Columbia University has decided to award the Louisa Gross Horwitz Prize 2018 to:
Institute of Advanced Study at the Strasbourg University and Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Strasbourg, France
Ronald M. Evans
Salk Institute, La Jolla, CA, USA and Howard Hughes Medical Institute, Chevy Chase, MD, USA and
Bert W. O’Malley
Baylor College of Medicine, Houston, TX, USA
“for their discoveries of how steroid hormones regulate the behavior of distant cells.”
Horwitz Prize Awarded for Work on Hormones
If you open up your medicine cabinet, it’s a safe bet that you’ll find a drug that targets a nuclear hormone receptor. Columbia University awards the 2018 Louisa Gross Horwitz Prize to Pierre Chambon, Ronald M. Evans, and Bert W. O’Malley for their research–spanning over 50 years–decoding how steroid hormones and nuclear receptors regulate cell function. This work has transformed our understanding of human physiology and disease.
Steroid hormones like cortisol and estrogens were first identified in the early 1900s. Researchers observed that these chemicals could travel long distances from one organ to another, and that they influenced a wide variety of biological processes including development, reproduction, growth, metabolism, and inflammation. But just how hormones worked remained a mystery for decades.
When molecular biology techniques became available in the 1960s, scientists could finally begin to more precisely probe at the mechanism by which hormones act. Using these tools, O’Malley’s laboratory demonstrated that steroid hormones modify gene expression. This was a paradigm shift, because until then many researchers thought that hormones worked by directly interacting with enzymes or manipulating the cell membrane. In a series of papers published between 1967 and 1972, O’Malley’s team showed that steroid hormones enter the cell and bind to nuclear receptors, a specialized protein that enters the nucleus and modifies gene activity. This tinkering of gene expression triggers biological changes in the cell and physiological changes in the body.
In the 1980s, scientists built on this work and isolated the genes that code for steroid hormone receptors. Teams led by Chambon and Evans were the first to discover and clone the genes for estrogen and cortisol receptors, respectively. Previously, researchers had predicted that the number of nuclear receptors would be small. But one of the big surprises that came from comparing the sequences of these nuclear receptors was that there were dozens of similar genes.
The laboratories of Chambon and Evans, in conjunction with others, proceeded to identify and isolate many of these related genes, mapping out a “superfamily” of 48 human nuclear receptors that collectively regulate a wide array of biological processes. Some of the genes they discovered had no hormone associated with them, and so were named “orphan receptors.” This work opened up a new field of biology, and showed that a variety of molecules–not just steroid hormones, but thyroid hormones, bile acids, fatty acids, and others–could also bind to nuclear receptors to regulate the gene expression of cells over great distances in the body.
Following these seminal discoveries, subsequent work by all three scientists has continued to add important details to the molecule-by-molecule picture of how the 10 trillion cells in our body communicate with each other and stay in functional harmony. Unravelling these mysteries has given us deeper insight into the pathways that lead to a variety of human diseases. Today, drugs targeting nuclear receptors comprise 13 percent of all U.S. FDA-approved pharmaceuticals. These drugs treat everything from the most commonplace to the most serious conditions–including over-the-counter topical cortisone for skin inflammation, prescription rosiglitazone for type II diabetes, and tamoxifen, the most widely used cancer drug in the world.
Our ability to treat such a diverse array of diseases began with scientists who connected the dots between hormone, receptor, and gene.
Comments from Committee Chair
Gerard Karsenty, MD, PhD, chair of the Horwitz Prize Committee and chair of the Department of Genetics and Development at Columbia University Irving Medical Center: “Nuclear receptors are a Rosetta Stone for physiology; their discovery and characterization helped solved mysteries about many of our most fundamental biological processes that were first unearthed nearly a century ago. The work of