David Mangelsdorf, professor and chair of pharmacology at the University of Texas Southwestern Medical Center, has a lifelong fascination with big, high-risk challenges in science. That fascination has led him to understand the role of an “orphan” nuclear receptor in liver metabolism — and the development of drugs that target liver disease. Mangelsdorf joined the Morgridge Institute Scientific Advisory Board in 2025.
Learn more about his pursuits in this Q&A, which first appeared in Fearless Science Magazine.
When did you realize metabolism and nuclear receptors would be your scientific path?
As a graduate student I worked in a laboratory at the University of Arizona that discovered the vitamin D receptor — a protein in the nucleus of the cell that helps regulate calcium metabolism. I credit my mentor, Mark Haussler, a scientific rock star who made science fun. In his lab, we had to join a journal club where we took turns presenting papers and one was on the new technique of cloning genes. That sparked my interest to clone the vitamin D receptor. My philosophy at the time was, I’m going to take the riskiest project that I can think of, knowing that if it fails, it fails, but I will have learned a lot. Or this could be something that would transform the field, which it did.
How did that philosophy influence your career?
For my postdoc I went to Ron Evans’ lab at the Salk Institute. He was this guru molecular biologist wizard who is one of the most cited scientists in the life sciences, and he had this same philosophy. The first time I met him, he said to me: To answer a big question, you have to ask a big question. So I decided to ask: Are there any more of these nuclear receptors? It was a high-risk project, but that’s what I did. I have a high tolerance for risk. I call it making the meal or cleaning it up. Cockroaches do a great job of cleaning up the meal. I don’t want to do cockroach science. You could be very successful building on what others have done, but I wanted to be the person writing the stuff that’s going into the textbooks. How did you build on your knowledge of receptors to reach your breakthrough on liver treatment? At Ron Evans lab, I discovered what were called orphan receptors, proteins that looked like nuclear receptors, but we had no idea what they did. It turns out there are 48 of them, and when I came to the University of Texas Southwestern Medical Center, I worked on one that turned out to be very important in liver metabolism and cholesterol homeostasis. The bile acid receptor that we discovered is now an FDA-approved drug target for diseases of the liver, and we were off to the races.
What is a current area of focus for you and your lab partner Steven Kliewer?
In animal models we found that FGF21 sends a signal to the brain to stop drinking more alcohol. If you knock out FGF21 receptors in the brain, or you knock out FGF21, they’ll drink more than they normally would, but if you give it as a drug, they have an aversion to alcohol. We also noticed they will drink three or four times as much water as normal, which is important because alcohol dehydrates you. We don’t know if this would work in humans, but in mice it also creates body heat, which can prevent hypothermia caused by alcohol. Does FGF21 have the potential to be like what Narcan does for opioid overdose?
Another outstanding question was whether FGF21 can also regulate how long an intoxicated animal remains unconscious. We gave mice a binge dose of alcohol after eliminating FGF21 from the body and they remained unconscious two to three times as long. Remarkably, if you do the same experiment and instead give a therapeutic dose of FGF21, the animals wake up three to four times faster. We figured out the brain mechanism that FGF21 works through to have this effect. And now we’re studying whether this mechanism can reverse binge drinking suppression of breathing and heart rate.
Clinically it could be very useful. If a person comes into the emergency room unconscious from alcohol, having a compound to give as a shot that wakes them up faster could potentially save their life. And it could save millions of dollars by not keeping them in the emergency room for as long. We’re exploring this now with a new startup biotech company.
What is the impact you think this work can bring to the world?
Steven Kliewer and I are truly 100% equal team, and we’ve discovered four or five things that turned out to be therapeutic. I’ve always wanted to strive to make change, not incrementally, but giant leaps forward that require that high tolerance for risk. Howard Hughes Medical Institute has funded my research for three decades, and at the end of every five-year funding cycle they ask: Where would this field be if David Mangelsdorf did not exist? Did you change the trajectory? And so that’s been my goal, to change the trajectory.
Fearless Science Magazine
This story was featured in Fearless Science Magazine. The inaugural issue focuses on regenerative biology. How do some of the world’s most clever and fascinating organisms redevelop critical body parts after injury? And what might it mean for future advances in human health, from heart repair to infectious disease?
