Elephants: Large, Long-Living and Less Prone to Cancer
In 1977, a University of Oxford statistician named Richard Peto pointed out a simple yet puzzling biological fact: We humans should have a lot more cancer than mice, but we don’t.
1977年，牛津大学(University of Oxford)的统计学家理查德·皮托(Richard Peto)指出了一个简单却令人费解的生物学现象：照理说，我们人类应该远比小鼠更容易患癌症才对，可事实却并非如此。
Dr. Peto’s argument was beguilingly simple. Every time a cell divides, there’s a small chance it will gain a mutation that speeds its growth. Cells that accumulate several of these mutations may become cancerous. The bigger an animal is, the more cells it has, and the longer an animal lives, the more times its cells divide. We humans undergo about 10,000 times as many cell divisions as mice — and thus should be far more likely to get cancer.
Yet humans and mice have roughly the same lifetime risk of cancer, a circumstance that has come to be known as Peto’s paradox.
A number of scientists have speculated that large, long-lived animals must evolve extra cancer-fighting weapons. And if that’s true, they reason, then the biggest, longest-lived animals should have an especially big arsenal. Otherwise, these species would go extinct.
“Every baby elephant should be dropping dead of colon cancer at age 3,” said Dr. Joshua D. Schiffman, a pediatric oncologist at the Huntsman Cancer Institute at the University of Utah.
拿大象这个物种来说，如若没有这样一种机制，“小象们在3岁前就会因为结肠癌而夭折殆尽。”犹他大学(University of Utah)亨斯迈癌症研究所(Huntsman Cancer Institute)的小儿肿瘤学家乔舒亚·D·希夫曼(Joshua D. Schiffman)如是说。
Writing Thursday in The Journal of the American Medical Association, Dr. Schiffman and his colleagues report that elephants appear to be exceptional cancer fighters, using a special set of proteins to kill off damaged cells.
希夫曼博士及其同事在10月8日的《美国医学协会杂志》(Journal of the American Medical Association)上报告，大象是杰出的抗癌斗士，它们可以利用一组特殊的蛋白质杀死受损的细胞。
Working independently, Vincent J. Lynch, an evolutionary biologist at the University of Chicago, and his colleagues have come to the same conclusion. Those researchers posted a draft of their paper on Wednesday on the bioRxiv server. It is currently in review at the journal eLife.
独立工作的另一组科学家——芝加哥大学(University of Chicago)的演化生物学家文森特·J·林奇(Vincent J. Lynch)及其同事也得出了相同的结论。这些研究人员10月6日在生物学预印网站bioRxiv的服务器上发布了他们的论文草稿，《eLife》期刊正在对该论文进行审稿。
Dr. Schiffman and his colleagues found in their research that elephants have a remarkably low rate of cancer. They reviewed zoo records on the deaths of 644 elephants and found that less than 5 percent died of cancer. By contrast, 11 percent to 25 percent of humans die of cancer — despite the fact that elephants can weigh a hundred times as much as we do. 纽约时报中英文网 http://www.qqenglish.com
To understand the elephants’ defenses, the scientists investigated a gene that is crucial for preventing cancer, called p53. The protein encoded by the gene monitors cells for damage to the DNA they contain. In some cases, it triggers the cells to repair the genes. In other cases, p53 stops cells from dividing further. And in still other cases, it even causes the cells to commit suicide.
One sign of how important p53 is for fighting cancer is what happens to people born with a defective copy of the gene. This condition, known as Li-Fraumeni syndrome, creates a lifetime risk of cancer of more than 90 percent. Many people with Li-Fraumeni syndrome get cancers as children and can have several types of cancer over their lifetimes.
Dr. Schiffman and his colleagues found that elephants have evolved new copies of the p53 gene. While humans have only one pair of p53 genes, the scientists identified 20 pairs in elephants.
Dr. Lynch and his colleagues also found these extra genes. To trace their evolution, the researchers made a large-scale comparison of elephants to other mammal species — including extinct relatives like woolly mammoths and mastodons whose DNA remains in their fossils.
The small ancestors of elephants, Dr. Lynch and his colleagues found, had only one pair of functional p53, like other mammals. But as they evolved to bigger sizes, they steadily evolved extra copies of p53.
“Whatever’s going on is special to the elephant lineage,” Dr. Lynch said.
To see whether these extra copies of p53 made a difference in fighting cancer, both teams ran experiments on elephant cells. Dr. Schiffman and his colleagues bombarded elephant cells with radiation and DNA-damaging chemicals, while Dr. Lynch’s team used chemicals and ultraviolet rays.
In all these cases, the elephant cells responded in the same way: Instead of trying to repair the damage, they simply committed suicide. Dr. Schiffman saw this response as a unique — and very effective — way to block cancer. “It’s almost as if they said, ‘We’re elephants — we’ve got plenty more cells where those came from,’ ” Dr. Schiffman said.
Patricia Muller, an oncologist at the MRC Toxicology Unit at the University of Leicester who was not involved in the studies, said the results, though compelling, didn’t firmly establish exactly how elephants use p53 to fight cancer. One possibility is that the extra copies don’t actually cause cells to commit suicide. Instead, they may act as decoys for enzymes that destroy p53 proteins. As a result, elephants can have higher levels of p53 than other animals. “All in all, it’s interesting, but the mechanism needs to be properly investigated,” she said.
未参与上述任一研究的莱斯特大学(University of Leicester)英国医学研究委员会毒理学部(MRC Toxicology Unit)肿瘤学家帕特里夏·马勒(Patricia Muller)表示，这些研究结果非常吸引人，但她也指出，它们并没有明确阐释大象是如何利用p53来对抗癌症的。一种可能性是额外的基因拷贝其实并不会导致细胞自杀。相反，它们只是充当了诱饵，消耗掉了破坏p53蛋白的酶，结果，大象体内的p53水平就会高于其他的动物。“总而言之，”她说，“这很有趣，但仍需要对个中机制进行适当的研究。”
Dr. Muller said it was especially important to understand precisely how elephants fight cancer before trying to mimic their strategies with drugs for humans. Experiments in which mice get extra amounts of p53 have shown that the molecule has a downside: It can accelerate aging. “It has to be kept under tight control,” Dr. Muller said.
Dr. Schiffman is now investigating how to translate the new findings on elephants into cancer treatments for people. But he said it would be useful to look at other big or long-lived animals as well. Naked mole rats, for example, live up to 30 years without ever getting cancer. One weapon they use is a protein that arrests the growth of fast-dividing cells. It senses when these cells bump into other cells and brings their division to a halt.
That is an entirely different solution from the one elephants appear to have evolved. And elephants are the only animals yet found that fight cancer with extra p53 genes. So Dr. Schiffman speculates that parrots, tortoises and whales may all have special longevity tactics of their own.
“The war on cancer was going on long before there were humans,” he said. “So let’s look at nature’s strategies.”