A profile of BWH's Lasker Award winning Stephen Elledge, PhD and a look at his work on eukaryotic DNA damage response, as well as a new focus on the mechanisms of cell cycle control.
In some ways, the eukaryotic cell is akin to a miniature city: Mitochondrial energy plants power the cell; lysosomes act as garbage disposals for cellular waste; cytoskeletal motor proteins move vesicles and organelles within cells. “Cells have ‘roads' and ‘machines' and all the physical things you see in our world,” says Stephen Elledge, PhD, the Gregor Mendel Professor of Genetics at Brigham and Women's Hospital and Harvard Medical School. “And to duplicate these cells, you need to protect the blueprint – the DNA.” For decades, Elledge's laboratory has examined how cells accomplish just that. “Machines scour the genome looking for alterations in DNA structure,” Elledge explains. “When they find an alteration, they set off an alarm signal – a protein kinase cascade that relays information to other proteins in the cell – alerting them to go to a specific place at a specific time to fix the alteration.” Hundreds, if not thousands, of proteins are involved in the detection and response to DNA damage, a signaling-driven process that Elledge likens to an ambulance siren at the scene of an emergency. Unraveling the complex mechanisms involved in the detection and repair of DNA damage has been a focus of Elledge's career, earning him numerous awards and honors over the years. A member of the National Academy of Sciences and a Howard Hughes Medical Institute Investigator, Elledge is no stranger to success. In 2012, he received the Lewis S. Rosenstiel Award for unveiling the mechanisms used by eukaryotic cells to detect and repair DNA damage. A year later, his contributions to medical science garnered the 2013 Canada Gairdner International Award. This year, Elledge rose to a new level of recognition when his work on the eukaryotic DNA damage response won the Albert Lasker Award for Basic Medical Research, one of the highest honors in science. Elledge shared the award with Evelyn Witkin, PhD, a professor emerita at the Rutgers University Waksman Institute of Microbiology who characterized the DNA damage response in bacteria. While Elledge continues to explore uncharted territory in the mechanisms of cell cycle control, his current research also branches out a bit, using genetic and computational technologies to parse the mechanisms of tumor growth, reveal autoimmune targets, and drive gene and drug discovery. This summer, Elledge and colleagues published a report in Science describing a simple blood test, dubbed VirScan, which can reveal an individuals' entire history of viral infection. The test has diverse applications from screening blood and organ donations to detecting the risk of adverse events associated with the use of immune modulating drugs. Pat Fortune, PhD, Partners Innovation Market Sector Leader and a former top level pharmaceutical executive and long time life sciences venture capitalist, notes that “I have evaluated and managed a very large number of technologies in my career and the VirScan antibody platform has the potential to be one of the most impactful. Virscan and its successor technologies address many, highly diverse applications having substantial impact on patients and markets. Potential product applications include blood screening, tissue and organ transplants, drug safety and discovery of new agents to treat autoimmune diseases.” Other ongoing research in Elledge's lab parses the role of abnormal chromosome number, a phenomenon known as aneuploidy, in cancer progression. “People have always focused on mutations in tumor suppressors as drivers of cancer, but there's another thing that all cancer cells have in common: an incorrect number of chromosomes,” says Elledge, who helped devise a mathematical explanation of aneuploidy's effects in a 2013 Cell report. “If you look carefully at different types of cancer cells, you'll see that there's a pattern governing which chromosomes or chromosomal arms are lost or gained.” His lab also focuses on the role of cell senescence – a resting state in which cells are not actively dividing – in inflammation and aging. “Damaged cells can either die, through apoptosis, or they can exit the cell cycle and enter senescence,” he explains. “When they enter senescence, the cells secrete cytokines and chemokines, and generate an inflammatory environment that people associate with the effects of aging. In a September report in Science, Elledge and colleagues identified a molecular switch that turns on this inflammatory response. He explains, “If we can undo the inflammatory effect, we might be able to prevent aging.” So what's the next step? He smiles. “Let's get this into products that can help patients.”