Gut feeling

Temperatures hit the 100-degree mark and just kept climbing on the summer day when Juanita Merchant tackled Lava, the most challenging rapid on her 8-day rafting trip through the Grand Canyon in 1993. Only the occasional splash of chilly river water offered relief as her oar dipped in and out of the churning froth. But the heat was hardly her main concern. Stroking in synchrony with her raft-mates, Merchant could only hope that they would slide into Lava at precisely the proper point and paddle at just the right moment to avoid crashing into boulders or flipping over. There was no turning back, no second-guessing. It was a matter of trusting their instincts, believing that the river would eventually smooth out and take them where they wanted to go.

Trusting one’s instincts is as important in research as in roiling rapids, says Merchant, a 1984 graduate of Yale’s M.D./Ph.D. program who is now an associate professor at the University of Michigan. Her recent work on stomach ulcers is a case in point. Ultimately, she and her co-workers showed last year that suppressing stomach acid with prescription drugs called proton pump inhibitors can allow bacteria to flourish, triggering inflammation and ulcers that may lead to cancer. But before they could reach that conclusion, the scientists had to rethink almost everything they had been taught about stomach acid secretion, and to trust clinical observations and experimental results that seemed to fly in the face of conventional wisdom.

The standard textbook explanation of how acid secretion is regulated revolves around the hormone gastrin, which is produced by specialized cells in the stomach when acid levels are low. Gastrin acts on acid-secreting cells to induce and maintain the proper level of acidity; then a feedback mechanism turns off further gastrin production and acid secretion. But this time-honored view doesn’t square with what Merchant and other gastroenterologists see in patients infected with Helicobacter pylori, the bacterium implicated in ulcers. Somehow, Helicobacter thwarts the feedback response, and the stomach just keeps pumping out acid, which eventually leads to ulcers. To better understand the process, Merchant’s research team developed a strain of mice that couldn’t produce gastrin. The plan was to infect these mice with Helicobacter and see if they would still develop inflammation and ulcers. The researchers ran into a snag that again challenged their assumptions: mysteriously, infecting the mice with Helicobacter was virtually impossible, and yet the uninfected animals were showing signs of inflammation, just as if they had bacteria in their guts.

“We could have just said, ‘Well, this isn’t working, so let’s chuck this model and move on to something else,’” says Merchant. “But I knew we had technically executed this experiment correctly, so I reasoned that the data must be telling us something. I always tell my postdocs that it’s almost like there’s a secret door waiting to be uncovered. If you sit down and really organize your data and look at it without tunnel vision, without being bound by assumptions, you’ll find a way to move through that door.”

By scrutinizing their data and carefully performing a series of experiments, the researchers figured out that low acid levels in the gastrin-deficient mice had allowed a variety of other bacteria to flourish in their stomachs, preventing Helicobacter from gaining a foothold. But far from protecting against the effects of Helicobacter, these other bacteria, such as Staphylococcus and Pseudomonas, were themselves triggering inflammation.

“It seems that the stomach is almost like a rheostat, with acid levels controlling which organisms end up growing there,” says Merchant. Helicobacter thrives when acid levels are high; when levels drop, other bacteria take over. The finding that these other bacteria can stir up their share of trouble overthrows the notion that Helicobacter is the only bug behind the kind of chronic stomach inflammation that can lead to cancer.

But the implications of Merchant’s research don’t end there. If low acid levels allow bacteria to run rampant, what does that mean for the millions of Americans who seek relief from heartburn and ulcers by gulping down acid-controlling pills every day? Merchant can’t say for sure, but another set of experiments in mice suggests that long-term use of such drugs may do more harm than good. In these experiments, Merchant and colleagues at the University of Michigan treated normal mice for two months with a proton pump inhibitor, a type of drug that blocks acid secretion (Prilosec and Prevacid are examples). Sure enough, the mice developed inflammation that subsided only when the burgeoning bacteria were controlled with antibiotics. Merchant isn’t telling patients to dump their pills, but she cautions against taking high doses over years or decades.

She plans to follow up the findings with studies of patients. “Mice obviously can’t tell you when something hurts or feels better,” says Merchant, a former Howard Hughes Medical Institute investigator who sees patients on rotation as an attending physician in the U-M Health System. “So we really need to correlate the inflammatory changes due to these other bacteria to symptoms that patients have.”

Though she never set out to overturn the view that Helicobacter is the sole culprit in ulcers or to question the use of popular acid-reducing drugs, once the results were published—in the January 2002 issues of Gastroenterology and the American Journal of Physiology/Gastrointestinal and Liver Physiology—Merchant felt prepared to stand behind her conclusions. She had braced herself for criticism, but says that so far it hasn’t come. In fact, in an article in the April American Society for Microbiology News, Martin J. Blaser, M.D., whose earlier work uncovered the Helicobacter-ulcer connection, agreed that getting rid of Helicobacter can allow other bacteria to colonize, with potentially harmful results. And in a commentary in the November 2002 issue of Gastroenterology, the journal of the American Gastroenterological Association, Richard M. Peek Jr., M.D., concurred with Merchant’s hypothesis that other bacteria can induce and perpetuate the inflammation.

Even if peers had been critical, Merchant probably wouldn’t have wavered. Wavering just isn’t in her makeup. That confidence comes in part from her scientific and medical training, she says, but also from earlier influences.

“My mother was a teacher, and she raised my brother and me by herself,” she explains. “My father left when I was in fourth grade, and seeing my mother struggle at such a young age made a lasting impression. She also instilled in us the importance of getting an education and not letting anything deter us.” That resolve, in turn, traces back to Merchant’s mother’s childhood on a small farm in Oklahoma, where her mother was determined to help the family get ahead. “It was a family of 13, and everyone was expected to work on the farm,” says Merchant, 46, who now has a daughter of her own, 3-year-old Olivia. “I remember my mother telling me that her mother used to take her place in the field so that she could go to school.”

Determination does run deep in Merchant’s lineage, but she would be the first to acknowledge that sheer will and ability aren’t always enough. Sometimes you need an expert guide to show you the way, she says, again drawing parallels between whitewater rafting and negotiating the career challenges of a physician-scientist.

“As a novice rafter, there were times when my well-being was completely dependent on the skill of the guide calling out orders from the rear of the raft,” she recalls. Similarly, she would have been adrift without mentors who guided her, from her undergraduate days at Stanford through her time at Yale, where she studied with Russell Barrnett, to her faculty position at Michigan. It was in Barrnett’s lab that she learned “how to think about science” while working on membrane biogenesis in the duck salt gland. Her very first mentor as a sophomore Stanford pre-med student was Renu A. Heller, Ph.D. ’69, who suggested she obtain both a doctorate and a medical degree at Yale. She’s also grateful to her first clinical mentor, Rosemarie L. Fisher, M.D., FW ’75, professor of medicine at Yale, who helped her stay focused on her goals and showed by example that a woman could succeed in a male-dominated subspeciality. Now in the mentor’s role, Merchant is the one at the rear of the raft, offering guidance to her students and postdocs. It’s not enough simply to expect them to follow her lead, she believes. To make sure they’re adequately equipped for their future careers, she meets with each person in her lab individually. “We have little training sessions: How do you write an abstract? How do you present a 10-minute talk? How do you present an hour-long talk? How do you write a five-page grant? How do you write a 10-page grant? I could just hand them a stack of examples, but it’s not the same as having me sit next to them explaining how to do it.” But unlike the whitewater guide, you won’t hear Merchant barking orders.

“I believe,” she says, “in a gentler approach to bringing people along.”