by Melissa Hendricks Joyce
It began as a mystery.
For years, Marsha Wills-Karp, PhD, had used the same strains of laboratory mice to study the molecular mechanisms of asthma. And for years standard tests had shown that one commonly used strain, A/J mice, was susceptible to asthma, while another standard strain, C3H mice, was resistant to the disease.
That changed when Wills-Karp moved her lab from the Bloomberg School to the Cincinnati Children’s Hospital Medical Center 13 years ago. Suddenly, the A/J mice were less asthmatic, while the C3H mice were more susceptible to the disease.
“We were baffled,” says Wills-Karp.
Other than geography, nothing had changed. The mice were the same genetic strains she had always used, ordered from the same company she had always patronized. Even the scientists handling the animals were the same—graduate students who had accompanied Wills-Karp to Cincinnati.
“When you want wisdom and insight as badly as you want to breathe, it is then you shall have it.”
The mystery renewed in 2012 when Wills-Karp returned to the Bloomberg School to chair the Department of Environmental Health Sciences and continue her asthma research. And the mice have resumed their old patterns: A/J’s are susceptible to asthma and C3H’s are resistant.
Wills-Karp’s group spent hours brainstorming what might account for the differences, and they painstakingly devised new protocols to adjust for the changes.
The mercurial mice had the potential to turn into “a big headache,” says Wills-Karp during a June interview in her seventh-floor office on Wolfe Street. “Sometimes, however, a big headache can turn out to be exciting because we can use it for our own devices.”
In this case, Wills-Karp says, the headache has helped her recognize a new paradigm for asthma, a model that could help explain some of the disease’s unsolved puzzles.
New ideas, new insights are welcome in a field that has seen asthma rates skyrocket over the past 30 years. Worldwide prevalence is now 300 million, with cases projected to reach 400 million by 2025. Genes and the environment clearly factor into asthma’s development, but cannot explain everything about the disease’s development or its rise. Severe asthma—the source for most asthma-associated hospitalizations, deaths and health costs—presents another conundrum. According to the CDC, asthma in the U.S. is responsible for 1.9 million emergency department visits per year and $56 billion in health costs and lost productivity. Why some patients develop severe forms of the disease while others experience only mild cases is not known.
Its symptoms—inflamed bronchi, wheezing, coughing, labored breathing—clearly mark asthma as a lung disease. Yet the mystery presented by the furry A/J’s and C3H’s has led Wills-Karp to focus on a different organ system: the gut. Specifically, she’s targeting the horde of bacteria that reside there. Known collectively as the intestinal microbiota, these microbes help us digest our food, metabolize certain vitamins and keep disease-causing bacteria in check. A growing body of evidence also links disruptions in the microbiota to a host of diseases. Asthma, says Wills-Karp, especially severe asthma, may be one of those diseases.
She now believes that different intestinal microbiota accounted for the discrepancies in asthma between the Baltimore and Cincinnati mouse colonies. Different types of feed in the two animal houses may have facilitated the growth of different microbiota, says Wills-Karp, a hypothesis she will examine in future studies. In the meantime, the unexpected discrepancy has given Wills-Karp the opportunity to understand the microbiota’s possible role in asthma.
The Disease Connection
Research on the microbiota and microbiome (all the genes of the microbiota) has grown exponentially in recent years. Scientists funded through NIH’s Human Microbiome Project are studying everything from the urethral microbiome of adolescent males, to the role of the gut microbiota in obesity in the Amish and the skin microbiome associated with acne. And at Hopkins, Wills-Karp has organized a Microbiome Interest Group, which includes more than 100 scientists from diverse disciplines (see sidebar).
“We’re born alone, we live alone, we die alone,” Orson Welles once lamented. Not from a biological perspective. Microbiome studies make it increasingly clear that we move through this world in congress with trillions of microbial companions—in our intestines, on our skin, in our eyes, and on every surface of the human body.
And some studies are beginning to produce tantalizing results showing microbial patterns that correlate with certain diseases. For instance, Cynthia Sears, MD, a Microbiome Interest Group member and professor of Medicine, has shown in mice that certain toxin-producing microbes are associated with colon cancer. When these microbes colonize the gut, they may induce conditions that cause or exacerbate colon cancer. Her findings and those from other labs are early but tantalizing, says Sears. “They raise real hope there is a bigger story and also hope that the microbiome will be manipulable in ways that help treat or diagnose disease,” she says.
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