a slight tendency to stoop. I’ve had a medically charmed life so far, as baby-boomers in the West may enjoy. Not too many signs of wear and tear yet. If I recall the image in the glass from 30 years ago, say, the current version of me has a thickening waist – and, I notice, toenails – and thinning hair. Otherwise I seem to look much the same.

That continuity, this body, is part of my sense of self. A human body, pretty large by the standards of Earth creatures, is a marker of individuality. I do not mean that in any philosophical sense – I am an autonomous human subject and this is my body. Or perhaps I do. I do not mean it, anyway, in any sense of the individual ‘me’ as unique.

But I do feel, for what it’s worth, that the infinitesimally tiny fraction of the universe’s matter and energy that is me can be separated out. The portion of biomass that I haul around – or that hauls me around – has the usual apertures and orifices where stuff goes in or comes out. If I want to stay alive, that has to happen with some regularity. But it looks to me as if this body has a pretty clear boundary. It seems clearly distinct from the rest of the world. I do experience conscious connections with other people, mainly because I have language. Today I am connected to thousands more, through our technologies. But the ‘I’ that is connected is also embodied. I am a biological entity; a human animal; an organism.

I have always felt that this organismic me, now one of 7 billion or so of the type, is a vessel built for a solo voyage. Artists and poets share that intuition. As Orson Welles said, we are born alone, we live alone, we die alone. He went on to say that love and friendship can still make life worthwhile – which is true. But the premise, it turns out, is entirely wrong. Science, quietly at first but with increasing insistence over the last decade or so, begs to differ. You, like me, are an individual human. But we’ve all got company. Lots of company.

Look again

Ever looked inside your mouth – not with a mirror, but a microscope? Chances are you did this at school. If you don’t remember, here’s what you do. Gently scrape the inside of your cheek. Use a clean cotton swab if you have one, the flat end of a toothpick or even the end of your fingernail if you don’t. Dab the goo on a microscope slide, add a drop of methylene blue dye, top with a cover slip, slide onto the microscope stand and … focus.

Even at low power, say ten times magnification, you’ll now see some cells. They are flat – and not just because they are squashed on the slide. Flat is normal for cells of this type, from the tissue known as squamous epithelium. You can see the nucleus, which looks after the hereditary instructions (the dye stains the DNA, among other things), separate from the rest, the cytoplasm. A single cell at this magnification doesn’t look that impressive. But every one is a reminder of an astonishing fact. Each of us is a vast, highly organised coalition of many such cells, tiny morsels of a much bigger organism, which can usually grow and divide in their own right. Far beneath the everyday scale of an upright mammal are the elementary particles of life. Growing and dividing from a single cell, a newly fertilised egg, they eventually number in the trillions,a and play their part in maintaining the highly organised assembly that is me, or you.

But there’s more. Up the magnification, and there will be small blue-dyed dots under and around the large, blobbier-looking epithelial cells. They are bacteria. They will be there even if you used the clean swab rather than your finger. Your mouth – cheeks, tongue, teeth, gums and all – is full of them. It is warm and moist in there, and you keep adding nutrients, on their way to the stomach. What’s not to like? You would find them, too, on every other surface of your body, including the internal ones like the intestine.

Until very recently, few gave much thought to the bacteria and other microbes to whom we give house room. But they have been there all through our evolution. Bacteria got here first. They are woven into our lives more closely than we ever imagined until recently. They congregate in complex, shifting communities that are shaped by, and help shape, the lives of our other cells. They carry out a surprisingly large portion of our digestion. They make essential vitamins and other molecules. They break down toxins and metabolise drugs. They exert an invisible influence on our hormones, our immune systems and perhaps even our brains. And they crowd out other, potentially harmful organisms by filling the niches that they would occupy if they could. We would miss our many, many microbes badly if they were not there.

Scientists call the whole ensemble of microbes that make their living as fellow travellers with some larger organism the microbiota, or more often these days the microbiome.b My microbiome is as alive as I am. It develops, responds, adapts as life goes on, just as my own body cells do. So does yours. What that means for how our lives play out, and how we should think of the enlarged cellular community that constitutes a person, is just beginning to become clear – with the aid of techniques more powerful than any microscope.

Show us your DNA

We have been looking at microscopic organisms for 300 years or so. But very recently we started looking at them in a new way. The first human genome – the complete set of genes in each of a person’s body cells – was completely sequenced a bit over a decade ago. That achievement paved the way for routine, large-scale sequencing. There is still lots to work out about our genes and how they operate, but what we do certainly know is how to sequence large amounts of DNA. That has given us an amazing new window on to the microbial world.

Biologists used to work on microbes – mainly bacteria and viruses – one at a time. Most of what we know about DNA and how genes work comes from studies that began in bacteria, especially one that became a laboratory workhorse: E. coli. ‘What’s true for E. coli is true for an elephant’ was a tongue-in-cheek slogan heard among the pioneers of molecular genetics in the 1960s, in recognition of how much they had invested in one small organism.

That research in turn was founded on good microbiological practice first laid down in the 19th century. Generations of 20th-century molecular geneticists worked with colonies of bacteria grown up from a single cell in a shallow dish layered with nutrient jelly. That is not how microbial life is lived outside the lab, and it works only for a minority of types of microbe. Bacteria, like us, normally live in a world that everywhere teems with other life. We knew that, in theory. But the new-style DNA analysis has been revelatory, especially in showing how varied and complex microbial life is.

Nowadays it does not matter if you have a pure sample of anything. Just take whatever mixed-up matter you can lay hands on, extract the genetic material and work on all of it at once. This is the new science of ‘metagenomics’. It begins with taking a bunch of stuff that may contain living cells, or maybe viruses, cutting up all the DNA, and sequencing it. Seawater, soil, and shit are good things to sample. What usually comes out of this rough-and-ready analysis is a huge higgledypiggledy list of genes. Then the researchers try to figure out what they all are, and where they come from.

This genetic window offers a startling new view of the complement of cells, human and microbial, that make up the person I see in the mirror. It is a quintessentially modern view. The kilo or so of bacteria in my colon, for example, are a considerable cell mass. They are also a great store of information.

How big a store? The answer comes as a jolt if you think that the self you can inspect in the mirror is you. Most of your genes do not really belong to you at all.

The Human Genome Project focused attention on our own chromosomes, the carefully packaged lengths of double-stranded DNA that reside in the nucleus of each human cell and help to define our individuality. They turned out to have 24,000 genes altogether. That was a lot fewer than the figure of 100,000 or so that was regularly quoted before we looked properly. Still, it appears to be enough to support a complex organism with trillions of cells divided into around 200 different cell types.

The way our microbes organise their genes is quite different from the one-size-fits-all approach that the cells in a large, multicellular creature adopt. First, the number of microbial cells is higher. Counting is hard, and calls for adding up population estimates for guts, mouths, noses and vaginas as well as sampling skin. Published figures for the number of bacterial cells we carry range from 30 to 400 trillion. If the total population of cells in a person decided what happened in our life by majority vote, the bacteria would probably win.c

But that is only half the story. How many microbial genes are there? Again it is hard to be precise. These microbial cells do not share a genome, and there are many different species involved. But the DNA tells us that the total number of genes in one typical human microbiome is around 2 million. That is a hundred times as many as we maintain in our own cells. Moreover, as you move through a human population the number of our genes stays the same. Every human microbiome is different, though, so the number of microbial species, and genes, keeps going up as more samples are analysed. The number of genes that have ever been registered in any human microbiome is now five times higher than in any single individual’s complete microbial complement. Let me spell that out again. Human cells have 24,000 genes. All the microbes that live on and in human beings incorporate 10 million of them.d

Genes allow organisms to do things, and this is an enormously rich genetic resource. We are just beginning to find out what it can do for us. We already know that our personal load of bacteria help digest our food, process drugs, and activate our immune systems. They are involved in a raft of diseases, especially those affecting the bowel. Indirectly, they may affect whether we get fat, develop cancer, or even suffer high blood pressure, heart disease or strokes. They seem to affect asthma. And there are hints that the precise make-up of the bacterial population in our guts can even affect brain development and behaviour.

This is just the start, though. Many of the microbial genes already found are of unknown function. We are still finding new species, new genes and new interactions. As well as bacteria in the microbiome, there are single-celled organisms of other kinds. There are numerous fungi that find humans congenial hosts. And there is a largely uncatalogued array of viruses, which add more depth to the genetic reservoir. We are covered in life, awash with it, saturated with it, in such variety that it is hard to take in.

As well as an impressive genetic resource, we are also finding that our microbiome is the wellspring of a vast, largely unmapped reservoir of human diversity. The range of species and strains of bacteria can differ wildly in different people. Even close relatives or those who live together maintain some microbial differences. And we all have different microbial populations in different parts of the body, from the armpits to the anus. They change over time, as we eat different foods, grow older, move from place to place, swab, scrub, or disinfect ourselves, or swallow antibiotics. For once, science really has revealed a new world. This one is in inner space. It is part of us.

What about me?

Sometimes science advances because of some radical conceptual breakthrough, from a Newton or an Einstein. More often, it moves ahead more slowly, as small observations alter the picture we are building of reality bit by bit. What is happening now is different again. It is one those times when a sudden leap in observational power transforms the view – and itself leads to a kind of scientific revolution.

That is exciting, fascinating, and, as the news filters through to the rest of us, a bit puzzling. I want to know what the emerging picture of the microbiome means for me. It seems amazing, when science recovers signals from the origins of the universe or probes the ultimate constituents of matter, that the profusion of life we carry, and have always carried, has largely eluded us for so long – hidden in plain sight, almost. If science is one of the ways in which we can know ourselves more completely, we have taken a long while to get round to this part of ourselves.

I am usually wary of stories about what this or that scientific revolution means for us. What do the latest findings in cosmology, particle physics or earth science mean for humanity – or even (and I am never sure what to make of this phrase) ‘what it means to be human’? But the revolution in understanding the human microbiome is actually about us, and about me. It seems fair to ask what it all means, if not for what it means to be human then certainly for what it is like to be alive in the world.

There is no single answer. Exploring this world is changing our view of many parts of our lives. The flow of new scientific publications about our innumerable microscopic companions is a steady stream now growing towards a flood. More and more labs are joining in the work of finding out who’s there and what they are up to. A crude measure gives one indication of how many. Google Scholar, which searches academic journal papers, finds just fifteen hits for ‘microbiome’ in 1995, and still a mere 30 five years later. There was a slight increase, to 76, by 2005, then an explosion of results and discussion: 2,190 papers in 2010, rising to 9,300 by 2013. At the moment, following microbiome research is not so much like keeping moving goalposts in view as tracking a rocket accelerating off the launch pad.

All this new research will change the way we tackle lots of problems, especially medical problems. It will change how we think of ourselves. We are still upright primates, who share a common ancestor with chimps and have chattered our way to a new kind of culture, technology and civilisation we are proud to call human. But now we look a little different. We have, some suggest, a whole new organ to look after – a microbiome. Alternatively, we are walking, talking bioreactors, wearing thousands of other species, and incubating thousands more in our guts. Then again, the whole assembly can be described as an ecosystem, or really a collection of ecosystems, all busily operating at the cellular level. But there is yet another description on offer, which may best sum up what it is to have such a huge collection of microbial fellow travellers. It is a description that recognises that many of them are useful, if not essential. They are not commensals, as biologists refer to cohabiting organisms that simply do no harm (it means ‘sharing a table’ in Latin); they are full, mutually supporting partners, each relying on the other for mutual support. That kind of sharing has another name: symbiosis. Microbiome studies tell us that we have more symbionts than we ever dreamed. And the whole ensemble they compose, along with us, is a superorganism.e

Taking a closer look

This book is my attempt to get to know the new, superorganismic me. That attempt leads down various paths. Superorganismic me is not completely new, so there will be a little history. Researchers are still working out how to study superorganisms, and getting to know my superorganism also means looking into how they uncover its workings. It also shows that focusing on the superorganism is changing science. Exploring the new world of the microbiome calls on many disciplines. Molecular geneticists, microbial ecologists, infectious disease specialists and immunologists are all having new, sometimes halting conversations with one another. All of them are having to talk to the new kids on the block, the bioinformaticians, who manage the databases and the software that help make sense of the microbiome as information. As these exchanges grow richer, the disciplines are changing in the course of the conversation. In particular, immunology is having its own conceptual revolution. Managing this new, carefully maintained consortium that makes up a superorganism turns out to be the reason our immune system evolved in the first place.

The rest of the book takes all this in stages, taking up a series of questions that follow from the big question: what does it mean to be a superorganism? Some of the individual answers are easy to get at, some are still emerging. But even where the details are still work in progress, we already know enough to glimpse the main outlines.

In Chapter 1, I start with an easy one. How did we first become aware of an invisible world of microbes? It is rather marvellous how an apparently simple instrument, the microscope, produced such an enlargement of our view of life, after hundreds of thousands of years during which humans remained oblivious to the smaller dimensions of biology. The first reaction, not surprisingly, was of wonderment. Then heroic scientists invented germ theory, which saved millions of lives but did microbes’ reputation no good at all.

Chapter 2 considers who we are actually sharing our lives with by asking what microbes can do, apart from cause disease. It turns out that even the simple ones, bacteria, can do almost everything multicellular life can do (OK, they don’t write books). Oh yes, and they run the planet, just as they always have done.

Then Chapter 3 asks how we know what we know about the microbiome. Why, for one thing, did it take us so long to realise that it is a vital part of human life? Partly, it is a matter of technique. The dazzling advances in DNA sequencing and genetic analysis are the main things that now afford a new view of the life within us. Now we know it is there, researchers have to devise new methods to study what it actually does, using experimental systems including germ-free mice carefully resupplied with intestinal bacteria in known combinations, artificial ecosystems living quietly in bench-top flasks, and bits of cultured intestine for the bugs to grow on. Many variations on these in a host of labs are helping us build up the new picture of the life on us, and how it lives.

What does this new observational arsenal tell us about who, and how, ‘we’ are? Chapters 4 and 5 ask, simply, ‘who’s there?’ – with the answers coming mainly out of DNA analysis. They vary between people, and depending on where you look. We can think of a complete microbiome, or many microbiomes: on the lips and teeth, on each finger, behind the knees, in the belly button, armpit and groin. I take a look at some of the well-studied sites – the mouth, the skin, the vagina, the lungs. Then in Chapter 5 I take the measure of the lusher pastures of the organ that contains by far the largest microbial community, the gut. This, if anywhere, is the heart of the superorganism.

Now we know something of who we are sharing our lives with, Chapter 6 asks: how did they all get there? There are two different answers to explore. There is the story of how these microbial communities get established in each of us. How is the human microbiome born and how does it develop? And there is a much longer story that we can piece together relating how humans, and all their ancestors, evolved with their microbial accomplices in on the act. What microbiomes do other primates have now? What might our proto-human ancestors have nourished in their guts? That leads to a question that is worrying some microbiome researchers: what changes has modern life, with surgical delivery of babies, antibiotics and fast food, brought to our microbial make-up? Is it possible that we are discovering the really important features of our microbiome at the same time as we are messing it up?

Chapter 7 looks more closely at how all these microbes interact with our own cells, tissues and organs. The immune system is at the heart of this interaction, and it turns out that for us to have useful ideas about how it relates to our microbiome we have to think about it in a new way. The idea that immune cells wage constant war on foreign agents of disease has dominated scientific and popular talk about immunity for decades. How can we reconcile that with the fact that trillions of microbes live inside us? A subtler, constantly shifting, but much more carefully negotiated relationship with microbes now looks like a more realistic picture. This shift in our view of this complex aspect of human being is the most important scientific development arising from microbiome research so far.

Negotiations can be subtle, but still break down. Chapter 8 asks what happens when our microbial colonists tear up their tenancy agreements and set about trashing the joint. The medical effects of alterations in microbial populations are many and varied, and not all well understood, but there are strong pointers to their importance. Changes in our microbiome can be charted in bowel disease, autoimmune conditions, cancers, obesity and more.

Many of the medical conditions linked with the microbiome originate in the gut. But what else can it affect? In particular, can these tiniest components of our superorganism influence the seat of reason, the brain? Chapter 9 moves into this more speculative territory, where the microbiome and the self truly interact, and asks how microbial influences on brain and behaviour might happen, and what we know about possible links with some mental illnesses such as depression.

Bacteria may rule the planet, but they have help. Not from multicellular organisms, but from still simpler entities – viruses. It is estimated there are ten viruses for every bacterium, wherever they are found. Our bodies are no exception. So what do we know about this next layer in our newly uncovered microbiome? Not so much, but Chapter 10 looks at what we do know. Investigation of our viral community is just beginning but may emerge to be just as important as the rest of the microbiome.

It looks as if our microbiome has changed in modern times. Now we know so much more about it, we will probably set about changing it again. Chapter 11 asks what we might decide to do with it. Should we try to restore it to some happier primeval state, or will we be more inventive and refashion our personal ecosystems to suit ourselves? The two methods now on offer are drastic: a faecal transplant to repopulate your bowel; or – gentler but not terribly effective – eating probiotics like yoghurt or sauerkraut. Both can be improved. We already genetically engineer lots of bacteria to suit ourselves. What are the prospects for a designer microbiome later this century?

That leaves just one question for the final chapter – the one I started with: what does it mean to be a superorganism? I cannot offer one big answer to my big question, so I give you lots of small ones. There is some advice, drawn from research, on how to look after your microbiome. I look at where the research is likely to go next, with some as yet unanswered questions and predictions for how answers might be teased out. And I go back to the mirror, to contemplate my new, composite self.

Whichever way we look at it, our bodily life is intimately involved with myriad other small lives. Reading genomes has already revealed a new dimension of our connection with the rest of life, in the genes we share with every other organism. Getting to know our own microbes shows yet another. Will we end up valuing them more, even admiring them? In a world of antibiotics, antisepsis, disinfection, and pasteurisation, will we try to look after them better? Or can a superorganism look after itself?

But before I try to take stock of present-day microbiome science, let’s go back to our very first direct encounter with microbes; an event so recent in history we can date it rather precisely.

Footnotes

a Humans are squishy, and quite variable. So are cells. Result: it is pretty hard to count how many cells the average adult has. You’ll find 10 trillion (10,000,000,000,000) to 100 trillion cited quite often as a rough total. A careful recent estimate, taking into account the volumes and main cell types of different organs, comes out at a bit over 37 trillion – see Bianconi (2013). There are, let us agree, trillions.

b Some use ‘microbiota’ to mean all the microorganisms that live in some defined space, and ‘microbiome’ for the total mass of genetic material they carry. The latter word, coined by geneticist Joshua Lederberg, is usefully (I think) ambiguous. It could refer to a microbe/biome, in the ecological sense where a biome is an interacting collection of different species. The more recent assumption would be that it is made by combining microbe and ‘-ome’ as in genome, proteome, and all the other ‘-omes’ biologists now like to go to. This embodies the tension, or collaboration, between different biological disciplines that contemplate the microbiome. In practice, the terms microbiota and microbiome seem to get used interchangeably, and the latter now often displaces the former. Here, I’ll use ‘microbiome’ in the sense of all the organisms, unless the context makes it clear we’re just talking about DNA.

c Many people cite 100 trillion, compared with 10 trillion body cells – but the bacterial figure is an old estimate based on analysis of a single gram of stool. The precise number does not matter much in what follows. See Smith (2014)

d When I drafted this section, the biggest catalogue listed 9,879,896 genes. See Li (2014). By the time this book went to print, the total had broken 10 million. See Karlsson, (2014).

e A term also proposed in this connection by Joshua Lederberg. Influential chap.

1Strange new world

In 1676 Antonie van Leeuwenhoek, a prosperous Dutch draper, was ten years into one of the most breathtaking observational binges in the history of science. A decade earlier, he pored over the images in Robert Hooke’s celebrated Micrographia (1665), marvelling at its mind-expanding drawings of things never seen before – the multifaceted eye of a fly, the barbs on a bee sting, a louse clasping a human hair.

Inspired, Leeuwenhoek perfected a way of making simple handheld microscopes with minute spherical lenses. He soon saw what Hooke saw, but his superior instruments allowed him to go further. Yes, large organisms had extraordinarily intricate small parts. But there was more going on beneath the level of normal human vision. In a drop of pond water he reported seeing minute single-celled creatures, ‘animalcules’, as he called them. He also saw even smaller creatures, the first of them in water in which he had ground up pepper in an effort to investigate its spicy taste. His claims, included in a 1676 letter to the Royal Society in London – then the best way of informing others of new scientific findings – seemed bizarre, but Hooke returned to his microscopes and confirmed it was true. When the Dutchman’s findings were published in the Society’s Proceedings, Leeuwenhoek’s animalcules were a sensation – the first entrancing glimpse of microbiology.a

Seven years on, and one of his now regular letters to the Royal Society described what he saw when he scraped some of the white matter from between his teeth, ‘as thick as wetted flour’, mixed it with rainwater or spittle, and examined it at high magnification. ‘To my great surprise … the aforesaid matter contained very many small living animals, which moved themselves very extravagantly’.

Motion was, for Leeuwenhoek, the sign of life. He assumed that the many small bodies he saw that did not seem to move were dead matter. Now we know they are just less mobile microbes. But his description of his miniature zoo was still a revelation. There were new kinds of life, invisible and unimagined in all earlier human history. And they were not just out there in the world but living on us.

The insatiably curious Dutchman was full of wonder at the life he had excavated from his own mouth. He described with delight the animalcules’ ‘pleasing motions’, the ways they moved, their variety of shapes, their sheer profusion. The smallest kind had motions that reminded him of ‘a swarm of flies or gnats flying and turning among one another in a small space’. They were so numerous that, he wrote, ‘I believe there might be many thousands in a quantity of water no bigger than a [grain of] sand’.

He found the same inhabitants in the mouths of two ladies – probably his wife and daughter – who, like Leeuwenhoek, cleaned their teeth regularly. Elsewhere he told how when he scraped the teeth of ‘an old gentleman, who was very careless about keeping them clean’, he found, ‘an incredible number of living animalcules, swimming about more rapidly than any I before had seen, and in such numbers, that the water which contained them (though but a small portion of the matter taken from the teeth was mixed in it) seemed to be alive.’ Urging his main conclusion on the Royal Society, he reached again for the right comparison. ‘The number of animals in the scurf of a man’s teeth are so many that I believe they exceed the number of men in a kingdom’.

The revelation that we teem with other life was a sensational exhibit in a catalogue of wonders that the microscope made visible. Along with the telescopic discoveries of Galileo, natural philosophers’ new access to the micro-world was the first thing to establish that science could only gain by using new instruments to go beyond the unaided human senses. At first, not everyone could accept that phenomena hidden from normal vision were real in the same way as those that pass the simpler naked-eye test of ‘seeing is believing’. But the majority believed that science was gaining unprecedented new access to important knowledge about things in the world. In this way, our own microbes had a starring role in the genesis of a recognisably modern way of doing science. That makes it more surprising, somehow, that so much about them remained unknown until so recently.

A molecular menagerie

A little over 300 years after Leeuwenhoek, another curious human scraped his own teeth in search of wildlife. To be accurate, David Relman got his dentist to do it. Instead of discarding the gunk from Relman’s gum crevices when he cleaned his teeth, the dentist put it in sterile collection tubes that the Stanford University researcher had taken with him to the surgery.

Relman had been getting to know new DNA-based techniques to pin down pathogenic bacteria that resisted identification because they refused to grow in culture in the lab. He got to wondering if many species were going overlooked in the complex population mixtures of our normal microbiota for the same reason. Back in the lab he followed normal microbiological routine and set up cultures from the samples. But the key results came from an addition to the routine.1 He used some of the sample for the latest DNA analysis, seeking small pieces of gene sequence characteristic of bacteria and comparing them with known sequences in scientific databanks.

It would have been easy to assume there was nothing much more to find in the pockets between teeth and gums, the subgingival crevices. Over the years, careful bacterial cultivators had logged almost 500 different species of bacteria recovered from this well-populated region of the mouth.

However, working over this one-shot sample from two teeth in one mouth, Relman’s team found 31 new strains of bacteria, identified by their DNA sequences. Another six turned up on the culture plates for a final tally of 37 new kinds – out of 77 in total. Probing bacterial DNA uncovered a whole new dimension of life on us.

In the sober language of the Proceedings of the National Academy of Sciences in 1999, Relman and his colleagues reckoned that ‘Our data suggest that a significant proportion of the resident human bacterial flora remain poorly characterized, even within this well studied and familiar microbial environment’. Or, as he later told the San Francisco Chronicle, ‘We found much, much more with the molecular methods than we found with cultivation. That meant we’d been missing this huge fraction of the microbial world for more than 100 years. That’s a humbling thing. We were playing with half a deck.’

That realisation fuelled a big effort to apply the new technologies of DNA sequencing to microbial samples from as many human body sites as people could poke, scrape, rinse or mop up. Since the millennium, the results of this effort have transformed our picture of the human microbiome, and of how we and a myriad of other species coexist.

But before we look any more closely at the results of these deeper probes into the unseen world, and the questions of meaning with which scientists are now grappling, let us go back. Because in the three centuries between these two enterprising observers of teeth, we learnt a few other things about microbes.

Good guys, bad guys

Leeuwenhoek’s animalcules were fascinating to enlightened society, but seemed mainly a harmless novelty. Some simple experimentation showed that the newly fashionable 17th-century beverage coffee, or a little vinegar, destroyed the life in his field of view. Besides, the idea that creatures so small could have any important effects on their hosts seemed fanciful.

Now we know better. The most significant changes in knowledge came in the 19th century. The germ theory of disease emerged from a combination of a closer investigation of infection with a newly systematised science of microbiology. Contagion, or close contact, had long been associated with the spread of some diseases – but contagion with what? Now it became clear that the crucial contact was with microbes, and it was thus convincing to claim that microscopic life had momentous effects on much larger organisms, with microbes as the main actors in a compelling new explanation of some deadly illnesses.

That also had a big effect on how people thought about microorganisms – two kinds of effects, in fact: scientific and cultural. Both are still very much with us.

Scientifically, part of the legacy of germ theory is a template for how to reason one’s way through causes and effects in the moist, mixed-up world of biology – a template for microbial logic, if you like. It still conditions a lot of our thinking about links between the human microbiome and disease, although, as we will see, it is much harder to apply to the kind of results modern research delivers.

Back in the 19th century, the mysterious organisms that showed up under the microscope were mostly recovered from outside us. Finding them inside mainly happened when people investigated disease. But were the minute creatures recovered from patients or sick animals (and perhaps kept alive as cultures in the lab) causing the symptoms? It is hard to recover this mindset now, but there were reasons to doubt it, and plenty of sceptics. Persuading them that the theory was sound demanded a mass of evidence, and then some clear rules of inference. Then you could build a watertight case.

The germ theory codified those rules. At its simplest, the theory assumed the form of the ‘OGOD’ hypothesis – One Germ, One Disease (this later spawned a close relative, One Gene, One Disease, but that’s another story).2

If OGOD is true, and there are lots of germs about, how can you tell you have found the guilty organism? The rules derive from a general approach to scientific experiments that we now take for granted. It was first described formally in the 19th century by the philosopher John Stuart Mill, who called it the method of agreement and difference. It is the recipe for the perfect experiment that we learn in school. Define all the conditions in some controlled set-up. Vary them one at a time, and see what happens. If variable X causes a change in result Y, then the two are linked in some way. The easy example is working out what caused some of the party to get food poisoning after dining out, by detailing who did, and who did not, eat various things.

For germs, the details came from the German bacteriologist Robert Koch (1843–1910). In the early 1880s, he and his great rival Louis Pasteur had established connections between a few diseases, mostly in animals, and specific infectious agents. Koch wanted to generalise, and to quiet doubters.3 Along with ferociously energetic lab work, and advances in method (he pioneered both the use of microbiological plates instead of flasks of broth for growing colonies, and staining bacteria with dye to aid microscopic identification), he formulated the rules known as Koch’s postulates. There were just four. They translated easily into instructions for demonstrating that a germ really caused a disease. Do these four things and you could be sure you had the answer, and convince everyone else:

Find the microorganism in all the subjects (animals or people) who have the disease, but not in healthy specimens.Isolate the microbe from a diseased organism and grow it in the lab, in culture.Dose a healthy host from the culture, and give it the same disease.Isolate the microbe again from the newly diseased host, and show that it is the same as the one you started with.

None of this was exactly easy, even in experimental animals, let alone human patients (step 2 was especially frustrating). But as methods improved, the four postulates proved their worth, advanced science and earned the gratitude of millions. The great scourge tuberculosis was the test case for these rules. Cholera, typhus, tetanus and plague followed and were all correctly identified as infectious diseases in the next dozen years.

The logic remains sound, provided it is the bug, and only the bug, that is involved in the disease. Many later cases – and quite a few of the classic ones, like tuberculosis – are a good deal more complicated than that. But it remains the often-cited gold standard for working out the links in chains of cause and effect that lead from other organisms to effects on people. Is it helpful in unravelling cause and effect in the complex ecologies of our microbiome? We will have to come back to that question later.

The power of Koch’s logic, though, reinforced the cultural impact of the germ theory. Along with spectacular medical successes, the newly white-coated microbiologists of the 19th century were also illuminating the beneficial roles of microbes. Pasteur, in particular, was interested in fermentation as well as infection. But the fanfare that accompanied demonstrations that microbes could cause disease tended to drown out the news about the good guys that were making cheese or wine. The idea took hold that germs, with a few honourable exceptions, were evil.

Don’t touch – dirty!

Here’s how to open a can of peaches. Remove the label, then scrub the can to remove all traces. Open the lid, and pour the peaches into a bowl. Do NOT let the can touch the bowl.

So staff were instructed in the kitchen of Howard Hughes, pioneering 1930s aviator, film-maker, billionaire recluse and long-time sufferer of obsessive-compulsive disorder.4 The same staff had to wash their hands until they were sore, and wrap them in paper towels when they served Hughes’ meals. There were detailed instructions on how to open the packaging for the towels.

Hughes’ deteriorating mental condition made him an extreme case of a common dread. He was fabulously wealthy, but had brain injuries from several air crashes and had contracted syphilis as a young man. Before any of these things happened he also acquired a lasting fear of germs. His later sad fixation on their dangers is emblematic of a culture preoccupied with an insidious microbial threat to health.

It is easy to see why. The germ theory of disease came when city dwellers were suffering from infections that spread through populations crowded together in unsanitary dwellings. The theory was a colossal success. It won over scientists when Koch, Pasteur and others showed that much-feared illnesses really were caused by tiny organisms. It won over the public by being easy to understand, and because – via vaccination and building proper sewers – it paved the way for their prevention and treatment. Some feared diseases were even eradicated. It remains a cornerstone of the new discipline of public health.

It was, in short, a scientific and medical triumph and the scientists who established it were heroes. Paul De Kruif’s classic The Microbe Hunters, a 1920s popular book by a writer who spent time at the Rockefeller Institute for Medical Research in New York, depicts a series of bacteriological pioneers in that light. It caught the tone of innumerable newspaper profiles and a clutch of later biopics.

They were heroes because they waged war against disease, and triumphed. And germs were the enemy. The celebration of science cemented a powerful association between germs, dirt, and disease. And the practical uses of antiseptics, disinfectants and antibacterials were impressive.

So avoiding germs is not just a matter of eschewing obvious sources of unpleasantness – don’t smear shit on the walls, don’t eat spoiled meat. It calls for dealing with threats that we cannot see.

This linked set of ideas has great power. Germs cause disease, come from dirt, and can spread through contamination you won’t even notice. It contains a core of truth. Some germs really do make people sick. You really can’t see them. And strict precautions will help prevent harm. You really should use the hand sanitiser when you visit the hospital.5

It has also been advertised endlessly, in public health campaigns and by companies making anti-microbial products. They are always on the lookout for new things to disinfect – toilets, bathrooms, kitchens, babies’ bottles, food packaging, telephones, keyboards and, not least, people.

The course of this never-ending campaign is laid out in historian Nancy Tomes’ 1998 book The Gospel of Germs. In the US, public health advocates set the early pace, urging a new standard of cleanliness and hygiene on everyone, but especially housewives and mothers. Later, medical wisdom altered to put less emphasis on sheer cleanliness, more on avoiding contact with infection and preventing those infected from spreading a disease organism. So industry took up the slack.

It was everyone’s duty to wage war on germs, but women were still in the front line. A US Lysol advertisement from 1941 hammers the point home. It seamlessly blends domestic with patriotic duty with a picture of a smiling housewife throwing a military salute. ‘You’re in the army, too,’ runs the ad. ‘Enlist now for the war on germs … A woman with a mop, a pail of water and a bottle of “Lysol” can rout an army of bacteria that cause infection … [Lysol] is the housewife’s home defense.’b

Disinfectant liquids, sprays and wipes are still big business, as a glance down the supermarket aisle shows. Lysol disinfectant spray now comes with ten different scents, but the main selling point remains that it allows you to ‘protect your family from germs they could come into contact with every day’. By killing them.

Many of us in the West have probably become a good deal more casual about using such products in the home, except in the lavatory. I certainly have. But we still recoil from public spaces that are obviously unhygienic. And it only takes the fear of a new or re-emerging disease to bring back old ideas about contagion and contamination.

Tomes ends her history by recounting the reaction to a case early in the AIDS epidemic, in 1984, in which a thirteen-year-old boy became HIV positive after regular blood transfusions for haemophilia.

When news of the diagnosis got out in Kokomo, Indiana, townsfolk refused to shake hands with him or use a toilet he had visited, spread rumours that he spat on vegetables in the greengrocers, and made him and his family sit in a pew out of cough range in church. The family eventually left town when the boy’s decision to return to school brought a bullet through the living room window. Fear of contagion can still turn law-abiding citizens into vigilantes.

Microbes in the lab

While the public wanted to have as little to do with germs as possible, microbial life came under more intense scientific scrutiny. Over the next century, scientists who were happy to get up close and personal with microbes learnt an immense amount about the varieties of minuscule life, and found new ways of probing their inner workings.

That involved adding to the simplest aid to observation, the microscope, with new ways of preparing and staining cells to enhance details, learning how to culture microbes for longer study, and investigating their chemistry and, eventually, their genes.

As microbiology developed in the time after Leeuwenhoek, slowly at first then much more productively from the mid-19th century on, many more subtle techniques came into use. The catalogue of microbes expanded enormously, and more and more species were found in more and more places, from hot springs to ocean depths.

The microbes living with us were part of this steady effort, and it was occasionally suggested that as they are our constant companions, and are so numerous, the vast majority probably do us no harm, and may even do good. (Pasteur had in fact suggested this back in 1885, but the message went unheard then.6)

This view surfaced again many years later, but before the era of DNA analysis, in a prescient book by the 1960s authority on humans and their microorganisms, Theodor Rosebury. After writing a textbook on the subject, he produced a quirky popular book in 1969 called Life on Man.c It is intriguing now partly for the growth in knowledge we have seen in the intervening decades. This was a summary of the state of the art by the man who owned the subject. But apart from describing some species and their prevalence, he had very little to say about the details of the microbiome, especially in the gut. He regarded most of the mass of bacteria we carry as harmless passengers, with a few side-benefits like discouraging colonisation by organisms that can cause disease. He mentions some other suggestions, such as microbes’ possible influence on development of the intestines, but only as matters that deserve further exploration. His summary of important things to know about actual life on humans runs to a scant 24 pages, with the rest of the book taken up with an entertainingly erudite discussion of the anthropology of disgust. It is less than a lifetime ago, but scientifically a totally different era.

Nevertheless, the wider science of microbiology had learnt a great deal about the crowds of smaller species that are part of the living world. As we try to build a picture of what it is like to share a life with a large cohort of microorganisms, let us take a closer look at how they live, focusing on the bacteria.

Footnotes

a Strictly speaking, we must credit Hooke with recording the first glimpse of a microbe: a fungus, which he described as ‘small and variously figured mushrooms’. See Gest (2004). Van Leeuwenhoek was the first person to describe bacteria.

b Not all Lysol ads are so easy to read. Some pre-war magazine ads read like a serious assault on the microbiome, suggesting that Lysol ‘truly cleanses the vaginal canal even in the presence of mucous matter. Thus Lysol acts in a way that makeshifts like soap, salt or soda never can. Appealing daintiness is assured, because the very source of objectionable odour is eliminated.’ And, women, you need to do that to ‘keep you desirable’. It should be said, though, that this ad is less about treating undesirable odour, more a none-too-heavily disguised advertisement for Lysol as a spermicidal douche.

c I see my copy dates from 1976, so I’m giving myself credit for finding the topic interesting back then.

2Microbes aren’t us – or are they?

Consider a single bacterium. Let us make it Escherichia coli. It is briefly airborne and drops on to the jellied surface of a warm, freshly prepared culture dish, rich in nutrients. It can do a variety of things, but its absolute top priority is turning into two bacteria. In these ideal conditions, with room to expand and no competition, that takes as little as twenty minutes.

In that time, it copies all the DNA in its single chromosome, and manufactures enough proteins, cell wall scaffolding, and other cellular constituents to double up everything it needs. Then it divides into two cells, each identical with the original. Twenty minutes later, each of the new cells divides again.

Unconstrained, in a culture dish the size of a planet, this will go on happening. The microbe is so eager to reproduce that the newly duplicated chromosome is already starting a new round of replication before cell division happens. Otherwise the enzymes copying the DNA could not do the job fast enough.

The daunting power of exponential growth leads, mathematically at any rate, to impressive results. In seven hours, there will be a million E. coli, still dividing. In The Andromeda Strain, Michael Crichton has one of the characters say, ‘It can be shown that in a single day one cell of E. coli could produce a super-colony equal in size and weight to the entire planet Earth.’ This is wrong, though: it would take nearly two days.

That never happens because E. coli exhausts the food supply and begins to choke on its own waste. It responds by abandoning division and going into a stationary phase, with many systems shut down, or merely ticking over, until another chance arises for glorious growth.

Speed of reproduction down among the microbes is one of the things that makes them so adaptable. There are many thousands of different bacteria. In any one place, whether it is a deep ocean vent or deep in our guts, the conditions will suit some of them. Others will still be around in much smaller numbers. For now, they have been outdone by their better-adapted competitors. If conditions change, perhaps they will get their chance for an exponential splurge.

The two extremes of fast reproduction and near-complete dormancy help make bacteria versatile, and ubiquitous. They can live practically anywhere, on more or less anything. They have been here practically for ever, and tried every possible metabolic trick. Even if none of them were interested in living on us, it would be worth knowing more about them just to understand the main part of the story of life on Earth. But their story is not separate from ours. It is tempting to think of them as very different. But we have much more in common with our dominant microbes than we once thought.

Dominant species