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(University of Guelph)，走進進化生物學家T·瑞安·格雷戈裏(T. Ryan Gregory)的實驗室，你會感覺好像走進了一個基因組學的大觀園，各種各樣活着或者已經死去的生物正等待着自身的DNA被解讀：蠍子潛伏在飼養箱裏；狼蛛在小盆下面打瞌睡；格雷戈裏和他的學生在北極探險時採集的蜘蛛和甲殼類動物的速凍標本存放在米色金屬液氮罐裏；軟體動物、飛蛾和甲蟲標本保存在一排立式冷凍櫃中；而櫥櫃裏則塞滿了果蝠、暹羅鬥魚和鴕鳥基因組的品紅染色塗片標本。

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，格雷戈裏學到了重要的一課：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。爲此，格雷戈裏的研究生尼克·傑弗裏(Nick Jeffery)從大學的溫室裏採了一棵小洋蔥拿到實驗室，然後遞給我一把單刃安全剃鬚刀，和我一起在培養皿中把洋蔥莖切碎。不一會兒，我的培養皿裏就堆起了一坨帶着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願者。傑弗裏拿出了一個小瓶，讓我把手指上的血抹在瓶沿上，隨後我們把洋蔥汁也倒入瓶中，看着綠色和紅色的液體混合起來，產生一種從色調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.

傑弗裏向瓶中加入了能與DNA相結合的熒光染料，然後將小瓶放進一種叫做流式細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，每當一個細胞被擊中，其DNA就會發出藍色輝光，細胞的基因組越大，發出的光也就越亮。在我們的注視下，顯示器上圖表的數據逐漸積累，它表明兩種細胞產生了兩種截然不同的光，一種暗淡，一種明亮，相應地在圖表上顯示爲兩個峯。

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.

其中一個峯代表我的基因組，也就是我的全套DNA。基因組就好比一本用名爲鹼基的遺傳學字母寫成的生物學大書。人類的基因組約包含32億個鹼基，如果把這些字母打印在紙上，足夠組成一本比《戰爭與和平》(War and Peace)還長一千倍的鉅作。格雷戈裏朝着屏幕俯下身來，今年39歲的他留着栗色的山羊鬍子，目光熱切，有點像劇集《絕命毒師》中成爲“海森堡(Heisenberg)”之前的主角瓦特·懷特(Walter White)。他用手指着代表洋蔥的峯。它表明，洋蔥的基因組是我的五倍大。

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

格雷戈裏宣佈：“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，爲什麼會這樣呢？爲什麼洋蔥會攜帶比人還多那麼多的遺傳物質？同樣的問題也適用於寬足蠑螈（655億對鹼基），非洲肺魚（1320億）和衣笠草（又名重樓百合，1490億）。這些生物並不比我們人類複雜，所以格雷戈裏不認爲這些多出來的DNA的作用是完善它們的機能。相反，他更贊同一個在20世紀70年代首次提出，但至今聽來仍然有些驚世駭俗的學說：動植物基因組的大小與其複雜程度基本無關，因爲——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，編碼蛋白質的DNA片段。但這些基因僅佔整個基因組的1.2%左右。其餘的98.8%稱爲非編碼DNA。格雷戈裏認爲，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，大多數生物學家都同意他的意見。他們利用手頭最好的工具對基因組進行了調查，發現現有證據表明，只有一小部分非編碼DNA具有生物學功能。

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，該領域的風向開始變化。近期的研究揭示，新發現的衆多非編碼DNA對我們生存的重要程度不亞於我們較爲熟悉的那些基因。例如，其中有許多DNA可編碼引導我們從受精卵發育爲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症之類的災難性後果。大規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爲的更加活躍。

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變發表了評論。在舊金山舉行的一次衛生會議上，一位聽衆就“垃圾DNA”向他提問。“我們已經不再使用這個術語了，”柯林斯回答道。“以爲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——就彷彿我們敢打包票它們沒有任何功能似的。”科林斯指出，在曾經被科學家們認爲只是白佔地方的基因組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.

這種想法在格雷戈裏和一羣與他志同道合的生物學家看來不僅荒謬而且危險，很可能會帶來“僞科學”。他們認爲，反對“垃圾DNA”的概念，不過是基於對少數證據的過度解讀，以及對多年來紮實的基因組研究的刻意忽視。於是，他們在學術會議上面對面地向對手發起了挑戰，還在生物學期刊上撰寫了詳細的評論文章，並在社交媒體上發聲。當N.I.H.的官方Twitter帳號轉發柯林斯有關不再使用“垃圾DNA”這一術語的聲明時，加州大學伯克利分校(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”之戰正在生物學的前沿上打響，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役罷了。在查爾斯·達爾文(Charles Darwin)發表著名的進化論之前，大多數博物學家都認爲自然界中的現象——從蘭花的花瓣到禿鷲喙上的鉤——都是上帝設計出來的傑作。在達爾文的理論得到廣泛接受之後，他們又開始將其視爲自然選擇的產物，認爲生物的方方面面都是精確適應的結果。然而，一些最偉大的生物學家卻提出了反對意見。在這些生物學家看來，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次錯誤的嘗試中偶然誕生的。有些人從這數十億鹼基裏看到一架調控精妙的機器，而在格雷戈裏等其他人眼裏，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》雜誌(Nature)上發表了一篇短文，展示了DNA的雙螺旋結構。這篇短文讓生物學家們投入了探索的狂潮之中，最後還產生了多個諾貝爾獎，人們對生物的生長和繁殖的瞭解達到了前所未有的深度。他們發現，要根據DNA來生產蛋白質，細胞要使用一種叫做RNA的分子來製作相關基因的單鏈拷貝，然後再利用該RNA來指導相應蛋白質的合成。

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.

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

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.

於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，它們可能是發揮了類似於開關的作用，管理着基因的活躍與關閉。但其他的科學家們意識到，即使按照這個想法，在數學角度上還是不合理。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，那麼這些突變中有很多都會導致重大的天生缺陷，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內滅絕。

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，克里克和其他科學家在20世紀70年代提出了關於基因組的新觀點：基因組並沒有塞滿編碼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。這些生物學家認爲，某些“垃圾DNA”片段最初也是基因，只是後來因爲突變的緣故失活了。其他的DNA片段稱爲轉座因子，它們就好像寄生蟲一樣，單純地複製自己並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.

當時，識別“垃圾DNA”是生物學研究的大趨勢之一。許多科學家都開始質疑所有生物體系都是進化“精心設計而來”的這一假設。1979年，哈佛大學(Harvard)的史蒂芬·傑伊·古爾德(Stephen Jay Gould)和理查德·列萬廷(Richard Lewontin)在《倫敦皇家學會會刊》(The Proceedings of the Royal Society of London)上發表了一篇文章，抱怨有太多的科學家縱容自己講故事般輕鬆自信地將每一個性狀——從鹿角到嫉妒心——都解釋成爲了實現什麼必不可少的功能而自然選擇出來的適應性。古爾德和列萬廷稱這種習慣是“盲目樂觀”(Panglossian)的典範——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)。古爾德和列萬廷並不否認自然選擇是一種強大的力量，但他們強調，它並不是解釋物種爲何會演化成現在這個模樣的唯一答案。例如，雄性的乳頭就不是一種適應性，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.

古爾德和列萬廷呼籲人們以更開闊的眼光來看待進化，爲其他的進化力量，如意外和歷史突發事件，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”。當時正值遺傳學家們第一次觸及人類基因組的分子祕密之時，古爾德和列萬廷發現了更多支持多元主義，反對盲目樂觀的證據。任何兩個人的基因組之間都可能存在數百萬個差異，其中大多數都不是自然選擇引導下的結果，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.

當克里克等人開始爲“垃圾DNA”而辯時，他們也抱持着類似的觀點：大自然是個漫不經心的傢伙。他們認爲，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。基因組遠未達到機械般的精確和完美，在很大程度上，它更像是一本被反覆擦去又重寫的抄本，又像是無害的寄生蟲們的巢穴。克里克和他的同事們指出，轉座因子之所以在我們的基因組中十分常見，不是因爲它們有什麼必不可少的功能，而是因爲它們可以利用我們來完成它們自身的複製。這種學術上的志同道合令古爾德十分欣喜，他也主張轉座因子的行爲與微生物相似，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’玩達爾文的遊戲罷了。”

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後不久，科學家們開始着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，他們才發表了第一稿研究結果。他們識別出了帶有“死基因”標誌的數千個DNA片段，還發現了數以百萬計的轉座因子。“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”，其中星星點點散佈着編碼蛋白質的基因“綠洲”。“垃圾DNA”最初只是一個理論上的爭論，但現在我們在進化上的雜亂無章已經是有目共睹。

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，哈佛大學幹細胞與再生生物學系(Department of Stem Cell and Regenerative Biology)亂糟糟地放滿了試驗檯、測序儀和顯微鏡的迷宮般的三樓是一個絕佳場所。這裏是約翰·裏恩(John Rinn)的實驗室，他今年38歲，曾是一名競技雪板滑雪運動員，現在依然喜歡駕馭着雪板從辦公室的一面牆滑到另一面牆，同時思考生物學問題。裏恩負責着十幾個項目，目的是研究一些曾經被視爲“垃圾”，其實卻爲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.

裏恩的研究對象是RNA，但不是我們的細胞用以作爲製造蛋白質的模板的那種RNA。科學家們早已知道，人類基因組中包含着一些其他類型的RNA的基因：這些鹼基組成的長鏈在細胞內執行着其他任務，比如協助蛋白質組裝等。21世紀初，裏恩和其他科學家發現，人類細胞可以閱讀數千個自身DNA片段（不僅包含編碼區），並在此過程中製造RNA分子。他們想知道這些RNA分子是否具有什麼生死攸關的功能。

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.)

裏恩在斯坦福大學(Stanford University)做博士後時就決定要嘗試證明這些新的RNA分子具有重要的作用。經過幾年的檢索，他與該大學的教授張元豪(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胞中廣泛存在，但在腰部以上卻完全不見蹤跡。裏恩和張都清楚地知道，這種模式可能毫無意義，但他們仍然開始了研究。他們給自己的神祕分子取了個頗具自嘲意味的名字：“hotair”。“如果最終證明它什麼也不是（hot air有“吹牛”、“空話”之意——譯註），起碼我們曾經努力過，”裏恩說。

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.

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

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隸屬於一組對於從受精卵到動物成體的發育過程必不可少的蛋白質。它們可在不同的模式下激活或關閉基因，從而使一羣細胞統一地發育成骨骼、肌肉或腦。Polycomb蛋白可以與多種基因相結合並使其失活，無法再生產蛋白質。裏恩的研究顯示，hotair的作用就像是Polycomb蛋白的嚮導，當它結合在Polycomb上後，就可以護送該蛋白穿過亂七八糟的細胞內環境，準確地結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，裏恩在《細胞》(Cell)雜誌上發表了自己的研究結果，震驚了遺傳學界。《細胞》雜誌稱其爲巨大的突破，並表示裏恩的這項研究是他們曾經發表過的最重要的論文之一。在隨後的幾年中，張和其他研究人員使用更復雜的工具繼續對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，並發現這些小鼠出現了一系列畸形，如腕部發育遲緩、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揮着重要的作用。

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，裏恩應邀來到哈佛大學，並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着好些個試管，裏面盛放着她精心剝離的各種器官和身體部件——肝臟、腿、腎臟、肺等，用於從其中搜尋製造RNA分子的細胞。爲了不打擾桑切斯的解剖工作，裏恩和我離開了，然後我們碰到了馬丁·索瓦若(Martin Sauvageau)，這個藍眼睛的魁北克人拿着一盒玻片，每片玻片上都固定着一片小鼠大腦切片，並以染色顯示了製造不同RNA分子的細胞。我隨同索瓦若前往黑暗的顯微鏡室，和一個有着粉紅色頭髮的研究生阿比·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鬍子。在格羅夫看來，每種模式都是一個驚喜。她曾經發現了一種RNA分子可以在小鼠體內產生數千個微小的環狀物，每個環都包繞着一個毛囊。“每天早上進來的時候，感覺都像在過聖誕節，”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，裏恩和同事們發表了第一批搜索結果：有三個新的潛在的RNA基因可能對小鼠的生存至關重要。爲了調查每個潛在基因，科學家設法刪除了小鼠體內該基因兩個拷貝中的一個。當這些小鼠交配時，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後不久死亡。“敲除了一個‘垃圾DNA’片段，小鼠就無法存活，”裏恩說。“如果你要提出批評意見，儘管說好了。但我已經很滿意了。我又發現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，科學家們也從中選出了幾個來進行分子層面上的詳細研究。裏恩站在白板前，用循環線圖示向我闡釋另一種被他命名爲“firre”的RNA分子，“我想我已經深深愛上它了，”他說。裏恩的團隊目前對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並把它們拉到一塊兒來。裏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摺紙手工，”裏恩這樣解釋他的理論。“每個細胞都擁有一張同樣的紙。幹細胞、腦細胞、肝臟細胞……全都是從同樣的紙上誕生的，是你的折法決定了最後會得到一架飛機還是一隻鴨子。你摺疊出來的形狀纔是最重要的。這是生物學的三維代碼。”

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.

一些生物學家認爲，裏恩這類新發現提示我們的基因組中隱藏着一座大寶庫。由於已有研究證明，有幾種這樣的RNA分子至關重要，他們認爲，基因組其餘的非編碼片段一定也蘊藏着豐富的寶藏。但是格雷戈裏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，我們的細胞製造的大多數RNA分子很可能並沒有像hotair或firre那樣的重要功能。相反，在大部分情況下，不過是製造RNA的蛋白質偶爾撞上了“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：‘我發現了美洲新大陸！’”多倫多大學(University of Toronto)的生化學家，與格雷戈裏協力在《公共科學圖書館：遺傳學》雜誌(PLOS Genetics)上撰文爲“垃圾DNA”堅決辯護的亞歷克斯·帕拉佐(Alex Palazzo)說，“但你發現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向了近期的一次大規模人類基因組調查的勝利宣言。一項N.I.H.項目最近發佈新聞稱：“人類基因組中之前被稱爲‘垃圾DNA’的片段其實大多是巨大的控制面板，內含數以百萬計的開關，調節着我們的基因活性。”格雷戈裏等研究人員認爲這是遠遠超出了實際證據的浮誇之辭。格雷戈裏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裏的黃金。“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。”格雷戈裏說；

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.

他預計，隨着我們更仔細地檢查基因組，還會發現許多瓶蓋和釘子。他和其他人表示，這個預測是基於我們基因組深厚的進化史做出的。數百萬年來，必需基因並沒發生多少變化，而“垃圾DNA”卻帶上了很多無害的突變。牛津大學(University of Oxford)的科學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：“現在我敢拍着胸脯說，我認爲其中只有8%（上下波動範圍不會超過1%）具有生物學功能。”那其他的92%呢？“似乎就沒那麼重要了，”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.”

格雷戈裏等研究人員認爲，虔誠的創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。（創世論研究學會[Institute for Creation Research]稱：近期關於非編碼DNA的研究“清楚地表明我們是造物主‘創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爲天然的“設計師”。晚年時期的達爾文也曾煞費苦心地強調，自然選擇只是進化的一個方面。看到許多讀者誤以爲他主張自然選擇是產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產生的變異”等持有相當開明的態度。

Darwin was certainly ignorant about genomes, as scientists would continue to be for decades after his death. But Gregory argues that genomes embody the very mix of adaptation and arbitrariness that Darwin had in mind. Over millions of years, the human genome has spontaneously gotten bigger, swelling with useless copies of genes and new transposable elements. Our ancestors tolerated all that extra baggage because it wasn’t actually all that heavy. It didn’t make them inordinately sick. Copying all that extra DNA didn’t require them to draw off energy required for other tasks. They couldn’t add an infinite amount of junk to the genome, but they could accept an awful lot. To subtract junk, meanwhile, would require swarms of proteins to chop out every single dead gene or transposable element — without chopping out an essential gene. A genome evolving away its junk would lose the race to sloppier genomes, which left more resources for fighting diseases or having children.

達爾文肯定對基因組一無所知，因爲直到他去世幾十年後，科學家們纔開始孜孜不倦地研究這一課題。但格雷戈裏認爲，基因組恰好體現了達爾文的初衷：適應性和隨意性的混合體。數百萬年來，人類基因組自發增大了不少，其中充斥着無用的基因拷貝和新的轉座因子。我們的祖先寬容地將所有這些額外的行李帶在了身上，因爲它們本來也不算多重的負擔。這些額外的DNA既不會導致重病，複製所需的能量也很少，不會影響其他正常工作的完成。當然，基因組不可能無限制地接納垃圾，但其垃圾容量確實相當巨大。另一方面，要清除垃圾則很麻煩，需要大批的蛋白質來刪除每一個“死基因”或轉座因子——同時還得保證不會傷及必需基因。一個冗餘的基因組可以保留更多的資源來進行繁殖或與疾病鬥爭，而丟失“垃圾DNA”的基因組則將淪爲進化中的輸家。

The blood-drenched slides that pack Gregory’s lab with their giant genomes only make sense, he argues, if we give up thinking about life as always evolving to perfection. To him, junk DNA isn’t a sign of evolution’s failure. It is, instead, evidence of its slow and slovenly triumph.

格雷戈裏認爲，只有當我們不再認爲生命總是朝着更完善的方向發展，才能理解塞滿他實驗室的那些血淋淋的切片中展示的巨大基因組。在他看來，“垃圾DNA”並不是進化失敗的標誌，相反，它表明進化是個緩慢的過程，其成功往往是不經意間的妙手偶得。