At the break, I was asked by several people about my comments about the aging debate. And this will be my only comment on it. And that is, I understand that optimists greatly outlive pessimists. (Laughter)
演講開始之前,我遇到幾個人 問我對於老化議題的看法 關於這個問題我唯一的 看法就是 樂觀的人比悲觀者要活的久的多 (笑聲)
What I'm going to tell you about in my 18 minutes is how we're about to switch from reading the genetic code to the first stages of beginning to write the code ourselves. It's only 10 years ago this month when we published the first sequence of a free-living organism, that of haemophilus influenzae. That took a genome project from 13 years down to four months. We can now do that same genome project in the order of two to eight hours. So in the last decade, a large number of genomes have been added: most human pathogens, a couple of plants, several insects and several mammals, including the human genome. Genomics at this stage of the thinking from a little over 10 years ago was, by the end of this year, we might have between three and five genomes sequenced; it's on the order of several hundred. We just got a grant from the Gordon and Betty Moore Foundation to sequence 130 genomes this year, as a side project from environmental organisms. So the rate of reading the genetic code has changed.
在這18分鐘內我將告訴各位的是 我們如何從破解基因編碼 進步到可以開始 自己編寫基因編碼 僅僅是10年前的同一個月 我們公佈了第一組取自一種 非寄生有機體的基因序列 叫做嗜血桿菌 它將原本耗時13年的 基因計畫縮短到4個月 我們現在只需要 2到8個小時 就能完成相同的計畫 因此過去10年間,我們研究了許多基因組 大部分是人類病源體 幾種植物的基因組 以及一些昆蟲和哺乳類的基因組 當然也包括人類 回顧10多年前剛剛起步的 基因組學科進行 到今年年底,我們可能已經完成了 三到五組基因組的測序 但這只是約幾百組中的一小部分 我們最近接受了「戈登與貝蒂‧摩爾基金」資助 作為對環境有機體研究的附屬計畫 在今年進行130組基因組的測序。 對基因編碼的讀取速度已經發生變化。
But as we look, what's out there, we've barely scratched the surface on what is available on this planet. Most people don't realize it, because they're invisible, but microbes make up about a half of the Earth's biomass, whereas all animals only make up about one one-thousandth of all the biomass. And maybe it's something that people in Oxford don't do very often, but if you ever make it to the sea, and you swallow a mouthful of seawater, keep in mind that each milliliter has about a million bacteria and on the order of 10 million viruses.
但是放眼世界, 我們對地球上的萬物 仍然知之甚少。 大部份人很難意識到是因為它們是肉眼所看不見的, 但微生物佔據了地球上生物總量的一半。 所有的動物只在生物總量 佔了大約千分之一。 可能住在牛津的人們通常不會這樣做。 但是你要是去海邊, 吞一口海水, 那麼請記住每一毫升的海水中 都有大約100萬隻細菌 和大約1000萬隻病毒。
Less than 5,000 microbial species have been characterized as of two years ago, and so we decided to do something about it. And we started the Sorcerer II Expedition, where we were, as with great oceanographic expeditions, trying to sample the ocean every 200 miles. We started in Bermuda for our test project, then moved up to Halifax, working down the U.S. East Coast, the Caribbean Sea, the Panama Canal, through to the Galapagos, then across the Pacific, and we're in the process now of working our way across the Indian Ocean. It's very tough duty; we're doing this on a sailing vessel, in part to help excite young people about going into science. The experiments are incredibly simple. We just take seawater and we filter it, and we collect different size organisms on different filters, and then take their DNA back to our lab in Rockville, where we can sequence a hundred million letters of the genetic code every 24 hours. And with doing this, we've made some amazing discoveries.
到兩年前位置,只有少於五千種 微生物被我們分類記載。 因此我們決定做些工作。 我們啓動了‘魔法師二號’海巡計畫, 進行遠大的海洋考察, 嘗試毎隔200英哩進行一次採樣。 我們先在百慕達進行前測。 然後移師到哈利法克斯, 一路往南經過美國東岸, 加勒比海,巴拿馬運河, 穿過加拉巴哥群島,橫渡太平洋, 現在我們正在橫越 印度洋的途中。 這是很吃重的工作;我們在帆船上進行此項任務, 也是希望引起年輕人的興趣 來投身科學研究。 實驗本身十分簡單。 只要取得海水、經過過濾, 通過不同的濾網來蒐集不同大小的微生物。 然後把它們的DNA帶回在岩城的實驗室, 在那裡我們可以在24小時內完成 一億個字符的基因編碼的測序。 通過這樣做, 我們有了驚人的新發現。
For example, it was thought that the visual pigments that are in our eyes -- there was only one or two organisms in the environment that had these same pigments. It turns out, almost every species in the upper parts of the ocean in warm parts of the world have these same photoreceptors, and use sunlight as the source of their energy and communication. From one site, from one barrel of seawater, we discovered 1.3 million new genes and as many as 50,000 new species.
舉例而言,一般認為人類眼中的視覺色素 在大自然中只有一兩種有機體 擁有相同的色素。 結果發現幾乎所有生活在 氣候溫暖的地區的 上層海域的物種 都有這些感光細胞, 並且以陽光作為能量的來源 並進行通訊。 在一個地方取得的一桶海水中, 我們發現了130萬種新基因 和多達5萬種新物種。
We've extended this to the air now with a grant from the Sloan Foundation. We're measuring how many viruses and bacteria all of us are breathing in and out every day, particularly on airplanes or closed auditoriums. (Laughter) We filter through some simple apparatuses; we collect on the order of a billion microbes from just a day filtering on top of a building in New York City. And we're in the process of sequencing all that at the present time.
目前我們獲得史隆基金的資助來 把這種方法應用到對大氣圈中。 測量大家每天所呼吸的空氣中 病毒和細菌的數量, 尤其是在飛機上 或是密閉的演講會場。 (笑聲) 我們利用一些簡單的儀器過濾; 僅僅一天之內我們在紐約市的一棟大樓 的樓頂就蒐集到大約10億微生物。 目前我們正在對這些微生物 的基因進行測序。
Just on the data collection side, just where we are through the Galapagos, we're finding that almost every 200 miles, we see tremendous diversity in the samples in the ocean. Some of these make logical sense, in terms of different temperature gradients. So this is a satellite photograph based on temperatures -- red being warm, blue being cold -- and we found there's a tremendous difference between the warm water samples and the cold water samples, in terms of abundant species. The other thing that surprised us quite a bit is these photoreceptors detect different wavelengths of light, and we can predict that based on their amino acid sequence. And these vary tremendously from region to region. Maybe not surprisingly, in the deep ocean, where it's mostly blue, the photoreceptors tend to see blue light. When there's a lot of chlorophyll around, they see a lot of green light. But they vary even more, possibly moving towards infrared and ultraviolet in the extremes.
在蒐集資料方面, 當我們穿過加拉巴戈群島時, 發現基本上每隔200英里, 我們所獲得的海水採樣中的 生物種類就大不相同。 這種多樣性有時候是很合理的, 考慮到海水不同層面的水溫差異。 這是一張反應溫度的 衛星照片-紅色是溫暖的地區, 藍色則水溫較低- 我們發現來自高溫區和低溫區的海水樣本 中的占主導數量的微生物種 顯示出極大差異。 另一件讓人頗感驚訝的是 這些色素細胞會感應不同波長的光線, 可以利用胺基酸測序來估計這些情況。 這些特質在不同的區域也產生巨大的變化。 或許不完全那麼讓人吃驚的是, 在幾乎完全只有藍色的深海中, 感光細胞比較容易看見藍色的光線。 當周圍有大量葉綠素時, 它們感應到的就是綠光。 不過情況可能有更多的變化, 很可能會擴展到紅外線和紫外線 這樣的極端的光線。
Just to try and get an assessment of what our gene repertoire was, we assembled all the data -- including all of ours thus far from the expedition, which represents more than half of all the gene data on the planet -- and it totaled around 29 million genes. And we tried to put these into gene families to see what these discoveries are: Are we just discovering new members of known families, or are we discovering new families? And it turns out we have about 50,000 major gene families, but every new sample we take in the environment adds in a linear fashion to these new families. So we're at the earliest stages of discovery about basic genes, components and life on this planet.
為了評估 自然界基因庫的大小, 我們匯整所有的資料 包括所有目前實地採集的樣本, 它囊括地球一半以上的生物基因資料 - 總計大約有2千9百萬組基因。 我們嘗試把它們排進基因族譜 以便獲得新的發現: 我們所發現的是已知族群中的新成員, 還是我們發現了新的族群? 世界上大約有50,000 個主要的基因族群, 但是每一個我們從自然中獲取的新樣本 都成為這些新族群的一個分支。 因此對基礎的基因, 及其成份和對生命的研究工作 才是剛剛起步而已。
When we look at the so-called evolutionary tree, we're up on the upper right-hand corner with the animals. Of those roughly 29 million genes, we only have around 24,000 in our genome. And if you take all animals together, we probably share less than 30,000 and probably maybe a dozen or more thousand different gene families. I view that these genes are now not only the design components of evolution. And we think in a gene-centric view -- maybe going back to Richard Dawkins' ideas -- than in a genome-centric view, which are different constructs of these gene components.
在所謂的演化樹圖上, 人類位於右上角,跟動物在同一區。 在總共的大約2900萬種基因中, 人類的基因組只具備其中 的大約2萬4千種。 如果把所有動物的基因算在一起, 我們所共有的 基因族群大概只有 三萬不到一點。 現在我並不認為這些基因 僅僅只是是進化的的設計元素。 我們從基因中心論來看- 或許回到了理查‧達金斯的想法 而不是基因組中心論, 那是以基因為組件所構造成的不同結果。
Synthetic DNA, the ability to synthesize DNA, has changed at sort of the same pace that DNA sequencing has over the last decade or two, and is getting very rapid and very cheap. Our first thought about synthetic genomics came when we sequenced the second genome back in 1995, and that from mycoplasma genitalium. And we have really nice T-shirts that say, you know, "I heart my genitalium." This is actually just a microorganism. But it has roughly 500 genes. Haemophilus had 1,800 genes. And we simply asked the question, if one species needs 800, another 500, is there a smaller set of genes that might comprise a minimal operating system?
製造DNA以及製造它們的能力 與DNA測序技術以差不多的速度 從一二十年前發展至今, 已經變得非常的省時 並且成本低廉。 我們關於人工制造基因組的想法起源 與生殖道支原體,那是在95年我們做 第二組基因組測序的時候。 我們還做了漂亮的T恤衫 上面有寫「我愛我的生殖道」 生殖道支原體只是一種微生物。 但有大約500對基因。 嗜血桿菌有1800對基因。 所以我們在想 有的物種有800對基因,有的500, 是否有更小的的基因組 是構成基本生物運作系統的基礎?
So we started doing transposon mutagenesis. Transposons are just small pieces of DNA that randomly insert in the genetic code. And if they insert in the middle of the gene, they disrupt its function. So we made a map of all the genes that could take transposon insertions and we called those "non-essential genes." But it turns out the environment is very critical for this, and you can only define an essential or non-essential gene based on exactly what's in the environment. We also tried to take a more directly intellectual approach with the genomes of 13 related organisms, and we tried to compare all of those, to see what they had in common. And we got these overlapping circles. And we found only 173 genes common to all 13 organisms. The pool expanded a little bit if we ignored one intracellular parasite; it expanded even more when we looked at core sets of genes of around 310 or so. So we think that we can expand or contract genomes, depending on your point of view here, to maybe 300 to 400 genes from the minimal of 500.
因此我們開始進行轉位子誘變。 轉位子是隨即插入基因編碼 的小段的DNA。 如果置入基因的正中間,會阻斷其功能。 我們將所有可以接受轉位子插入 的基因列在一張圖表上。 我們稱之為「非必要基因」 不過我們發現環境起到了非常重要的作用, 我們只能依據環境中 所存在的基因來定義一個基因是必要還是非必要。 是必要還是非必要。 我們還嘗試了更直接而巧妙的方法 來研究13種相似有機物的基因組, 互相比較,尋找共性。 在其重疊的特性中,我們找到了173種基因。 是這13種有機體所共有的。 如果不算其中一種細胞寄生物 共有的基因數量會略增。 如果只考慮核心基因組 還會再多一些。 大約310組。 因此我們認為可以根據目標 來將前面所提到的最少的500組的基因組 擴展或者是縮減 至300到400組。
The only way to prove these ideas was to construct an artificial chromosome with those genes in them, and we had to do this in a cassette-based fashion. We found that synthesizing accurate DNA in large pieces was extremely difficult. Ham Smith and Clyde Hutchison, my colleagues on this, developed an exciting new method that allowed us to synthesize a 5,000-base pair virus in only a two-week period that was 100 percent accurate, in terms of its sequence and its biology. It was a quite exciting experiment -- when we just took the synthetic piece of DNA, injected it in the bacteria and all of a sudden, that DNA started driving the production of the virus particles that turned around and then killed the bacteria. This was not the first synthetic virus -- a polio virus had been made a year before -- but it was only one ten-thousandth as active and it took three years to do. This is a cartoon of the structure of phi X 174. This is a case where the software now builds its own hardware, and that's the notions that we have with biology.
唯一可以驗證這些想法的方法 就是製造一條包含有一些基因的染色體, 我們不得不以一種模塊式的方法來試驗。 結果發現要精確地製造 大段的DNA超難的。 史密斯和賀金森,它們是我的兩位同事, 研發出令人振奮的新方法 能讓我們在兩週內製造一隻 5000個鹼基對的病毒 基因序列和生物特性上 的精準度達到100%。 實驗非常令人振奮!就在我們將人造的DNA 植入細菌中的那一刻, DNA立刻開始運作,製造病毒粒子 反噬宿主,消滅了那隻細菌。 這不是人造病毒的首度問世- 小兒麻痺病毒一年前成功被製出 但只有原病毒1/100的活性 并且花了3年时间来制造。 這是噬菌體Phi X-174的結構图。 這是一個軟體能打造自身硬體的實際例子, 也是我們在生物學研究中的一個目標。
People immediately jump to concerns about biological warfare, and I had recent testimony before a Senate committee, and a special committee the U.S. government has set up to review this area. And I think it's important to keep reality in mind, versus what happens with people's imaginations. Basically, any virus that's been sequenced today -- that genome can be made. And people immediately freak out about things about Ebola or smallpox, but the DNA from this organism is not infective. So even if somebody made the smallpox genome, that DNA itself would not cause infections. The real concern that security departments have is designer viruses. And there's only two countries, the U.S. and the former Soviet Union, that had major efforts on trying to create biological warfare agents. If that research is truly discontinued, there should be very little activity on the know-how to make designer viruses in the future.
談到這些人們很容易就會產生對生物武器的擔憂, 我最近在參議院委員會舉行前發表了證詞, 也參加了一個美國政府設立的的專門委員會來 監管這個領域。 我認為以對現實的深刻理解來應對 人們的空想是非常重要的。 基本上,今天任何已經完成測序的病毒 它們的基因組都可以人為製造。 人們會對馬上對伊波拉病毒或天花感到驚恐萬分, 但這種人工病毒的DNA不具傳染性。 所以即使製造出天花的基因組, DNA本身也不會造成傳染。 真正讓國安部門擔憂的 是特製的病毒。 世界上只有美國和前蘇聯兩國, 曾經投注大量資源 企圖製造生物武器元件。 如果那些研究真的被終止了, 那將來在製造設計病毒上 就應該不會再有甚麼進展了。
I think single-cell organisms are possible within two years. And possibly eukaryotic cells, those that we have, are possible within a decade. So we're now making several dozen different constructs, because we can vary the cassettes and the genes that go into this artificial chromosome. The key is, how do you put all of the others? We start with these fragments, and then we have a homologous recombination system that reassembles those into a chromosome.
我認為2年內就有可能製造出單細胞生物。 且很有可能在10年內 製造出人類身上 也俱有的真核細胞。 目前我們正在製作數十種不同的構造。 因為我們可以變更這些放入 人造染色体中的序列模块和基因。 关键问题是,如何与其他的部分排列在一起? 我们 从 这些片段着手 研发出了一个同源基因重组系统 能将这些片段组合进染色体当中
This is derived from an organism, deinococcus radiodurans, that can take three million rads of radiation and not be killed. It reassembles its genome after this radiation burst in about 12 to 24 hours, after its chromosomes are literally blown apart. This organism is ubiquitous on the planet, and exists perhaps now in outer space due to all our travel there. This is a glass beaker after about half a million rads of radiation. The glass started to burn and crack, while the microbes sitting in the bottom just got happier and happier. Here's an actual picture of what happens: the top of this shows the genome after 1.7 million rads of radiation. The chromosome is literally blown apart. And here's that same DNA automatically reassembled 24 hours later. It's truly stunning that these organisms can do that, and we probably have thousands, if not tens of thousands, of different species on this planet that are capable of doing that. After these genomes are synthesized, the first step is just transplanting them into a cell without a genome.
这是从一种生物上得到的启发, 它能够承受三百万拉德(輻射計量單位)的辐射並且存活下來。 在輻射爆發過後它會在12至24小時內 重組自己的基因, 在它的染色體被完全拆散後。 這種生物在地球上普遍存在, 甚至可能因為我們飛上太空 而也將它們帶進了宇宙。 這是經過50萬拉德輻射 照射過後的高腳酒杯。 玻璃開始 碎裂, 這微生物附在杯底 越發的高興。 這是一張實際狀況的照片 上邊的圖片顯示的是經過一百七十萬 拉德輻射後的基因組。 其染色體被完全粉碎。 而這邊十同樣的DNA經過 24時後自行重組。 這些生物的能耐真是令人吃驚! 地球上大概存在着成千上萬種 不同的物種擁有 這樣的能力。 在這些基因組被製造以後。 第一步就是要將它們移植進 一個沒有基因組的細胞。
So we think synthetic cells are going to have tremendous potential, not only for understanding the basis of biology but for hopefully environmental and society issues. For example, from the third organism we sequenced, Methanococcus jannaschii -- it lives in boiling water temperatures; its energy source is hydrogen and all its carbon comes from CO2 it captures back from the environment. So we know lots of different pathways, thousands of different organisms now that live off of CO2, and can capture that back. So instead of using carbon from oil for synthetic processes, we have the chance of using carbon and capturing it back from the atmosphere, converting that into biopolymers or other products. We have one organism that lives off of carbon monoxide, and we use as a reducing power to split water to produce hydrogen and oxygen. Also, there's numerous pathways that can be engineered metabolizing methane. And DuPont has a major program with Statoil in Norway to capture and convert the methane from the gas fields there into useful products.
所以我們認為人造細胞將會有巨大的前景。 不光是增進對生物學科最基本的理解 希望也包括環境以及社會問題。 例如,從我們所測序的第三個生物上 詹氏甲烷鏈球菌:它生存在沸湯的水中 其能量來源於氫 它所獲得的碳元素則從周圍環境中汲取。 我們瞭解到了許多不同的可能性, 數千種不同的生物 以二氧化碳為生。 並能將其捕捉回來 與其從使用從石油中取得的 來進行製造。 我們可以選擇使用碳元素 並將它從大氣層中捕捉回來, 轉化成生物高分子 或者其他產品。 還有一種微生物是依靠一氧化碳而存活的, 我們使用它作為一種低能耗的方式 來分解水來產生氫和氧。 同樣的也是有很多的 被改造成排放出甲烷。 杜邦正在於挪威石油公司開展一項重大的項目 從天然氣田中將甲烷捕獲 並轉變成有用的商品。
Within a short while, I think there's going to be a new field called "Combinatorial Genomics," because with these new synthesis capabilities, these vast gene array repertoires and the homologous recombination, we think we can design a robot to make maybe a million different chromosomes a day. And therefore, as with all biology, you get selection through screening, whether you're screening for hydrogen production, or chemical production, or just viability. To understand the role of these genes is going to be well within reach.
不需要多久,我認為就會有一個全新的領域出現 我們成為染色體重組 因為這些新的製造能力 大量的基因群 以及同源重組方法的存在, 我想我們可以設計一個機器人, 每天可以製造或許百萬種不同的染色體。 所以,在生物學的試驗中, 你可以通過篩選來達到目的。 無論是想要獲得產生氫氣的特性, 或者化工生產,又或者是驗證某種生存性。 理解這些基因所發揮的功能 將會變得非常容易。
We're trying to modify photosynthesis to produce hydrogen directly from sunlight. Photosynthesis is modulated by oxygen, and we have an oxygen-insensitive hydrogenase that we think will totally change this process. We're also combining cellulases, the enzymes that break down complex sugars into simple sugars and fermentation in the same cell for producing ethanol. Pharmaceutical production is already under way in major laboratories using microbes. The chemistry from compounds in the environment is orders of magnitude more complex than our best chemists can produce. I think future engineered species could be the source of food, hopefully a source of energy, environmental remediation and perhaps replacing the petrochemical industry.
我們正在嘗試修改光合作用的過程 當被當陽光照射後直接產生氫氣。 光合作用是由氧氣來調節的, 我們認為有一種氧不敏感的 氢化酶將會完全改變這個過程。 我們也在進行纤维素酶的混合, 將複雜糖分子拆解成簡單糖分子的酶 在同一個培養皿里一起發酵 來製造乙醇。 利用微生物進行製藥生產 的實踐早已在各大 實驗室里展開。 這些從自然環境的組成部份中 獲的藥品比任何世界上最好的藥房 所生產的還要複雜許多。 我認為將來通過改造的物種 可以成為食物的來源, 希望也可以是能源的來源, 環境的補救措施 或許 替代整個化工行業。
Let me just close with ethical and policy studies. We delayed the start of our experiments in 1999 until we completed a year-and-a-half bioethical review as to whether we should try and make an artificial species. Every major religion participated in this. It was actually a very strange study, because the various religious leaders were using their scriptures as law books, and they couldn't find anything in them prohibiting making life, so it must be OK. The only ultimate concerns were biological warfare aspects of this, but gave us the go ahead to start these experiments for the reasons we were doing them.
請讓我以倫理以及政策的研究來做結尾。 在1999年我們延遲了試驗的開始 直到我們完成了一個一年半的生物倫理審核 是否應該嘗試製造人造物種。 每一個主要的宗教都參與了這個審核。 其實這是一個非常奇怪的研究, 因為各種宗教領袖使用他們的教義作為律法, 卻找不到任何關於禁止創造生命的條款, 所以這方面就沒問題了。最終的 卻是生物戰的方面的擔憂, 為我們亮起繼續 這些試驗的綠燈。
Right now the Sloan Foundation has just funded a multi-institutional study on this, to work out what the risk and benefits to society are, and the rules that scientific teams such as my own should be using in this area, and we're trying to set good examples as we go forward. These are complex issues. Except for the threat of bio-terrorism, they're very simple issues in terms of, can we design things to produce clean energy, perhaps revolutionizing what developing countries can do and provide through various simple processes. Thank you very much.
史隆基金會為此剛剛資助了 一個多機構的研究項目, 來分析出該項技術對社會而言所存在的風險與益處, 以及各個科研團隊就比如我自己的團隊 所應該在這個領域遵守的準則。 隨著前進過程中我們試着樹立起一個好的榜樣。 有許多復長複雜的問題。 不包括生物恐怖襲擊的威脅, 那些其實是簡單的多的狀況。 是否能夠設計用來產生結晶能源的物種, 甚至對發展中國家 的生產方式進行革新 提供各種便捷的處理方法。 謝謝!