Stephen J. Elledge grew up the small town of Paris, Illinois, during the 1960s. Influenced by the space program and by science books he read at school, Elledge became fascinated at a young age by the atomic nature of matter and tried to learn as much about chemistry as he could. At around the age of 10, he successfully lobbied his grandmother, with whom he lived, to buy him a chemistry set — a gift that soon became one of his favorite possessions. His interest in chemistry continued into high school, where he joined the chemistry team and received first place in a regional science competition. “I had never won anything before,” he recalls. “That made me think that I could actually do something in science.”
Elledge decided to major in chemistry at the University of Illinois at Urbana-Champaign, which offered him a tuition scholarship. He was the first person in his family to attend college. One of his roommates, a pre-med student, tried to interest Elledge in biology, but he dismissed the idea. “I had a negative attitude about biology, because in high school it had seemed to be mostly about dissecting frogs and looking at plants and learning their weird names,” he says. Then, during his senior year, Elledge took a biochemistry course. “One of the lectures was on recombinant DNA, and it just blew me away,” he recalls. “Once I realized that biology was molecular, I got interested. I realized all the things that you could do with it.”
After receiving his undergraduate degree in 1978, Elledge decided to pursue biochemistry at the Massachusetts Institute of Technology (MIT) Biology Department. “It was a real mecca of molecular biology,” he says. “But I was far behind in biology. I had to take a large course-load to catch up, but I did catch up.” He ended up working at MIT with bacterial geneticist Graham Walker. For his thesis, Elledge identified and described the regulation of a group of proteins involved in the repair of DNA (known as the SOS response) in the bacterium Escherichia coli. While at MIT, he also developed a new method of cloning that greatly enhanced the ability to identify new genes — the first of many such genetic tools he has invented during his career.
In 1984, Elledge travelled west to begin his postdoctoral studies at Stanford University with biochemist Ronald Davis. “I didn’t go there to study DNA damage,” he recalls. “I didn’t even want to study DNA damage.” But while searching for a yeast gene that allows DNA to recombine homologously to allow gene targeting, Elledge accidentally came across a family of genes called ribonucleotides reductases (RNRs), which became activated when the yeast DNA was damaged or failed to copy itself properly. “That fact caught my interest,” he says. “I thought maybe there’s a system that signals this pathway.” He also wondered if the mechanism might be at play in mammals — including humans.
That idea embarked Elledge on an extraordinary journey of scientific inquiry and discovery that has transformed our understanding of how cells respond to DNA damage and, subsequently, our approach to treating cancer and other serious diseases. Working with his own team of graduate students and postdoctoral researchers — first at the Baylor College of Medicine (1989-2003) and later at Harvard Medical School (2003-present), Elledge discovered and described — in elegant detail — the molecular mechanisms of what is now known as the DNA-damage response pathway, first in yeast and then in mammalian cells. Going against what was conventional scientific wisdom at the time, Elledge defined the DNA damage response — the protective gene functions that delay the progression of a cell’s cycle when its DNA is damaged and regulate the expression and activity if proteins needed for DNA replication and repair — as a signaling cascade that starts within the cell itself. He was the first to identify that a pair of “watchdog” protein kinases (proteins that modify other proteins) work together to detect and then notify each other when DNA damage is presence in a cell. He also described how that joint action then sets off a complex cascade of other molecular activity within the cell to repair the damaged DNA. Elledge and his team not only characterized how this detect-and-repair process works, but also how and why it sometimes fails — a breakdown that can lead to the formation of cancer. Indeed, many of the genes and proteins Elledge has identified as part of the DNA-damage response — including BRCA1, BRCA2, CHEK2, ATM, ATR, 53BP1, and USP28 — are now known to be key contributors to familial and sporadic cancers.
When talking with non-scientists about the extraordinary molecular complexity of the DNA-damage response, Elledge sometimes compares the different kinds of DNA repair to road work. “Many common types of DNA damage –like an oxidized base- are very simple cut and patch repairs, much like filling in a pothole on the road. However, other repairs are much more complex, for example fixing a collapsed DNA replication fork is much more like repairing a collapsed bridge, and that takes a lot of coordination,” he says. “It also takes a lot of materials — and you have to make the materials and get the different materials to the right spot in the right order and at the right time. You also have to suspend things and shore them up from underneath. That’s also what happens when you break a DNA replication fork. You need machinery that senses the problem and organizes all the workers to send out the right repair response at the right time.”
In addition to his pioneering discoveries regarding the DNA-damage response pathway, Elledge is also renowned for inventing numerous genetic technologies that have helped advance the field. With molecular biologist Greg Hannon, for example, he developed the first genome-wide shRNA libraries, as well as methods to screen them, thus making large-scale genetic screening a reality. More recently, Elledge has led the development of an antibody detection tool (VirScan) that can determine — from a simple blood test — which of more than 200 viruses have infected a patient during his or her lifetime. Elledge and his team are currently investigating other possible applications for this technology, including for the early detection of cancer.
Elledge continues to work and teach at Harvard Medical School, where he is the Gregor Mendel Professor of Genetics and Medicine. He has received numerous honors and awards for his work over the years, including memberships in the National Academy of Sciences and the American Academy of Arts and Sciences. Elledge is also an investigator with the Howard Hughes Medical Institute. His wife, Mitzi Kuroda, PhD, is a Harvard geneticist. They have two grown children, Daniel and Susanna.