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George Daley aims to efficiently reprogram cells, with help from lessons learned on cellular senescence.
Adding just four genes can turn adult cells back into embryonic-like cells, able to develop into any cell type in the body, according to Daley's studies. In culture dishes, cells from a younger postdoctoral fellow in Daley's group were “youthful and vigorous,” he says; many of them morphed into stem cells. But Daley's cells were stubborn, refusing to reverse their clocks. It seems as a person ages, cells get increasingly stuck in their ways.
Daley isn't taking it too personally. “I'm deficient in a lot of things, and reprogramming seems to be one of them,” he says. He plans to use the observation to understand how to reprogram cells most efficiently.
His finding points out an important concept: cells might not sprout gray hair, get achy joints, or forget where they put their car keys, but they do age. Several HHMI researchers are just beginning to learn what happens to cells as they grow old, and they're making connections between those changes and cancer, deficiencies in wound healing, and other problems that increase in likelihood as a person ages.
The first inkling that cells might grow old came in the early 1960s, when gerontologist Leonard Hayflick was playing with cells in culture. The conventional wisdom at the time held that cells in a culture dish could split an indefinite number of times. But Hayflick found that after 50 or so divisions—now called the Hayflick limit—cells stopped dividing. The cells turned into zombies. They didn't die but remained in a kind of hibernation, a state known as cellular senescence.
Over the following decades, researchers elucidated the environmental conditions that push cells to senesce and defined many of the genes and molecules that control the process. Several signals can put cells to sleep. Accumulating DNA mutations can send cells into senescence. Fraying chromosomes also serve as a trigger. Protective caps of DNA called telomeres keep chromosomes from unraveling, but each time a cell divides, its telomeres get a little shorter. When telomeres get too short, chromosomes can break or fuse with other chromosomes, shuffling the genome and possibly causing cancer. A third signal also links to cancer. In 1997, HHMI investigator Scott Lowe of Cold Spring Harbor Laboratory, New York, and his colleagues found that activating a cancer-causing gene forces cultured cells into senescence.
Photo: Leah Fasten