Many clues to how cancer develops have come from probing the cell cycle—the predictable, yet complex series of steps that culminate with cell division. Research by geneticist Stephen J. Elledge has uncovered important clues about what drives the cell cycle and how cells sense and respond to DNA damage.
He has also contributed on a broad level to advances in scientific disciplines by developing new cloning methods, as well as building cDNA libraries, collections of DNA snippets that code for proteins.
Growing up in Paris, Illinois, in the 1960s, one of Elledge's favorite toys was a chemistry set, and he spent countless hours carrying out all sorts of experiments. "God only knows what I thought I was doing, but I loved it," he recalled. Eventually, however, one of his concoctions blew up in his grandmother's kitchen, staining the ceiling. Elledge was sent to his room, and the chemistry set was banished to the basement. But this setback did not quell his desire to become a chemist.
The first in his family to go to college, Elledge attended the University of Illinois on a scholarship and majored in chemistry. But he was drawn to the field of biology after hearing about recombinant DNA during a senior year biochemistry course. "The potential for transforming biology was very clear, even stunning," Elledge remembers. "And I decided I wanted to be a part of that."
While pursuing a Ph.D. at the Massachusetts Institute of Technology, Elledge often found time for side projects, and he made a hobby out of developing new methods for generating recombinant DNA. Once, frustrated by his lack of success in using existing cloning methods, Elledge combined one of his earliest discoveries, the hybrid lambda-plasmid cloning vector, which was capable of making very large cDNA libraries, with his knowledge of yeast genetics, to invent a cloning technique that could genetically select protein-protein interactions from a very large library. "This technique and the 20 different cDNA libraries I made and freely distributed had a large impact on helping other labs identify important interacting partners for the proteins they were interested in," Elledge explained. "I firmly believe that new technology drives science and generally has a much larger impact than individual basic science discoveries."
It was during a postdoctoral fellowship at Stanford University that Elledge began to focus his attention on the cell cycle. By accident, he cloned a family of genes known as ribonucleotide reductases, and later found that they were activated by DNA damage and regulated by the cell cycle. Soon after this discovery, Elledge attended a lecture by Paul Nurse, a scientist who later won the Nobel Prize in Physiology or Medicine for his cell cycle research. Nurse had recently isolated the human homolog of a key cell cycle gene, Cdc2, and his studies indicated that cell cycle regulation was functionally conserved from yeast to humans and that many human cell cycle genes could be isolated by looking for complementary genes in yeast.
This message struck a chord with Elledge, and he set to work by first building a human cDNA library that could be expressed in yeast. Using this library, he identified a gene known as Cdk2, which is related to the gene previously isolated by Nurse. Cdk2, Elledge discovered, controls the transition from the G1 to the S phase of the cell cycle, and errors in this step that often lead to cancer.
Elledge, with his colleague Wade Harper, also isolated the p21 gene, which he demonstrated was the first of a family of Cdk2 inhibitors. The same gene was also found to be regulated by the cancer gene p53. Mutations in this gene occur in about half of all cancers. Elledge also discovered that the p57 gene, a member of the p21 family, is mutated in individuals with the Beckwith-Wiedemann syndrome, a disease that causes familial overgrowth and an increased risk of cancer.
While looking for additional cell cycle genes, Elledge and his colleagues identified the F-box, a conserved motif that is present in some proteins. F-box-containing proteins recognize specific protein sequences and mark them with ubiquitin for destruction by the cell's built-in shredder, a multiprotein structure called the proteasome. Increased levels of certain proteins can disrupt the cell cycle, so destroying them is one way to ensure that cells continue to divide normally or stop dividing all together, as required by the organism.
Elledge's research has also led to important discoveries about how cells detect and repair DNA damage, uncovering a whole signal transduction mechanism that alerts cells to chromosome defects. He recently identified the Chk2 enzyme, which activates the tumor-suppressor p53 to prevent cells with damaged DNA from dividing. When this enzyme is missing or defective, the "brakes" on cell division are released, increasing the risk of cancer. In other studies, he demonstrated that a protein known as ATM is a "trigger" for the protein BRCA1 to repair DNA damage. Mutations in ATM and BRCA1 together may account for nearly 10 percent of all breast cancers.
The point of the research, for Elledge, is not just merely an academic exercise in how things work, but an attempt to get to the roots of cancer and other health problems. "I have always wanted to make an impact on the world, to have my life on earth count for something," he said. "By contributing to basic research, I hope my work can accelerate discoveries to improve the lives and health of people."