That aging and cancer were related was common knowledge, since the risk of cancer increases with age. But few suspected they might be two sides of the same coin, sharing a mechanism through which the scales could be tipped either way.
As I researched and wrote p53: The Gene That Cracked the Cancer Code, I became intrigued by how often apparent experimental failures have provided vital clues to unraveling the mysteries of this particular gene.
Even the discovery of p53, in 1979, was arguably the result of failure. By coincidence, four different labs, working independently and unaware of each other’s quests, discovered p53 simultaneously. Three were working with the oncogenic monkey virus SV40, trying to isolate the specific viral gene and its protein product responsible for causing tumors. But no matter how hard they tried, none of the groups was able to separate the viral protein from one produced by the host cell—a protein with a molecular weight of 53 kilodaltons, which seemed to piggyback on the viral protein. Fellow scientists were apt to dismiss the pesky cell protein as a contaminant. Fortunately, the researchers—David Lane in London, Arnie Levine in Princeton, and Pierre May in Paris—recognized something significant, though they had little clue as to just how significant it would turn out to be. They published their results and turned their attention to figuring it all out.
The first step was to clone the gene coding for the mysterious piggybacking host protein in order to obtain endless copies for research. But those early clones turned out to be mutants, which led everyone up a blind alley. They suggested p53 was an oncogene, a tumor driver, rather than a tumor suppressor. It was only when Levine’s clone failed repeatedly to reproduce everyone else’s results that the light bulb went on: his was the only normal clone, and it didn’t cause cancer. Clearly, normal p53 was not an oncogene.
Not long after researchers recognized p53 as a tumor suppressor, experiments showed that the gene product’s modus operandi is to ensure faithful copying of DNA when cells divide. If DNA is damaged during mitosis, p53 stops the cell cycle in its tracks, and sends in the repair team before allowing the process to proceed. Once again, it was a failed experiment that revealed yet another, more potent ploy in the gene’s anticancer repertoire: p53’s product can induce senescence and even suicide in cells that are beyond repair.
At Israel’s Weizmann Institute in 1990, Moshe Oren was moving his small lab to another room. Unbeknownst to him and his team, the thermostat malfunctioned on one of two cabinets containing rat embryo fibroblast cultures with identical p53 mutants plus the oncogene ras. In the affected cabinet, where the temperature was lower, the cells’ transformation was inhibited and their growth was arrested, while they continued to transform and proliferate in the neighboring cabinet under what the researchers believed were the exact same conditions. It took time and repeated failure of the experiment in the faulty cabinet for Oren to grasp what was happening, and to realize that they had stumbled across an invaluable tool in molecular biology: a p53 mutant that was temperature-sensitive, behaving like wild type below 32 °C and a mutant at 37 °C. But most importantly, working with this new tool they soon made the heady discovery that the wild-type gene can force cancer cells to kill themselves by apoptosis.
Many other apparent failures pepper the study of p53, and most suggest a universally relevant lesson: never be too ready to dismiss as scientific failures things that don’t go the way we expect, for setbacks may prove fruitful after all.
Sue Armstrong is a science writer and foreign correspondent. Her previous book, A Matter of Life and Death: Inside the Hidden World of the Pathologist, was published in 2010. Read an excerpt of p53: The Gene That Cracked the Cancer Code.