‘Mighty Mouse and the Conqueror Worm’
By Deborah Wormser
What do a cartoon mouse and a poem by Edgar Allan Poe have in common? The UT Southwestern Medical Center community is invited to find out when Dr. David Mangelsdorf, Chairman of Pharmacology, delivers the next President’s Lecture: “The Mighty Mouse and the Conqueror Worm: Superheroes in the Fight to Cure Obesity, Kill Parasites, and Extend Lifespan.”
Dr. Mangelsdorf said his presentation, scheduled for 4 p.m. Sept. 20 in the Tom and Lula Gooch Auditorium, will describe the divergent paths his investigations have taken, the unique ways the UT Southwestern community enabled his quest, and the role of serendipity in his career.
“In many cases you have to be able to allow yourself to expand your horizons when the opportunity arises and follow a lead that’s unexpected,” said Dr. Mangelsdorf, a Howard Hughes Medical Institute (HHMI) investigator at UTSW.
“The HHMI is very good at funding a person and not simply a project. In fact, it is mandated that you be innovative, that you do something that is risky, outside the norm,” he said.
The open atmosphere at UT Southwestern makes it easy to follow basic science wherever it leads, even if that means crossing disciplines, he added.
Dr. Mangelsdorf is renowned for the things he never set out to do: finding a therapy for treatment-resistant skin cancer based on his postdoctoral work; identifying possible new ways to lower cholesterol or treat type 2 diabetes; and outlining a revolutionary strategy to eradicate a group of parasites that have plagued humans for centuries. Yet, he has done all that and more simply by devoting himself to pure, basic research.
In March, the Karolinska Institutet, the prestigious Swedish medical university that is home to the Nobel Assembly, honored him with the 2012 Rolf Luft Award, an international prize for advances in diabetes and endocrinology research.
Dr. Mangelsdorf, also Professor of Biochemistry, never expected to study roundworms when he did postdoctoral work under Dr. Ronald Evans at the Salk Institute for Biological Studies in California. There, the young researcher became fascinated by proteins called orphan nuclear receptors. They were known as orphans because no one knew what they did in the body or even what hormones bound to them.
Their very mystery attracted Dr. Mangelsdorf, and inspired him to pursue the research that showed how they act as on-off switches for the genes in pathways controlled by hormones, he recalled.
His early experiments with Dr. Evans confirmed that humans have 48 nuclear receptors, and that they are part of one family, a hotly disputed idea at the time.
Many years later, Dr. Mangelsdorf thought it would be interesting to see if there were any nuclear hormone receptors in a lower-order creature such as the tiny nematode roundworm C. elegans.
By then, Dr. Steven Kliewer, Professor of Molecular Biology and Pharmacology and also a former postdoctoral student from the Evans lab who shared a fascination with the orphan receptors, had teamed up with Dr. Mangelsdorf. To their surprise, the C. elegans worm has 284 receptors – nearly six times as many as humans – all of which were orphans. These orphan receptors were just too tempting of a research target, Dr. Mangelsdorf said.
Nematodes have another interesting feature: the ability to enter suspended animation as a larva. That feature, called dauer, allows the worm to extend its lifetime by going dormant until conditions improve, a process controlled by an orphan nuclear receptor that senses and responds to conditions of starvation and of plenty, Dr. Mangelsdorf said.
He and his colleagues showed that the nuclear receptor gene that is central to dauer has two evolutionarily related receptors in humans, which happened to be two his lab was already studying: FXR and LXR, another case of serendipity, Dr. Mangelsdorf said.
Although C. elegans is not a parasite, most nematodes are parasites. Finding a way to make the parasitic worms exit the dauer stage before they get to the host would theoretically vanquish the conqueror worm. Lab researchers tried that strategy in a cell culture dish and achieved eradication, he added.
The mighty mouse of his title refers to his work on the orphan nuclear receptors involved in insulin metabolism in mice. Studies under way in his lab hold the promise of reducing obesity, and maybe even extending human life.
Locally, Dr. Mangelsdorf is known for many things, including his sense of humor, which is obvious from the origami paper airplanes hanging in his office, the star-shaped confetti scattered on his rug, and even by the name of the research group – the Mango Lab – that he has run jointly since 2002 with Dr. Kliewer.
Dr. Mangelsdorf’s many career recognitions include election to the prestigious National Academy of Sciences in 2008 and receipt of the 2007 Edith and Peter O’Donnell Award in Medicine from The Academy of Medicine, Engineering and Science of Texas. A graduate of Northern Arizona University, Dr. Mangelsdorf earned a doctorate in biochemistry from the University of Arizona.
Dr. Mangelsdorf holds the Distinguished Chair in Pharmacology, and the Raymond and Ellen Willie Distinguished Chair in Molecular Neuropharmacology in Honor of Harold B. Crasilneck, Ph.D.
Dr. Kliewer holds the Nancy B. and Jake L. Hamon Distinguished Chair in Basic Cancer Research.