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Ruslan Medzhitov and Brett Finlay are investigating how changing a person’s microbiota impacts health.
These researchers and a growing number of other scientists study the microbiota—the microbes that make our bodies their homes. While bacteria call to mind disease-causing germs that require antibacterial soaps and drugs to exterminate them, the bacteria in healthy intestines are relatively tame. In fact, animals from snakes to mice to humans wouldn’t survive without them. They turn food into energy, synthesize vitamins that their hosts’ bodies can’t produce, and engage in a complex and vital interplay with the immune system.
Researchers are also showing that the composition of a person’s microbiota can predispose him or her to diseases—from asthma and allergies to cancers, infections, and inflammatory bowel disease.
“Our individuality is not just us genetically, it’s us plus all the microbes we carry,” says HHMI investigator Ruslan Medzhitov of the Yale School of Medicine, who also studies the microbiota. “And that’s not just a metaphor; they really shape our biology in many ways.”
While the studies of Knight, Gewirtz, and Ley hint at the importance of the microbiota in human health, scientists have more questions than answers. After all, most of the bacteria swarming in our guts remain unidentified. Many cannot survive outside the complex environment of the intestines and so are difficult to culture in the lab. Plus, the microbiota of any one person is shaped not only by genetics but also by diet and environment, meaning that they change over time, complicating experiments even more.
Knight’s background is in ecology, studying the interplay of plants and animals in natural environments. He views the human body as another environment to study, in the same way he would study a jungle, marsh, or arctic tundra. Except, he says, bacteria are a lot more convenient to study. “Instead of having to do field seasons every year for a decade, you can draw out four quadrants on your forearm and have your field season in your office in fifteen minutes.”
The first thing an ecologist does in an environment is take a census of what’s there. So that’s Knight’s first task when it comes to the intestines, and it’s the goal of microbiota researchers worldwide. Rather than a butterfly net and microscope, they use cutting-edge DNA sequencing technology to get snapshots of the genetic makeup—called the microbiome—of individuals’ particular microbial mixtures.
Knight takes samples of bacteria—from skin, feces, and the intestines of mice or humans—and sorts out every copy of one particular gene encoding a bacterial ribosome. The ribosome is the cellular factory that produces proteins. It varies enough among bacteria that its sequence can place a bacterium (even a previously unknown one) into what’s called a phylotype—essentially, “a spot on the tree of life,” says Knight. Similar ribosomes are from similar bacteria and therefore appear on nearby branches of the tree. Knight originally developed a computational method, called UniFrac, to study the ribosomal differences among bacterial communities in sediment, ice, and water. Now, his team is using the same technique to tackle medical questions.
In a 2009 Science paper, Knight’s lab group reported using UniFrac to analyze bacteria from 27 sites on the bodies of nine individuals, collected on four different dates. He found that bacterial communities varied drastically from person to person and changed to a lesser extent in one person over time. Only 3 percent of bacterial phylotypes appeared in all individuals on all occasions. In a separate paper, Knight and collaborators showed that people’s skin bacteria differ enough that you leave behind unique molecular fingerprints on everything you touch—a finding that could change forensic science.
While Knight’s initial goal is to use UniFrac to characterize the microbiomes of healthy individuals, he says it will take the field only so far. Significant findings in ecology often come not from studies of healthy environments but from observations of disturbances within a community.
“If you went to Yellowstone and ground up a cubic mile of it and analyzed the DNA, you wouldn’t find a lot of wolf DNA,” says Knight. But scientists know that wolves are a species crucial to maintaining Yellowstone’s diversity because of the radical changes that took place when they were removed from Yellowstone in the early part of the 20th century. Elk populations skyrocketed and the condition of the woodlands deteriorated. In 1995, scientists reintroduced wolves to Yellowstone and have since observed the elk population stabilize at a healthier number.
In the gut, Knight says, there could be bacteria that, while not abundant, keep the populations of other microbes in check.
With that in mind, he wants to use UniFrac to observe the complicated dynamics between human health and the diversity of phylotypes in the gut.
Medzhitov: Chris Jones, Finlay: Birthe Piontek