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Path to Excellence: From NAU to the National Academy of Sciences

David Mangelsdorf

Professor and Chairman: Department of Pharmacology at the University of Texas Southwestern Medical Center

1981 BS in Aquatic Biology and Chemistry

David Mangelsdorf's research is leading to important breakthroughs in treating such vexing health conditions as heart disease, cancer, cholestasis, atherosclerosis, infectious parasitic disease, and gallstone disease. As the first Northern Arizona University alumnus to be elected to the prestigious National Academy of Sciences, he's also the first to admit he never imagined his research would lead to new drugs that could potentially battle metabolic syndrome or obesity.

But Mangelsdorf learned a long time ago—in a classroom on NAU's campus, circa 1976, en route to undergraduate degrees in aquatic biology and chemistry —to follow the science.

"You can be as smart as you want, you could do all the right experiments," he says, sitting in his office at the University of Texas Southwestern Medical Center, where he is the chairman of the Department of Pharmacology, "but it's nothing if you don't have a little bit of serendipity."

In the lab, Mangelsdorf's focus has been on discovering the components of pathways that turn genes on and off in a cell's nucleus, as well as the nuclear receptor proteins that turn genes on and off when they meet a trigger molecule called a ligand. The research has led to greater understanding of the effects of hormones. For example, Mangelsdorf discovered that a cholesterol derivative is the ligand for a nuclear receptor called LXR, which has a key role in cholesterol regulation. From there came the discovery that bile acids serve as ligands for another receptor, FXR, which works with LXR to reset lipid metabolism after a meal.

"There are a couple of clinical trials going on based on the pharmacology that we developed around discovering that receptor," he says. "So, it's now in the clinical trial phase for fighting cardiovascular disease."

Without the ability to keep an open mind—a skill Mangelsdorf implores the up-and-coming generation of scientists to hone—it's likely those crucial findings may still be left undiscovered.

As a high school student in Kingman, AZ, Mangelsdorf grew up with a bit of a fascination with Jacques Cousteau, dreaming about the day he could learn to be a marine biologist. As such, he wrote to the admissions office of Scripps Institute of Oceanography, or at least he thought he did. As it turns out, his letter ended up at Scripps Women's College by mistake, though it eventually landed in the right hands. He received a letter in return, explaining that the college only offered graduate programs, but he should consider getting the "good, solid undergraduate experience" he needed closer to home: at NAU.

"They directed me toward NAU's programs…I was blown away by that," Mangelsdorf says. "They said that NAU had one of the best vertebrate biology programs in the country…and one of the best forestry schools in the world."

When he landed in a class taught by John Wettaw—to this day, still a friend to Mangelsdorf—he was turned on to chemistry so much that he added it as another major. It was another course in biology, taught by a parasitologist named Stanley Wilkes, that is "burned into my memory," he recalls.

David Mangelsdorf and John Wettaw standing infront of the Wettaw building at Northern Arizona University Dr. Mangelsdorf, with his mentor, Dr. Wettaw, in front of the Wettaw building where Dr. Mangelsdorf returned to NAU to give the seminar A Lesson in Biology: How Studying a Metabolic Pathway in Worms can impact Human Health.

"The scientific background I got from the courses I took at NAU clearly helped when I went out on the market for a graduate school," he says. "My faculty members in graduate school were so impressed with what I already knew…the education and foundation that was laid was important."

It wasn't just a foundation—it was also the springboard to excellence in science. Mangelsdorf's groundbreaking work in the development of new treatments for battling high cholesterol and other diseases is highly regarded and highly rewarded. The appointment to the National Academy of Sciences is one of the highest honors for an American scientist.

"That's the grand prize—that tells you that what you did was worth it and you're respected for it and people understand it," Mangelsdorf says. "It's the culmination of every scientist in America's dream."

It's a dream Mangelsdorf hopes that the budding scientists on the NAU campus realize is not impossible, if they take advantage of the opportunities surrounding them.

"You need the wisdom and ability to understand that things aren't always what they seem," he says. "Don't fit the experiment to your hypothesis; fit your hypothesis to your experiment."