We're here today to announce the first synthetic cell, a cell made by starting with the digital code in the computer, building the chromosome from four bottles of chemicals, assembling that chromosome in yeast, transplanting it into a recipient bacterial cell and transforming that cell into a new bacterial species. So this is the first self-replicating species that we've had on the planet whose parent is a computer. It also is the first species to have its own website encoded in its genetic code. But we'll talk more about the watermarks in a minute.
我們今天在此宣佈 第一個合成細胞製作成功 這細胞我們先以數碼的方式 在電腦裡建構 再從四瓶化學物質 築出染色體 並在酵母中組合該細胞的染色體 然後再把它移植到 接收的細菌細胞裡 使那個細胞轉化 成為一個新的菌種 於是成為我們這個地球上 第一個誕生於電腦 而能自我複製的物種 它也將是第一個 把自己的網址寫入 自己的基因密碼裡的物種 不過我們稍後 再多談浮水印之事
This is a project that had its inception 15 years ago when our team then -- we called the institute TIGR -- was involved in sequencing the first two genomes in history. We did Haemophilus influenzae and then the smallest genome of a self-replicating organism, that of Mycoplasma genitalium. And as soon as we had these two sequences we thought, if this is supposed to be the smallest genome of a self-replicating species, could there be even a smaller genome? Could we understand the basis of cellular life at the genetic level? It's been a 15-year quest just to get to the starting point now to be able to answer those questions, because it's very difficult to eliminate multiple genes from a cell. You can only do them one at a time. We decided early on that we had to take a synthetic route, even though nobody had been there before, to see if we could synthesize a bacterial chromosome so we could actually vary the gene content to understand the essential genes for life. That started our 15-year quest to get here.
這個研究專案肇始於 15年前 當時我們的研究團隊- 稱為TIGR研究所- 進行了有史以來首次的 兩個基因組排序工作 我們先為流感嗜血桿菌 然後又為能自行複製的生物體 生殖支原體的最小基因組做了排序 我們一旦有了 這兩個排序 我們想, 如果這被認為是能自行複製的 物種的最小基因組 那麼還有更小的嗎? 我們能在基因的層面上理解 細胞生命的基礎嗎? 這一問就是15年 今天我們才剛走到開始 可以回答那些問題的地步 由於很難消除細胞裡的 多重基因 只能一次消除一個 所以我們很早就決定 即使以前沒有人做過 我們必須採取合成的辦法 看看我們能否合成 一個細菌的染色體 由此我們改變了基因內容 以便理解生命的基本基因 於是開始了我們15年的探索 終於達到今天的地步
But before we did the first experiments, we actually asked Art Caplan's team at the University of Pennsylvania to undertake a review of what the risks, the challenges, the ethics around creating new species in the laboratory were because it hadn't been done before. They spent about two years reviewing that independently and published their results in Science in 1999. Ham and I took two years off as a side project to sequence the human genome, but as soon as that was done we got back to the task at hand.
開始進行首先的實驗之前 我們確實先向當時在賓州大學的 Art Caplan研究團隊尋求 進行評估審查 以確定在實驗室裡創造 新物種的風險、挑戰 和道德方面的問題 因為這是史無前例的 他們花了大約兩年時間 獨立完成評審 將其結果發表於1999年《科學雜誌》 當時我和Ham離開兩年 進行人類基因組排序的另一個研究專案 完成工作後 我們立即回到這個工作
In 2002, we started a new institute, the Institute for Biological Energy Alternatives, where we set out two goals: One, to understand the impact of our technology on the environment, and how to understand the environment better, and two, to start down this process of making synthetic life to understand basic life. In 2003, we published our first success. So Ham Smith and Clyde Hutchison developed some new methods for making error-free DNA at a small level. Our first task was a 5,000-letter code bacteriophage, a virus that attacks only E. coli. So that was the phage phi X 174, which was chosen for historical reasons. It was the first DNA phage, DNA virus, DNA genome that was actually sequenced. So once we realized that we could make 5,000-base pair viral-sized pieces, we thought, we at least have the means then to try and make serially lots of these pieces to be able to eventually assemble them together to make this mega base chromosome. So, substantially larger than we even thought we would go initially.
2002年, 我們開始 一個新的研究所 生物能源替代方案研究所 我們設定了兩個目標 其一是要理解 我們的科技對環境的影響並確定 如何更妥善理解環境問題 其二是開始建構 製作合成生命的過程 以便理解基礎生命 在2003年 我們發表了初步的成果 Ham Smith和Clyde Hutchison 開發了一些新的方法 用來小規模製作 無差錯的DNA 當時的第一個工作是 一個5000字母代碼的噬菌體 是一種只會攻擊大腸桿菌的病毒 那就是編號 ΦX174的噬菌體 選擇它有歷史的緣由 它是第一個真正受到完整 排序的DNA噬菌體、DNA病毒、 DNA基因組 那麼我們一旦明白 我們能製作出5000個在 病毒般大小內的核酸鹼基對 我們想,我們至少有了方法 進一步嘗試批量製作這些配對 以便在最後把它們組合起來 製作成這個兆基的染色體 這個進展基本上甚至 比我們原先所想要組合的還大出許多
There were several steps to this. There were two sides: We had to solve the chemistry for making large DNA molecules, and we had to solve the biological side of how, if we had this new chemical entity, how would we boot it up, activate it in a recipient cell. We had two teams working in parallel: one team on the chemistry, and the other on trying to be able to transplant entire chromosomes to get new cells. When we started this out, we thought the synthesis would be the biggest problem, which is why we chose the smallest genome.
達到這個地步有幾個步驟,分兩方面來說 我們必須在化學方面解決 製作大型DNA分子的問題 另外在生物學方面我們必須解決 有了這個新的化學實體之後 如何在一個接收細胞裡 將它啟動、將它活化的問題 因此我們有兩個團隊併列進行 一個團隊處理化學的問題 另一個團隊嘗試 如何能夠移植 整個染色體 以獲得新的細胞 開始時我們以為最大的問題會在於合成 那是我們當時選擇最小的基因組的原因
And some of you have noticed that we switched from the smallest genome to a much larger one. And we can walk through the reasons for that, but basically the small cell took on the order of one to two months to get results from, whereas the larger, faster-growing cell takes only two days. So there's only so many cycles we could go through in a year at six weeks per cycle. And you should know that basically 99, probably 99 percent plus of our experiments failed. So this was a debugging, problem-solving scenario from the beginning because there was no recipe of how to get there.
各位有人注意到我們改用相當大的基因組 而沒有採用最小的 我們可以略過這個改動的原因 不過基本上, 採用小型的細胞 要得到結果 需要花費一到兩個月時間 但若採用較大、成長較快的細胞 只需要兩天 因此我們在一年內 以六週為一期,只能進行那麼多週期 而且各位應該知道 基本上我們的實驗有99% 甚至可能99%以上會是失敗的 因此整個工作從一開始 就是糾錯, 解決問題的戲碼 因為當時還沒有 達到成功的訣竅
So, one of the most important publications we had was in 2007. Carole Lartigue led the effort to actually transplant a bacterial chromosome from one bacteria to another. I think philosophically, that was one of the most important papers that we've ever done because it showed how dynamic life was. And we knew, once that worked, that we actually had a chance if we could make the synthetic chromosomes to do the same with those. We didn't know that it was going to take us several years more to get there.
我們最重要的發表之一 是在2007年 Carole Lartigue主持的那個研究 說明如何將細菌染色體 從一個細菌移植到另一個 哲學意義上,我認為那是我們做過的研究中 最為重要的報告之一 因為該報告顯示了生命具有多大的動能 我們知道, 只要這方法奏效 那麼我們很有可能 做到讓合成的染色體 同樣能夠移植到細菌細胞裡 只是當時還不知道還要 多少年才能做到那個地步
In 2008, we reported the complete synthesis of the Mycoplasma genitalium genome, a little over 500,000 letters of genetic code, but we have not yet succeeded in booting up that chromosome. We think in part, because of its slow growth and, in part, cells have all kinds of unique defense mechanisms to keep these events from happening. It turned out the cell that we were trying to transplant into had a nuclease, an enzyme that chews up DNA on its surface, and was happy to eat the synthetic DNA that we gave it and never got transplantations. But at the time, that was the largest molecule of a defined structure that had been made.
2008年 我們發表了完成合成 生殖支原體基因組的報告 比500,000字母稍多一點的基因密碼 但是我們還未成功地啟動該染色體 我們認為部分原因是由於成長緩慢 另外部分原因是 細胞都具有各種特殊的防衛機制 使得啟動植入困難 我們發現我們嘗試植入的細胞 有一種會在其表面啃蝕DNA的核酸酵素 吃起我們給它的合成DNA 特別痛快 因此移植一直沒有成功 不過那是我們當時 所知做過的分子結構 最大的一個
And so both sides were progressing, but part of the synthesis had to be accomplished or was able to be accomplished using yeast, putting the fragments in yeast and yeast would assemble these for us. It's an amazing step forward, but we had a problem because now we had the bacterial chromosomes growing in yeast. So in addition to doing the transplant, we had to find out how to get a bacterial chromosome out of the eukaryotic yeast into a form where we could transplant it into a recipient cell.
因此兩方面當時都在進展之中 但合成有部分必須完成 或說仍須完成 使用酵母-把片段放入酵母中 酵母就會幫我們組合 這是令人驚訝的進步 但是我們卻有了新的問題 因為我們的細菌染色體現在是在酵母中成長的 因此除了要進行移植之外 我們還得找出一個方法從真核酵母中 取出細菌染色體 而且要確保取出後 能被移植到一個接收細胞裡
So our team developed new techniques for actually growing, cloning entire bacterial chromosomes in yeast. So we took the same mycoides genome that Carole had initially transplanted, and we grew that in yeast as an artificial chromosome. And we thought this would be a great test bed for learning how to get chromosomes out of yeast and transplant them. When we did these experiments, though, we could get the chromosome out of yeast but it wouldn't transplant and boot up a cell. That little issue took the team two years to solve.
因此我們的研究團隊開發了一個新技術 用來在酵素中促長 並複製整著細菌染色體 因此我們採用相同於Carole原本移植的 柔膜菌支原體基因組 作為人造染色體 讓它在酵母中成長 我們當時認為, 這會是學習如何從酵母中 取出染色體並做移植的 很好的試驗床 但當我們做實驗時 我們雖能從酵母中取出染色體 但無法移植並啟動細胞 這麼個小問題花了研究團隊兩年才解決
It turns out, the DNA in the bacterial cell was actually methylated, and the methylation protects it from the restriction enzyme, from digesting the DNA. So what we found is if we took the chromosome out of yeast and methylated it, we could then transplant it. Further advances came when the team removed the restriction enzyme genes from the recipient capricolum cell. And once we had done that, now we can take naked DNA out of yeast and transplant it.
結果發現在細菌細胞裡的DNA 原來是經過甲基化的 而甲基化保護它不接受限制酶 不能消化DNA 因此我們發現, 如果從酵母 取出染色體並將它甲基化 我們就可以移植了 當研究團隊 將限制酶基因從山羊支原體移除時 我們便更進了一步 一旦達到這一步 我們便能從酵母中取出裸露的DNA進行移植
So last fall when we published the results of that work in Science, we all became overconfident and were sure we were only a few weeks away from being able to now boot up a chromosome out of yeast. Because of the problems with Mycoplasma genitalium and its slow growth about a year and a half ago, we decided to synthesize the much larger chromosome, the mycoides chromosome, knowing that we had the biology worked out on that for transplantation. And Dan led the team for the synthesis of this over one-million-base pair chromosome. But it turned out it wasn't going to be as simple in the end, and it set us back three months because we had one error out of over a million base pairs in that sequence.
於是去年秋天 我們在《科學雜誌》發表該研究成果時 我們都變得過於自信 確信我們只須 再幾個星期的時間 就能夠啟動 從酵母中取出的染色體 由於約一年半前 有過生殖支原體以及其 成長緩慢的問題 我們決定合成 較大的柔膜菌支原體染色體 因為我們在生物學方面已經解決了 此等染色體的移植問題 當時Dan帶領合成這個 超過百萬核酸鹼基對染色體的研究團隊 但終究發現沒有那麼簡單 這讓我們損失三個月時間 因為我們在那個超過 百萬核酸鹼基對排序中有一個錯誤
So the team developed new debugging software, where we could test each synthetic fragment to see if it would grow in a background of wild type DNA. And we found that 10 out of the 11 100,000-base pair pieces we synthesized were completely accurate and compatible with a life-forming sequence. We narrowed it down to one fragment; we sequenced it and found just one base pair had been deleted in an essential gene. So accuracy is essential. There's parts of the genome where it cannot tolerate even a single error, and then there's parts of the genome where we can put in large blocks of DNA, as we did with the watermarks, and it can tolerate all kinds of errors. So it took about three months to find that error and repair it. And then early one morning, at 6 a.m. we got a text from Dan saying that, now, the first blue colonies existed.
於是研究團隊開發了新的糾錯軟體 用來測試每個合成的片段 查看它能否 在雜型的DNA背景下成長 結果發現我們合成的每十萬個核酸鹼基對裡 11個之中有10個 是完全精確的 而且也與 形成生命的排序相容 我們縮小問題的範圍至那一個片段 為那一個片段作基因排序 發現只有一個重要基因的 一個核酸鹼基對被消除了 因此精確是至關緊要的 有些基因組的部分 一點小錯都不能容忍 還有些基因組的部分 我們可以放入大塊的DNA 我們就是這麼放入浮水印的 這些部分很能容忍各種錯誤 於是花費了大約三個月時間找到那個錯誤 並予修正 然後有一天早上六點鐘 我們收到Dan發來簡訊 說是第一個藍色菌落已經形成了
So, it's been a long route to get here: 15 years from the beginning. We felt one of the tenets of this field was to make absolutely certain we could distinguish synthetic DNA from natural DNA. Early on, when you're working in a new area of science, you have to think about all the pitfalls and things that could lead you to believe that you had done something when you hadn't, and, even worse, leading others to believe it. So, we thought the worst problem would be a single molecule contamination of the native chromosome, leading us to believe that we actually had created a synthetic cell, when it would have been just a contaminant.
那麼,達到今天的地步是一條很長的路- 從開始到現在整整15年 我們覺得 這個領域的信條之一是 要做到完全確定 我們要能切實分辨合成DNA 和自然DNA的區別 在科學的一個新領域中進行研究工作時 很早就要想到所有可能的陷阱 以及會誤導你相信有了成果 但實際並沒有成就什麼的情況 更糟糕的是也誤導了別人相信 因此我們認為最糟糕的 問題會是由於原本的染色體 有某個單分子受到污染 誤導我們相信我們真的創造出 一個合成的細胞 而可能只是一個污染的產物
So early on, we developed the notion of putting in watermarks in the DNA to absolutely make clear that the DNA was synthetic. And the first chromosome we built in 2008 -- the 500,000-base pair one -- we simply assigned the names of the authors of the chromosome into the genetic code, but it was using just amino acid single letter translations, which leaves out certain letters of the alphabet. So the team actually developed a new code within the code within the code. So it's a new code for interpreting and writing messages in DNA. Now, mathematicians have been hiding and writing messages in the genetic code for a long time, but it's clear they were mathematicians and not biologists because, if you write long messages with the code that the mathematicians developed, it would more than likely lead to new proteins being synthesized with unknown functions.
因此我們很早就有了 要在DNA裡放入浮水印的想法 以弄清楚那個DNA 絕對毫無疑問是合成的 我們建構的第一個染色體 在2008年 那個有五十萬個核酸鹼基對的 染色體內, 我們放入了 作者們的姓名 在其基因密碼中, 但當時只採用胺基酸 的單字母代碼, 這個系統省略了字母系統裡的某些字母 因此研究團隊開發了一套新密碼 那是在密碼裡的密碼裡的密碼 那麼就是一種新密碼 用來解讀和書寫在DNA裡的信息 是的,數學家長久以來已經在進行著 隱藏和書寫基因密碼的工作 但清楚的是他們是數學家不是生物學家 因為如果你使用數學家開發的密碼 書寫長的信息 其結果很可能導致 新蛋白質的合成 而其功能卻不清楚
So the code that Mike Montague and the team developed actually puts frequent stop codons, so it's a different alphabet but allows us to use the entire English alphabet with punctuation and numbers. So, there are four major watermarks all over 1,000 base pairs of genetic code. The first one actually contains within it this code for interpreting the rest of the genetic code. So in the remaining information, in the watermarks, contain the names of, I think it's 46 different authors and key contributors to getting the project to this stage. And we also built in a website address so that if somebody decodes the code within the code within the code, they can send an email to that address. So it's clearly distinguishable from any other species, having 46 names in it, its own web address. And we added three quotations, because with the first genome we were criticized for not trying to say something more profound than just signing the work.
那麼Mike Montague和他的團隊開發的密碼 確實放入常見的停止密碼子 因此這是一套不同的字母系統 但卻讓我們能使用 整個英文字母系統裡的字母 包含標點和數字 於是有四種主要的浮水印 散布在上千個基因密碼的核酸鹼基對裡 實際包含在內的第一種 是用來解讀其它 基因密碼的密碼 因此在其餘的訊息中 在浮水印裡 包含了-我想沒錯-是 46位不同的作者 以及主要的貢獻者 他們推動研究專案到達這個地步 而且我們也植入 一個網站的位址 因此如果有人解開 密碼裡的密碼裡的密碼 就可以傳送一封電子郵件到那個位址 因此可以清楚地分辨出 它與其它物種的區別 因為裡頭有46個姓名 還有它自己的網址 我們還添加了三句引文 因為做出第一個基因組時 我們被批評沒有嘗試說些有點深度的言語 只為研究工作簽了名
So we won't give the rest of the code, but we will give the three quotations. The first is, "To live, to err, to fall, to triumph and to recreate life out of life." It's a James Joyce quote. The second quotation is, "See things not as they are, but as they might be." It's a quote from the "American Prometheus" book on Robert Oppenheimer. And the last one is a Richard Feynman quote: "What I cannot build, I cannot understand." So, because this is as much a philosophical advance as a technical advance in science, we tried to deal with both the philosophical and the technical side.
那麼不多說其它的密碼 我們只說那三句引文 第一句是 「活著、犯錯、 跌跤、獲勝, 還要從生命中創造生命。」 這是引自James Joyce的言語 第二句引文是「見事物勿僅見其然, 亦當見其或可以然。」 這是引自談論Robert Oppenheimer的 《美國的普羅修斯》的言語 最後一句是Richard Feynman的言語 「若是我無法建構, 即因我不全然理解。」 那麼由於這是在科學技術上的進步 也同樣是在哲學上的進步 我們試圖處理技術方面的事 同時也處理哲學方面的事
The last thing I want to say before turning it over to questions is that the extensive work that we've done -- asking for ethical review, pushing the envelope on that side as well as the technical side -- this has been broadly discussed in the scientific community, in the policy community and at the highest levels of the federal government. Even with this announcement, as we did in 2003 -- that work was funded by the Department of Energy, so the work was reviewed at the level of the White House, trying to decide whether to classify the work or publish it. And they came down on the side of open publication, which is the right approach -- we've briefed the White House, we've briefed members of Congress, we've tried to take and push the policy issues in parallel with the scientific advances.
轉到提問之前 我最後要說的是 我們大費周章 請求道德方面的評審 在那方面推到極限 也在技術方面推到極限 這在科學社群裡已經受到廣泛討論 在政策制訂社群裡 還有在聯邦政府的最高層也討論 甚至這次的宣佈- 如同2003年那次- 那個研究是由能源部所資助的- 那麼我們的研究工作 受到白宮層級的評審 以決定此研究是否列為保密或得以發表 他們最後的決定是站在公開發表這邊 這是正確的做法 我們向白宮做過了報告 我們也向國會做了報告 在科學進步的同時 我們嘗試了 研擬和推動政策討論
So with that, I would like to open it first to the floor for questions. Yes, in the back.
這些都做過了 所以我們現在可以開始接受提問 好的,後面那一位請提問
Reporter: Could you explain, in layman's terms, how significant a breakthrough this is please?
記者:可否請您用簡單的語言 解釋這個突破到底有多重大?
Craig Venter: Can we explain how significant this is? I'm not sure we're the ones that should be explaining how significant it is. It's significant to us. Perhaps it's a giant philosophical change in how we view life. We actually view it as a baby step in terms of, it's taken us 15 years to be able to do the experiment we wanted to do 15 years ago on understanding life at its basic level. But we actually believe this is going to be a very powerful set of tools and we're already starting in numerous avenues to use this tool.
CV:可否解釋這個突破有多重大? 我不確定我們有資格做這種解釋 對我們而言確是重大突破 也許在哲學上這是巨大的改變 它改變我們看待生命的方式 我們其實把這當作嬰兒學步看待 因為我們花費15年 才得以做出 這15年前想做出 在生命基礎上理解生命的實驗 不過我們確實相信 這將會是一套非常強大的工具 我們在許多研究上 已經實際開始 應用這些工具
We have, at the Institute, ongoing funding now from NIH in a program with Novartis to try and use these new synthetic DNA tools to perhaps make the flu vaccine that you might get next year. Because instead of taking weeks to months to make these, Dan's team can now make these in less than 24 hours. So when you see how long it took to get an H1N1 vaccine out, we think we can shorten that process quite substantially. In the vaccine area, Synthetic Genomics and the Institute are forming a new vaccine company because we think these tools can affect vaccines to diseases that haven't been possible to date, things where the viruses rapidly evolve, such with rhinovirus. Wouldn't it be nice to have something that actually blocked common colds? Or, more importantly, HIV, where the virus evolves so quickly the vaccines that are made today can't keep up with those evolutionary changes.
我們研究所現在 正在向NIH集資準備 與諾華合作進行一個方案 以便測試並使用這些 新的合成DNA的工具 或許用來製作明年 可能就會用到的流感疫苗 因為以往需要花費好幾個星期或好幾個月 Dan的研究團隊現在可以 在24小時內完成這些工作 那麼想一想H1N1疫苗花費了多少時間 我們認為我們可以 大幅縮短那個過程 在疫苗的領域裡 「合成基因組學」和研究所 正在組織一個新的疫苗公司 因為我們認為這些工具對於至今可能 還無法控制的病毒變體快速演化的 疾病之疫苗-例如鼻病毒- 可能會有所影響 要是能有可以阻絕一般感冒的東西,不是很好嗎? 或更重要的是HIV 那種病毒變體演化之快 今天製作的疫苗 根本跟不上 那些病毒的演化改變
Also, at Synthetic Genomics, we've been working on major environmental issues. I think this latest oil spill in the Gulf is a reminder. We can't see CO2 -- we depend on scientific measurements for it and we see the beginning results of having too much of it -- but we can see pre-CO2 now floating on the waters and contaminating the beaches in the Gulf. We need some alternatives for oil. We have a program with Exxon Mobile to try and develop new strains of algae that can efficiently capture carbon dioxide from the atmosphere or from concentrated sources, make new hydrocarbons that can go into their refineries to make normal gasoline and diesel fuel out of CO2.
還有,在「合成基因組學」 我們一直進行著重大 環境問題的研究工作 我想最進的海灣漏油事件 正是一個提醒我們的話題 我們看不見二氧化碳 我們依靠科學的測量 我們才剛開始看到 二氧化碳過多的結果 卻看到二氧化碳的前身 現在就浮動在水面上 污染著海灣的沙灘 我們必須找到一些 替代石油的方案 我們和埃克森美孚有個計畫 嘗試並開發能夠 從大氣中或從高濃度的來源裡 有效捕捉二氧化碳的新種海藻 製作新的碳水化合物用於他們的煉油廠 用以製造不產生二氧化碳的 正常汽油和柴油燃料
Those are just a couple of the approaches and directions that we're taking.
這些只是舉例說明 我們的做法和走向
(Applause)
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