Reverse genetics

Werner's syndrome is an inherited disease that causes premature aging. People who have the disease appear old by the time they've reached their twenties. In addition, they often suffer from a variety of other age-related ailments such as arteriosclerosis, osteoporosis, cataracts, and malignant growths.

Several years ago, researchers isolated and cloned the gene that, when mutated, is responsible for this disease. The achievement capped a bit of painstaking detective work called reverse genetics. Take a physical trait, isolate the gene that causes the trait, and then isolate the protein produced by the gene. The process enables researchers to pinpoint the genetic mutations responsible for pathologies. It also enables them to pinpoint the genes responsible for normal function -- in this case how the body fends off aging.

Researchers traced Werner's syndrome to a gene dubbed WRN. If both copies are mutant, the gene can't repair DNA damage and the carrier ages much more quickly than normal. In healthy people, however, the gene is active and repairs certain types of DNA damage that cause aging. Even if someone has one mutant copy, the other good copy works. Hoping to take this research even further, Campisi is studying just how the protein produced by the gene repairs DNA damage.

Unraveling with age

Shoelaces have plastic caps at each end to keep them from unraveling. Chromosomes in cell nuclei have caps at each end too, also to keep them from unraveling. The caps are protein complexes called telomeres, and they are extremely important for maintaining the stability of the genome and preventing cancer.

Simply stated, telomeres mark the ends of chromosomes. They stabilize the free end of chromosomes so they don't fuse together. In addition, their presence indicates to the cell that the end of a chromosome is normal, and not a broken piece of DNA in need of repair. But each time a cell divides, the telomeres become shorter. Eventually, after many divisions, the telomere becomes too short to protect the chromosome from unraveling. At this critical stage, a signal is sent to the cell to begin senescence. The cell stops dividing, rather than risk an unraveled, unstable genome that may cause cancer.

Campisi is studying this fundamental process. She wants to learn more about the structure of the human telomere, how its length is regulated, and how this length regulates cell senescence. "We are trying to understand how telomeres function and how they prevent the instability of the genome that occurs with aging," she says.