Why Your DNA Isnt Your Destiny╲tDNA不是一切(英语原文+中文译文)).doc

Why Your DNA Isnt Your Destiny DNA不是一切 （中英对照）By John Cloud, TIME magazine Wednesday, Jan. 06, 2010中文翻译：Quintessence瑞典北方，遥远而辽阔的冰天雪地中，似乎不会是顶尖遗传科学的发轫地。瑞典国境最北的北博滕省（Norrbotten）寥无人烟，平均每平方公里只有两个人。然而，透过这一小撮人，我们却能更加认识基因在日常生活中的作用。The remote, snow-swept expanses of northern Sweden are an unlikely place to begin a story about cutting-edge genetic science. The kingdoms northernmost county, Norrbotten, is nearly free of human life; an average of just six people live in each square mile. And yet this tiny population can reveal a lot about how genes work in our everyday lives.十九世纪的北博滕省对外交通不便，因此若当地收成欠佳，居民只好挨饿。由于难以事先预测荒年，使得情况更加严峻。比如说，1800、1812、1821、1836、1856年灾情惨重；但是1801、1822、1828、1844、1863年却是五个大丰年，使得之前挨饿的居民忽然能够暴饮暴食好几个月。Norrbotten is so isolated that in the 19th century, if the harvest was bad, people starved. The starving years were all the crueler for their unpredictability. For instance, 1800, 1812, 1821, 1836 and 1856 were years of total crop failure and extreme suffering. But in 1801, 1822, 1828, 1844 and 1863, the land spilled forth such abundance that the same people who had gone hungry in previous winters were able to gorge themselves for months.白葛恩（Lars Olov Bygren）博士是一名预防医学家，目前任职于斯德哥尔摩声望卓著的卡洛林斯卡医学研究院（Karolinska Institute）。他在八年代开始研究十九世纪的北博滕省，想了解丰年与荒年对于当地孩童成长的长期影响。他的研究不仅针对当时的孩童，还包括那些孩童的儿孙辈。他随机挑选了99个1905年在北博滕省奥佛卡利克斯区（Overkalix）出生的人为样本，并利用历史数据回溯他们的父母与祖父母辈出生时的情形。藉由分析详实的农业纪录后，白葛恩博士与另外两名伙伴便能推知那些人年轻时的农作收成状况。In the 1980s, Dr. Lars Olov Bygren, a preventive-health specialist who is now at the prestigious Karolinska Institute in Stockholm, began to wonder what long-term effects the feast and famine years might have had on children growing up in Norrbotten in the 19th century and not just on them but on their kids and grandkids as well. So he drew a random sample of 99 individuals born in the Overkalix parish of Norrbotten in 1905 and used historical records to trace their parents and grandparents back to birth. By analyzing meticulous agricultural records, Bygren and two colleagues determined how much food had been available to the parents and grandparents when they were young.在白葛恩博士着手收集数据的时候，当时有一支研究方向令他深深着迷。该方向探讨孕妇的子宫环境对胎儿、甚至是小孩成人后的健康影响。举例而言，知名医学期刊刺胳针（The Lancet）在1986年刊登了两篇具有划时代贡献的文章，其中的第一篇文章发现，孕妇若不注重饮食，她的孩子成年后得到心血管疾病的风险高于一般人。白葛恩博士想了解，这样的影响是否在受孕前就产生了？也就是说，父母早期的生活历程是否会改变遗传给后代的性状？Around the time he started collecting the data, Bygren had become fascinated with research showing that conditions in the womb could affect your health not only when you were a fetus but well into adulthood. In 1986, for example, the Lancet published the first of two groundbreaking papers showing that if a pregnant woman ate poorly, her child would be at significantly higher than average risk for cardiovascular disease as an adult. Bygren wondered whether that effect could start even before pregnancy: Could parents experiences early in their lives somehow change the traits they passed to their offspring?这是一个不为主流科学接受的想法。我们毕竟都学过传统的生物学，知道生活中的大小决择，顶多会影响我们的短期记忆、身材胖瘦或寿命长短，但是却不会改变基因，真正的遗传物质DNA。这表示当我们生了孩子后，他们遗传到的是我们原本干干净净的基因。It was a heretical idea. After all, we have had a long-standing deal with biology: whatever choices we make during our lives might ruin our short-term memory or make us fat or hasten death, but they wont change our genes our actual DNA. Which meant that when we had kids of our own, the genetic slate would be wiped clean.再说，任何后天环境因素都不该立即影响某物种的先天基因。去年11月是达尔文发表物种原始150周年，根据他的理论，要产生演化上的变异，需要好几个世代与数百万年的天择。但是白葛恩博士与其它科学家目前已经收集了很多的历史数据，这些数据显示强而有力的环境条件，如饥饿濒死的环境，能够在精子或卵子的遗传物质上留下某种印记。这种遗传印记能够缩短演化的正常途径，仅一个世代的时间就能将新的性状遗传给下一代。Whats more, any such effects of nurture (environment) on a species nature (genes) were not supposed to happen so quickly. Charles Darwin, whose On the Origin of Species celebrated its 150th anniversary in November, taught us that evolutionary changes take place over many generations and through millions of years of natural selection. But Bygren and other scientists have now amassed historical evidence suggesting that powerful environmental conditions (near death from starvation, for instance) can somehow leave an imprint on the genetic material in eggs and sperm. These genetic imprints can short-circuit evolution and pass along new traits in a single generation.举例来说，白葛恩博士对奥佛卡利克斯区的研究显示，那些有幸享受丰年，而在当年冬季由正常饮食变成暴饮暴食的男孩，他们的儿孙寿命都比较短，而且差距显著。2001年，白葛恩博士在荷兰的期刊Acta Biotheoretica上发表了第一篇对于北博滕省的研究，该研究指出，那些暴饮暴食的男孩的孙子，比起欠收挨饿的男孩的孙子，平均短了6岁。当白葛恩博士的团队控制住一些社会经济因子之后，寿命差距更大到32岁。后来一些对北博滕省其它同期出生族群的研究也发现显著的寿命差异，而此结果也出现在女孩与她们的孙女身上。因此简单地说，这些数据显示，若某人年轻时在某个冬季暴饮暴食，将会开启一连串生理反应，造成其孙儿比同辈短命。怎么会这样呢？For instance, Bygrens research showed that in Overkalix, boys who enjoyed those rare overabundant winters kids who went from normal eating to gluttony in a single season produced sons and grandsons who lived shorter lives. Far shorter: in the first paper Bygren wrote about Norrbotten, which was published in 2001 in the Dutch journal Acta Biotheoretica, he showed that the grandsons of Overkalix boys who had overeaten died an average of six years earlier than the grandsons of those who had endured a poor harvest. Once Bygren and his team controlled for certain socioeconomic variations, the difference in longevity jumped to an astonishing 32 years. Later papers using different Norrbotten cohorts also found significant drops in life span and discovered that they applied along the female line as well, meaning that the daughters and granddaughters of girls who had gone from normal to gluttonous diets also lived shorter lives. To put it simply, the data suggested that a single winter of overeating as a youngster could initiate a biological chain of events that would lead ones grandchildren to die decades earlier than their peers did. How could this be possible?表观基因体登场答案其实和先天、后天都有关。白葛恩博士与其它科学家在过去20年间独立研究所收集的资料，催生了一门称为表观遗传学（epigenetics, 又作后生学）的新科学。该学门研究的根本问题，便是不改变遗传密码，却仍能向下遗传至少一代的基因活动。英文前缀epi就是在之上，因为该基因的表现形式受制于基因体外侧上头的细胞物质，称为表观基因体（epigenome）。这些表观基因的标记指引基因表现的开关与强弱。饮食、压力、出生前营养状况等环境因素能影响表观基因标记，在基因上形成印记而遗传给下一代。Meet the EpigenomeThe answer lies beyond both nature and nurture. Bygrens data along with those of many other scientists working separately over the past 20 years have given birth to a new science called epigenetics. At its most basic, epigenetics is the study of changes in gene activity that do not involve alterations to the genetic code but still get passed down to at least one successive generation. These patterns of gene expression are governed by the cellular material the epigenome that sits on top of the genome, just outside it (hence the prefix epi-, which means above). It is these epigenetic marks that tell your genes to switch on or off, to speak loudly or whisper. It is through epigenetic marks that environmental factors like diet, stress and prenatal nutrition can make an imprint on genes that is passed from one generation to the next.表观遗传学同时带给我们希望与恶耗。先看看坏消息吧。证据显示，生活型态如抽烟或饮食过量等，都会改变DNA之上的表观基因，因而强化肥胖基因的表现，或是弱化长寿基因的表现。我们都知道，吸烟或暴饮暴食会缩短自己的寿命，而今却逐渐发现这些坏习惯甚至能在我们的孩子出生前，就预先让他们易于生病早逝。Epigenetics brings both good news and bad. Bad news first: theres evidence that lifestyle choices like smoking and eating too much can change the epigenetic marks atop your DNA in ways that cause the genes for obesity to express themselves too strongly and the genes for longevity to express themselves too weakly. We all know that you can truncate your own life if you smoke or overeat, but its becoming clear that those same bad behaviors can also predispose your kids before they are even conceived to disease and early death.而好消息是，科学家正在实验室中学习如何操控表观基因标记。他们正在研发药物，仅透过压抑坏基因、促进好基因表现的方法来治疗疾病。美国食品药物管理局（FDA）在2004年首次核准了一项表观基因药物。骨髓发育不良症候群（MDS）是罕见且易致死的血液疾病，其治疗用药Azacitidine便是使用表观基因标记，来抑制血液前驱细胞中过度活跃的基因。根据位于纽泽西州萨密特市（Summit）的Azacitidine制造商Celgene Corp.表示，被诊断为重度MDS的患者，在接受Azacitidine后的平均存活期间为24个月；而接受传统血液疗法的仅15个月。The good news: scientists are learning to manipulate epigenetic marks in the lab, which means they are developing drugs that treat illness simply by silencing bad genes and jump-starting good ones. In 2004 the Food and Drug Administration (FDA) approved an epigenetic drug for the first time. Azacitidine is used to treat patients with myelodysplastic syndromes (usually abbreviated, a bit oddly, to MDS), a group of rare and deadly blood malignancies. The drug uses epigenetic marks to dial down genes in blood precursor cells that have become overexpressed. According to Celgene Corp. the Summit, N.J., company that makes azacitidine people given a diagnosis of serious MDS live a median of two years on azacitidine; those taking conventional blood medications live just 15 months.自2004年起美国 FDA又核准了另外三种表观基因药物，其部份作用至少是激活因疾病而未表现的肿瘤抑制基因。表观遗传学的研究持续进行，其宏图是有朝一日我们能够轻轻一拨生化开关，就让造成很多疾病的基因不再活跃。这些疾病包括癌症、精神分裂症、自闭症、阿兹海默氏症、糖尿病等。在历经千辛万苦之后，我们终于握有一张能对付达尔文的王牌了。Since 2004, the FDA has approved three other epigenetic drugs that are thought to work at least in part by stimulating tumor-suppressor genes that disease has silenced. The great hope for ongoing epigenetic research is that with the flick of a biochemical switch, we could tell genes that play a role in many diseases including cancer, schizophrenia, autism, Alzheimers, diabetes and many others to lie dormant. We could, at long last, have a trump card to play against Darwin.有趣的是，科学家至少从七年代就已经知道表观基因标记了，但是在九年代末期之前，咸认为表观遗传现象不过是DNA的配角。当然，无人否认表观基因标记的重要性：毕竟大脑与肾脏细胞拥有的DNA完全相同，而科学家也早就知道，子宫中未成熟的细胞要能够分化，表观遗传程序得要开启或关闭正确的基因。The funny thing is, scientists have known about epigenetic marks since at least the 1970s. But until the late 90s, epigenetic phenomena were regarded as a sideshow to the main event, DNA. To be sure, epigenetic marks were always understood to be important: after all, a cell in your brain and a cell in your kidney contain the exact same DNA, and scientists have long known that nascent cells can differentiate only when crucial epigenetic processes turn on or turn off the right genes in utero.然而直到最近，研究人员才开始了解，表观遗传学能助于解释传统遗传学无法回答的科学迷题，如为何双胞胎中的一人会罹患躁郁症或气喘，而另一个却健康无事？为何男童的自闭症发生率为女童的四倍？又或是为何北博滕省居民在短期内急剧改变饮食习惯，导致寿命跟着急剧改变？在这些案例中，基因虽都相同，但是它们表现的形式明显地改变了。More recently, however, researchers have begun to realize that epigenetics could also help explain certain scientific mysteries that traditional genetics never could: for instance, why one member of a pair of identical twins can develop bipolar disorder or asthma even though the other is fine. Or why autism strikes boys four times as often as girls. Or why extreme changes in diet over a short period in Norrbotten could lead to extreme changes in longevity. In these cases, the genes may be the same, but their patterns of expression have clearly been tweaked.生物学家作了一个比喻：若基因体是硬件，那么表观基因体便是软件。美国沙克研究院（Salk Institute）的生物学家与首席表观遗传学家艾克（Joseph Ecker）说：只要愿意，我可以在Mac上安装Windows。芯片相同、基因体相同，但是软件不同，这就成了一个不同类型的细胞。Biologists offer this analogy as an explanation: if the genome is the hardware, then the epigenome is the software. I can load Windows, if I want, on my Mac, says Joseph Ecker, a Salk Institute biologist and leading epigenetic scientist. Youre going to have the same chip in there, the same genome, but different software. And the outcome is a different cell type.如何培养更佳的小鼠表观遗传学听起来是个重大发现，但是其所依赖的化学机制，至少有一项十分简单。达尔文告诉我们，基因体要花好几个世代的时间来演化；但是研究人员却发现，要改变一个表观基因体，只需添加一个甲基（methyl group）就行了。甲基是有机化学中的基本元素，由一个碳原子与三个氢原子构成。在基因的某个特定位置添加一个甲基的程序称为DNA甲基化。这个程序能够改变基因表现，包括将其开启、关闭、抑制或增强。How to Make a Better MouseAs momentous as epigenetics sounds, the chemistry of at least one of its mechanisms is fairly simple. Darwin taught us that it takes many generations for a genome to evolve, but researchers have found that it takes only the addition of a methyl group to change an epigenome. A methyl group is a basic unit in organic chemistry: one carbon atom attached to three hydrogen atoms. When a methyl group attaches to a specific spot on a gene a process called DNA methylation it can change the genes expression, turning it off or on, dampening it or making it louder.DNA甲基化可作为改变生物体生理特征的重要方法，这一点早在1970年代便已有人提出。然而，大部份的实验结果都不够显著，直到2003年杜克大学的肿瘤学家杰托（Randy Jirtle）与博士后研究生瓦特兰（Robert Waterland）所进行的实验，才有了显著结果。他们两人针对小鼠身上的agouti基因进行实验。当agouti基因持续表现时，能让小鼠的毛色变黄，易于肥胖并得到糖尿病。针对两群基因相同的怀孕母鼠，杰托的团队用富含维他命B群（叶酸与维他命B12）的饲料喂养其中一群；而另一群则无。The importance of DNA methylation in altering the physical characteristics of an organism was proposed in the 1970s, yet it wasnt until 2003 that anyone experimented with DNA methylation quite as dramatically as Duke University oncologist Randy Jirtle and one of his postdoctoral students, Robert Waterland, did. That year, they conducted an elegant experiment on mice with a uniquely regulated agouti gene a gene that gives mice yellow coats and a propensity for obesity and diabetes when expressed continuously. Jirtles team fed one group of pregnant agouti mice a diet rich in B vitamins (folic acid and vitamin B12). Another group of genetically identical pregnant agouti mice got no such prenatal nutrition.维他命B群能够提供甲基，使子宫中的幼鼠agouti基因有更多机会被甲基附着，并进而改变其基因表现。在不改变小鼠DNA基因组成下，杰托与瓦特兰仅透过提供富含维他命B群的食物，便让母鼠生出了健康的棕色小鼠，体重正常且不易患糖尿病。The B vitamins acted as methyl donors: they caused methyl groups to attach more frequently to the agouti gene in utero, thereby altering its expression. And so without altering the genomic structure of mouse DNA simply by furnishing B vitamins Jirtle and Waterland got agouti mothers to produce healthy brown pups that were of normal weight and not prone to diabetes.近期的其它研究也显示了环境对基因表现的影响。比如说，暴露于含有格尔德霉素（geldanamycin）环境的果蝇，眼睛会长得异常地大。在DNA没有变化的情况下，眼睛特大的征状仍可持续13代，即使第2代到第13代都未直接接触格尔德霉素。去年在生物学季刊（Quarterly Review of Biology）上有篇文章，是由表观遗传学先锋雅布兰卡（Eva Jablonka）与以色列特拉维夫大学（Tel Aviv University）的拉兹（Gal Raz）共同发表。该文章也显示，喂食蛔虫某种细菌能够让它们体型短小肥胖，并抑制其产生荧光绿的蛋白。这种改变能持续40代之久。雅布兰卡与拉兹的研究结果被列为100种表观遗传现象之一。Other recent studies have also shown the power of environment over gene expression. For instance, fruit flies exposed to a drug called geldanamycin show unusual outgrowths on their eyes that can last through at least 13 generations of offspring even though no change in DNA has occurred (and generations 2 through 13 were not directly exposed to the drug). Similarly, according to a paper published last year in the Quarterly Review of Biology by Eva Jablonka (an epigenetic pioneer) and Gal Raz of Tel Aviv University, roundworms fed with a kind of bacteria can feature a small, dumpy appearance and a switched-off green fluorescent protein; the changes last at least 40 generations. (Jablonka and Razs paper catalogs some 100 forms of epigenetic inheritance.)表观基因的改变能否永久持续下去？有可能。但是我们必须记住，表观遗传不是演化，没有改变DNA，而仅是生物体对于环境压力的反应。这种反应能透过表观遗传标记传递好几世代，但是一旦该压力因子移除，表观遗传标记最终还是会随着时间慢慢褪去，而让DNA原本的组态彰显。毕竟，目前的看法仍是：惟有天择才能造成基因永久的改变。Can epigenetic changes be permanent? Possibly, but its important to remember that epigenetics isnt evolution. It doesnt change DNA. Epigenetic changes represent a biological response to an environmental stressor. That response can be inherited through many generations via epigenetic marks, but if you remove the environmental pressure, the epigenetic marks will eventually fade, and the DNA code will over time begin to revert to its original programming. Thats the current thinking, anyway: that only natural selection causes permanent genetic change.然而，表观遗传虽然无法天长地久，却也对我们帮助良多。2009年2月神经科学期刊（Journal of Neuroscience）有一篇文章显示，即使像记忆这样复杂的生理与心理复合机制，也能够藉由表观遗传而增进下一代的表现。该文章是由塔夫斯大学（Tufts University）的生化学家费格（Larry Feig）对小鼠所进行的实验。费格把一群有遗传性记忆力问题的小鼠安置于充满玩具、训练活动与特别照料的环境中。实验结果发现，这些小鼠的长期增益效果（long-term potentiation, LTP）明显地进步了。LTP是一种神经传导形式，对于形成记忆至关重要。出乎意料的是，这些小鼠的后代即使没有获得特殊照料，其LTP也有改善。And yet even if epigenetic inheritance doesnt last forever, it can be hugely powerful. In February 2009, the Journal of Neuroscience published a paper showing that even memory a wildly complex biological and psychological process can be improved from one generation to the next via epigenetics. The paper described an experiment with mice led by Larry Feig, a Tufts University biochemist. Feigs team exposed mice with genetic memory problems to an environment rich with toys, exercise and extra attention. These mice showed significant improvement in long-term potentiation (LTP), a form of neural transmission that is key to memory formation. Surprisingly, their offspring also showed LTP improvement, even when the offspring got no extra attention.上述现象让我们知道何以科学界对于表观遗传学如此兴奋。科普作家申克（David Shenk）在他即将出版的新书人人都是天才：关于遗传、才能、智商，你所知道的一切都是错的（The Genius in All of Us: Why Everything Youve Been Told About Genetics, Talent and IQ Is Wrong暂译）中说，表观遗传学将有助于型塑新典范，能够显示所谓”先天vs后天”一语是多么地无意义。他宣称表观遗传学可能是自基因发现以来，非主流科学中最重要的发现。All this explains why the scientific community is so nervously excited about epigenetics. In his forthcoming book The Genius in All of Us: Why Everything Youve Been Told About Genetics, Talent and IQ Is Wrong, science writer David Shenk says epigenetics is helping usher in a new paradigm that reveals how bankrupt the phrase nature versus nurture really is. He calls epigenetics perhaps the most important discovery in the science of heredity since the gene.遗传学家悄悄承认，我们可能太轻忽了一位早期的博物学家。这位博物学家虽一直被进化论者藐视，但却预见了现代的表观遗传学。他就是主张进化能够在一、两个世代内发生的拉马克（Jean-Baptiste Lamarck, 1744-1829）。他认为，由于环境与选择之故，动物能在有生之年获得某些新性状。拉马克举的最有名的例子便是长颈鹿。他认为，长颈鹿的脖子变长，是因为前几代祖先努力伸长脖子，以觅得高处营养丰富的树叶。Geneticists are quietly acknowledging that we may have too easily dismissed an early naturalist who anticipated modern epigenetics and whom Darwinists have long disparaged. Jean-Baptiste Lamarck (1744-1829) argued that evolution could occur within a generation or two. He posited that animals acquired certain traits during their lifetimes because of their environment and choices. The most famous Lamarckian example: giraffes acquired their long necks because their recent ancestors had stretched to reach high, nutrient-rich leaves.相反地，达尔文认为演化的动力不是生物体自身的努力，而是无情客观的天择。依据达尔文学说，长颈鹿的长脖子乃是历经千年，长脖子基因慢慢占了优势的结果。达尔文比拉马克晚了84年，是一名更出色的科学家。他的理论获得胜利，而拉马克的演化观则