Bone and Mineral Research Award Celebrates Career of Michael A. Levine, MD

For Michael A. Levine, MD, a pediatric endocrinologist, scientist, and fixture in the bone and mineral research community for nearly four decades, few things are a greater source of pride than to be honored by one’s own peers. The medical director of the Center for Bone Health at Children’s Hospital of Philadelphia and chief emeritus of the hospital’s Division of Endocrinology and Diabetes, was recognized Sept. 29 by the American Society of Bone and Mineral Research (ASBMR) — an organization he describes fondly as his “home society” — with the 2018 Frederic C. Bartter Award.

Given each year to an ASBMR member for their “outstanding clinical investigation” in disorders of bone and mineral metabolism, the Bartter Award is a testament to Dr. Levine’s robust research career. Over the last 40 years, he has led numerous scientific breakthroughs that advance our understanding of the complex genetic and molecular basis of inherited bone and mineral disorders, from hypoparathyroidism to genetic rickets. Dr. Levine has also published over 300 manuscripts, chapters, and reviews on the subject of bone and mineral metabolism and remains an active member of numerous organizations in addition to the ASBMR.

“It’s always extremely gratifying to be recognized by one’s home society and to have your work and contributions acknowledged as significant,” Dr. Levine said. “The [ASBMR] consists of individuals around the world who do similar work to mine, who I write papers with and for, and whom I consider my fellow scientists, my peers.”

This social and convivial aspect of science — getting to know one’s fellow scientists as individuals — plays a big part in how Dr. Levine entered the bone and mineral metabolism field in the first place. While interviewing for a postdoctoral position at the National Institutes of Health, Dr. Levine knew he was interested in cellular metabolism, particularly in the signals that inform cells to multiply and function, but he hadn’t yet settled on a clinical subspecialty. He chose the lab of the late Gerald Aurbach, MD, primarily because of the characters of the individuals within it.

“I felt that their personalities and their approach to science and life were in total alignment with my own,” said Dr. Levine of Dr. Aurbach and his research associates, Stephen Marx, MD, and Allen Spiegel, MD. “I selected that lab to pursue my training based on their outlook on life. I knew they did cellular signaling, but I didn’t know what particular organ they focused on or what kind of patients they saw until I had already committed myself to working with them.”

Though Dr. Levine acknowledges that this approach is a somewhat backwards way to choose a specialty (many scientists select a clinical focus first and then seek a mentor), looking back on a career that spans 40 years, he calls it an “excellent choice.”

In the years to follow, Dr. Levine and his research teams identified the gene mutations that cause pseudohypoparathyroidism, a disorder in which the body is unable to respond to parathyroid hormone, and its contrasting syndrome, McCune-Albright Syndrome. Dr. Levine showed that these two syndromes — the former characterized by hormone resistance and the latter by hormone excess — are both due to mutations in the same gene, GNAS. In pseudohypoparathyroidism, GNAS is inactive, while in McCune-Albright Syndrome, the gene possesses a gain-of-function mutation that turns off cell signaling (leading to hormone excess).

“It was remarkably satisfying to take two clinical syndromes that appear, from an endocrine point of view, to be opposite ends of the spectrum, and to actually show that both of these processes reflect contrasting either loss-of-function or gain-of-function mutations,” Dr. Levine said.

Dr. Levine’s work has also been instrumental in advancing our understanding of parathyroid gland function and development. Many years ago, he made the first observations that genetic hypoparathyroidism constituted a diverse number of distinct genetic disorders, and described the first loss-of-function mutation in the gene encoding parathyroid hormone (PTH). Since then, his lab has been an international leader in extending our knowledge of the different genes that can cause inherited hypoparathyroidism.

Most recently, in the realm of vitamin D homeostasis, Dr. Levine led novel research that identified two new forms of genetic vitamin D deficiency in patients with genetic mutations that cause vitamin D-dependent rickets (VDDR), a disorder associated with impaired growth, weak bones, and skeletal mineralization. Dr. Levine described how the latest mutation that his group described leads to activation of an enzyme that causes rapid degradation, or clearance, of vitamin D metabolites, thus elucidating a new mechanism for vitamin D deficiency.

With this new knowledge in hand, Dr. Levine and his team are now studying the effectiveness of rifampin, a drug used for years as an antibiotic to treat infections, as a potential treatment for patients who have an opposite condition, idiopathic infantile hypercalcemia. Individuals with this condition have high levels of vitamin D metabolites because they have mutations in CYP24A1, the gene that provides the pathway that normally reduces vitamin D metabolites.

“We were able to figure out the molecular basis for low vitamin levels in a number of unusual patients with severe rickets, and then by understanding the regulation of the causative gene, we were able to come up with the idea to repurpose rifampin to activate an auxiliary clearance pathway for patients who lack the normal mechanism for degradation of vitamin D metabolites,” Dr. Levine said.

Over the next years, Dr. Levine hopes to continue studying the genetic basis of rare forms of bone and mineral disorders, identifying novel mechanisms and genes that reveal fresh insights into the physiology of the bone and mineral systems that regulate calcium, phosphorous, and bone strength. His research goals also include developing a therapeutic research program for patients with hypoparathyroidism involving the regeneration of parathyroid tissues. He plans to continue evaluating the efficacy and safety of rifampin as a treatment for patients with CYP24A1 mutations.

As for what the Frederic C. Bartter Award means to him, Dr. Levine says that the success he has enjoyed would not have been possible without his fellow scientists.

“Science isn’t the result of one person,” Dr. Levine said. “It’s the result of collaborations, and I’ve been very fortunate to have great collaborators working with me here at CHOP and around the world. I’ve also been very lucky to have wonderful fellows, postdocs, and other junior faculty, who are extremely bright and who have taught me a great deal. So this award is something that has one person’s name on it, but it really recognizes a large team of investigators.”