Features

Michael Glenwood

Tools of the Trade

by Melissa Hendricks Joyce

When Marsha Wills-Karp organized the Microbiome Interest Group in early 2012, one of its first tasks was to ascertain Johns Hopkins’ resources and what it needs to advance microbiome research.

Germ-free mice were one item on that list.

For them, she looked to Daniel Peterson, MD, PhD, an assistant professor of Pathology, and a small windowless room at the School of Medicine. The room houses 300 very special mice. The animals do not look unusual—just your average furry black creatures with large ears and perpetually twitching whiskers. But their microbiology tells a different story: It doesn’t exist.

A normal mouse harbors trillions of bacteria, in its gut, skin and other tissues. These germ-free, or gnotobiotic, mice possess none. Bred in sterile environments, they are an invaluable tool for microbiome researchers like Peterson.

As microbiological blank slates, the mice offer researchers a way to study how the microbiota affects health and disease and to parse the role of individual members of the microbial horde. “Our main question is understanding how different microbes influence the development of the immune system,” says Peterson.

“We begin with a clean palette,” he explains. “We then can add a single type of immune cell and a single species of bacteria. Then we see how the two interact.” He adds, “I am really obsessed with reductionism.”

Another key approach to microbiome research is metagenomics. In contrast to Peterson’s reductionist approach, metagenomics surveys all the microbial DNA in a particular environment, such as the gut. To acquire this genomic gestalt, scientists use next-generation sequencing tools, which can isolate and sequence tiny amounts of DNA.

Some scientists call these new tools “a new type of microscope,” just as transformative as the microscope that Dutch tradesman Antonie van Leeuwenhoek developed in the 17th century. Today’s methods show a human body swarming with 100 times more microbial life than previously recognized, a finding that has inspired a new vocabulary to describe the total package of human + microbes: Each of us is a “metaorganism,” a “super-organism,” a “vessel” for microbes.

Metagenomics generates tons of data—reams of DNA sequences. “How to analyze that data is the biggest hurdle,” says infectious disease researcher Richard Markham, MD. Bioinformatics specialists can apply analytical tools to such sequences to discover the identity of the microbe and clues about its role in health or disease.

“In some ways it’s analogous to the problem the NSA faces in data captured from phone calls,” says Markham. In trying to find a clue to terrorist activities, “how do you pick out the critical phone call?”