Bugs in the System
From a microbial perspective, the human colon is a teeming metropolis, home to the most densely populated collection of microbes on the planet. Remarkably, these organisms are not only tolerated but also often required for normal body functioning—as much a part of human biology as our own cells.
“We’re used to thinking about microbes as enemies—as major threats to our health—but most microbes don’t cause disease. They actually help us live better,” says Wendy Garrett, professor of immunology and infectious diseases at the Harvard T. H. Chan School of Public Health. “We are symbionts: human cells coexisting with bacterial cells, fungi, viruses, and parasites. We’re multispecies beings.”
Garrett explores the vast community known as the microbiota, which is increasingly recognized for its central role in human health. Her laboratory has a particular focus on the gut, where more than 1,000 types of microbial habitués reside. Working with a team of postdoctoral scholars, graduate students, and other lab members, she seeks to understand how the microbiota contributes to major diseases of the gastrointestinal system, including colorectal cancer—the fourth-leading cause of death globally and second-leading cause of cancer death in the U.S.—and inflammatory bowel disease (IBD).
Garrett is also intrigued by how gut microbes might shed light on cancer development and cancer treatments. Why do some tumors respond to certain cancer-fighting therapies—immunotherapy, for example—while others do not? With a deeper knowledge of the microbiota, it may become possible to manipulate microbes in ways that boost the effectiveness of cancer treatments and perhaps prevent the disease from arising in the first place.
Doctor-scientist
Garrett’s fascination with science began in childhood, when she conducted improvised experiments in her parents’ basement—among other things, culturing various types of mold on bread—and later joining her elementary school electronics club. These early exposures made her not only a passionate mentor to young researchers inside and outside her lab but also deeply supportive of STEM (science, technology, engineering, and math) initiatives for grade-schoolers. She has also steeped her own two children in science, and her entire laboratory visits her kids’ elementary school to lead microbiology lessons. As Garrett sees it, “Everyone’s a scientist.”
Garrett’s current study of microbes stems in part from her role as an attending physician specializing in gastrointestinal malignancies at the Dana-Farber Cancer Institute. She was influenced by a series of seminal discoveries in the 1980s and ’90s about the bacterium Helicobacter pylori. Those studies revealed it was H. pylori—not stress or spicy foods, as the conventional wisdom had it—that triggered stomach inflammation and ulcers, which in turn raise the risk of gastric cancer. When first proposed in the early 1980s, the bacterium-ulcer model was derided; today, it is the accepted paradigm.
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“We’re used to thinking about microbes as enemies—as major threats to our health—but most microbes don’t cause disease. They actually help us live better.”
—Wendy Garrett, Professor of Immunology and Infectious Diseases
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“Cancer is really complex, and microbes are complex too,” Garrett says. “But if we could work on both sides of the challenge simultaneously—the cancer and the microbes—we might find something new that can help treat or even prevent malignancy.”
Her dual roles as a physician-scientist—“the broad, thoughtful process of medicine and the experimental, reductionist path in basic science”—feed each other, Garrett adds. In the hospital, she talks to colleagues about how the microbiota affects patient care and well-being; witnessing her patients’ struggles up close, meanwhile, spurs her to do the research that may someday ease such suffering.
Microbial revival
The microbiota (sometimes called the “microbiome,” although technically that term refers to the microbes’ aggregate genomes) may seem like a new concept, but scientists have been talking about and studying it for at least a century. In the early 1900s, Élie Metchnikoff, a Russian zoologist known for his Nobel Prize–winning work on the immune system, theorized that toxic bacteria in the gut caused aging and senility. He was particularly taken with the idea of replacing native gut microbes with “host-friendly” microbes, such as those found in yogurt, to promote health and longevity—work that presaged the now-booming field of probiotics.
While the notion of “good bacteria” hearkens back to the days of Metchnikoff, Garrett’s work draws on technological capabilities that the 19th-century experimentalist could only dream of. Today’s tools for studying microbial communities—hundreds or thousands of species at once—include large-scale DNA sequencing, which has evolved rapidly over the last 20 years. Instead of culturing bacteria and other microbes in the laboratory to study them, scientists can now directly analyze their DNA, bypassing the need to precisely match microbes with their preferred growth conditions.
Similar technological leaps have helped expand scientists’ view beyond microbial DNA to RNA, metabolites (by-products of the body’s metabolism), and other sources of biological information. “Now when we study the microbiota, there are many ‘omes’ beyond the conventional genomes that we can think about,” says Garrett, referring to such biological data sets as the metabolome (the small-molecule metabolic chemicals found in tissue), proteome (the complement of proteins expressed in an organism), exposome (all of an individual’s nongenetic exposures over a lifetime), and others.
Gut signatures
Harnessing this information could help scientists construct new models of how host cells and symbiont microbes communicate. Alongside the gut’s dense microbial community, for example, are patrols of immune cells perpetually on high alert against infection. When these cells and the defensive inflammation they trigger careen out of control, however, IBD can develop. Garrett’s laboratory seeks to pinpoint what provokes this extreme response: Is it driven by the immune system, the microbes, or a mix of both?
In some IBD patients, the immune systems are altered in critical ways, and these differences affect key immune gatekeepers known as regulatory T cells. There are also notable differences in the types and number of bacteria that live in the guts of healthy individuals, compared with those suffering from IBD.
“We thought about the bacteria that are decreased in people with IBD or increased in people without IBD, and that got us thinking about bacterial metabolism in the colon,” explains Garrett. “We had this idea that maybe short-chain fatty acids, which are an abundant bacterial metabolite in the colon, might play an important role.”
These molecules have relatively compact chemical backbones, comprising just a handful of carbon atoms. Gut microbes make them by using building blocks from fiber-rich foods. Remarkably, when Garrett’s team fed short-chain fatty acids to mice, healthy or not, they found that the number of regulatory T cells rose. And in a mouse model of IBD, the treatment dramatically improved their disease. Garrett and her colleagues are now extending this line of research by exploring the biological mechanisms behind the therapeutic effect and extrapolating how these mechanisms might play out in humans.
“Tasting” parasitic intruders
The gastrointestinal tract is also home to parasites—both single-celled organisms and large, multicellular ones such as roundworms and other wormlike creatures. “One of the next frontiers of microbiota research is to better understand how the gut senses and determines whether a parasite is friend or foe, and how those differences contribute to health and disease,” says Garrett.
In a paper published in Science in 2016, Garrett and her colleagues describe how specialized cells in the gut detect parasites. Known as tuft cells, for the clumps of hairlike projections at their tip, they can sample intestinal contents using a form of taste similar to the one taste buds use to signal whether foods are bitter, savory, or sweet. When tuft cells encounter parasites, the cells release a chemical that not only triggers the immune system but also orchestrates tuft cell proliferation, thereby expanding their own numbers in the gut. This in turn rallies the immune system, enabling it to fight off parasitic intruders.
“It’s an elegant system, and one that can teach us a lot about diseases with a significant global impact—like giardiasis, roundworm, and hookworm,” says Garrett. “This will teach us how parasites influence the immune system, which has implications not only for how we fight parasitic diseases of the gut but also how we think about allergic and inflammatory diseases.” Research from other labs suggests that people with microbiota that harbor or have harbored parasites are less likely to suffer from IBD and other autoimmune diseases.
Sticky business
Although her laboratory studies a variety of microbes, Garrett has focused on one in particular: Fusobacterium nucleatum. About five years ago, she and her colleagues, including scientists at the Broad Institute and Dana-Farber Cancer Institute, discovered that these bacteria live inside colorectal tumors. “A subset of patients with colon cancer had large numbers of these bacteria in their tumors,” she says.
Fusobacteria, which typically thrive in the mouth, are more than mere biological bystanders. In the gut, they appear to incite tumor growth, acting via the immune system itself. Garrett’s group found that the microbes recruit certain immune cells that, instead of rallying the immune system, actively suppress it, allowing colorectal tumors to grow unchecked.
In the last few years, Garrett and her colleagues have delved more deeply into these subversive tactics through collaborations with Gilad Bachrach and Ofer Mandelboim at the Hebrew University of Jerusalem in Israel. In a paper published in Immunity in 2015, they revealed some of the key molecular players that inhibit the immune system. Last August, in a study published in Cell Host & Microbe, the team described how fusobacteria find their way to colon tumors—through a special sugar-binding protein that sits on the bacterial cell surface and enables the microbes to stick to the sugary coatings on colon cancer cells.
“These bacteria have evolved a mechanism to avoid the immune system. If the bacteria are inside a cancer, the consequence is that it helps the cancer escape the immune system too,” says Garrett. “If we can find a way to block the sugar-binding proteins on these bacteria, then we may be able to prevent their role in tumor progression.”
Such groundbreaking ideas have earned Garrett accolades from colleagues. “By deciphering the mechanistic bases of the interactions between the microbiota and the immune system, Dr. Garrett and her colleagues have revealed stunning new insights into the causes of inflammatory and neoplastic diseases,” says Matthew Waldor, the Edward H. Kass Professor of Medicine at Harvard Medical School. “She is one of the rare remaining ‘triple threats’: amazing clinician, teacher, and scientist.”
Search for gold
Colorectal cancer is squarely in the sights of medical research. Over the last four decades, timely screening beginning at age 50 has helped detect precancerous polyps (which can be removed) as well as early cancer (for which treatment is most effective). New therapies are also in the pipeline.
But prevention—precisely targeted, powerful means to block tumors from growing in the first place, particularly in high-risk individuals—is equally urgent and equally promising, Garrett says. “We understand so much about the disease and its risk factors, both within the microbiota and within the host, that we may someday prevent colon cancer from ever developing.”
Garrett’s lab has a Latin motto: Aurum ex Stercore. It means “to gold from dung,” a phrase that dates back to the classic challenge in medieval alchemy of transforming something seen as repugnantly useless into something inestimably precious. “Gold represents a scientific discovery that has the potential to help humanity,” Garrett says. “My sincere wish is to build a better system from a microbial perspective, so that we don’t even meet the eventuality of cancer.”
Nicole Davis is a science writer and communications consultant specializing in biomedicine and biotechnology. She holds a PhD in genetics from Harvard University.
