西亚试剂：The elephant's tale

Uncovering TP53's role has taken a few years. Joshua Schiffman, a paediatric oncologist and scientist at the University of Utah in Salt Lake City, first heard about Peto’s paradox three years ago at an evolution conference, when Carlo Maley, an evolutionary biologist now at Arizona State University in Tempe, revealed he had found multiple copies of TP53 in the African elephant's genome.

Schiffman specializes in treating children missing one of their TP53 gene's two alleles, which leads them to develop cancer. So after hearing Maley's talk, he wondered whether elephants held some biological insight that could help his patients. He teamed up with Maley, who had not yet published his work, and asked elephant keepers at Salt Lake City’s zoo whether they could spare some elephant blood so that he could test how the p53 protein works in the mammals' white blood cells.

At about the same time, in mid-2012, Vincent Lynch, an evolutionary geneticist at the University of Chicago in Illinois, was preparing for a lecture on Peto’s paradox, and wondered about mechanisms that could explain it. “Right before I gave the lecture, I searched the elephant genome for p53, and 20 hits came up,” says Lynch.

Schiffman and Lynch’s teams have now independently revealed their findings — Schiffman's in theJournal of the American Medical Association¹, and Lynch's in a paper² posted to the bioRxiv.org preprint site, but which is in review at the journal eLife.

Using zoo autopsy records for 36 mammals — from striped grass mice to elephants — Schiffman’s team recorded no relationship between body size and cancer rate. (Around 3% of elephants get cancer, according to the team’s analysis of hundreds of captive-elephant deaths).

The researchers found that elephants produce extra copies of the p53 protein, and that elephant blood cells seem exquisitely sensitive to DNA damage from ionizing radiation. The animals' cells carry out a controlled self-destruction called apoptosis in response to DNA damage at much higher rates than do human cells. Schiffman suggests that, instead of repairing the DNA damage, compromised elephant cells have evolved to kill themselves to nip nascent tumours in the bud. “This is a brilliant solution to Peto’s paradox,” he says.

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