Diabetes Dateline
Winter 2009

NIDDK News

NIDDK Grantee Wins National Medal of Science

Bert O’Malley, M.D., a long-term grantee of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), was awarded a National Medal of Science for his outstanding contributions to knowledge in the biological sciences.

Former President Bush presented the award to O’Malley on September 29, 2008, recognizing “his pioneering work on the molecular mechanisms of steroid hormone action and hormone receptors and co-activators, which has had a profound impact on our knowledge of steroid hormones in normal development and in diseases, including cancer.”

O’Malley, chair of Baylor College of Medicine’s department of molecular and cellular biology, is the first scientist in the field of molecular endocrinology to receive the medal, considered the highest national honor in biological sciences.

“O’Malley’s prodigious career is a tribute to the importance of basic research,” said NIDDK Director Griffin P. Rodgers, M.D., M.A.C.P. “His research revolutionized the understanding of hormone action and the molecular regulation of processes as basic as metabolism and reproduction.”

Much of O’Malley’s early work focused on the steroid hormones—glucocorticoids, mineralocorticoids, androgens, estrogens, and progestagens—that regulate reproduction and basic metabolism. He used the tools of physiology and biochemistry to study the hormones’ role in reproduction and developmental diseases and was one of the first to apply new methods as they were introduced.

Unique Properties

In the 1980s, evidence was growing that receptors for steroid hormones had unique structural properties and belonged to a common family of receptors. Instead of attaching to receptors on the cell surface, these hormones linked up with receptors in the cell and its nucleus and acted as transcription factors to change the expression of genes.

After the first nuclear receptor was cloned, scientists went on to find 49 more, including those for steroid hormones, thyroid hormones, certain vitamins, and still-unknown hormone receptors. These “orphan receptors” also turned out to have profound effects on cells.

“O’Malley was one of the first to create an in vitro transcription assay, or a test tube system, that could recapitulate what happened inside a cell to study the changes in gene expression,” said Ronald Margolis, Ph.D., NIDDK senior adviser for molecular endocrinology. “His assay stimulated much research that led to an even greater understanding of hormone action because scientists could use the method to study their favorite hormone and receptor.”

Master Genes

“Hormones control almost all cellular physiology,” O’Malley explained. “Receptors for steroid hormones, the most important class of hormones, are activated by the hormone. They then go into the cell’s DNA and search out and find the target genes to be turned on or off. In the final step, they recruit complexes of co-regulators, including co-activators, that perform all the functions to turn the genes on. In a sense, these co-activators are master genes because they can activate different transcription factors at the same time, so you get a coordinated physiologic outcome.”

Forging ahead, O’Malley and colleagues came to a stunning conclusion: Nuclear receptor co-regulators control physiologic processes as basic as cell growth, metabolism, inflammation, and reproduction. And if defective, these “little molecules with big goals” can lead to disease.

“When the activities of these master genes are compromised, cellular processes can quickly deteriorate,” said O’Malley. In overdrive, some can spur the uncontrolled growth of cancer cells.

O’Malley is principal investigator of the Nuclear Receptor Signaling Atlas, a trans-National Institutes of Health consortium that provides a central source of information about hormones, nuclear receptors, and co-regulators. To date, 300 co-regulators for 49 nuclear receptors have been found, and 165 co-regulators have been linked to disease.

For more information about the Nuclear Receptor Signaling Atlas, go to www.nursa.org.

NIH Publication No. 09–4562
March 2009

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