In an application of the technique called RNA interference, or RNAi, Lowe and his research team isolated liver stem cells and genetically altered them with both an oncogene (ras) and small RNA molecules specially designed to keep p53 silent. They then seeded the livers of live mice with these engineered cells and, not surprisingly, the animals developed a virulent kind of liver cancer. As the cancers advanced, the mice were fed doxycycline, an antibiotic that by virtue of the researchers' genetic engineering blocked the RNAi. As a result, p53 switched on. And yes, the cancer did care.

With p53 active, the tumors disappeared. Whether Lowe gave the mice doxycycline continuously or intermittently, the results were the same.

"But when we looked at what exactly was going on in the tumor when p53 was on, that was the real surprise," says Lowe. They expected to see apoptosis, or cell suicide. Instead, they saw that the cancer cells had simply stopped dividing—a phenomenon called cell senescence—and that as soon as the cancer cells reached this senescent state, the immune system kicked in and attacked the tumor. Lowe suspects, though he cannot yet prove, that certain inflammatory cytokines (regulatory proteins that generate an immune response) secreted by senescent cancer cells might be attracting immune cells.

The Jacks team created a strain of transgenic mice whose genomes contained bits of DNA that functioned as a p53 lock, restraining the gene from any activity. These mice developed sarcomas (a type of solid tumor cancer), as well as blood cancers such as lymphoma. The mice had also been genetically engineered so that the drug tamoxifen could be used to switch on p53 activity. When the mice were given the drug, it induced an enzyme to splice the DNA lock out of the genome, thereby freeing p53. Unlike the cells in Lowe's experiment, Jacks found that p53 caused the lymphoma cancer cells to commit suicide. The sarcomas, on the other hand, stopped growing, the same senescent activity that Lowe witnessed. Jacks, however, didn't investigate any potential immune-system connection.

Jacks did discover, importantly, that while p53 was activated in every tissue of the mice, not just the cancer tissues, there were no adverse effects on healthy cells. Researchers aim for treatments that harm only the cancer and not healthy tissue.

Jacks and Lowe agree that any therapeutic approach aimed at reactivating p53 would have to take into consideration the ability of cancer cells to adapt and deactivate or circumvent the p53 pathway. But that hasn't dampened their enthusiasm for using p53 to fight cancer. Jacks plans to test p53 reactivation in other cancers and Lowe is digging deeper into that immune response sparked by cancer cell senescence.

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