The Cure for Broken DNA

Stephen Elledge returned from a pleasant weekend trip in 1985 to find that the research project he’d been working on for months had failed. That disaster was one of the best things that ever happened to him.

A postdoctoral fellow at Stanford University, Elledge was trying to develop a method to knock out mammalian genes. That capability would be a boon for researchers trying to pinpoint the functions of particular genes and delineate their roles in diseases. A key step in his plan entailed isolating the mammalian version of a bacterial gene called RecA that he thought would allow him to make the DNA changes necessary to disable a gene. The difficulty was that nobody had identified RecA’s mammalian counterpart. Elledge reasoned that capturing the yeast equivalent first would help him detect mammals’ version.

His strategy appeared to work. Analyzing yeast cells, Elledge used antibodies that latch onto the bacterial version of RecA to fish out what he thought was the right protein. Then he isolated and sequenced the corresponding gene. Before leaving for the weekend, he took what should have been the last step. He handed the DNA sequence over to a colleague, who was going to search the rudimentary gene database available at the time to confirm the discovery.

But the next Monday, his colleague said that Elledge had found the wrong gene. It had nothing to do with RecA and instead encoded a portion of ribonucleotide reductase, an enzyme that helps cells synthesize building blocks of DNA. “It was a blow,” says Elledge, now a geneticist at Harvard Medical School. “I was depressed.”

“Many other scientists would have gotten to that point and said, ‘I’ve got to find another way to find RecA,’” says molecular biologist and geneticist James Haber of Brandeis University. “Steve saw a much bigger picture.” Albeit reluctantly at first, Elledge delved into the functions of that unexpected gene, which codes for a protein he dubbed RNR2. He discovered that RNR2 was part of the DNA damage response, a cellular system that senses DNA breakage and orchestrates the requisite repairs. Researchers knew little then about the DNA damage response outside bacteria, but it became the focus of Elledge’s research for nearly 20 years. During that time, he and colleagues filled in the details of the process for yeast and mammals, uncovering many involved proteins and working out how they operate. Although other scientists also contributed to the effort, Elledge “put it all together” into a comprehensive view of the response, Haber says.

The DNA damage response is vital because our DNA takes a beating from external and internal insults, including sunlight, ionizing radiation, and destructive molecules produced by metabolism. Together, those assaults induce more than 30 quadrillion DNA alterations every hour in our bodies. “We couldn’t survive if we couldn’t cope with the natural processes that damage our DNA,” says Michael Kastan, a pediatric oncologist and cancer biologist at Duke University School of Medicine. In cancer, that protective system often breaks down, and its failures may contribute to other diseases such as Alzheimer’s.

“Steve was always at the forefront of the field, asking the next questions,” Kastan says. Elledge’s work on the DNA damage response earned him the 2015 Albert Lasker Basic Medical Research Award, which he shared with geneticist Evelyn Witkin of Rutgers University. But that research was just one of his contributions. “He’s not a one-hit wonder,” says molecular biologist Matthew O’Connell of the Icahn School of Medicine at Mount Sinai. “The breakthrough discoveries he made early in his career have continued to come out at a regular clip.”

Getting a Break
To succeed in science, Elledge overcame a tumultuous childhood. He was born in 1956 in Paris, Illinois, a farming town of about 10,000 people. In some ways, “it was kind of idyllic,” he recalls. “You could ride your bike all over town, play sports, and go exploring in the woods.” Elledge’s home life, however, was far from idyllic. Both parents were alcoholics. “I didn’t think anything of the police showing up or the couch being burned up” because one of his parents had fallen asleep holding a lit cigarette. Elledge’s father was sacked from several jobs because of his drinking. The family’s financial situation was so precarious that after his parents divorced, Elledge, his two sisters, and his father had to squeeze into a two-bedroom duplex with his grandmother. Although she had a good job as an accountant at a local department store, she sometimes took in boarders to earn extra cash. Elledge says that he didn’t realize until later that all families weren’t like his.

Science had interested Elledge from an early age, and chemistry had been his favorite subject since grade school. He attended college—the first in his family to do so—thanks to a scholarship to the University of Illinois. Elledge planned to become a chemical engineer because he’d heard “that’s what you do if you are good at math and chemistry.” But he changed course at the beginning of his second year. The mandatory course for chemical engineering majors didn’t fit into his schedule. He asked whether he could place out of the class by taking the final exam. When the teacher said no, Elledge changed his major to chemistry. In retrospect, it was the right choice, he says. Had he stuck with chemical engineering, “I’d probably be building acetic acid plants somewhere.”

Elledge admits that until late in his college career, he avoided biology. His high school biology class had been boring, and “I’d always thought it was like stamp collecting.” Then he took a biochemistry class that introduced him to the DNA manipulations that researchers were beginning to perform. “I said, wow, this is what I want to do.” Still, for graduate school he applied to—and was accepted by—biology and chemistry programs. He decided to study biology at MIT because it offered him more research opportunities. His undergraduate biology training consisted of that one biochemistry course, however. “I was completely behind everyone in my class,” he says. Elledge spent the next 18 months cramming in extra courses to catch up.

MIT introduced Elledge to bacteria’s SOS response to DNA damage, which Witkin had discovered. For his PhD research, Elledge dug deeper into the mechanism in the microbes, showing that a gene called umuC promoted a quick-and-dirty type of DNA repair. Meanwhile he took on a side project, devising a faster technique for cloning bacterial genes that became a standard approach in molecular biology labs.

Even at that early stage, Elledge showed two qualities that characterize the rest of his career. His curiosity is broad and restless. He doesn’t limit himself to studying just one topic. Elledge pursued other research questions while investigating the DNA damage response, making significant findings about immunology, protein breakdown, and other subjects. “It’s a rare scientist who can change fields dramatically and make such an impact in more than one field,” says molecular biologist David Cortez of Vanderbilt University, who was Elledge’s postdoctoral student between 1997 and 2002.

That Elledge spent so much time and effort on the cloning method also shows his commitment to creating and improving research technologies. “I have an engineering streak,” he says. Even if Elledge hadn’t invented a particular technique, “he would take what someone else had developed and make it more efficient and usable,” Cortez says. The technologies that Elledge fine-tuned include two-hybrid screening, a staple approach for identifying interactions between proteins. After nailing down a method, Cortez says, Elledge often distributed kits at his own expense so that other researchers could apply it.

Cellular Networking
Elledge started his postdoc at Stanford in 1984. “I didn’t intend to work on the DNA damage response,” he says. He planned to study plants but felt the field wasn’t yet advanced enough. Instead, he started the project to knock out mammalian genes that led to the accidental discovery of RNR2. Elledge uncovered an intriguing fact: The protein’s levels shot up in cells with DNA damage. But that wasn’t the protein he was looking for, so he shelved the findings.

About a year later, however, he mentioned the result to a visiting professor, who pointed out that ribonucleotide reductase levels were under precise control during the cell cycle, during which a cell prepares to divide. That conversation convinced Elledge that RNR2 was worth a second look. He determined that chemicals that prevent cells from copying their DNA also trigger a surge in RNR2. Elledge also identified the other two components of ribonucleotide reductase that partner with RNR2 in the DNA damage response. “Now that I had the pieces, I thought I’d figure out how it works,” he says.

After starting his own lab at Baylor College of Medicine in 1989, Elledge elucidated the DNA damage response in yeast. By analyzing mutants, he and colleagues identified many of the proteins that turn the system on and off. “He is the master of the genetic screen,” Haber says. Once Elledge and his team mapped the yeast system, they turned to the more elaborate and sophisticated response network in mammalian cells. As Elledge and other researchers have shown, the DNA damage response in mammals involves over 1,000 genes, including many that are mutated in cancer patients. p53, for example, is faulty in over half of cancers.

The system that Elledge and other researchers pieced together includes sensors that search for problems, intermediaries that pass on an alert, and managers that stimulate other proteins to take corrective measures. It reacts not only to DNA damage but also to other stressful events. For example, the system kicks in when the DNA duplication machinery gets stuck. Before Elledge started his research, “people thought very simplistically about DNA damage and repair,” Kastan says.” “It was looked at in isolation.” Elledge helped researchers see that the DNA damage response is systemic, involving many cellular processes. Moreover, it shapes the fate of a cell, influencing whether it can reproduce and whether it will live or die.

Elledge made two big moves in the early 2000s. He moved his lab to Harvard Medical School and stepped away from the DNA damage response. He says the field was relying more and more on biochemistry, whereas his expertise was genetics. “I thought, if I need to contribute I will go elsewhere. I have a lot of interests,” he says. In the last two decades, Elledge has probed the cancer-promoting condition aneuploidy, in which cells carry an abnormal number of chromosomes. He’s studied a cellular disposal system that breaks down proteins and that goes awry in illnesses such as Parkinson’s and Alzheimer’s. And he’s investigated how immune cells detect microbial invaders. “He’s constantly evolving and finding critically important new problems,” Haber says.

Elledge has continued to innovate. In 2015, he and colleagues debuted VirScan. By analyzing antibodies in a blood sample, that tool can determine which viruses a person has been infected with and how they affected the immune system. Using VirScan, the scientists showed in 2019 that the measles virus can scrub the immune system’s memory of past infections, potentially leaving people more vulnerable to reinfection. Elledge and his team also have built a library of proteins from all human viruses to probe how they pull off feats such as dodging the immune system. And Elledge hopes to make even more advances. “I have some exciting work going on. I don’t want to stop it.”

By Mitchell Leslie