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MARGINALIA

All Things Small and Great

It's time for a new, conservation-minded view of the microbial communities that live on and in us

Robert L. Dorit

Those who favor the big stomp approach to our interactions with the living world often point to the Bible for justification. As heavyweight sources go, the Bible is hard to beat, and sure enough, there it is, right at the beginning, an injunction to master the earth. God tells our forbears to "Be fruitful, and multiply, and replenish the earth, and subdue it: and have dominion over the fish of the sea, and over the fowl of the air, and over every living thing that moveth upon the earth" (Genesis 1:28). The commandment to "replenish the earth" has long been overshadowed by the drive toward "dominion" over nature. No wonder our ancestors thought the world was at their disposal.

If modern sensibilities recoil at this Biblical passage, it's because times have changed, and recently some commentators have worked hard to interpret the verse out of existence. But before we do so, it is worth remembering that the words were written some 3,000 years ago, at a time when the notion of subduing the natural world was no more than fantasy. The authors of these texts lived a hard, nomadic existence in an arid, inhospitable land. They survived at the mercy of natural forces that they could not understand, let alone control. Dominion over nature must have sounded pretty good.

And yet the authors of Genesis spell out an entirely different relationship to the natural world just a few verses later (2:15; 2:19). Adam is enjoined to dress and to keep the Garden of Eden. And, in his last act as a man alone, Adam gives every living thing a name. Adam the dominator has become Adam the gardener and Adam the taxonomist, a man responsible for curating and tending all of creation. From this point on, plenty of biblical metaphors suggest that a greener, more nurturing approach to other living things, and even to the land itself, may work out better for us in the end.

Our Debt to the Unsung Masses

Fortunately for the planet, we are beginning to realize the folly of acting as though we can have dominion over it. Belatedly, we now acknowledge that we are part of the vast network of interactions that sustain life on this planet (even if we do not always act accordingly). In my lifetime, the notion of conservation as both an ethical and a pragmatic imperative has finally begun to take hold in the collective imagination.

And yet our ecological sensibilities seem to stop at the edge of the visible. For anything alive that we cannot see with the naked eye, we tend to act in keeping with the old 13th-century Crusaders' approach: "Kill them all, and let God sort them out." But the limits of human vision mark no important boundary in the living world, and our fear of the invisible makes no biological sense at all.

Our overuse of antibacterials and antibiotics and the common belief that all microorganisms are harmful reflect our obsession with destroying the unseen. In much of the developed world, and certainly in the United States, we appear determined to make the planet microbe-free. The advertising, pharmaceutical and home-products industries have tried to persuade the public that every microbe is the enemy. But the more we learn about the biological world, the less this perspective makes sense. I argue instead for a new take on the world of the unseen—one that acknowledges the vital and subtle relationships that all plants and animals have with microorganisms. Without the microbial worlds that accompany us, human life would not exist. We should honor these relationships. We should develop a conservation ethic towards the organisms that we cannot see with the naked eye.

We have known for some time how important microorganisms are to the functioning of the planet. Microbes provide vital ecological services: They break down complex molecules into simpler ones, they recycle essential raw materials, they detoxify dangerous chemicals, they sequester CO2. But those are merely the macro-level life-sustaining activities of the microbial world. What we are only now beginning to realize is how much our individual survival depends on the ability of the invisible world to live in and on us. In exchange for room, board and a steady thermostat, our microbial partners—with few exceptions—work tirelessly on our behalf, supplying us with key nutrients and keeping infections and invaders at bay.

Let's start with the numbers: As a first approximation, each of us harbors approximately 10 bacterial cells for every one of our eukaryotic cells—about 5 × 1014 bacterial cells keeping our 50 trillion human cells in business. Although we are, strictly speaking, eukaryotic organisms, we might more accurately be described as a series of linked and densely populated ecosystems, each a rich mixture of interacting eukaryotic, bacterial and archaeal cells. But the importance of single-celled organisms goes far beyond their numbers. Over the past decade, we have discovered how vital to us these bacterial communities really are.

Exposing the Unseen

Why did it take so long to acknowledge our inner microbe? The answer stems, in part, from the fact that most bacteria cannot be grown in the laboratory. Consequently, until recently, microbiologists could not identify—let alone understand—microbes that refused to live in the world of Petri dishes and culture flasks. Until recently, if we had been interested in describing microbial diversity, we would have collected a sample from some well-defined habitat—a hot spring or a water-treatment plant, for instance—then spread that sample on a variety of culture media and waited to see what grew. Yet for a long time, microbiology has known that only a tiny, biased sliver of microbial diversity could be cultured in the lab. As a result, we could guess, but we could never really know, what was out there.

Microbial%20population%20from%20skinClick to Enlarge Image Today the procedure is different. Over the past decade the constraints of the laboratory have been lifted. New methods in molecular biology now make it possible to identify microorganisms without having to grow them in the lab. These new methods rely on our ability to read the DNA sequence from certain deeply informative stretches of the genome, stretches that are unique to every microorganism. We now collect samples and identify the resident microbial species without having to grow them in the lab. Instead, we disrupt their outer membranes and so release their DNA. The resulting mix of DNA contains the genomes of every microbe in the sample. We then amplify short, distinctive, species-specific fragments from this DNA mixture, revealing the identity of virtually every microbe in that sample. Imagine the heavens first seen through a telescope—such is the impact of these new approaches on our conception of the diversity and complexity of microbial communities. We no longer glimpse stars; now we can comprehend galaxies.

Equipped with these new molecular tools, we have refocused our attention on the microorganisms living on and in us. From the outset, these studies suggest that human microbiota are more diverse, more complex, more structured and more fascinating than we could have imagined. Hundreds, possibly thousands, of different species make us their home. But is this diversity just the result of living in a world dense with microbes? Do our surface cracks and crevices simply collect microbial dust? Far from it. Each location in the human body appears to harbor its own structured, organized and site-specific community. These communities reflect the characteristics of the specific environments: the crook of your elbow is not, in fact, the same environment as your nearby forearm.

And microbes are everywhere within the digestive tract. A 2006 study by Elizabeth M. Bik of Stanford University and her colleagues demonstrates, for example, that the microbiota of the human stomach are both far more diverse and far more distinctive than previously imagined. The aggressive environment of the human stomach was considered until recently an inhospitable environment. All but the heartiest extremophiles would surely die in this acid vat of protein-degrading enzymes. But an analysis of telltale molecular signatures reveals 128 different species of stomach microorganisms. Fully half of these bacteria had never been cultured and had thus gone unnoticed. And these 128 resident species are not simply the descendants of an original colonist: They span eight phyla and reflect a broad cross-section of bacterial diversity. (One stomach even included Deinococcus, a genus previously found only in the effluent of nuclear-power plants and in arsenic-laden waste.) Not just the stomach, but the entire human gut turns out to be a patchwork of complex, dynamic, microbial ecosystems engaged in intimate conversations with their host. This new appreciation is based on the work of David A. Relman of Stanford University, Jeffery I. Gordon of Washington University, Claire M. Fraser-Liggett of the University of Maryland and others.

Many studies have underscored the distinct character of our microbial communities. The skin on our right forearm, for example, harbors a different microbial community than that of our left forearm. Both of these communities change over time. Even single regions of the body, such as the vagina, consist of multiple defined subenvironments, each with its own subset of tenants. The presence of such distinct communities is even more surprising when one thinks of the human body, as topologists do, as a cylinder with a hollow core. Given this kind of a picture, why exactly do distinct microbial communities persist on the inside and the outside of our bodies?

Part of the answer, as I suggested earlier, lies in the specialized environments that characterize the different sections of this hollow cylinder. As microbes colonize these specialized habitats, they further enhance the differences between environments. Bacterial guilds, in which one species's waste is another's food, begin to emerge. As these guilds expand, each new member contributes to the location-specific identity of the overall assemblage. Furthermore, these environments are all interconnected, and members of each community can and do travel far from home. We are now finding that certain groups of bacteria succeed in many different locations, whereas others seem tethered to single environments. We know there is movement, but the details of the microbial traffic patterns within our bodies are mostly unknown.

More than a Truce

As we seek to explain the diversity and composition of the human microbiome, local environmental characteristics clearly matter: pH in the mouth is near 7, but that of the stomach is about 2. Host characteristics also matter, as age, gender and genetics all play a part. And as always in biology, an individual's life-history matters too. In fact, it matters from our very first minute: Babies delivered by caesarean section have different initial microbial communities than do vaginal-birth babies. Babies emerging from the germ-free amniotic sac into the birth canal are immediately colonized by bacteria from their mother's vaginal and fecal communities. As unsavory as these bacteria sound, they're highly desirable, as this welcome-to-the-world present is critical to the health of the newborn.

Slowly, inevitably, the growing infant's environment and genes reshape that maternal gift into the child's own microbiome. The microbiomes of identical twins resemble one another more than the microbiomes of unrelated infants—but no more than the microbiomes of fraternal twins. We can now track the ways in which this newly seeded microbial complement adapts to the newborn, adjusting first to a diet of mother's milk and later to the varied diet that accompanies weaning. Other studies show that babies born vaginally have a lower risk of developing food allergies, and this reduced risk is related to the microbial makeup of the gut and to the family history of allergy. This first gift from mom leaves a profound imprint.

As details of the partnership with our microbial friends come into focus, we are very much in Adam's position. We are seeing this world clearly for the first time and naming its inhabitants. And we should accept our role as custodians and caretakers of this unseen world. Perhaps the most important implication of this perspective involves our use of antibiotics. Over the past 60 years, broad-spectrum antibiotics have saved countless lives, and antibiotics remain a powerful weapon in our medical arsenal. But broad-spectrum antibiotics are coarse tools in an age where we are beginning to understand the subtleties of microbial environments and genomes.

Because antibiotics kill bacteria indiscriminately, collateral damage far exceeds target destruction, and our microbial supporting cast is decimated in pursuit of the pathogen. Under the old view of human-microbe interactions, we accepted this collateral damage as a small cost to pay for ridding ourselves of bacteria. Under our proposed ecological model, however, we can understand that we no longer need to destroy the village in order to save it. Broad-spectrum antibiotics are properly seen as agents of major perturbation. Recent studies make clear that antibiotic exposure reduces the diversity of resident microbial communities and makes it easier for pathogens to invade.

A clearer picture of the genetic changes that make bacteria "go bad" and become pathogens is also coming into focus. Pathogens are thugs. The lives of these bacterial delinquents are all about competing aggressively for scarce resources (iron, for instance), clinging to surfaces, and producing bacteriostatic and bactericidal molecules that clear away the established residents. Yet delinquency comes at a cost: The pathogen lifestyle is expensive and burdensome for the pathogen itself. Pathogenesis is a fringe occupation for most bacteria, and the conditions that give pathogens an opportunity are rare. Ironically, our scorched-earth approach to the microbial world increases the opportunities for pathogens to gain a foothold. Excessive antibiotic use sows chaos in our resident microbiota, and pathogens thrive on such chaos. Well-organized, stable resident communities can normally resist thugs; weakened and disrupted communities cannot.

Let me be clear—there are, of course, specific situations where bacteria are certainly not welcome. A surgical field needs to remain sterile. Catheters inserted into patients must be free of bacteria. Hands need to be washed before eating. Little dishes of unwrapped mints in restaurants should be avoided at all costs. But these scenarios, too, are better understood when framed as ecological problems: The ingestion of the overhandled mints or the presence of non-sterile instruments introduces non-native microorganisms into established communities (or into fully sterile internal environments). Just as introductions of non-native organisms perturb and can destroy ecological communities at the macroscopic level, non-native bacteria disturb the unseen world. Bacterial pathogenesis hinges on the ability of pathogens to displace established bacteria and occupy their niches, their homes: us. The indiscriminate use of broad-spectrum antibiotics and the resulting selection for antibiotic resistance (the topic of a later column) simplify the task.

Ultimately, our survival depends on following the second set of instructions issued to Adam—on thinking of ourselves as part of the living world, rather than above it. We now know that most of the living world is smaller than we are and even smaller than what we can see with our naked eye. Our size and our senses make us oddities in the living world, but they do not set us apart. The beginning of the 21st century is as good a time as any to acknowledge our deep dependence on the microbial world. Within our bodies, bacteria outnumber us, but they also support us. It is time to create rules of engagement with infectious diseases that reflect our longstanding partnership with the unseen world.

 

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