This is how the researchers discovered a population they named DARE cells. "Not only did these cells survive the irradiation — they multiplied, repaired the damaged tissue and replenished nearly half of it within 48 hours," Braun says.

That raised a follow-up question: if DARE cells accounted for nearly half of the repaired tissue, where did the rest come from? The team found a second group of death-resistant cells, which they called NARE cells. These differed from DARE cells in one crucial way: their initiator caspase had never been activated.

"Although NARE cells ultimately contribute to tissue regeneration, they cannot do it alone," Braun notes. "When we removed DARE cells from the system, compensatory proliferation disappeared entirely. We also found that dying cells in the tissue play a role in the burst of regeneration — DARE cells were activated by signals from their dying neighbors."

How DARE cells escape their death sentence

The death process in DARE cells begins normally: the initiator caspase switches on. But the pathway then stalls before the effector caspases can complete the cell's destruction.

"We observed that although the initiator caspase is activated in these cells, the cellular death process stops there and does not progress to the next stage," Arama explains. The researchers suspected that a protein acting as a molecular motor was responsible. This motor can tether the initiator caspase to the cell membrane, blocking it from activating the executioner caspases.

"Indeed, when we silenced this motor protein, DARE cells proceeded to die and tissue regeneration was impaired," Arama says. "Overactivation of the same motor protein has previously been linked to cancerous tumor growth, which suggests that this might be one of the mechanisms that enables cancer cells to evade apoptosis."

That connection matters because treatments such as radiation therapy often work by damaging tumor cells enough to trigger their self-destruction.

Survivors pass on their toughness

Tumors that return after radiation therapy are frequently more aggressive and more difficult to treat. The researchers therefore asked whether cells surviving an initial dose of radiation pass their resistance on to future generations.

"We found that when the same tissue is irradiated a second time, the number of cells that die during the first few hours is half that seen after the first irradiation, and most of the dead cells belong to the NARE population," Arama says. "In other words, the descendants of DARE cells were found to be exceptionally resistant — seven times more resistant to cell death than cells in the original tissue. This may help explain why recurrent tumors become more resistant after radiation."

The discovery carries a double edge. A lasting survival advantage is useful when healthy tissue must recover from injury. But in cancer, the same trait could allow dangerous cells to persist despite treatment.

A built-in braking system

Rapid regeneration carries its own risk: growth must eventually stop, or a repair response could spiral into uncontrolled proliferation. In the final stage of the study, the researchers uncovered a signaling system between the two cell populations that appears to hold this balance.

"DARE cells promote the growth of nearby NARE cells, apparently by secreting growth signals," Arama notes. "In turn, NARE cells secrete signals that inhibit the growth of DARE cells. In fact, we've discovered a negative-feedback loop between the two cell populations that prevents overgrowth."

From flies to humans — with caveats

All of these experiments were performed in fruit flies, so additional research will be needed to establish how closely the same mechanisms operate in people. Fruit fly models have, however, repeatedly helped scientists uncover fundamental biological processes that later proved to have important parallels in humans.

"We hope that, as has often been the case with fly models, the knowledge gained here can be translated into an understanding of the mechanisms that balance growth and confer resistance to cell death in human tissues," Arama concludes. "Many cancers originate in epithelial cells that have lost normal growth control, and many traditional cancer treatments aim to cause them to self-destruct through apoptosis. Our findings pave the way for understanding why such treatments sometimes fail and how they could be improved. The results also point toward new ways in which we might be able to accelerate beneficial regeneration of healthy tissue after injury."

The study also included contributions from Naama Afgin, Dr. Lena Sapozhnikov, and Dr. Keren Yacobi-Sharon of Weizmann's Molecular Genetics Department; Dr. Ehud Sivan from Weizmann's Life Sciences Core Facilities Department; Prof. Andreas Bergmann of UMass Chan Medical School in Worcester, Massachusetts; and Prof. Luis Alberto Baena-Lopez of the Severo Ochoa Molecular Biology Center in Spain.