As time goes by, the tips of your chromosomes—called telomeres—become shorter. This process has long been viewed as an unwanted side-effect of aging, but a recent study shows it is in fact good for you.
隨著時間流逝，染色體被稱為端粒的末端，變得較短。長久以來，此過程一直被視為老化的一種有害副作用。不過，最近一項研究顯示，實際上這對人們是有益的。
圖1. 人類染色體(藍色)末端的端粒(綠色)。
“Telomeres protect the genetic material,” says Titia de Lange, Leon Hess Professor at Rockefeller. “The DNA in telomeres shortens when cells divide, eventually halting cell division when the telomere reserve is depleted.”
美國洛克菲勒大學萊昂·赫斯教授，Titia de Lange宣稱：「端粒保護遺傳物質。當細胞分裂時，端粒中的DNA縮短。最終，當端粒儲存量耗盡時，終止細胞分裂。」
New results from de Lange’s lab provide the first evidence that telomere shortening helps prevent cancer in humans, likely because of its power to curtail cell division. Published in eLife, the findings were obtained by analyzing mutations in families with exceptional cancer histories, and they present the answer to a decades-old question about the relationship between telomeres and cancer.
來自de Lange實驗室的新研究結果提供了，端粒縮短有助於防禦人類癌腫，可能是因為其削減細胞分裂之能力的首度證據。此些發表於《eLife》期刊的研究發現，是藉由分析具有特殊癌症史家庭中之突變體獲得的。因此，她們提出了有關，端粒與癌腫之間關係，一個數十年之久的問題答案。
In stem cells, including those that generate eggs and sperm, telomeres are maintained by telomerase, an enzyme that adds telomeric DNA to the ends of chromosomes. Telomerase is not present in normal human cells, however, which is why their telomeres wither away. This telomere shortening program limits the number of divisions of normal human cells to about 50.
在包括那些產生卵子及精子的幹細胞中，端粒是由端粒酶，一種將端粒DNA添加到染色體末端的酵素所維持。不過，端粒酶不存在於正常的人類細胞中，那是正常細胞端粒枯萎掉的原因。該端粒縮短的程序，將正常人的細胞分裂數限制到大約50次。
The idea that telomere shortening could be part of the body’s defense against cancer was first proposed decades ago. Once an early-stage tumor cell has divided 50 times, scientists imagined, depletion of the telomere reserve would block further cancer development. Only those cancers that manage to activate telomerase would break through this barrier.
端粒縮短可能是人體防禦癌腫之一部分的見解，數十年前首度被提出。一旦初期腫瘤細胞已經分裂50次，科學家們認為，端粒儲存量的耗盡，會阻礙進一步的癌腫發展。僅那些勉力達成活化端粒酶的癌腫，才能突破此障礙。
Clinical observations seemed to support this hypothesis. “Most clinically detectable cancers have re-activated telomerase, often through mutations,” de Lange says. Moreover, mouse experiments showed that shortening telomeres can indeed protect against cancer.
諸多臨床觀察似乎支持這種假設。de Lange宣稱：「大多數臨床上可檢測到的癌腫，具有經常透過突變、重新被活化的端粒酶。此外，諸多小鼠實驗顯示，縮短端粒確實能防禦癌腫。」
Nonetheless, evidence for the telomere tumor suppressor system remained elusive for the past two decades, and its existence in humans remained controversial.
然而，過去二十年中，端粒腫瘤抑制物體系的證據，仍然難以捉摸。因此，其在人類中的存在，仍有爭議。
The telomere tumor suppressor pathway can only work if we are born with telomeres of the right length; if the telomeres are too long, the telomere reserve would not run out in time to stop cancer development. Longer telomeres will afford cancer cells additional divisions during which mutations can creep into the genetic code, including mutations that activate telomerase.
倘若人們天生具有適當長度的端粒，端粒腫瘤抑制物途徑才能起作用，及倘若端粒夠長，則端粒儲存量不會及時耗盡，來阻止癌腫發展。較長的端粒能提供癌細胞額外的分裂，在此分裂期間，包括活化端粒酶的諸多突變體，能潛入到遺傳密碼中。
For decades, de Lange’s lab has been studying the complex process by which telomeres are regulated. She and others identified a set of proteins that can limit telomere length in cultured human cells, among them a protein called TIN2. When TIN2 is inhibited, telomerase runs wild and over-elongates telomeres. But it was not known whether TIN2 also regulated telomere length at birth.
數十年來，de Lange的實驗室一直進行研究，端粒藉以被調節的複雜過程。她及其他人確認了一組，能在培養之人類細胞中，限制端粒長度的蛋白質。其中一種蛋白質，被稱為TIN2。當TIN2遭抑制時，端粒酶失控地運作且過度拉長端粒。不過，並不清楚在開始時，是否TIN2也調節端粒長度。
The stalemate on the telomere tumor suppressor continued until physicians at the Radboud University Medical Center in Holland reached out to de Lange about several cancer-prone families. The doctors found that these families had mutations in TINF2, the gene that encodes the TIN2 protein instrumental to controlling telomere length. That’s when they asked de Lange to step in.
在端粒腫瘤抑制物上的相持不下持續直到，荷蘭拉德布德大學醫學中心的醫師們向de Lange申援了，若干容易罹患癌腫的家庭。此些醫師們發現，在有助於左右端粒長度之為TINF2蛋白質編碼的TINF2基因中，這些家庭具有諸多突變體。那是他們要求de Lange介入的時候。
Isabelle Schmutz, a Women&Science postdoctoral fellow in the de Lange lab, used CRISPR gene-editing technology to engineer cells with precisely the same mutations as those seen in the Dutch families and examined the resulting mutant cells. She found that the mutant cells had fully functional telomeres and no genomic instability. They were, for all intents and purposes, normal healthy cells.
在de Lange實驗室的Women&Science博士後特別研究員，Isabelle Schmutz使用了群聚、規律性間隔開的短迴文結構複製(CRISPR：Clustered Regularly Interspaced Short Palindromic Repeat)的基因編輯技術，精確地使用如同在上述荷蘭家庭中，被發現的相同突變體，來工程改造細胞並檢查了，從而產生的突變細胞。她發現，此些突變細胞具有完整功能的端粒，且沒有基因體的不穩定性。就所有意圖及目的而言，它們是正常健康的細胞。
But there was one thing wrong with the cells. “Their telomeres became too long, ” de Lange says. Similarly, the patient’s telomeres were unusually long. “These patients have telomeres that are far above the 99th percentile,” de Lange says.
不過，此些細胞有件不對勁的事。de Lange宣稱：「它們的端粒變得太長。」同樣地，病患的端粒也異常的長。de Lange宣稱：「此些病患具有，遠超過第99百分位數(統計學術語，如果將一組數據從小到大排序，並計算相應的累計百分位，則某一百分位所對應數據的值就稱為這一百分位的百分位數)的端粒。」
“The data show that if you’re born with long telomeres, you are at greater risk of getting cancer, ” says de Lange. “We are seeing how the loss of the telomere tumor suppressor pathway in these families leads to breast cancer, colorectal cancer, melanoma, and thyroid cancers. These cancers would normally have been blocked by telomere shortening. The broad spectrum of cancers in these families shows the power of the telomere tumor suppressor pathway.”
de Lange宣稱：「此些數據顯示，倘若出生具有長的端粒，則冒用罹癌的較高風險。她們正進行瞭解，喪失此端粒腫瘤抑制物途徑，在此些家庭中，如何導致乳腺癌、結腸直腸癌、黑色素瘤及甲狀腺癌。通常，這些癌腫會遭端粒縮短所阻礙。這些家族中的各種不同癌腫顯示，端粒腫瘤抑制物途徑的影響力。」
The study is demonstration of the power of basic science to transform our understanding of medicine. “How telomeres are regulated is a fundamental problem,” de Lange says. “And by working on a fundamental problem, we were eventually able to understand the origins of a human disease.”
該項研究證明了，基礎科學改變咱們對醫學的理解能力。de Lange宣稱：「端粒如何被調節是一項基本問題。因此，藉由針對此基本問題進行研究，她們最終能瞭解人類疾病的起源。」
原文網址：https://www.rockefeller.edu/news/29625-telomere-shortening-protects-cancer/
翻譯：許東榮
文章定位：
