A Molecular Pathfinder

Call it a happy accident: Stephen Elledge (BS ’78, chemistry) was doing his postdoctoral research at Stanford University in 1984 when he stumbled across a family of genes known as RNRs. Through RNRs, he discovered the genes that sense damaged DNA and trigger its repair—a process vital to the prevention of cancer and other diseases.

“It was all an accident,” says Elledge. “I found this gene by chance, and then I just happened to look at whether it could be induced by DNA damage.”

Whenever cells were damaged, he noticed that the levels of RNR shot up by 20 to 100 times—the biggest clue to their role in the DNA repair process. This was Elledge’s first major finding, and it put him on a path of discovery that continues today in his position as a leading genetics professor at Harvard University. “Path” is the operative term because an important part of his research has been analyzing and understanding the pathways that cells take to sense and repair DNA damage. This work puts him at the forefront of using genomic approaches to combat cancer and has earned him a 2013 LAS Alumni Achievement Award.

Elledge’s personal pathway began in Paris—that’s Paris, Ill., (population 8,664). After an elementary school fascination with dinosaurs, his interests went to the opposite extreme—from the largest creatures on the planet to the smallest.

“When I first learned about atoms and molecules in grade school, I saw that the more you pulled back, the more that was there,” he says. “I was fascinated by the intricacies of matter.”

In his early years, Elledge used his chemistry set to blow up things in his kitchen, but his fascination with molecular matter eventually led him to the University of Illinois, where he received his bachelor’s in chemistry in 1978. During his U of I years, a study abroad program in England drew him to biology, and he went on to receive his PhD in biology from the Massachusetts Institute of Technology in 1983. The next stop on his path was Stanford, where he discovered the role of RNRs in repairing cell damage. This discovery, in turn, led him to Baylor College of Medicine, where he taught and did research for the next 13 years.

The DNA damage response pathway is crucial because without it, damaged cells will proliferate, creating mutations that fuel cancer, Elledge explains.

“Basically, there are proteins that scour your chromosomes, testing them to find out if there is a problem,” he says. “If they find damage, they send out signals to recruit other proteins to come and fix the problem, and they send out messengers that say they don’t want the damaged cells to divide right now. They’re flipping a lot of switches and marshaling all of these events to fix the chromosome before it is duplicated.”

In the 1990s, Elledge’s lab found the Cdk2 inhibitor p21—a gene that shuts down the cell duplication process when problems arise. They also identified F-box proteins, which tag certain proteins so they will be destroyed.

“Sometimes, you want to get rid of a protein very fast because it’s doing something you do not want at that moment,” he says.

Elledge says that duplicating a cell is analogous to duplicating a small city. “In a cell, there are lots of structures you have to remake. There have to be blueprints and building blocks, and if mistakes are made, you have to identify them and fix them. In the end, proteins are just little machines. They move things around, and they turn things on and off. Cells also have power plants and purification systems to get rid of waste products—like a city.”

Elledge and his wife, who is also a genetics professor, both left Baylor in 2003 and took positions with Harvard, and they remain there today, living on the edge of Boston. His lab has gone on to discover numerous tumor suppressors, as well as genes that control the duplication of various viruses, such as HIV, hepatitis C, and influenza. For instance, they identified genes that trigger the system that shuts down the flu virus.

“It turns out that some people are missing this gene, and they are 20 times more likely to be in the hospital with the flu,” he says. People of Asian descent are especially prone to having two defective copies of this important gene, making them more susceptible. In addition, there is a whole family of these genes, which protect people from many other dangerous viruses, including the West Nile virus, yellow fever virus, and SARS.

Elledge’s research has earned him many awards, such as the Paul Marks Prize for Cancer Research in 2001, an election to the National Academy of Sciences in 2003, a DAMD Breast Cancer Innovator Award in 2004, and the Lewis S. Rosenstiel Award for Distinguished Work in the Basic Medical Sciences in 2013. He was even given the “keys to the city” of Paris, Ill., in 2011.

Many investigators have contributed to research on a cell’s response to DNA damage, but “Dr. Elledge stands out because he contributed to every single aspect of this process in a major way,” says Angelika Amon, an investigator at the Howard Hughes Medical Institute. “His research has framed a major approach to human disease for the last 20 years, and will continue to do so.”