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The deep symbiosis between bacteria and their human hosts is forcing scientists to ask: Are we organisms or living ecosystems?
Feature / by Courtney Humphries / April 14, 2009
As soon as we are born, bacteria move in. They stake claims in our digestive and respiratory tracts, our teeth, our skin. They establish increasingly complex communities, like a forest that gradually takes over a clearing. By the time we’re a few years old, these communities have matured, and we carry them with us, more or less, for our entire lives. Our bodies harbor 100 trillion bacterial cells, outnumbering our human cells 10 to one. It’s easy to ignore this astonishing fact. Bacteria are tiny in comparison to human cells; they contribute just a few pounds to our weight and remain invisible to us.
It’s also been easy for science to overlook their role in our bodies and our health. Researchers have largely concerned themselves with bacteria’s negative role as pathogens: The devastating effects of a handful of infectious organisms have always seemed more urgent than what has been considered a benign and relatively unimportant relationship with “good” bacteria. In the intestine, the bacterial hub of the body that teems with trillions of microbes, they have traditionally been called “commensal” organisms — literally, eating at the same table. The moniker suggests that while we’ve known for decades that gut bacteria help digestion and prevent infections, they are little more than ever-present dinner guests.
But there’s a growing consensus among scientists that the relationship between us and our microbes is much more of a two-way street. With new technologies that allow scientists to better identify and study the organisms that live in and on us, we’ve become aware that bacteria, though tiny, are powerful chemical factories that fundamentally affect how the human body functions. They are not simply random squatters, but organized communities that evolve with us and are passed down from generation to generation. Through research that has blurred the boundary between medical and environmental microbiology, we’re beginning to understand that because the human body constitutes their environment, these microbial communities have been forced to adapt to changes in our diets, health, and lifestyle choices. Yet they, in turn, are also part of our environments, and our bodies have adapted to them. Our dinner guests, it seems, have shaped the very path of human evolution.
In October, researchers in several countries launched the International Human Microbiome Consortium, an effort to characterize the role of microbes in the human body. Just over a year ago, the National Institutes of Health also launched its own Human Microbiome Project. These new efforts represent a formal recognition of bacteria’s far-reaching influence, including their contributions to human health and certain illnesses. “This could be the basis of a whole new way of looking at disease,” said microbiologist Margaret McFall-Ngai at the 108th General Meeting of the American Society for Microbiology in Boston last June. But the emerging science of human-microbe symbiosis has an even greater implication. “Human beings are not really individuals; they’re communities of organisms,” says McFall-Ngai. It’s not just that our bodies serve as a habitat for other organisms; it’s also that we function with them as a collective. As the profound interrelationship between humans and microbes becomes more apparent, the distinction between host and hosted has become both less clear and less important — together we operate as a constantly evolving man-microbe kibbutz. Which raises a startling implication: If being Homo sapiens through and through implied a certain authority over our corporeal selves, we are now forced to relinquish some of that control to our inner-dwelling microbes. Ironically, the human ingenuity that drives us to understand more about ourselves is revealing that we’re much less “human” than we once thought.
To find a biological answer to the question “Who are we?” we might look to the human genome. Certainly, when the Human Genome Project first produced a draft of the 3 billion-base-pair sequence, it was touted as a blueprint for human life. Less than a decade later, however, most experts recognize that our genomes capture only a part of who we are. Researchers have become aware, for example, of the influence of epigenetic phenomena — imprinting, maternal effects, and gene silencing, among others — in determining how genetic material is ultimately expressed. Now comes the notion that the genomes of microbes within us must also be considered. Our bodies are, after all, composites of human and bacterial cells, with microbes together contributing at least 1,000 times more genes to the whole. As we discover more and more roles that microbes play, it has become impossible to ignore the contribution of bacteria to the pool of genes we define as ourselves. Indeed, several scientists have begun to refer to the human body as a “superorganism” whose complexity extends far beyond what is encoded in a single genome.
The physiology of a superorganism would likely look very different from traditional human physiology. There has been a great deal of research into the dynamics of communities among plants, insect colonies, and even in human society. What new insights could we gain by applying some of that knowledge to the workings of communities in our own bodies? Certain body functions could be the result of negotiations between several partners, and diseases the result of small changes in group dynamics — or of a breakdown in communication between symbiotic partners.
Recently, for instance, evidence has surfaced that obesity may well include a microbial component. In ongoing work that is part of the Human Microbiome Project, researchers in Jeffrey Gordon’s lab at the Washington University School of Medicine in St. Louis showed that lean and obese mice have different proportions of microbes in their digestive systems. Bacteria in the plumper rodents, it seemed, were better able to extract energy from food, because when these bacteria were transferred into lean mice, the mice gained weight. The same is apparently true for humans: In December Gordon’s team published findings that lean and obese twins — whether identical or fraternal — harbor strikingly different bacterial communities. And these bacteria, they discovered, are not just helping to process food directly; they actually influence whether that energy is ultimately stored as fat in the body.
Even confined in their designated body parts, microbes exert their effects by churning out chemical signals for our cells to receive. Jeremy Nicholson, a chemist at Imperial College of London, has become a champion of the idea that the extent of this microbial signaling goes vastly underappreciated. Nicholson had been looking at the metabolites in human blood and urine with the hope of developing personalized drugs when he found that our bodily fluids are filled with metabolites produced by our intestinal bacteria. He now believes that the influence of gut microbes ranges from the ways in which we metabolize drugs and food to the subtle workings of our brain chemistry.
Scientists originally expected that the communication between animals and their symbiotic bacteria would form its own molecular language. But McFall-Ngai, an expert on animal-microbe symbiosis, says that she and other scientists have instead found beneficial relationships involving some of the same chemical messages that had been discovered previously in pathogens. Many bacterial products that had been termed “virulence factors” or “toxins” turn out to not be inherently offensive signals; they are just part of the conversation between microbe and host. The difference between our interaction with harmful and helpful bacteria, she says, is not so much like separate languages as it is a change in tone: “It’s the difference between an argument and a civil conversation.” We are in constant communication with our microbes, and the messages are broadcast throughout the human body.
The first study of a microbial community living on the human body was made back in 1683, when Antony van Leeuwenhoek wrote a letter to the Royal Society including his observations through the microscope of his own dental plaque, in which he described seeing “many very little living animalcules, very prettily a-moving.” But despite this very early interest in the microbe communities on the body, over the next three centuries, microbiologists focused mainly on “isolating” bacteria: removing them from their natural contexts and growing them in culture dishes in the lab. This approach was the only way to observe and understand bacterial cells in great detail. But it also created huge gaps in knowledge about bacterial life. It focused on the fraction of microorganisms that can be grown in culture, and it overlooked the highly complex and diverse ways in which they actually live together — an approach akin to studying humans by confining them in prison cells while ignoring the cities and communities that make up their natural habitat.
This narrow view of microorganisms began to change when new genetic sequencing technologies — which fished the genes directly out of water or soil samples — made it possible to collect information about microorganisms without having to isolate them. These studies revealed an incredible amount of genetic abundance and diversity; the microbial world was a far bigger and denser landscape than anyone had previously known. A further leap in technology has been the ability to sequence large numbers of genes rapidly. Even without “seeing” the organisms themselves, scientists can now sequence tens or hundreds of thousands of genetic fragments from an environmental sample. The resulting science of metagenomics eschews traditional ideas about studying the natural history of a particular organism in favor of a global view of the genes that exist in a community.
Using these new metagenomic methods, environmental microbiologists have delved into uncharted territories — acidic lakes, deep-ocean hydrothermal vents, and frozen tundra, to name but a few — to see what life might exist there. Gradually, some have applied the new tools to explore the “environments” of humans and other animals, with recent surveys, for instance, of the bacterial communities in various microclimates of the human body, from rear molars to intestines to nasal passages. And with these studies and the launch of the Human Microbiome Project, the fields of medical and environmental microbiology have begun to merge. The resulting hybrid discipline embraces the complexity of a larger system; it’s integrative rather than reductive, and it supports the gathering view that our bodies, and the bodies of other animals, are ecosystems, and that health and disease may depend on complex changes in the ecology of host and microbes.
In 2007, Cornell University microbiologist Ruth Ley coauthored a paper arguing that human microbiome studies could bridge the divide between biomedical and environmental microbiology. Like Jeffrey Gordon, her coauthor and mentor, Ley studies bacteria in the human gut. But while Gordon, Ley, and their fellow microbial sleuths might have hoped for a core set of organisms that would define the human microbiome, so far the reality is proving far more complicated. While only a few major groups of the world’s bacteria live in the human body, within these groups are countless bacterial species that vary greatly from person to person. “The more people look at it, it seems like an endlessly diverse system,” says Ley. The landscape of the body presents a wide range of habitats. In the nutrient-rich land of the intestines, communities appear to be fairly stable over time, while early indications show the harsher environment of the skin attracting itinerant communities that come and go. Communities can be as localized as the neighborhoods of a city; the inner elbow contains a different group of residents than the forearm.
Furthermore, in contrast to habitats such as the deep sea, where emigration and immigration are rare events, many microbial communities associated with humans are affected by constant interactions with microorganisms coming in from the environment. Microbes in the gut, for instance, encounter bacteria that ride in on the food we consume. These visitors introduce a huge, unpredictable component that makes any determination of a core microbiome all the more difficult. In order to develop well-framed research questions, it’s crucial that microbiologist learn how to differentiate between co-evolved species and these itinerant “tourists.”
What we do know, however, is that our own personal microbiomes tend to be partly inherited — most of us pick up bacteria from our mothers and other family members early in life — and partly shaped by lifestyle. Ley, who has surveyed the gut bacteria of several species, says that diet is an important factor in determining the communities that live in an organism. Even with our processed foods and sterilized kitchens, Ley says, humans are not radically different from other animals that share our eating habits.
The individuality of each person’s microbiome might complicate the project of studying human-microbe relationships, but it also presents opportunities — for instance, the possibility that medical treatments could be tailored to a person’s particular microbiota. Much like a genetic profile, a person’s microbiome can be seen as a sort of natural identification tag. As David Relman, a microbiologist at Stanford University, puts it, “It’s a biometric — a signature of who you are and your life experience.” With support from the Human Microbiome Project, Relman is currently developing novel microfluidic devices that can isolate and sequence the genomes of individual bacterial cells. (Extracting genetic information from a complex sample normally mixes together hundreds if not thousands of unique species, so this single-microbe technology could well revolutionize the speed and scope of the entire field of metagenomics.) Personal microbiome information will also have implications for practical concerns, such as how we deploy antibiotics. Might those antibiotics we down at the first sign of an upset stomach be waging an unjustified civil war? Where do the massive quantities of antibiotics we feed to our livestock ultimately end up, and do they disrupt delicate ecological balances? We have lived with microbes for our entire evolutionary history; how has the widespread use of chemicals that kill them changed those long-forged evolutionary relationships?
Few people are more familiar with life’s interdependence and the blurriness of its distinctions than microbiologists. The recent metagenomic studies have revealed a daunting amount of diversity in microbial life, with none of the clear divisions we’re used to in the “macro” world. Among bacteria, the entire concept of species breaks down; it’s difficult for scientists to even categorize what they are seeing. Microbes offer a picture of life that is fluid and ever changing.
To come to terms with this diversity, microbiologists are today relinquishing the desire to name names. When studying a community, they no longer focus on developing a roster of who is there; instead, they ask what kinds of genes are present and what their functions are. In the human microbiome, which species we harbor may be less important than what they are doing.
William Karasov, a physiologist and ecologist at University of Wisconsin–Madison, believes that the consequences of this new approach will be profound. “We’ve all been trained to think of ourselves as human,” he says. Bacteria have been considered only as the source of infections, or as something benign living in the body. But now, he says, it appears that “we are so interconnected with our microbes that anything studied before could have a microbial component that we hadn’t thought about.” It will take a major cultural shift, says Karasov, for nonmicrobiologists who study the human body to begin to take microorganisms seriously as a part of the system.
Equally challenging, though in a different respect, will be changing long-held ideas about ourselves as independent individuals. How do we make sense of this suddenly crowded self? David Relman suggests that how well you come to terms with symbiosis “depends on how comfortable you are with not being alone.” A body that is a habitat and a continuously evolving system is not something most of us consider; the sense of a singular, continuous self is a prerequisite for sanity, at least in Western psychology. A symbiotic perspective depends on a willingness to see yourself as the product of evolutionary timescales. After all, our cells carry an ancient stamp of symbiosis in the form of mitochondria. These energy-producing organelles are the vestiges of
symbiotic bacteria that migrated into cells long ago. Even those parts of us we consider human are part bacterial. “In some ways, we’re an amalgam and a continuously evolving collective,” Relman says.
He also believes that we might have something to gain by embracing our bacterial side. Bacteria are often dismissed as simpler, less sophisticated, and less worthy of our consideration. “We put a lot of weight on a life form’s ability to think independently,” Relman says, but microbes have achieved fantastic evolutionary success by operating on a very different principle. Microbial communities are filled with examples of self-sacrifice for the benefit of the larger colony. They form physically close communities in which some cells exist solely to provide structural support or protection for others. This “intertwining of fate,” as Relman puts it, is something that humans could consider more seriously in the dynamics of their own societies, instead of focusing so keenly on individual identity and success.
Perhaps we could learn a lesson in fluidity from our symbionts. Science is always challenging us to let go of treasured categories and divisions. The theory of evolution, for instance, forced us to see species as points along a shared history, rather than as fixed identities. Symbiosis goes a step further by showing us how species are linked by more than history; they are living together in a continuous, interconnected now.
When scientists in 1977 first discovered life in the deep-sea hydrothermal vents, including gigantic tubeworms living in scalding-hot water filled with hydrogen sulfide, they could not explain it. Until then, all life was thought to derive its energy from the sun, but this habitat was far from any light. Then scientists found that the worms harbored symbiotic bacteria, which fed on hydrogen sulfide, turning this poison into something usable by other life forms. The discovery underscored the fact that life as we know it is built upon microbes, whether we look in the deepest oceans or our own intestines. We once had the luxury of ignoring the diminutive members of our bodies and other ecosystems. Now the blinders are off.
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