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A More Perfect Union
Illustrations by Brad Yeo

A More Perfect Union (continued)

Defense of the Lung

The lung disease known as chronic obstructive pulmonary disease (COPD) is the fourth-leading cause of death in the U.S. An irreversible condition, it results from environmental insult—mainly cigarette smoke but also air pollution—and as pollution and smoking rates increase, so do the death rates from COPD.

In our bodies, there are hundreds of antioxidant genes that can be switched on to prevent cell damage in the event of environmental insult or stress from oxidants such as cigarette smoke or pollution. According to Shyam Biswal, PhD, EHS associate professor, all of our lungs’ defenses—the entire pulmonary antioxidant network—are regulated by signaling pathway Nrf2, the same one targeted by Groopman and Kensler. The pathway not only protects our lungs but regulates many carcinogen-fighting enzymes throughout our bodies.

“With such a complex environmental stress response network as Nrf2,” Biswal asks, “how come people are still getting lung disease?” Further vexing is the question of why 20 percent of ex-smokers develop COPD, sometimes years after quitting.

In their attempts to answer such questions, Biswal and colleagues conducted experiments and found that COPD was linked with significantly reduced levels of Nrf2 activity. The research has yielded insight into lung conditions that extend beyond COPD. With Patrick Breysse, PhD ’85, MHS ’80, director of the Center for Childhood Asthma in the Urban Environment, Biswal is working to explore the role of Nrf2 in asthma.

In fact, drug development is in progress, as Biswal’s lab explores how “small molecule activators” can spur the Nrf2 pathway to “turn on” and tackle more toxicants. Biswal, Breysse and colleagues are hopeful that asthmatics will soon have access to a therapy that will kill the symptoms and halt the disease.

Biswal’s lab may soon make another big leap with its explorations into the lung health/Nrf2 partnership. The lab has found that the pathway is important in the body’s defense against lung infection, which can lead to pneumonia, one of the world’s most ruthless killers. An intervention that stimulates the gene and protects against pneumonia would be a great advance in public health.

Is the aging of cells merely an accumulation of
damage resulting from insult after insult over time,
or do age-related “events” also make cells
particularly susceptible to acute insult? A team of
reproductive biologists, a cell biologist and a
genome biochemist want to know.

The Mysteries of Age

Last summer, BMB professor Barry Zirkin, conducted an experiment using people, not rats. “We put a bunch of scientists in a room to see what would happen,” he says. “As usual, things happened.”

What resulted was a collaboration among BMB reproductive biologists, a cell biologist and a genome biochemist, all of whom want to answer questions about how, when and why cells are damaged as they age. “We know that when a cell ages, there is an altered balance between pro- and antioxidants, and that the imbalance may do irreversible damage,” says Zirkin, PhD. What’s unclear, however, is whether “aging” is merely an accumulation of damage that results from insult after insult over time, or whether, in addition, age-related events make cells particularly susceptible to an acute insult. These scientists—Haolin Chen, Mike Matunis, Paul Miller, Bill Wright and Zirkin—are writing a project program grant that would fund studies into both questions.

The team studies the mechanisms that affect the cell’s ability to protect and repair itself as it ages. They research the aging cell’s increased susceptibility to stress, its decreased ability to fend off insult and its diminished skill at repairing itself. Among its participants, biochemist Paul Miller, the grant’s principal investigator, is an expert in genome integrity and DNA repair; Zirkin, a reproductive biologist, knows stem cells and Leydig cells, which provide a tractable system for genome chemistry. “Studying genome integrity with these elegant methods [used by Miller] is not something a reproductive biologist would have thought about doing on his own,” says Zirkin. “It’s the coolest chemistry I’ve ever seen applied to a reproductive cell.”

Aging is a field rife with questions that beg to be explored. There is no real consensus, even, on what it means for a cell to be “aged.” How do we measure aging? “It differs from type of cell to type of cell,” says Zirkin. Do stem cells age? “We think they do.” Can we prevent cells from aging? “We can in a rat.”

The goal of BMB’s forays into the basic science of aging is intervention that would prevent or postpone conditions afflicting the elderly—osteoporosis, Alzheimer’s, decreased cognition and vitality, to name a few. Zirkin credits the public health mindset with guiding his own and the team’s research toward this kind of translation.

“You get seduced here,” says Zirkin, “and you ask yourself, ‘Is this basic science applicable to a population?’ ”

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