大象很少得癌是因爲它們的細胞會自殺
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，牛津大學(University of Oxford)的統計學家理查德·皮託(Richard Peto)指出了一個簡單卻令人費解的生物學現象：照理說，我們人類應該遠比小鼠更容易患癌症纔對，可事實卻並非如此。
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.
皮託博士的理論依據乍一看似乎很簡單。細胞每次分裂時都有極小的機率會產生可以加速其生長的突變。如果此類突變累積到一定程度，細胞就可能癌變。動物的體型越大，它身上的細胞就越多；動物的壽命越長，其細胞分裂次數也就越多。我們人類一生中要經歷的細胞分裂次數約爲小鼠的1萬倍，因此患癌症的風險也應比小鼠高得多。
Yet humans and mice have roughly the same lifetime risk of cancer, a circumstance that has come to be known as Peto’s paradox.
然而，事實上，人類與小鼠的癌症終生風險卻大致相同，這一現象被稱爲“皮託悖論(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.
許多科學家推測，體型較大、壽命較長的動物必定是演化出了其他的武器來抗擊癌症。如果事實果真如此，那麼，體型最大、壽命最長的動物就應該擁有一個超大號的抗癌軍火庫，要不然這些物種早就該滅絕了。
“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.
拿大象這個物種來說，如若沒有這樣一種機制，“小象們在3歲前就會因爲結腸癌而夭折殆盡。”猶他大學(University of Utah)亨斯邁癌症研究所(Huntsman Cancer Institute)的小兒腫瘤學家喬舒亞·D·希夫曼(Joshua D. Schiffman)如是說。
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《美國醫學協會雜誌》(Journal of the American Medical Association)上報告，大象是傑出的抗癌鬥士，它們可以利用一組特殊的蛋白質殺死受損的細胞。
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.
獨立工作的另一組科學家——芝加哥大學(University of Chicago)的演化生物學家文森特·J·林奇(Vincent J. Lynch)及其同事也得出了相同的結論。這些研究人員10月6日在生物學預印網站bioRxiv的服務器上發佈了他們的論文草稿，《eLife》期刊正在對該論文進行審稿。
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.
希夫曼博士和他的同事們在研究中發現，大象中的癌症發生率非常低。他們審查了644頭動物園大象的死亡報告，發現其癌症死亡率還不到5%。相比之下，儘管人類的體重只有大象的百分之一，卻有11%至25%因癌症喪命。
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.
爲了瞭解大象的癌症防禦機制，科學家們研究了一個對預防癌症非常關鍵的基因——p53。由該基因編碼的蛋白質可監視細胞內的DNA損傷。某些情況下，它會促使細胞修復受損的基因；另外一些情況下，p53會阻止細胞進一步分裂；還有一些情況下，它甚至會引起細胞自殺。
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.
下面我們通過一個實例來闡釋p53對於抵禦癌症的重要意義：如果人生來p53基因就有一個拷貝存在缺陷，就會患上李-佛美尼綜合徵(Li-Fraumeni syndrome)，患者的癌症終生風險高達90%以上。許多李-佛美尼綜合徵患者在童年時就開始患癌症，而且一生中還可能患有多種不同類型的癌症。
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.
希夫曼博士和同事們發現，大象的p53基因演化出了數對新的拷貝——人類只有一對p53基因，在大象的細胞內，科學家們卻發現了20對這種基因！
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.
林奇博士及其同事也發現了這些額外的p53基因。爲了追溯它們的演化過程，研究人員對大象和其他哺乳動物（包括猛獁象和乳齒象等雖然已經滅絕，但DNA在化石中得到保存的現代象的“親戚們”）的基因組進行了大規模的比對。
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.
林奇博士和同事們發現，大象的體型較小的祖先們與其他哺乳動物一樣，只有一對有功能的p53基因。然而，當它們隨着演化體型不斷增大後，就開始不斷地出現額外的p53基因拷貝。
“Whatever’s going on is special to the elephant lineage,” Dr. Lynch said.
林奇博士說：“這些都是大象這個譜系所特有的。”
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.
研究人員們想知道這些多出來的p53基因拷貝是否在抗癌方面發揮了什麼作用，於是兩個研究團隊都對大象的細胞進行了實驗。希夫曼博士及其同事使用輻射和可造成DNA損傷的化學物質來處理大象的細胞，而林奇博士的團隊使用的是化學品和紫外線。
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.
雖然處理方法各有不同，大象的細胞做出的應對卻完全相同：它們並未嘗試修復損傷，而是直接就自殺了。希夫曼博士認爲這種反應是一種獨特而且非常有效的阻斷癌症的方式。他說：“這基本上就像是在宣稱：‘我們大象纔不怕這點損失——還有很多很多細胞可以補充上來呢。’ ”
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.
未參與上述任一研究的萊斯特大學(University of Leicester)英國醫學研究委員會毒理學部(MRC Toxicology Unit)腫瘤學家帕特里夏·馬勒(Patricia Muller)表示，這些研究結果非常吸引人，但她也指出，它們並沒有明確闡釋大象是如何利用p53來對抗癌症的。一種可能性是額外的基因拷貝其實並不會導致細胞自殺。相反，它們只是充當了誘餌，消耗掉了破壞p53蛋白的酶，結果，大象體內的p53水平就會高於其他的動物。“總而言之，”她說，“這很有趣，但仍需要對箇中機制進行適當的研究。”
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.
馬勒博士指出，在試圖用藥物模仿大象的抗癌策略並應用於人類之前，準確地認識其中的原理尤其重要。在小鼠實驗中，額外的p53顯示出該分子具有一個缺點：它會加速衰老。“它必須受到嚴格的控制，”馬勒博士說。
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.
希夫曼博士目前正在研究如何將從大象身上得到的新發現轉化爲可造福於人類的癌症新療法。但他也表示，考察下其他大型或長壽的動物應該也會很有用。例如，裸鼴鼠可以活到30歲而從不患癌症。它們使用的抗癌武器是一種蛋白質，可以遏止快速分裂的細胞的生長，這些細胞碰上其他細胞就會讓它們停止分裂。
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.
這是對大象的演化歷程的一個截然不同的解釋。而且，鑑於大象是迄今爲止發現的唯一一種通過額外的p53基因拷貝來抵禦癌症的動物，希夫曼博士推測，鸚鵡、烏龜和鯨魚很可能都有各自獨特的長壽策略。
“The war on cancer was going on long before there were humans,” he said. “So let’s look at nature’s strategies.”
“對抗癌症的戰爭早在人類誕生之前就久已打響了，”希夫曼博士說。“那麼，就讓我們來看看大自然的戰術吧。”
