The importance of molecular endocrinology: A conversation with Mitchell A. Lazar, MD, PhD
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Key takeaways:
- Lazar will receive the Fred Conrad Koch Lifetime Achievement Award at ENDO 2023.
- Lazar is a molecular endocrinologist with specific focus on the regulation of gene expression and metabolism by nuclear receptors.
CHICAGO — Mitchell A. Lazar, MD, PhD, has always been interested in organic chemistry, biochemistry and mental illness, which led him to delve into research on the regulation of gene expression in response to hormones, metabolites and drugs.
“I love science because its goal is to discover and understand natural phenomena, finding laws and mechanisms underlying all aspects of the world that we live in,” Lazar, the Willard and Rhoda Ware professor in diabetes and metabolic diseases at the Perelman School of Medicine and founding director of the Institute for Diabetes, Obesity and Metabolism at the University of Pennsylvania, told Healio.
Though he partakes in many hobbies outside of endocrinology, such as solving puzzles, reading, watching movies and keeping active, Lazar holds a strong interest in the history and philosophy of science.
Lazar is the recipient of the Fred Conrad Koch Lifetime Achievement Award from the Endocrine Society presented at ENDO 2023 because of his lifetime achievements and exceptional contributions to endocrinology. Previously, Lazar has received many awards including two Method to Extend Research in Time (MERIT) Awards from the NIH, the Karolinska Institute’s 2019 Rolf Luft Award and the Endocrine Society’s Richard E. Weitzman Memorial, Edwin Astwood and Gerald D. Aurbach Awards.
Healio: What was the defining moment that led you to your field?
Lazar: In school I loved organic chemistry and biochemistry, and at the same time, I had a family history of mental illness. When I put that together, my interests and my realization that we didn’t understand mental illness, I decided to try to understand the biochemistry of behavior. I went to Stanford’s MD/PhD program, and once I was there, I learned how complex behavior is. I loved what I was doing, but realized I was not going to solve the problem of the biochemistry of behavior. In fact, it probably wouldn’t be solved in my scientifically productive lifetime. But studying the biosynthesis of a neurotransmitter called dopamine was so exciting.
My project focused on how dopamine levels could feed back and inhibit the enzyme, which was rate-limiting in the pathway making dopamine, starting with an amino acid tyrosine, which is a metabolic pathway. When I went to clinical training and learned about different fields of medicine, I learned feedback inhibition and the maintenance of the internal milieu by regulatory mechanisms were the basic tenets of endocrinology. When I went to the clinic and got more experience in endocrinology, I fell in love with the breadth and science of this exciting field.
Molecular endocrinology provides an opportunity to understand how our bodies maintain themselves, sensing the internal and external environments and adapting by sending hormonal signals that respond or adapt. This is important because if we don’t eat, we must produce more glucose by hormones that stimulate that, and if we eat, we must put away the sugar by glucose and simulate that. Understanding the basic underpinnings of this process is not only satisfying from the point of view of someone who really wants to understand scientific mechanisms, but has a great impact for human health.
Healio: What area of research in endocrinology most interests you right now and why?
Lazar: I’m interested in organismal metabolism, how our bodies regulate our internal metabolism. This is a complex function of what we eat, how our bodies process it and the machinery in our cells that regulates gene expression. This is driven by several factors, but one of them is called nuclear receptors. These receptors sense classical hormones like thyroid hormone and steroid hormone. But also, we’ve learned of other metabolites that need to be sensed to then adapt to whether they’re high or low.
The adaptive mechanisms that I study are circadian clocks in the body, which anticipate the relatively predictable changes that occurred during the 24-hour day. We’re living in an over nutritive environment where food is plentiful. Although there is starvation and hunger in the world, there’s even more obesity. We’re interested in understanding the adaptive and maladaptive responses that occur in response to excess nutrition leading to obesity, and then importantly, complications including diabetes and fatty liver.
Healio: Have you ever been fortunate enough to witness or to have been part of health care history in the making? If so, what was it?
Lazar: In 1994, my lab simultaneously and independently from another lab run by Bruce Spiegelman, PhD, at Harvard, discovered that a nuclear receptor, PPAR gamma, was critical for the biology of fat cells. We were looking for a factor that was important for making fat cells and controlling their activity for a long time, and our work made it clear that PPAR gamma was a great candidate.
Around the same time, a class of drugs called thiazolidinediones drugs, or TZD drugs, were developed to treat type 2 diabetes. These drugs improved insulin resistance, but the mechanism was unknown, although it was known that obesity is the major cause of insulin resistance. PPAR gamma was a nuclear receptor from that family that is regulated by hormones, but what regulated it was unknown. These drugs were already going into the clinic for insulin resistance, but what they regulated was unknown.
In 1995, a year after the discovery of PPAR gamma as an adipocyte factor, Steve Kliewer, PhD, and his colleagues at GlaxoSmithKline discovered that TZDs were binding to PPAR gamma receptors, which put it all together. This helped that field because we like to feel like we know how a drug works when we’re giving it to people. These TZDs were a mainstay of type 2 diabetes therapy. Unfortunately, they have side effects that limit their use. Since then, other medicines are prescribed in preference to TZDs, but they remain the most powerful way to improve insulin resistance and reduce insulin levels in type 2 diabetes.
Looking back and looking forward, I believe that better understanding of how these drugs work will allow future development of more effective medications with fewer side effects, which are still needed given this immeasurable rise in the prevalence of type 2 diabetes.
Healio: What do you think will have the greatest influence on your field in the next 10 years?
Lazar: My field is focused on the regulation of gene expression in response to hormones, metabolites and drugs. That gene expression comes from the genome, and the nuclear receptors that we study act in the genome. They bind, read the code of the “dark matter” of the non-protein coding genome and do their job in different cell types. Sequencing of the human genome was a major breakthrough, but we don’t yet have the sequences of full genome for every individual, although we’re on our way there. It’s becoming less expensive to do that.
Over the next 10 years, access to these genomes of every person will allow predictability and basic understanding of individual gene expression as it relates to all aspects of health, including drug responses. This will open huge opportunities for personalized medicine by knowing which individuals will be better off with certain types of diets, how people respond to psychosocial stresses that might affect their gene expression and how they might benefit or be harmed by different medicines.
Healio: Do you have any good ideas that would have a positive benefit for the world?
Lazar: I am deeply concerned that science and scientists are increasingly influenced by unconscious bias regarding their hypotheses. This has led to what’s become a crisis of reproducibility in science. It’s happening at a time when the concepts of truth and even facts are being challenged in all parts of our society, politics and social lives, as well as in science. For example, we saw unproven ideas being falsely hailed as effective in the treatment of COVID-19.
Science must remain a trusted bastion of truth and facts. The problem that we have is partially perpetuated by the reward systems for promotion and awards for scientists. These are largely based on the number of publications and the status of the journals. We have a peer review system that’s intended to keep the system in check, but it seems to be not good enough. Too many things are getting by that turn out to be false and the public can lose confidence in science.
My good idea is to find a way to reward reproducibility by quantifying the impact of science, not only by the status of the journal or the number of times it’s cited by other scientists, but by the number of times the results have been reproduced by other scientists and by more advanced discoveries made possible by earlier foundational work. That should be quantified, recognized and rewarded. In the same spirit, we should reward studies reproducing important results, even those that didn’t find it for the first time. In our current system, studies inspiring confidence in the original results aren’t easy to publish and aren’t rewarded. My good idea is to reward aspects of science consistent with our goal of improving and ensuring reproducibility.
Healio: Whom do you admire and what would you ask that person if you had 5 minutes them?
Lazar: There are so many people that I admire, and especially singer songwriters. I’m going to give a shout out to Mark Knopfler. He is an amazing guitarist and songwriter, and was the front man for Dire Straits before transitioning to a great career as a solo artist. I would love to ask him to teach me to play guitar like he does, but since that would be impossible, I would ask him how he gets inspired to write his songs. In particular, he has a knack of writing cool songs about interesting celebrities and news events that he poetically addresses and sets to beautiful music that he composes, which matches the story. I am just a big fan. I’d enjoy talking to him about how he puts it all together to be such a great writer and artist.
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