我們身上的絕大部分DNA都是垃圾嗎?

Is Most of Our DNA Garbage?

我們身上的絕大部分DNA都是垃圾嗎?

T. Ryan Gregory’s lab at the University of Guelph in Ontario is a sort of genomic menagerie, stocked with creatures, living and dead, waiting to have their DNA laid bare. Scorpions lurk in their terrariums. Tarantulas doze under bowls. Flash-frozen spiders and crustaceans — collected by Gregory, an evolutionary biologist, and his students on expeditions to the Arctic — lie piled in beige metal tanks of liquid nitrogen. A bank of standing freezers holds samples of mollusks, moths and beetles. The cabinets are crammed with slides splashed with the fuchsia-stained genomes of fruit bats, Siamese fighting fish and ostriches.

來到安大略省圭爾夫大學(xué)(University of Guelph)，走進進化生物學(xué)家T·瑞安·格雷戈里(T. Ryan Gregory)的實驗室，你會感覺好像走進了一個基因組學(xué)的大觀園，各種各樣活著或者已經(jīng)死去的生物正等待著自身的DNA被解讀：蝎子潛伏在飼養(yǎng)箱里;狼蛛在小盆下面打瞌睡;格雷戈里和他的學(xué)生在北極探險時采集的蜘蛛和甲殼類動物的速凍標(biāo)本存放在米色金屬液氮罐里;軟體動物、飛蛾和甲蟲標(biāo)本保存在一排立式冷凍柜中;而櫥柜里則塞滿了果蝠、暹羅斗魚和鴕鳥基因組的品紅染色涂片標(biāo)本。

Gregory’s investigations into all these genomes has taught him a big lesson about life: At its most fundamental level, it’s a mess. His favorite way to demonstrate this is through what he calls the “onion test,” which involves comparing the size of an onion’s genome to that of a human. To run the test, Gregory’s graduate student Nick Jeffery brought a young onion plant to the lab from the university greenhouse. He handed me a single-edged safety razor, and then the two of us chopped up onion stems in petri dishes. An emerald ooze, weirdly luminous, filled my dish. I was so distracted by the color that I slashed my ring finger with the razor blade, but that saved me the trouble of poking myself with a syringe — I was to supply the human genome. Jeffery raised a vial, and I wiped my bleeding finger across its rim. We poured the onion juice into the vial as well and watched as the green and red combined to produce a fluid with both the tint and viscosity of maple syrup.

在對所有這些基因組進行研究的過程中，格雷戈里學(xué)到了重要的一課：從最根本的層面上來說，生命真是一團亂麻。他很喜歡用“洋蔥測試”來對此加以證明。這個測試的目的是比較洋蔥與人類的基因組孰大孰小。為此，格雷戈里的研究生尼克·杰弗里(Nick Jeffery)從大學(xué)的溫室里采了一棵小洋蔥拿到實驗室，然后遞給我一把單刃安全剃須刀，和我一起在培養(yǎng)皿中把洋蔥莖切碎。不一會兒，我的培養(yǎng)皿里就堆起了一坨帶著古怪光澤的翡翠色軟泥。這奇異的顏色讓我走了神，一不小心切到了自己的無名指，不過這樣也好，省得我用注射器再戳自個兒一次了——這次測試中，我是提供人類基因組的志愿者。杰弗里拿出了一個小瓶，讓我把手指上的血抹在瓶沿上，隨后我們把洋蔥汁也倒入瓶中，看著綠色和紅色的液體混合起來，產(chǎn)生一種從色調(diào)和粘度上都跟楓糖漿十分相似的東西。

After adding a fluorescent dye that attaches to DNA, Jeffrey loaded the vial into a boxy device called a flow cytometer, which sprayed the onion juice and blood through a laser beam. Each time a cell was hit, its DNA gave off a bluish glow; bigger genomes glowed more brightly. On a monitor, we watched the data accumulate on a graph. The cells produced two distinct glows, one dim, one bright, which registered on the graph as a pair of peaks.

杰弗里向瓶中加入了能與DNA相結(jié)合的熒光染料，然后將小瓶放進一種叫做流式細(xì)胞儀的四四方方的裝置中。這種儀器可以將洋蔥汁和血液噴灑在激光束的光路上，每當(dāng)一個細(xì)胞被擊中，其DNA就會發(fā)出藍色輝光，細(xì)胞的基因組越大，發(fā)出的光也就越亮。在我們的注視下，顯示器上圖表的數(shù)據(jù)逐漸積累，它表明兩種細(xì)胞產(chǎn)生了兩種截然不同的光，一種暗淡，一種明亮，相應(yīng)地在圖表上顯示為兩個峰。

One peak represented my genome, or the entirety of my DNA. Genomes are like biological books, written in genetic letters known as bases; the human genome contains about 3.2 billion bases. Print them out as letters on a page, and they would fill a book a thousand times longer than “War and Peace.” Gregory leaned toward the screen. At 39, with a chestnut-colored goatee and an intense gaze, he somewhat resembles a pre-Heisenberg Walter White. He pointed out the onion’s peak. It showed that the onion’s genome was five times bigger than mine.

其中一個峰代表我的基因組，也就是我的全套DNA。基因組就好比一本用名為堿基的遺傳學(xué)字母寫成的生物學(xué)大書。人類的基因組約包含32億個堿基，如果把這些字母打印在紙上，足夠組成一本比《戰(zhàn)爭與和平》(War and Peace)還長一千倍的巨作。格雷戈里朝著屏幕俯下身來，今年39歲的他留著栗色的山羊胡子，目光熱切，有點像劇集《絕命毒師》中成為“海森堡 (Heisenberg)”之前的主角瓦特·懷特(Walter White)。他用手指著代表洋蔥的峰。它表明，洋蔥的基因組是我的五倍大。

“The onion wins,” Gregory said. The onion always does.

格雷戈里宣布：“洋蔥勝出。”一如既往。

But why? Why does an onion carry around so much more genetic material than a human? Or why, for that matter, do the broad-footed salamander (65.5 billion bases), the African lungfish (132 billion) and the Paris japonica flower (149 billion)? These organisms don’t appear to be more complex than we are, so Gregory rejects the idea that they’re accomplishing more with all their extra DNA. Instead, he champions an idea first developed in the 1970s but still startling today: that the size of an animal’s or plant’s genome has essentially no relationship to its complexity, because a vast majority of its DNA is — to put it bluntly — junk.

只是，為什么會這樣呢?為什么洋蔥會攜帶比人還多那么多的遺傳物質(zhì)?同樣的問題也適用于寬足蠑螈(655億對堿基)，非洲肺魚(1320億)和衣笠草(又名重樓百合，1490億)。這些生物并不比我們?nèi)祟悘?fù)雜，所以格雷戈里不認(rèn)為這些多出來的DNA的作用是完善它們的機能。相反，他更贊同一個在20 世紀(jì)70年代首次提出，但至今聽來仍然有些驚世駭俗的學(xué)說：動植物基因組的大小與其復(fù)雜程度基本無關(guān)，因為——說穿了——絕大部分的DNA都是“垃圾”。

The human genome contains around 20,000 genes, that is, the stretches of DNA that encode proteins. But these genes account for only about 1.2 percent of the total genome. The other 98.8 percent is known as noncoding DNA. Gregory believes that while some noncoding DNA is essential, most probably does nothing for us at all, and until recently, most biologists agreed with him. Surveying the genome with the best tools at their disposal, they believed that only a small portion of noncoding DNA showed any evidence of having any function.

人類基因組約含2萬個基因，或者說，編碼蛋白質(zhì)的DNA片段。但這些基因僅占整個基因組的1.2%左右。其余的98.8%稱為非編碼DNA。格雷戈里認(rèn)為，雖然某些非編碼DNA是必不可少的，但大部分很可能沒有任何用處。直到最近，大多數(shù)生物學(xué)家都同意他的意見。他們利用手頭最好的工具對基因組進行了調(diào)查，發(fā)現(xiàn)現(xiàn)有證據(jù)表明，只有一小部分非編碼DNA具有生物學(xué)功能。

But in the past few years, the tide has shifted within the field. Recent studies have revealed a wealth of new pieces of noncoding DNA that do seem to be as important to our survival as our more familiar genes. Many of them may encode molecules that help guide our development from a fertilized egg to a healthy adult, for example. If these pieces of noncoding DNA become damaged, we may suffer devastating consequences like brain damage or cancer, depending on what pieces are affected. Large-scale surveys of the genome have led a number of researchers to expect that the human genome will turn out to be even more full of activity than previously thought.

然而，在過去的幾年中，該領(lǐng)域的風(fēng)向開始變化。近期的研究揭示，新發(fā)現(xiàn)的眾多非編碼DNA對我們生存的重要程度不亞于我們較為熟悉的那些基因。例如，其中有許多DNA可編碼引導(dǎo)我們從受精卵發(fā)育為健康成年人的特殊分子。如果這些非編碼DNA片段受損，因其具體功能的不同，我們將可能遭受腦損傷或癌癥之類的災(zāi)難性后果。大規(guī)模的基因組研究給大批研究人員帶來了這樣的期望：或許，人類基因組比以前認(rèn)為的更加活躍。

In January, Francis Collins, the director of the National Institutes of Health, made a comment that revealed just how far the consensus has moved. At a health care conference in San Francisco, an audience member asked him about junk DNA. “We don’t use that term anymore,” Collins replied. “It was pretty much a case of hubris to imagine that we could dispense with any part of the genome — as if we knew enough to say it wasn’t functional.” Most of the DNA that scientists once thought was just taking up space in the genome, Collins said, “turns out to be doing stuff.”

今年1月，美國國立衛(wèi)生研究院(National Institutes of Health, N.I.H)主任弗朗西斯·柯林斯(Francis Collins)就目前共識意見的轉(zhuǎn)變發(fā)表了評論。在舊金山舉行的一次衛(wèi)生會議上，一位聽眾就“垃圾DNA”向他提問。“我們已經(jīng)不再使用這個術(shù)語了，” 柯林斯回答道。“以為我們可以擯棄基因組的某些部分，這實在是一種非常狂妄自大的想法——就仿佛我們敢打包票它們沒有任何功能似的。”科林斯指出，在曾經(jīng)被科學(xué)家們認(rèn)為只是白占地方的基因組DNA中，大部分“其實都各有用途”。

For Gregory and a group of like-minded biologists, this idea is not just preposterous but also perilous, something that could yield bad science. The turn against the notion of junk DNA, they argue, is based on overinterpretations of wispy evidence and a willful ignorance of years of solid research on the genome. They’ve challenged their opponents face to face at scientific meetings. They’ve written detailed critiques in biology journals. They’ve commented on social media. When the N.I.H.’s official Twitter account relayed Collins’s claim about not using the term “junk DNA” anymore, Michael Eisen, a professor at the University of California, Berkeley, tweeted back with a profanity.

這種想法在格雷戈里和一群與他志同道合的生物學(xué)家看來不僅荒謬而且危險，很可能會帶來“偽科學(xué)”。他們認(rèn)為，反對“垃圾DNA”的概念，不過是基于對少數(shù)證據(jù)的過度解讀，以及對多年來扎實的基因組研究的刻意忽視。于是，他們在學(xué)術(shù)會議上面對面地向?qū)κ职l(fā)起了挑戰(zhàn)，還在生物學(xué)期刊上撰寫了詳細(xì)的評論文章，并在社交媒體上發(fā)聲。當(dāng)N.I.H.的官方Twitter帳號轉(zhuǎn)發(fā)柯林斯有關(guān)不再使用“垃圾DNA”這一術(shù)語的聲明時，加州大學(xué)伯克利分校 (University of California, Berkeley)的教授邁克爾·艾森(Michael Eisen)在Twitter上罵了回去。

The junk DNA wars are being waged at the frontiers of biology, but they’re really just the latest skirmish in an intellectual struggle that has played out over the past 200 years. Before Charles Darwin articulated his theory of evolution, most naturalists saw phenomena in nature, from an orchid’s petal to the hook of a vulture’s beak, as things literally designed by God. After Darwin, they began to see them as designs produced, instead, by natural selection. But some of our greatest biologists pushed back against the idea that everything we discover in an organism had to be an exquisite adaptation. To these biologists, a fully efficient genome would be inconsistent with the arbitrariness of our genesis, with the fact that every species emerged through pure happenstance, over eons of false starts. Where some look at all those billions of bases and see a finely tuned machine, others, like Gregory, see a disorganized, glorious mess.

如今，“垃圾DNA”之戰(zhàn)正在生物學(xué)的前沿上打響，但它們事實上不過是近200年來知識界紛爭中最近的幾場小戰(zhàn)役罷了。在查爾斯·達爾文 (Charles Darwin)發(fā)表著名的進化論之前，大多數(shù)博物學(xué)家都認(rèn)為自然界中的現(xiàn)象——從蘭花的花瓣到禿鷲喙上的鉤——都是上帝設(shè)計出來的杰作。在達爾文的理論得到廣泛接受之后，他們又開始將其視為自然選擇的產(chǎn)物，認(rèn)為生物的方方面面都是精確適應(yīng)的結(jié)果。然而，一些最偉大的生物學(xué)家卻提出了反對意見。在這些生物學(xué)家看來，充分高效的基因組與我們起源的隨意性不符，事實上，每一個物種都是在無數(shù)次錯誤的嘗試中偶然誕生的。有些人從這數(shù)十億堿基里看到一架調(diào)控精妙的機器，而在格雷戈里等其他人眼里，那只是一片狼藉。

In 1953, Francis Crick and James Watson published a short paper in the journal Nature setting out the double-helix structure of DNA. That brief note sent biologists into a frenzy of discovery, leading eventually to multiple Nobel Prizes and to an unprecedented depth of understanding about how living things grow and reproduce. To make a protein from DNA, they learned, a cell makes a single-stranded copy of the relevant gene, using a molecule called RNA. It then builds a corresponding protein using the RNA as a guide.

1953年，弗朗西斯·克里克(Francis Crick)和詹姆斯·沃森(James Watson)在《自然》雜志(Nature)上發(fā)表了一篇短文，展示了DNA的雙螺旋結(jié)構(gòu)。這篇短文讓生物學(xué)家們投入了探索的狂潮之中，最后還產(chǎn)生了多個諾貝爾獎，人們對生物的生長和繁殖的了解達到了前所未有的深度。他們發(fā)現(xiàn)，要根據(jù)DNA來生產(chǎn)蛋白質(zhì)，細(xì)胞要使用一種叫做RNA的分子來制作相關(guān)基因的單鏈拷貝，然后再利用該RNA來指導(dǎo)相應(yīng)蛋白質(zhì)的合成。

This research led scientists to assume that the genome was mostly made up of protein-coding DNA. But eventually scientists found this assumption hard to square with reality. In 1964, the German biologist Friedrich Vogel did a rough calculation of how many genes a typical human must carry. Scientists had already discovered how big the human genome was by staining the DNA in cells, looking at the cells through microscopes and measuring its size. If the human genome was made of nothing but genes, Vogel found, it would need to have an awful lot of them — 6.7 million genes by his estimate, a number that, when he published it in Nature, he admitted was “disturbingly high.” There was no evidence that our cells made 6.7 million proteins or anything close to that figure.

這項研究促使科學(xué)家們猜想基因組的絕大部分應(yīng)該是編碼蛋白質(zhì)的DNA，但后來他們發(fā)現(xiàn)，這種假設(shè)與現(xiàn)實相去甚遠。科學(xué)家們通過對細(xì)胞中的DNA進行染色，并以顯微鏡觀察和測量，估算出了人類基因組的大小。1964年，德國生物學(xué)家弗里德里希·福格爾(Friedrich Vogel)在《自然》雜志上發(fā)表了一篇文章，粗略計算了如果人類基因組完全由基因組成，一般來說，一個人應(yīng)該攜帶的基因數(shù)目是670萬個基因。這個數(shù)字簡直驚人地大，福格爾自己也承認(rèn)它“高得令人不安”。沒有任何證據(jù)表明，我們的細(xì)胞可以產(chǎn)生670萬種或接近這一數(shù)字的蛋白質(zhì)。

Vogel speculated that a lot of the genome was made up of essential noncoding DNA — possibly operating as something like switches, for example, to turn genes on and off. But other scientists recognized that even this idea couldn’t make sense mathematically. On average, each baby is born with roughly 100 new mutations. If every piece of the genome were essential, then many of those mutations would lead to significant birth defects, with the defects only multiplying over the course of generations; in less than a century, the species would become extinct.

于是福格爾推測基因組大部分是由必需的非編碼DNA組成——舉例來說，它們可能是發(fā)揮了類似于開關(guān)的作用，管理著基因的活躍與關(guān)閉。但其他的科學(xué)家們意識到，即使按照這個想法，在數(shù)學(xué)角度上還是不合理。平均而言，每個嬰兒出生時約帶有100個新的基因突變。如果基因組中的所有片段都是必不可少的，那么這些突變中有很多都會導(dǎo)致重大的天生缺陷，即使這些缺陷只有在傳代過程中才會成倍增加，該物種也會在一個世紀(jì)內(nèi)滅絕。

Faced with this paradox, Crick and other scientists developed a new vision of the genome during the 1970s. Instead of being overwhelmingly packed with coding DNA, the genome was made up mostly of noncoding DNA. And, what’s more, most of that noncoding DNA was junk — that is, pieces of DNA that do nothing for us. These biologists argued that some pieces of junk started out as genes, but were later disabled by mutations. Other pieces, called transposable elements, were like parasites, simply making new copies of themselves that were usually inserted harmlessly back in the genome.

面對這一悖論，克里克和其他科學(xué)家在20世紀(jì)70年代提出了關(guān)于基因組的新觀點：基因組并沒有塞滿編碼DNA，事實上，基因組絕大部分是非編碼 DNA。更重要的是，大多數(shù)非編碼DNA都是“垃圾”——也就是說，這些DNA片段對我們來說一無所用。這些生物學(xué)家認(rèn)為，某些“垃圾DNA”片段最初也是基因，只是后來因為突變的緣故失活了。其他的DNA片段稱為轉(zhuǎn)座因子，它們就好像寄生蟲一樣，單純地復(fù)制自己并插入到基因組的新位置上去(這種插入通常是無害的)。

Junk DNA’s recognition was part of a bigger trend in biology at the time. A number of scientists were questioning the assumption that biological systems are invariably “well designed” by evolution. In a 1979 paper in The Proceedings of the Royal Society of London, Stephen Jay Gould and Richard Lewontin, both of Harvard, groused that too many scientists indulged in breezy storytelling to explain every trait, from antlers to jealousy, as an adaptation honed by natural selection for some essential function. Gould and Lewontin refer to this habit as the Panglossian paradigm, a reference to Voltaire’s “Candide,” in which the foolish Professor Pangloss keeps insisting, in the face of death and disaster, that we live in “the best of all possible worlds.” Gould and Lewontin did not deny that natural selection was a powerful force, but they stressed that it was not the only explanation for why species are the way they are. Male nipples are not adaptations, for example; they’re just along for the ride.

當(dāng)時，識別“垃圾DNA”是生物學(xué)研究的大趨勢之一。許多科學(xué)家都開始質(zhì)疑所有生物體系都是進化“精心設(shè)計而來”的這一假設(shè)。1979年，哈佛大學(xué) (Harvard)的史蒂芬·杰伊·古爾德(Stephen Jay Gould)和理查德·列萬廷(Richard Lewontin)在《倫敦皇家學(xué)會會刊》(The Proceedings of the Royal Society of London)上發(fā)表了一篇文章，抱怨有太多的科學(xué)家縱容自己講故事般輕松自信地將每一個性狀——從鹿角到嫉妒心——都解釋成為了實現(xiàn)什么必不可少的功能而自然選擇出來的適應(yīng)性。古爾德和列萬廷稱這種習(xí)慣是“盲目樂觀”(Panglossian)的典范——這個字眼來自伏爾泰(Voltaire)的小說《憨第德》(Candide)中那位一再堅持，即使面對死亡和災(zāi)難，人們的處境仍然是“在所有可能的情況中最理想”的愚蠢教授潘格羅士 (Professor Pangloss)。古爾德和列萬廷并不否認(rèn)自然選擇是一種強大的力量，但他們強調(diào)，它并不是解釋物種為何會演化成現(xiàn)在這個模樣的唯一答案。例如，雄性的乳頭就不是一種適應(yīng)性，它們不過是在進化中湊湊熱鬧罷了。

Gould and Lewontin called instead for a broader vision of evolution, with room for other forces, for flukes and historical contingencies, for processes unfolding at different levels of life — what Gould often called “pluralism.” At the time, geneticists were getting their first glimpses of the molecular secrets of the human genome, and Gould and Lewontin saw more evidence for pluralism and against the Panglosses. Any two people may have millions of differences in their genomes. Most of those differences aren’t a result of natural selection’s guiding force; they just arise through random mutations, without any effect for good or ill.

古爾德和列萬廷呼吁人們以更開闊的眼光來看待進化，為其他的進化力量，如意外和歷史突發(fā)事件，以及在生命的不同層面上展開的過程留下空間——也就是古爾德常說的“多元主義”。當(dāng)時正值遺傳學(xué)家們第一次觸及人類基因組的分子秘密之時，古爾德和列萬廷發(fā)現(xiàn)了更多支持多元主義，反對盲目樂觀的證據(jù)。任何兩個人的基因組之間都可能存在數(shù)百萬個差異，其中大多數(shù)都不是自然選擇引導(dǎo)下的結(jié)果，它們只是些隨機突變，無所謂好壞。

When Crick and others began to argue for junk DNA, they were guided by a similar vision of nature as slipshod. Just as male nipples are a useless vestige of evolution, so, in their theory, is a majority of our genome. Far from the height of machine-like perfection, the genome is largely a palimpsest of worthless instructions, a den of harmless parasites. Crick and his colleagues argued that transposable elements were common in our genome not because they did something essential for us, but because they could exploit us for their own replication. Gould delighted at this good intellectual company, arguing that transposable elements behaved like miniature organisms, evolving to become better at adding new copies to their host genomes. Our genomes were their ocean, their savanna. “They are merely playing Darwin’s game, but at the ‘wrong level,’ ” Gould wrote in 1981.

當(dāng)克里克等人開始為“垃圾DNA”而辯時，他們也抱持著類似的觀點：大自然是個漫不經(jīng)心的家伙。他們認(rèn)為，雄性的乳頭只是進化中的一個無用的痕跡，我們的絕大部分基因組也是如此?；蚪M遠未達到機械般的精確和完美，在很大程度上，它更像是一本被反復(fù)擦去又重寫的抄本，又像是無害的寄生蟲們的巢穴?？死锟撕退耐聜冎赋?，轉(zhuǎn)座因子之所以在我們的基因組中十分常見，不是因為它們有什么必不可少的功能，而是因為它們可以利用我們來完成它們自身的復(fù)制。這種學(xué)術(shù)上的志同道合令古爾德十分欣喜，他也主張轉(zhuǎn)座因子的行為與微生物相似，在進化過程中，它們越來越擅長在宿主基因組中增加新的自身DNA拷貝。我們的基因組就好比它們生存的海洋和草原。古爾德在1981年寫道：“它們不過是在‘錯誤的層面上’玩達爾文的游戲罷了。”

Soon after Gould wrote those words, scientists set out to decipher the precise sequence of the entire human genome. It wasn’t until 2001, shortly before Gould’s death, that they published their first draft. They identified thousands of segments that had the hallmarks of dead genes. They found transposable elements by the millions. The Human Genome Project team declared that our DNA consisted of isolated oases of protein-coding genes surrounded by “vast expanses of unpopulated desert where only noncoding ‘junk’ DNA can be found.” Junk DNA had started out as a theoretical argument, but now the messiness of our evolution was laid bare for all to see.

就在古爾德寫下上面那番話后不久，科學(xué)家們開始著手破譯整個人類基因組的精確序列。但直到2001年，古爾德去世前不久，他們才發(fā)表了第一稿研究結(jié)果。他們識別出了帶有“死基因”標(biāo)志的數(shù)千個DNA片段，還發(fā)現(xiàn)了數(shù)以百萬計的轉(zhuǎn)座因子。“人類基因組計劃(Human Genome Project)”團隊宣稱，我們的DNA就像“一大片由‘垃圾DNA’組成的荒漠”，其中星星點點散布著編碼蛋白質(zhì)的基因“綠洲”。“垃圾DNA”最初只是一個理論上的爭論，但現(xiàn)在我們在進化上的雜亂無章已經(jīng)是有目共睹。

If you want to see the genome in a fundamentally different way, the best place to go is the third floor of Harvard’s Department of Stem Cell and Regenerative Biology, in a maze of cluttered benches, sequencing machines and microscopes. This is the lab of John Rinn, a 38-year-old former competitive snowboarder who likes to ponder biological questions on top of a skateboard, which he rides from one wall of his office to the other and back. Rinn is overseeing more than a dozen research projects looking for pieces of noncoding DNA that might once have been classified as junk but actually are essential for life.

如果你想要用一種迥然不同的方式去考察基因組，哈佛大學(xué)干細(xì)胞與再生生物學(xué)系(Department of Stem Cell and Regenerative Biology)亂糟糟地放滿了試驗臺、測序儀和顯微鏡的迷宮般的三樓是一個絕佳場所。這里是約翰·里恩(John Rinn)的實驗室，他今年38歲，曾是一名競技雪板滑雪運動員，現(xiàn)在依然喜歡駕馭著雪板從辦公室的一面墻滑到另一面墻，同時思考生物學(xué)問題。里恩負(fù)責(zé)著十幾個項目，目的是研究一些曾經(jīng)被視為“垃圾”，其實卻為生命所必需的非編碼DNA片段。

Rinn studies RNA, but not the RNA that our cells use as a template for making proteins. Scientists have long known that the human genome contains some genes for other types of RNA: strands of bases that carry out other jobs in the cell, like helping to weld together the building blocks of proteins. In the early 2000s, Rinn and other scientists discovered that human cells were reading thousands of segments of their DNA, not just the coding parts, and producing RNA molecules in the process. They wondered whether these RNA molecules could be serving some vital function.

里恩的研究對象是RNA，但不是我們的細(xì)胞用以作為制造蛋白質(zhì)的模板的那種RNA。科學(xué)家們早已知道，人類基因組中包含著一些其他類型的RNA的基因：這些堿基組成的長鏈在細(xì)胞內(nèi)執(zhí)行著其他任務(wù)，比如協(xié)助蛋白質(zhì)組裝等。21世紀(jì)初，里恩和其他科學(xué)家發(fā)現(xiàn)，人類細(xì)胞可以閱讀數(shù)千個自身DNA片段(不僅包含編碼區(qū))，并在此過程中制造RNA分子。他們想知道這些RNA分子是否具有什么生死攸關(guān)的功能。

As a postdoctoral fellow at Stanford University, Rinn decided he would try to show that one of these new RNA molecules had some important role. After a couple years of searching, he and a professor there, Howard Chang, settled on an RNA molecule that, somewhat bizarrely, was produced widely by skin cells below the waist but not above. Rinn and Chang were well aware that this pattern might be meaningless, but they set out to investigate it nevertheless. They had to give their enigmatic molecule a name, so they picked one that was a joke at their own expense: hotair. (“If it ends up being hot air, at least we tried,” Rinn said.)

里恩在斯坦福大學(xué)(Stanford University)做博士后時就決定要嘗試證明這些新的RNA分子具有重要的作用。經(jīng)過幾年的檢索，他與該大學(xué)的教授張元豪(Howard Chang)選定了一種特殊的RNA分子，這種分子非常奇怪，它在腰部以下的皮膚細(xì)胞中廣泛存在，但在腰部以上卻完全不見蹤跡。里恩和張都清楚地知道，這種模式可能毫無意義，但他們?nèi)匀婚_始了研究。他們給自己的神秘分子取了個頗具自嘲意味的名字：“hotair”。“如果最終證明它什么也不是(hot air有“吹牛”、“空話”之意——譯注)，起碼我們曾經(jīng)努力過，”里恩說。

Rinn ran a series of experiments on skin cells to figure out what, if anything, hotair was doing. He carefully pulled hotair molecules out of the cells and examined them to see if they had attached to any other molecules. They had, in fact: they were stuck to a protein called Polycomb.

里恩對皮膚細(xì)胞進行了一系列的實驗，想看看hotair有什么功能(就是說，如果有的話)。他小心翼翼地將hotair分子從細(xì)胞中提取出來，并檢查它們是否曾與任何其他分子相連接。事實上，是的：它們可與一種名為Polycomb的蛋白質(zhì)緊密結(jié)合。

Polycomb belongs to a group of proteins that are essential to the development of animals from a fertilized egg. They turn genes on and off in different patterns, so that a uniform clump of cells can give rise to bone, muscle and brain. Polycomb latches onto a number of genes and muzzles them, preventing them from making proteins. Rinn’s research revealed that hotair acts as a kind of guide for Polycomb, attaching to it and escorting it through the jungle of the cell to the precise spots on our DNA where it needs to silence genes.

Polycomb隸屬于一組對于從受精卵到動物成體的發(fā)育過程必不可少的蛋白質(zhì)。它們可在不同的模式下激活或關(guān)閉基因，從而使一群細(xì)胞統(tǒng)一地發(fā)育成骨骼、肌肉或腦。Polycomb蛋白可以與多種基因相結(jié)合并使其失活，無法再生產(chǎn)蛋白質(zhì)。里恩的研究顯示，hotair的作用就像是Polycomb蛋白的向?qū)?，?dāng)它結(jié)合在Polycomb上后，就可以護送該蛋白穿過亂七八糟的細(xì)胞內(nèi)環(huán)境，準(zhǔn)確地結(jié)合到需要被沉默的基因位點上。

When Rinn announced this result in 2007, other geneticists were stunned. Cell, the journal that released it, hailed it as a breakthrough, calling Rinn’s paper one of the most important they had ever published. In the years since, Chang and other researchers have continued to examine hotair, using even more sophisticated tools. They bred engineered mice that lack the hotair gene, for example, and found that the mice developed a constellation of deformities, like stunted wrists and jumbled vertebrae. It appears very likely that hotair performs important jobs throughout the body, not just in the skin but in the skeleton and in other tissues too.

2007年，里恩在《細(xì)胞》(Cell)雜志上發(fā)表了自己的研究結(jié)果，震驚了遺傳學(xué)界。《細(xì)胞》雜志稱其為巨大的突破，并表示里恩的這項研究是他們曾經(jīng)發(fā)表過的最重要的論文之一。在隨后的幾年中，張和其他研究人員使用更復(fù)雜的工具繼續(xù)對hotair深入研究。例如，他們利用基因工程，培育出了缺乏 hotair基因的小鼠，并發(fā)現(xiàn)這些小鼠出現(xiàn)了一系列畸形，如腕部發(fā)育遲緩、椎骨混雜等。顯然hotair很可能在皮膚、骨骼以及全身的其他組織中也發(fā)揮著重要的作用。

In 2008, having been lured to Harvard, Rinn set up his new lab entirely in hopes of finding more hotair-like molecules. The first day I visited, a research associate named Diana Sanchez was dissecting mouse embryos the size of pinto beans. In a bowl of ice next to her were tubes for the parts she delicately removed — liver, leg, kidney, lung — that would be searched for cells making RNA molecules. After Rinn and I left Sanchez to her dissections, we ran into Martin Sauvageau, a blue-eyed Quebecer carrying a case of slides, each affixed with a slice of a mouse’s brain, with stains revealing cells making different RNA molecules. I tagged along with Sauvageau as he headed to a darkened microscope room to look at the slides with a pink-haired grad student named Abbie Groff. On one slide, a mouse’s brain looked as if it wore a cerulean mustache. To Groff, every pattern comes as a surprise. She once discovered an RNA molecule that created thousands of tiny rings on a mouse’s body, each encircling a hair follicle. “You come in in the morning, and it’s like Christmas,” she said.

2008年，里恩應(yīng)邀來到哈佛大學(xué)，并在此建立了自己的新實驗室，一心一意希望能找到更多類似hotair的分子。我去參觀的第一天，正趕上他的研究助理戴安娜·桑切斯(Diana Sanchez)在解剖只有斑豆大小的小鼠胚胎。她旁邊的冰浴槽中插著好些個試管，里面盛放著她精心剝離的各種器官和身體部件——肝臟、腿、腎臟、肺等，用于從其中搜尋制造RNA分子的細(xì)胞。為了不打擾桑切斯的解剖工作，里恩和我離開了，然后我們碰到了馬丁·索瓦若(Martin Sauvageau)，這個藍眼睛的魁北克人拿著一盒玻片，每片玻片上都固定著一片小鼠大腦切片，并以染色顯示了制造不同RNA分子的細(xì)胞。我隨同索瓦若前往黑暗的顯微鏡室，和一個有著粉紅色頭發(fā)的研究生阿比·格羅夫(Abbie Groff)一起查看了這些切片。有一張切片上的小鼠腦部就像留了一簇天藍色的小胡子。在格羅夫看來，每種模式都是一個驚喜。她曾經(jīng)發(fā)現(xiàn)了一種RNA分子可以在小鼠體內(nèi)產(chǎn)生數(shù)千個微小的環(huán)狀物，每個環(huán)都包繞著一個毛囊。“每天早上進來的時候，感覺都像在過圣誕節(jié)，”她這樣形容道。

In December 2013, Rinn and his colleagues published the first results of their search: three potential new genes for RNA that appear to be essential for a mouse’s survival. To investigate each potential gene, the scientists removed one of the two copies in mice. When the mice mated, some of their embryos ended up with two copies of the gene, some with one and some with none. If these mice lacked any of these three pieces of DNA, they died in utero or shortly after birth. “You take away a piece of junk DNA, and the mouse dies,” Rinn said. “If you can come up with a criticism of that, go ahead. But I’m pretty satisfied. I’ve found a new piece of the genome that’s required for life.”

2013年12月，里恩和同事們發(fā)表了第一批搜索結(jié)果：有三個新的潛在的RNA基因可能對小鼠的生存至關(guān)重要。為了調(diào)查每個潛在基因，科學(xué)家設(shè)法刪除了小鼠體內(nèi)該基因兩個拷貝中的一個。當(dāng)這些小鼠交配時，一部分胚胎將帶有兩個基因拷貝，有的帶有一個，有的則一個也沒有。不論是缺少這三種DNA片段中的哪一個，小鼠都會胎死宮中或在出生后不久死亡。“敲除了一個‘垃圾DNA’片段，小鼠就無法存活，”里恩說。“如果你要提出批評意見，盡管說好了。但我已經(jīng)很滿意了。我又發(fā)現(xiàn)了一個新的生命必需的基因組片段。”

As the scientists find new RNA molecules that look to be important, they are picking out a few to examine in close molecular detail. “I’m totally in love with this one,” Rinn said, standing at a whiteboard wall and drawing a looping line to illustrate yet another RNA molecule, one that he calls “firre.” The experiments that Rinn’s team has run on firre suggest that it performs a spectacular lasso act, grabbing onto three different chromosomes at once and drawing them together. Rinn suspects that there are thousands of RNA molecules encoded in our genomes that perform similar feats: bending DNA, unspooling it, bringing it in contact with certain proteins and otherwise endowing it with a versatility it would lack on its own.

在尋找新的具有重要功能的RNA分子的同時，科學(xué)家們也從中選出了幾個來進行分子層面上的詳細(xì)研究。里恩站在白板前，用循環(huán)線圖示向我闡釋另一種被他命名為“firre”的RNA分子，“我想我已經(jīng)深深愛上它了，”他說。里恩的團隊目前對firre進行的實驗表明，它的功能像一個巨大的套索，可以同時抓住三個不同的染色體并把它們拉到一塊兒來。里恩懷疑我們的基因組編碼了成千上萬個可以進行類似壯舉的RNA分子，它們可以彎曲DNA、解開DNA螺旋，使其與某些特定的蛋白質(zhì)接觸或者賦予其本身沒有的廣泛功用。

“It’s genomic origami,” Rinn said about this theory. “In every cell, you have the same piece of paper. Stem cell, brain cell, liver cell, it’s all made from the same piece of paper. How you fold that paper determines if you get a paper airplane or a duck. It’s the shape that you fold it into that matters. This has to be the 3-D code of biology.”

“這就好比在基因組層面上做折紙手工，”里恩這樣解釋他的理論。“每個細(xì)胞都擁有一張同樣的紙。干細(xì)胞、腦細(xì)胞、肝臟細(xì)胞……全都是從同樣的紙上誕生的，是你的折法決定了最后會得到一架飛機還是一只鴨子。你折疊出來的形狀才是最重要的。這是生物學(xué)的三維代碼。”

To some biologists, discoveries like Rinn’s hint at a hidden treasure house in our genome. Because a few of these RNA molecules have turned out to be so crucial, they think, the rest of the noncoding genome must be crammed with riches. But to Gregory and others, that is a blinkered optimism worthy of Dr. Pangloss. They, by contrast, are deeply pessimistic about where this research will lead. Most of the RNA molecules that our cells make will probably not turn out to perform the sort of essential functions that hotair and firre do. Instead, they are nothing more than what happens when RNA-making proteins bump into junk DNA from time to time.

一些生物學(xué)家認(rèn)為，里恩這類新發(fā)現(xiàn)提示我們的基因組中隱藏著一座大寶庫。由于已有研究證明，有幾種這樣的RNA分子至關(guān)重要，他們認(rèn)為，基因組其余的非編碼片段一定也蘊藏著豐富的寶藏。但是格雷戈里和其他人表示這種想法不過是潘格羅士博士那樣的盲目樂觀罷了。相比之下，他們倒是對這項研究的前景深感悲觀。事實上，我們的細(xì)胞制造的大多數(shù)RNA分子很可能并沒有像hotair或firre那樣的重要功能。相反，在大部分情況下，不過是制造RNA的蛋白質(zhì)偶爾撞上了“垃圾DNA”而已。

“You say, ‘I found it — America!’ ” says Alex Palazzo, a biochemist at the University of Toronto who co-wrote a spirited defense of junk DNA with Gregory last year in the journal PLOS Genetics. “But probably what you found is a little bit of noise.”

“你興奮地宣稱：‘我發(fā)現(xiàn)了美洲新大陸!’”多倫多大學(xué)(University of Toronto)的生化學(xué)家，與格雷戈里協(xié)力在《公共科學(xué)圖書館：遺傳學(xué)》雜志(PLOS Genetics)上撰文為“垃圾DNA”堅決辯護的亞歷克斯·帕拉佐(Alex Palazzo)說，“但你發(fā)現(xiàn)的很可能只是一點點噪音罷了。”

Palazzo and his colleagues also roll their eyes at the triumphant declarations being made about recent large-scale surveys of the human genome. One news release from an N.I.H. project declared, “Much of what has been called ‘junk DNA’ in the human genome is actually a massive control panel with millions of switches regulating the activity of our genes.” Researchers like Gregory consider this sort of rhetoric to be leaping far beyond the actual evidence. Gregory likens the search for useful pieces of noncoding DNA to using a metal detector to find gold buried at the beach. “The idea of combing the beach is a great idea,” he says. But you have to make sure your metal detector doesn’t go off when it responds to any metal. “You’re going to find bottle caps and nails,” Gregory says.

帕拉佐和同事們還將目光轉(zhuǎn)向了近期的一次大規(guī)模人類基因組調(diào)查的勝利宣言。一項N.I.H.項目最近發(fā)布新聞稱：“人類基因組中之前被稱為‘垃圾 DNA’的片段其實大多是巨大的控制面板，內(nèi)含數(shù)以百萬計的開關(guān)，調(diào)節(jié)著我們的基因活性。”格雷戈里等研究人員認(rèn)為這是遠遠超出了實際證據(jù)的浮夸之辭。格雷戈里將尋找有用的非編碼DNA片段比作使用金屬探測器搜索埋在沙灘里的黃金。“把海灘徹底搜查一番是個好主意，”他說。但你必須確保你的金屬探測器不會遇到任何金屬都警鈴大作。“不然你找到的絕大部分都將是瓶蓋和釘子。”格雷戈里說;

He expects that as we examine the genome more closely, we’ll find many bottle caps and nails. It’s a prediction based, he and others argue, on the deep evolutionary history of our genome. Over millions of years, essential genes haven’t changed very much, while junk DNA has picked up many harmless mutations. Scientists at the University of Oxford have measured evolutionary change over the past 100 million years at every spot in the human genome. “I can today say, hand on my heart, that 8 percent, plus or minus 1 percent, is what I would consider functional,” Chris Ponting, an author of the study, says. And the other 92 percent? “It doesn’t seem to matter that much,” he says.

他預(yù)計，隨著我們更仔細(xì)地檢查基因組，還會發(fā)現(xiàn)許多瓶蓋和釘子。他和其他人表示，這個預(yù)測是基于我們基因組深厚的進化史做出的。數(shù)百萬年來，必需基因并沒發(fā)生多少變化，而“垃圾DNA”卻帶上了很多無害的突變。牛津大學(xué)(University of Oxford)的科學(xué)家們衡量了過去一億年來人類基因組的每個位點在進化上的改變。該研究的作者之一，克里斯·龐廷(Chris Ponting)說：“現(xiàn)在我敢拍著胸脯說，我認(rèn)為其中只有8%(上下波動范圍不會超過1%)具有生物學(xué)功能。”那其他的92%呢?“似乎就沒那么重要了，”他說。

It’s no coincidence, researchers like Gregory argue, that bona fide creationists have used recent changes in the thinking about junk DNA to try to turn back the clock to the days before Darwin. (The recent studies on noncoding DNA “clearly demonstrate we are ‘fearfully and wonderfully made’ by our Creator God,” declared the Institute for Creation Research.) In a sense, this debate stretches back to Darwin himself, whose 1859 book, “On the Origin of Species,” set the course for our understanding natural selection as a natural “designer.” Later in his life, Darwin took pains to stress that there was more to evolution than natural selection. He was frustrated to see how many of his readers thought he was arguing that natural selection was the only force behind life’s diversity. “Great is the power of steady misrepresentation,” Darwin grumbled when he updated the book for its sixth edition in 1872. In fact, he wrote, he was quite open-minded about other forces that might drive evolution, like “variations that seem to us in our ignorance to arise spontaneously.”

格雷戈里等研究人員認(rèn)為，虔誠的創(chuàng)世論者不約而同地利用“垃圾DNA”觀念中的最新變化，這絕非偶然，他們這是試圖讓時間倒退回達爾文時代之前。(創(chuàng)世論研究學(xué)會[Institute for Creation Research]稱：近期關(guān)于非編碼DNA的研究“清楚地表明我們是造物主‘創(chuàng)造的奇妙又可怕的作品’”。)從某種意義上說，這場辯論可以追溯到達爾文本人，他在1859年出版的著作《物種起源》(“On the Origin of Species”)中將我們對自然選擇的理解定位為天然的“設(shè)計師”。晚年時期的達爾文也曾煞費苦心地強調(diào)，自然選擇只是進化的一個方面。看到許多讀者誤以為他主張自然選擇是產(chǎn)生生物多樣性的唯一動力，令他十分沮喪。“接連不斷的錯誤闡釋的力量真大。”達爾文在1872年更新該書第六版時抱怨道。事實上，他對有可能推動進化的其他力量，比如“在我們毫不知情的情況下自發(fā)產(chǎn)生的變異”等持有相當(dāng)開明的態(tài)度。