Why Your DNA Isn't 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 [/blog/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 kingdom's 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、汪洪超
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。 杀人者死
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，文化沙龙
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 won't 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。
What's 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 chang
es 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, Bygren's 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 one's grandchildren to die decades earlier than their peers did. How could this be possible?
托克维尔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皮老师是谁就是「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. Bygren's 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 b y 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: there's 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 t
runcate your own life if you smoke or overeat, but it's becoming clear that those same bad behaviors can also predispose your kids — before they are even conceived — to disease and early death.巫语
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（MDS）是罕见且易致死的血液疾病，其用药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 e
pigenetic 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, Alzheimer's, 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 sc
ientists 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. "You're going to have the same chip in there, the same genome, but different software. And the outcome is a different cell type."
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