经济学人215:钳住癌症的新武器

 　　Oncology and genetics

　　肿瘤遗传学

　　Grabbing cancer by the short and curlies

　　短发卡——钳住癌症的新武器

　　A new technique for analysing tumours⁴ promises better understanding and more effective treatment

　　一项研究肿瘤的新技术为人类更加深入地了解肿瘤并找到更加有效的治疗方法带来了希望

　　Sep 24th 2011 | SAN FRANCISCO | from the print edition

　　ONE of the great hopes nurtured⁵ by the Human Genome Project was that it would crack cancer open. Knowing which genes⁶ were going wrong would, the theory went, allow specifically tailored drugs to be developed. And this is, indeed, happening. Only last month America’s Food and Drug Administration approved a medicine called Xalkori (generically, crizotinib) for patients who have a particular type of non-small-cell lung cancer, the most common form of that disease. Xalkori blocks the growth of tumours caused by a mutant form of the gene¹ which encodes a signalling molecule⁷ known as anaplastic lymphoma kinase. This mutation⁸ occurs in 3-5% of lung-cancer patients, and in trials Xalkori caused a dramatic shrinkage of the tumour³ in around half of those treated.

　　找到克服癌症的方法，是人类基因组计划带给人们最大的希望之一。理论上，只要找到出错的基因，就能研发出针对它的特定药物。事实上，这些期望正在被逐步实现。就在上个月美国食品药品管理局批准了一种名为Xalkori（通用名：克里唑蒂尼）的新药上市，用于治疗非小细胞肺癌（最常见的一种肺癌）。Xalkori能够抑制由编码信号分子间变性淋巴瘤激酶基因的突变体所导致的癌细胞的增长。3-5%的肺癌患者体内存在这种突变。临床试验中，大约一半受试者在服过此药后体内癌细胞数量显著减少。

　　The catch is that the respite⁹ does not last. Typically, someone will respond for about a year, but after that his tumour starts growing again and the disease continues on its course. This is a pattern seen again and again with the new generation of drugs that genomics has helped to create. They slow the disease, but only for a few months. The presumption¹⁰ is that further mutations are arising in a tumour all the time, and that eventually one of them makes a molecular¹¹ change that nullifies the effect of the drug. Researchers would dearly like to find a way to deal with this.

　　但问题是Xalkori对病情的缓解作用持续时间不长。一般来说，持续服药一年后患者将产生抗药性，体内癌细胞恢复增长导致病情恶化。这是一代代利用基因组学开发出的药物共同的治疗效果变化模式，最终都只能短暂地缓解病情。其机制可能是，癌细胞会不断地产生新的突变体，最终其中的某个突变体编码产生了使药物作用失效的蛋白分子。研究人员正致力于找出对付这种机制的办法。

　　One who is trying to do so is René Bernards of the Netherlands Cancer Institute. On September 18th he told a meeting of the American Association for Cancer Research, held in San Francisco, about a way that the sensitivity of tumour cells to Xalkori might be restored. More important than that, though, is the way he discovered the solution—for this could be applied¹² to many other cases in which an anti-cancer drug is having its useful life curtailed¹³ by the development of resistance.

　　来自荷兰癌症研究所的勒内.伯纳兹博士便是其中一位。9月18日，他在旧金山一个由美国癌症研究协会组织的研讨会上宣布，发现了使癌细胞恢复对Xalkori敏感性的方法。然而比这更具意义的是，此种方法的原理，同样适用于打破其他多种由于产生抗药性而导致其疗效减退的抗癌药物所遭遇的瓶颈。

　　One of the problems with cancer is that the mutations which cause it are often hidden in a plethora¹⁴ of others that have no direct bearing on the disease. Normal DNA¹⁵ sequencing cannot distinguish which mutations are important and which are not. Dr Bernards, however, thinks he can, by using molecules¹⁶ called short hairpin¹⁷ RNAs.

　　攻克癌症的困难之一，是致癌突变通常都隐藏在其他众多非致癌突变之中，而正规的DNA测序不能检测区别出两者的不同。不过现在，伯纳兹博士称，利用一种叫做短发夹RNA的分子，他找到了区别二者的方法。

　　On the pin money

　　深入探究

　　RNA is a molecule similar to DNA, except that its molecules are usually much smaller. One of its jobs is to act as a messenger carrying genetic² information from a cell’s nucleus¹⁸ to the machinery¹⁹ which makes proteins. Each messenger is an edited copy of one strand²⁰ of the DNA double helix. Double-stranded RNA does exist, but mostly in viruses. Mammalian cells make only the single-stranded variety. If a cell’s defence mechanisms²¹ detect double-stranded RNA they destroy it, to protect against infection.

　　RNA是一种类似于DNA的分子，但是其分子量比DNA小得多。它的职能之一是充当信使将遗传信息从细胞核运送至制造蛋白质的机器——核糖体。每一个信使RNA都是由双螺旋DNA的一个单链编码转录而成。双链RNA通常只存在于病毒体内。哺乳动物细胞只能正常识别单链RNA，如果发现双链RNA就会迅速将其销毁，以保护机体免受病毒感染。

　　This aversity to double-stranded RNA means short hairpins²² can be used to knock out the messengers, thus nullifying the signal from the underlying²³ gene. It is just a question of making a hairpin with an appropriate genetic sequence—one that is the same as the missing strand of the original DNA—so that the hairpin will combine eagerly with the messenger to form a double-stranded molecule. Modern gene-synthesis techniques mean this is not hard to do. Dr Bernards therefore did it with the messengers of 20,000 genes, to see which, if any, are implicated²⁴ in the development of resistance to Xalkori.

　　机体对双链RNA的排斥性意味着可以利用短发卡RNA破坏信使RNA，从而阻断相应基因的信号传递。问题的关键是设计出合适的发卡结构，其遗传序列必须与其替代的DNA序列一致，才能迅速准确地结合其编码的RNA成为双链RNA分子。利用DNA合成技术很容易完成这项任务。因此，伯纳兹博士对2000个基因的信使RNA进行一一实验，以确认与产生Xalkori抗药性有关的基因是否存在其中、是具体的哪一个。

　　In fact, he found three. Mediator-12 (MED 12), which helps to transcribe²⁵ genes from DNA into RNA messengers, was one. The other two were genes that help maintain the structure of chromosomes²⁶. Presumably, resistance to Xalkori is being caused by disabling mutations in one or more of these genes.

　　实际上，伯纳兹博士最后确认了三个。一个是Mediator-12(MED 12)，即控制基因转录成信使RNA的中介体复合物亚基12基因，其他两个是帮助维护持染色体结构的基因。可以推断，针对Xalkori的抗药性是由于这三个基因中的一个或多个发生了突变导致的结果。

　　That is interesting, but not of immediate²⁷ assistance to the dying. What Dr Bernards and his colleagues did next, though, could be of such help. They looked for hairpin RNAs that restored sensitivity to Xalkori in cells whose MED12 messengers were being blocked—and they found one. Disabling the messengers of the gene that encodes a receptor protein called TGF beta-R2, which is found on cell surfaces, caused cells that had once been resistant²⁸ to Xalkori to shrivel in its presence. Moreover, treating these same Xalkori-resistant cells with an experimental drug designed to block TGF beta-receptors restored sensitivity to Xalkori, though it had no effect on cancer-cell growth on its own.

　　这个发现十分有趣，但是对治疗患者没有直接帮助。伯纳兹博士与同事们接下来所做的工作正符合这个目的。他们尝试寻找能够拦截MED12基因的信使RNA从而恢复细胞对Xalkori敏感性的发夹结构，并取得了成功。TGF beta-R2是一种存在于细胞表面的蛋白质受体，只要破坏编码这种受体DNA的信使RNA，就能消除细胞对Xalkori的抗药性。此外，设计药物针对同样的抗药细胞，使其表面的TGF beta受体被药物屏蔽，也会得到相同的实验结果，即使这种药物本身并没有阻止癌细胞增长的疗效。

　　Dr Bernards thinks that in MED12 he has discovered a pathway crucial for the development of drug resistance. Subsequent studies by members of his group have found that interfering²⁹ with MED12 messengers causes resistance to numerous other drugs. These include Iressa and Tarceva, which are prescribed for lung cancer; Zelboraf, which is effective against melanoma; and Nexavar, which is used for kidney and liver cancers. If these lab-based results are confirmed in people then TGF beta-receptor inhibitors may prove a way of extending the useful lives of a plethora of medicines.

　　伯纳兹博士认为，通过MED12基因他找出了一个对于细胞产生抗药性十分关键的路径。伯纳兹博士的研究组同事在随后的研究中发现，干扰MED12基因的信使RNA会导致产生对多种药物的抗药性，包括用于治疗肺癌的药物易瑞沙（Iressa）和特罗凯（Tarceva）、黑色素瘤药物左博拉（Zelboraf）以及肾癌和肝癌药物多吉美（Nexavar）。如果这项实验结果在人体内也得到证实，TGF beta受体抑制剂将被用来延长多种药物的使用寿命。

　　Dr Bernards’s work, indeed, is just the vanguard. At least three other groups of researchers are using short hairpin RNA to study cancer in this way, and one of them, led by William Hahn of the Dana-Farber Cancer Institute in Boston, has already found what may be an important molecular link in the development of ovarian tumours. Turning these sorts of laboratory discoveries into treatments is a long and tedious process that often fails. What is crucial about Dr Bernards’s work, though, is that short hairpin RNAs do exactly what the genome project promised: they crack the problem open.

　　伯纳兹博士的研究工作只是这个领域的先头部队，同期至少还有其他三组人也在利用短发卡RNA朝相同方向进行肿瘤研究。其中，由威廉姆.哈恩带领的波斯顿法波癌症研究院研究小组，已经发现可能对卵巢癌发生过程十分重要的分子链。将实验室发现的成果运用到实际治疗中是一个冗长而乏味的过程，其中伴随着无数次失败。而伯纳兹博士的研究工作的决定性意义是，短发卡RNA正像人类基因组计划承诺的那样，找到了问题的突破点。

1 gene   

n.遗传因子，基因

参考例句：

• A single gene may have many effects.单一基因可能具有很多种效应。
• The targeting of gene therapy has been paid close attention.其中基因治疗的靶向性是值得密切关注的问题之一。

2 genetic   

adj.遗传的，遗传学的

参考例句：

• It's very difficult to treat genetic diseases.遗传性疾病治疗起来很困难。
• Each daughter cell can receive a full complement of the genetic information.每个子细胞可以收到遗传信息的一个完全补偿物。

3 tumour   

n.(tumor)(肿)瘤，肿块

参考例句：

• The surgeons operated on her for a tumour.外科医生为她施行了肿瘤切除手术。
• The tumour constricts the nerves.肿瘤压迫神经。

4 tumours   

肿瘤( tumour的名词复数 )

参考例句：

• Blood vessels develop abnormally in cancer tumours. 在癌肿瘤中血管出现不正常。
• This apparatus scans patients' brains for tumours. 这台仪器扫描检查病人的脑瘤。

5 nurtured   

养育( nurture的过去式和过去分词 )； 培育； 滋长； 助长

参考例句：

• She is looking fondly at the plants he had nurtured. 她深情地看着他培育的植物。
• Any latter-day Einstein would still be spotted and nurtured. 任何一个未来的爱因斯坦都会被发现并受到培养。

6 genes   

n.基因( gene的名词复数 )

参考例句：

• You have good genes from your parents, so you should live a long time. 你从父母那儿获得优良的基因，所以能够活得很长。 来自《简明英汉词典》
• Differences will help to reveal the functions of the genes. 它们间的差异将会帮助我们揭开基因多种功能。 来自英汉非文学 - 生命科学 - 生物技术的世纪

7 molecule   

n.分子，克分子

参考例句：

• A molecule of water is made up of two atoms of hygrogen and one atom of oxygen.一个水分子是由P妈̬f婘̬ 妈̬成的。
• This gives us the structural formula of the molecule.这种方式给出了分子的结构式。

8 mutation   

n.变化，变异，转变

参考例句：

• People who have this mutation need less sleep than others.有这种突变的人需要的睡眠比其他人少。
• So far the discussion has centered entirely around mutation in the strict sense.到目前为止，严格来讲，讨论完全集中于围绕突变问题上。

9 respite   

n.休息，中止，暂缓

参考例句：

• She was interrogated without respite for twenty-four hours.她被不间断地审问了二十四小时。
• Devaluation would only give the economy a brief respite.贬值只能让经济得到暂时的缓解。

10 presumption   

n.推测，可能性，冒昧，放肆，[法律]推定

参考例句：

• Please pardon my presumption in writing to you.请原谅我很冒昧地写信给你。
• I don't think that's a false presumption.我认为那并不是错误的推测。

11 molecular   

adj.分子的；克分子的

参考例句：

• The research will provide direct insight into molecular mechanisms.这项研究将使人能够直接地了解分子的机理。
• For the pressure to become zero, molecular bombardment must cease.当压强趋近于零时，分子的碰撞就停止了。

12 applied   

adj.应用的；v.应用，适用

参考例句：

• She plans to take a course in applied linguistics.她打算学习应用语言学课程。
• This cream is best applied to the face at night.这种乳霜最好晚上擦脸用。

13 curtailed   

v.截断，缩短( curtail的过去式和过去分词 )

参考例句：

• Spending on books has been severely curtailed. 购书开支已被大大削减。
• Their public health programme had to be severely curtailed. 他们的公共卫生计划不得不大大收缩。 来自《简明英汉词典》

14 plethora   

n.过量，过剩

参考例句：

• Java comes with a plethora of ready-made types.Java配套提供了数量众多的现成类型。
• A plethora of new operators will be allowed to enter the market.大批新的运营商将获准进入该市场。

15 DNA   

(缩)deoxyribonucleic acid 脱氧核糖核酸

参考例句：

• DNA is stored in the nucleus of a cell.脱氧核糖核酸储存于细胞的细胞核里。
• Gene mutations are alterations in the DNA code.基因突变是指DNA密码的改变。

16 molecules   

分子( molecule的名词复数 )

参考例句：

• The structure of molecules can be seen under an electron microscope. 分子的结构可在电子显微镜下观察到。
• Inside the reactor the large molecules are cracked into smaller molecules. 在反应堆里，大分子裂变为小分子。

17 hairpin   

n.簪,束发夹，夹发针

参考例句：

• She stuck a small flower onto the front of her hairpin.她在发簪的前端粘了一朵小花。
• She has no hairpin because her hair is short.因为她头发短，所以没有束发夹。

18 nucleus   

n.核，核心，原子核

参考例句：

• These young people formed the nucleus of the club.这些年轻人成了俱乐部的核心。
• These councils would form the nucleus of a future regime.这些委员会将成为一个未来政权的核心。

19 machinery   

n.(总称)机械，机器；机构

参考例句：

• Has the machinery been put up ready for the broadcast?广播器材安装完毕了吗？
• Machinery ought to be well maintained all the time.机器应该随时注意维护。

20 strand   

vt.使（船）搁浅，使（某人）困于（某地）

参考例句：

• She tucked a loose strand of hair behind her ears.她把一缕散发夹到了耳后。
• The climbers had been stranded by a storm.登山者被暴风雨困住了。

21 mechanisms   

n.机械( mechanism的名词复数 )；机械装置；[生物学] 机制；机械作用

参考例句：

• The research will provide direct insight into molecular mechanisms. 这项研究将使人能够直接地了解分子的机理。 来自《简明英汉词典》
• He explained how the two mechanisms worked. 他解释这两台机械装置是如何工作的。 来自《简明英汉词典》

22 hairpins   

n.发夹( hairpin的名词复数 )

参考例句：

• The price of these hairpins are about the same. 这些发夹的价格大致相同。 来自互联网
• So the king gives a hundred hairpins to each of them. 所以国王送给她们每人一百个漂亮的发夹。 来自互联网

23 underlying   

adj.在下面的，含蓄的，潜在的

参考例句：

• The underlying theme of the novel is very serious.小说隐含的主题是十分严肃的。
• This word has its underlying meaning.这个单词有它潜在的含义。

24 implicated   

adj.密切关联的；牵涉其中的

参考例句：

• These groups are very strongly implicated in the violence. 这些组织与这起暴力事件有着极大的关联。 来自《简明英汉词典》
• Having the stolen goods in his possession implicated him in the robbery. 因藏有赃物使他涉有偷盗的嫌疑。 来自《现代汉英综合大词典》

25 transcribe   

v.抄写，誉写；改编(乐曲)；复制，转录

参考例句：

• We need volunteers to transcribe this manuscript.我们需要自愿者来抄写这个文稿。
• I am able to take dictation in English and transcribe them rapidly into Chinese.我会英文记录，还能立即将其改写成中文。

26 chromosomes   

n.染色体( chromosome的名词复数 )

参考例句：

• Chromosomes also determine the sex of animals. 染色体也决定动物的性别。 来自《简明英汉词典》
• Each of four chromosomes divide longitudinally. 四种染色体的每一种都沿着纵向分裂。 来自《现代汉英综合大词典》

27 immediate   

adj.立即的；直接的，最接近的；紧靠的

参考例句：

• His immediate neighbours felt it their duty to call.他的近邻认为他们有责任去拜访。
• We declared ourselves for the immediate convocation of the meeting.我们主张立即召开这个会议。

28 resistant   

adj.(to)抵抗的，有抵抗力的

参考例句：

• Many pests are resistant to the insecticide.许多害虫对这种杀虫剂有抵抗力。
• They imposed their government by force on the resistant population.他们以武力把自己的统治强加在持反抗态度的人民头上。

29 interfering   

adj. 妨碍的 动词interfere的现在分词

参考例句：

• He's an interfering old busybody! 他老爱管闲事！
• I wish my mother would stop interfering and let me make my own decisions. 我希望我母亲不再干预，让我自己拿主意。