At this moment, you probably think of yourself as an I. As in, “I’m going to the grocery store to get some bread.” Or, “I’m running a slight fever.” Maybe even, “I’m so excited to read this new issue of Findings!”
But what if you’re using the wrong pronoun? What if, despite your conscious perception, despite everything that you may have learned and felt and seen and heard up until this point in your life, you are actually a we?
You see, for every human cell in our bodies, there exist 10 other cells belonging to resident microorganisms. Put another way, Ross Perot, who won 18.8 percent of the popular vote in 1992, had a stronger claim to the presidency than we do to calling ourselves human.
It turns out that we’re nothing more than an organic hotel. Sure, we’re staffed by 10 trillion or so human cells. But the vast majority of the 100 trillion cells occupying our bodies belongs to the infinitesimal visitors lodging on our skin, in our mouths and deep within our digestive tracts.
Those lodgers are all the bacteria and other microscopic organisms that colonize our bodies. They fall into three basic categories: generally harmless freeloaders; symbiotic organisms, which derive some sort of benefit from us but also do something helpful in return; and, in very small numbers, pathogens, like bacteria or viruses.
“We’ve had this perception of microbes as germs, as pathogens, as disease-bearing organisms,” said Lita Proctor, a scientist at the National Human Genome Research Institute and program director of the Human Microbiome Project, in a recent issue of the magazine Genome. “Much of the scientific literature for decades and decades has been completely focused on pathogens, and that has also framed our point of view about microbes. But it has become clear that the vast majority of microbes we come in contact with on a daily basis are not pathogenic. They are either benign and couldn’t care less that there is a human nearby or they actually provide a benefit.”
Until recently, medical researchers basically ignored the vast majority of the microbial population that lives on and, in much greater numbers, inside us. But that, says OMRF’s Dr. Patrick Gaffney, has changed.
“There’s been a growing interest in and understanding of the microorganisms in our bodies,” says Gaffney, a genetics researcher who has turned his attention to the genes of the tiny creatures who, on average, make up 2.5 pounds of our body weight. “We’ve realized they do important things to maintain our health, to produce important vitamins, for educating our immune systems, and to help us metabolize foods and maintain a healthy body weight.”
In 2007, the National Institutes of Health launched the Human Microbiome Project, an effort to catalog the microorganisms living in and on human bodies. Using DNA sequencing technologies to analyze samples taken from hundreds of healthy people, researchers pieced together the first comprehensive picture of a normal human microbiome, a term scientists use to describe the collective genetic materials of all the microbes that live inside and on the human body. The next step, says Gaffney, “is to learn how changes in the microbiome correlate with physiology and disease.”
Already, research has shown that disorders in our internal ecosystem may predispose us to obesity and a range of chronic diseases. They may be responsible for a rise in allergies to nuts and other compounds. Evidence is mounting that intestinal microbes exacerbate or perhaps even cause some of the symptoms of autism.
Gaffney is among the growing ranks of scientists now digging deeper into the microbiome to understand how, exactly, it affects our health. Although he and his peers are careful not to promise that their work will lead to cures, the implications of what they’ve learned are staggering. And what we know today may represent only the tip of the iceberg.
Gaffney came to study the microbiome by a circuitous route. A physician by training, he began his research career during a fellowship at the University of Minnesota. Although the fellowship was supposed to be cancer-focused, he ended up focusing on the genetics of the immune system. He liked the work and the field so much that he stayed on at the university, first as a post-doctoral fellow and then as a faculty researcher, investigating autoimmune diseases. All of these illnesses share a common trait: The immune system confuses the body’s own cells for pathogens and, as a result, it begins attacking itself.
Gaffney concentrated on lupus, an autoimmune disease that can strike any organ but commonly affects the joints, skin and kidneys. He focused on the genetic roots of this disease. Using an approach known as genome-wide association studies, his research team identified particular genes linked to lupus.
In 2007, that work brought him to OMRF, where he joined the foundation’s Arthritis and Clinical Immunology Research Program and now holds the J.G. Puterbaugh Chair in Medical Research. Working with other OMRF scientists, his interest broadened to include the genetic origins of other autoimmune diseases like Sjögren’s syndrome.
Not long before Gaffney came to OMRF, researchers finished the first scan of the entire human genome, the technical term for all the genes in our body. That colossal project took more than a decade to complete and cost upwards of $1 billion. But rapid advances made the technology more efficient and affordable, making genetic scanners—and the vast array of information they yield—widely available.
In 2009, Gaffney established a “next-generation” DNA sequencing facility at OMRF. With this technology and increasing expertise at his fingertips, Gaffney began looking not just at the genomes of patients suffering from autoimmune diseases, but also at their microbiomes.
Research had begun to point to links between lupus and certain intestinal microbes. In particular, says Gaffney, “There’s a possibility the trigger that sets off lupus might be hiding in the gut.” So he decided to take a look at the microbiomes of lupus patients to see what he could find.
Working with physicians in OMRF’s Autoimmune Disease Clinic, he collected saliva and stool samples, where bacteria flourish, from 20 patient volunteers. He also gathered the same biological materials from 20 healthy individuals. Using sequencing technology, his team completed a genetic analysis of the two sets of samples, then looked for variations between the two groups.
The lupus patients exhibited a wide range of microbial species in their guts. But, says Gaffney, “Their colonies were less diverse than those of healthy individuals.”
Scientists can’t yet say with confidence what a healthy microbiome looks like. Still, says Gaffney, “There’s a generally emerging consensus that more diversity is better.”
Researchers believe that a wide variety of factors can contribute to a more uniform (and, presumably, less resilient) population of gut bacteria. In particular, they point to widespread use of antibiotics, diets heavy in processed food, exposure to environmental toxins, and generally “cleaner” environments that minimize contact with bacteria in everyday life. More uniform microbiomes have been linked to the risk of some cancers and gastrointestinal disorders.
Although Gaffney’s study showed that the digestive tracts of lupus patients were more uniform than their healthy counterparts, that observation, says Gaffney, simply pointed to a larger chicken-or-egg question: “Did the lack of diversity cause lupus, or did the disease cause the lack of diversity?”
To find an answer, he has embarked on a larger follow-up study. That analysis will involve larger numbers of samples gathered from patients and matched controls, and it will look more probingly at the genetic profiles of the gut bacteria they find. “We’re going to look at specific genes to try and separate cause from effect,” he says.
While Gaffney knows that the results of the new study won’t lead to specific health recommendations—“Eat more yogurt with live cultures and cut your chances of developing lupus!”—he says that research projects like this are crucial if we’re to gain a deeper understanding of what many are calling the “second human genome.”
The modernization of Western society has brought with it many positive changes: increased lifespans, improved quality of life, countless technologies that enrich our lives. But with these developments has, apparently, come a change for the worse. In our guts.
Led by Dr. Cecil Lewis, researchers at the University of Oklahoma analyzed microbiome samples taken from people who lived long ago, including a soldier frozen for nearly a century on a glacier and Otzi the Iceman, a 5,000-year-old specimen who is Europe’s oldest known natural human mummy. The recent analysis showed that our guts were once far more diversified and used to look more like those of other non-human primates and rural people living in less- developed countries.
In particular, says Lewis, “The team concluded that the last 100 years has been a time of major change to the human gut microbiome in cosmopolitan areas.” Dietary changes and the widespread adoption of antibiotic and sanitary practices have largely benefited humans and our health. Still, he says, these alterations may also have come at a cost, “such as a recent increase in autoimmune-related risks.”
Indeed, bacteria play essential roles in the development of our immune systems, which are colonized at birth and later by microbes from our mothers and the environment. Once established, those microorganisms provide us with energy and vitamins that we can’t make on our own. They produce compounds that act as anti-inflammatories. Beneficial microbes help us fend off the pathogens. So it’s not surprising that having less of them would lead to health problems.
Nevertheless, Lewis cautions against running out and buying the latest food labeled as “probiotic” or changing your diet radically in an effort to bolster your gut’s bacterial population. “We see a lot of pseudo-science and fiction out there about influencing the microbiome. But scientists still don’t understand the microbiome’s biology or exactly how it works inside the body.”
As he compares the modern Western microbiome to those of other populations, Lewis has begun a scientific collaboration with Gaffney, who uses OMRF’s next-generation sequencing facilities to analyze the samples Lewis gathers in the field. “This technology is sort of like the printing press for genomics,” says Lewis. “It’s unlocking vital information that we didn’t have even 10 years ago.”
In particular, with access to OMRF’s sequencing expertise, Lewis found he could more easily analyze the bacteria present in ancient samples. This allowed him to form a more complete picture of ancient microbiomes. “It’s like looking through a whole new lens. It exposes an extraordinary picture, one we never expected to see.”
Lewis does not limit his work to ancient civilizations, though. He and his team also traveled by canoe into the Amazon to study the diet and health of Peru’s Matses community, who are among the last hunter-gatherers in the world. The Matses still hunt monkey, sloth and alligator, gather wild tubers in the forest, and fish in the rivers.
Although Gaffney says he will not be joining Lewis on a jungle trek anytime soon—“I’m not exactly the Indiana Jones type,” he laughs—he played a vital role in analyzing the samples that Lewis brought back from the Matses and also from the Tunapuco, a traditional community of potato farmers from the Andean highlands. That analysis showed that the hunter-gatherers’ and farmers’ gut bacteria were far more diverse than those of residents of Norman, Oklahoma. The South American indigenous peoples carried bacteria usually absent in Western industrialized populations. Those microbes play a role in digesting carbohydrates. So, says Gaffney, “The next question is whether their absence in Western guts leaves us without an important player in the metabolism of food? And whether that could contribute to the increase in digestive disorders like colitis and Crohn’s disease?”
In Gaffney’s lab, the soft whir of machines at work fills the air. It’s a hub of high-tech activity. Yet for all its mystique, next-generation DNA sequencing occurs inside equipment that looks like big, beige boxes. No multi-colored fluids pulsing through tubes. No whooshing or clanging sounds, no flashing lights. Just oversized rectangles with windows and slots where scientists insert bacterial samples for examination.
In spite of their seeming simplicity, though, those boxes produce mind-boggling amounts of scientific information. From a slide about the size of a Band-Aid, the sequencing process can yield seven to eight million bits of information and generate files upward of 500 megabytes in size. Sophisticated computer programs then scan the data for similarities and differences in the makeup of the bacteria. The resulting information helps scientists pinpoint patterns that signal the paths they should study.
All this new information, though, has generated as many questions as it has answers. Through the work of Gaffney, Lewis and others, we’re learning more each day. In that process, we’re gathering clues about the hordes of microbes that reside within and upon us. That work has given us some ideas—things like diversifying our diets and using antibiotics only when absolutely necessary—of how to begin taking better care of these invisible visitors.
After all, our lives may depend on them.
