Craig Venter即将实现人造生命

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http://dotsub.com/view/f65605d0-c4f6-4f13-a685-c6b96fba03d0
Craig Venter即将实现人造生命
在这之前我已经讨论过这些项目中的一部分 关于人类基因组和它们的意义。 以及发现新的基因组。 这次我们要从一个新的角度来看： 我们在从事数字化生物学的工作。 并且现在我们正尝试从那些数字代码走向 一个生物学的全新阶段, 设计与人工合成生命。
我们经常试图提出一些较大的问题。 “生命是什么”我想是许多生物学家 不断地尝试在 在不同层面去理解的问题。 我们尝试了许多方法， 把它分解到最小的组成部分。 到目前我们几乎已经用了20年来将其数字化。 当我们在排序人类基因组的时候， 它从生物学的模拟分析世界 走进了计算机的数字世界。 现在我们在尝试提问，我们是否能够再造生命， 或者我们是否从这个数字世界中 能创造新的生命?
这是一种微生物的基因序列图, 生殖支原体, 它有着对于一个物种来说最小的基因组 能使其在实验室中自我复制。 并且我们在尝试了解是否 我们能找到一种更小的基因组。 我们能够从500组基因中 分离出一百组就是我们眼前的这些。 但当我们来看它的新陈代谢的时候， 这其实是相对简单的 相对我们的来说。 相信我，这算简单的。 但当我们在看所有这些 我们能一个一个分离出的基因组的时候， 很难相信它们能产生出 一个活生生的细胞。 所以，我们认为唯一能继续研究的方法 就是人工合成这些染色体 以便我们能改变它的组成部分 来继续提问这些最基本的问题。 于是我们开始沿着这条路走下去 “我们能人工合成染色体吗？” 化学原则真的允许我们制造 这些我们从未实现过的 超大分子吗？ 而且，就算我们可以，我们能激活它吗？ 一对染色体，顺便说下，只是一些无活性的化学物质。 我们数字化生命的速度不断地 以指数速度加快。
我们写基因编码的能力 进步地却非常慢， 不过也还是在增加的。 我们最近的状况将会把速度提升到指数曲线。 我们于15年前开始这项工作。 实际上它经过了好几个阶段。 在我们做最初的试验前，先进行了一次生物伦理学的评估。 但结果是人工合成DNA 是非常困难的。 全世界有十几万台设备 在制造小片断的DNA， 长度在30到50个字符， 并且这是一个会倒退的过程，制造的片断越是长， 产生的错误就越是多。 所以我们不得不创造一种新的方法 把这些小的片断排放在一起并纠正所有的错误。
这是我们的第一次尝试，从Phi X 174基因组（噬菌体） 的数字信息开始。 是一种能杀死细菌的小型病毒。 我们设计了它的基因片断，经过了错误纠正， 就拥有了一条 5000字符长度的DNA。 最另人兴奋的阶段是当我们把这段没有活性的化学物质 放进细菌内， 细菌开始读取基因编码， 制造了病毒粒子。 接着细胞释放出病毒粒子， 再返回来杀死了E.coli（革兰氏阴性菌）。 我最近与石油行业有一些交流， 我觉得他们对这个模式理解的非常透彻。
（笑声）
他比你们笑的大声多了。
因此我们认为这种情况实际上 是软件能在一个生物系统内 打造自己的硬件。 但我们还想再扩大规模。 我们希望制造整条细菌染色体， 一条超过580，000字符长度的基因编码。 我们认为应该在以病毒大小的“盒”中制造它们 这样我们可以改变这些“盒” 来理解 一个活的细胞的实际组成部分是什么？ 设计是非常重要的， 并且如果你在计算机上开始使用数字信息。 那这些数字信息必须十分准确。 当我们在1995年第一次对这组基因排序时， 准确率的标准是每10000个基本对一个错误。 实际上我们发现，在重新排序时， 平均是30个错误。如果我们使用原先的序列， 这组基因永远不可能被启动。 设计工作的一部分是设计 50个字符长度的片断 并和其他的50字符长的片段叠加 以构建更小的次单元。 我们要设计过他们才能聚到一起。 其中有我们设计过的独特部分。
你们可能听说过我们在其中加入了水印 想想看 基因编码有四个字符：A,C,G和T。 这些字符的三联体 - 以及这些字符 编成了大约20种氨基酸 这样每个氨基酸就有了 一个字符标记 所以我们能使用基因编码来书写言语 句子，想法。 最初，我们所做的就是用它来签名。 有些人有点失望我们没用它来做首诗。 我们设计了这些片断 并能使用酶来裁切。 有些酶是用来修复他们并把他们放到一起的。 接着我们开始制造片断， 从7000字符长度的片断开始 把他们拼在一起制造24，000字符长度的片断 再把几组片断合并，变成了72，000长的片断
在每个阶段，我们大量培养了这些片断 因此我们可以给他们排序 因为我们希望创造一个异常可靠的过程 一分钟内你就将看见 我们试着达到自动化的层面 这看起来就像是一场篮球赛的对阵图 当这些非常大的片断超过 100，000基本对时 他们就很难继续在E.coil里长的更长了。 在试尽了各种现代分子生物学的工具后 我们转向其他的途径。 我们知道有个方法叫同源重组， 生物学上用来修复DNA， 它能把片断组合到一起 这里有一个例子 有一种微生物叫 耐辐射球菌 能够承受三百万度的辐射量。
你能看到在顶部的视图里，它的染色体四散在各个地方 12到24小时以后，它将自己 又组合回之前的原状。 我们有数千种微生物有这种能耐 这些微生物能够完全脱离水。 他们能存活在真空中 我完全确信外层空间存在着生命， 四处移动，遇到一个新的有水的环境 实际上，NASA已经展示过很多这样的例子。
这里有一组我们拍摄的这个分子的显微图像。 通过这些过程，其实就是前面所提到的酵母的方法 同时放入经过我们正确设计的片断。 酵母自动地将他们聚合。 这并不是电子显微图像； 它仅仅是普通的光学显微镜。 这是如此之大的一个分子 我们能用一个光学显微镜观察它。 这些是时长约为六秒的图像。
这是我们所公开的最近的试验成果。 这是超过580000字符长的基因编码。 这也是由人类设定结构并制造的最大的分子。 它超过了3亿分子重量。 如果我们以10号字体不间隔地将其打印出来。 总共需要142页 来打印这些基因编码 那我们该如何来启动一段染色体，我们该如何激活它? 显然处理一个病毒非常简单 处理一个细菌就复杂多了 处理像我们自身这样的 真核生物也相对简单 你能取出一个细胞核 然后塞进另一个细胞中， 这就是大家听到的关于克隆的手法 对于古细菌，它们的染色体与整个细胞连成一体， 但最近我们也明确了我们能完成一个完整的移植 将染色体从一个细胞转移到另一个细胞中 并激活它。 我们从一个种群的微生物中提取出染色体。 基本上，这两个的差别就如同人类和老鼠般。 我们加上了一些新的基因 这样我们就能选择这些染色体。 我们用酶来分解它们 去除所有的蛋白质 当我们将它放入细胞时发生的情形非常惊人 你们应该会喜欢 我们所制作的非常精密的演示图像 -- 新的染色体进入细胞。 实际上我们原以为这个过程就到此为止了。 但是我们试图将这个过程设计得更深入一些。
这是一个重大的进化机制。 我们发现所有接受了 第二段染色体的物种 或来自其他地方的第三方染色体， 在一秒钟内增加了 数千种新特征到其自身。 原本人们所持有的在进化的过程中 每次只会有一个基因发生变化 的观念忽略了生物的许多实际情况。
有一种酶叫做限制酶 是能够消化DNA的 原先细胞中的染色体没有这种酶 没有这种酶 而当我们置入一段拥有这种酶的染色体 它表现了出来，并且辨认出 另一段染色体是外来物质， 它就将其消化，最后我们就有了 一个包含有新的DNA的细胞 我们放入的基因导致它变成了蓝色。 在非常短的一段时间里， 所有的原先物种的特征全部消失了， 并且完全转化成了一个新物种， 基于我们放入细胞的新“软件”。 所有的蛋白质都改变了， 细胞膜也改变了 -- 当我们读取它的基因编码，实际上就是我们植入的那种。
这可能听起来像基因炼金术， 但我们的确能通过转移DNA， 来急剧地改变事物。 现在，我要声明这不是创世纪 -- 这是建立在35亿年的进化上的 并且我认为我们可能 会创造新一版的寒武纪生命大爆发 出现大量基于这种数字化设计 的新物种
为什么要这样做？ 我认为出于一些需求我们这样做的原因是非常明显的。 我们的人口将在接下来的40年中从 65亿变成90亿 以我自己的例子来说 我出生于1946年 现在世界上就变成了三个人 相对于我们中每一个从1946年就存在的人； 在接下来的四十年内，就变成了四个。 我们在为65亿人提供食物，洁净的淡水， 医药，燃料上 都十分困难。 换作90亿人那真是捉襟见肘了。 我们使用超过50亿顿的煤， 300多亿桶的石油。 也就是每天一千万桶。 当我们尝试思考这个生物程序 或者任何能替代它的程序， 这会是一个巨大的挑战。 接下来，当然，是这份材料 中所显示的被排放在大气层中 的二氧化碳。
我们现在从全球各地的发现 有了一个包含约两千万组基因的数据库， 并且我乐于把它们看作是未来的设计组件。 电气行业只有十来种组件， 再看看从中能得到的多样性。 目前我们主要的限制来自于 生物学的现实情况 以及我们的想像力。 我们现在拥有这样的技术， 是因为这些能制造我们称之为“混合染色体组”的 快速的人工合成方法。 我们现在所拥有的制造一个大型机器人的能力 能让我们每天制造一百万个染色体。 当你想着加工这两千万组不同的基因， 并尝试去优化这个步骤 以产生辛烷或者制造药物制剂， 以及新的疫苗， 我们就能改变，即使是一个小团队， 也能做比过去20年科学史所做过的 更多的分子生物学工作。 并且这只是标准选择。 我们可以以生存能力来选择， 化学或燃料生产， 疫苗生产等等。
这是一张屏幕截图 截取的是一些我们 实际坐下来工作时在电脑中 真正用来设计物种的设计软件。 我们并不一定要知道它(设计的物种)看起来是怎样。 我们确切地知道它们的基因编码究竟是什么样的。 我们目前把注意力放在“第四代燃料”上。 你们最近看到了将谷物转化成乙醇 只是一个糟糕的试验。 很快我们将会拥有 第二及第三代燃料。 就是糖转化成更高价值的燃料 例如辛烷或不同种类的丁醇。
但我们认为生物学唯一能 产生一个巨大影响的同时又不 增加食物的支出与限制其可利用性的方法 是在于我们是否能开始用二氧化碳作为它的原料。 所以我们正在进行设计新的细胞能朝这条路发展下去。 并且我们认为在18个月里我们会取得 第一份第四代燃料。 阳光和二氧化碳是其中一个方法 --
（掌声） -- 但我们从全世界各地的发现中， 我们还有许多种其他方法。
这是一种微生物,1996年被记载 它生活在深海。 大约1.5英里深， 几乎是在沸腾的水温中。 它将二氧化碳转化成甲烷 使用氢分子最为它的能量来源。 我们在看是否能把 收集到的二氧化染, ，它们非常方便就能被引进处理站， 转化成燃料， 来驱动这个过程。
因此在很短的时间内， 我们觉得我们或许可以增加对于"生命是什么?" 的基本问题的理解。 我们的确 有着替换整个 石油化工行业的小小目标。
（笑声）（掌声）
如果你不能在TED做到这些,哪里还有可能呢?
（笑声）
成为一项主要的能源。 并且我们也在使用同样的工具 制造了几组即时疫苗。 你们都看到今年出现的流感， 我们总是要慢上一年的时间并且在缺乏资金的情况下 才等到有用的疫苗。 我认为这情形是可以通过 预先制造混合疫苗来改变的。 这是未来可能会呈现的情况 伴随着改变,目前,进化树 随着人造细菌，古物种 最后是真核生物 而加速进化 我们正在一条离改善人类生活越来越远的路上。 我们的目标就是确保我们能有机会活到 足够长的时间或许就能做到这件事了。非常感谢大家。
（掌声）
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Craig Venter is on the verge of creating synthetic life
You know, I've talked about some of these projects before, about the human genome and what that might mean, and discovering new sets of genes. We're actually starting at a new point: we've been digitizing biology, and now we're trying to go from that digital code into a new phase of biology, with designing and synthesizing life.

So, we've always been trying to ask big questions. "What is life?" is something that I think many biologists have been trying to understand at various levels. We've tried various approaches, paring it down to minimal components. We've been digitizing it now for almost 20 years. When we sequenced the human genome, it was going from the analog world of biology into the digital world of the computer. Now we're trying to ask, can we regenerate life, or can we create new life, out of this digital universe?

This is the map of a small organism, Mycoplasma genitalium, that has the smallest genome for a species that can self-replicate in the laboratory. And we've been trying to just see if we can come up with an even smaller genome. We're able to knock out on the order of a hundred genes out of the 500 or so that are here. But when we look at its metabolic map, it's relatively simple compared to ours. Trust me, this is simple. But when we look at all the genes that we can knock out one at a time, it's very unlikely that this would yield a living cell. So, we decided the only way forward was to actually synthesize this chromosome so we could vary the components to ask some of these most fundamental questions. And so we started down the road of, "Can we synthesize a chromosome?" Can chemistry permit making these really large molecules where we've never been before? And, if we do, can we boot up a chromosome? A chromosome, by the way, is just a piece of inert chemical material. So, our pace of digitizing life has been increasing at an exponential pace.

Our ability to write the genetic code has been moving pretty slowly, but has been increasing. And our latest point would put it on now an exponential curve. We started this over 15 years ago. It took several stages, in fact, starting with a bioethical review before we did the first experiments. But it turns out synthesizing DNA is very difficult. There's tens of thousands of machines around the world that make small pieces of DNA, 30 to 50 letters in length, and it's a degenerate process, so the longer you make the piece, the more errors there are. So we had to create a new method for putting these little pieces together and correct all the errors.

And this was our first attempt, starting with the digital information of the genome of Phi X 174. It's a small virus that kills bacteria. We designed the pieces, went through our error correction, and had a DNA molecule of about 5,000 letters. The exciting phase came when we took this piece of inert chemical and put it in the bacteria, and the bacteria started to read this genetic code, made the viral particles. The viral particles then were released from the cells, then came back and killed the E. coli. I was talking to the oil industry recently, and I said they clearly understood that model.

(Laughter)

They laughed more than you guys are.

And so we think this is a situation where the software can actually build its own hardware in a biological system. But we wanted to go much larger. We wanted to build the entire bacterial chromosome. It's over 580,000 letters of genetic code. So we thought we'd build them in cassettes the size of the viruses, so we could actually vary the cassettes to understand what the actual components of a living cell are. Design is critical, and if you're starting with digital information in the computer, that digital information has to be really accurate. When we first sequenced this genome in 1995, the standard of accuracy was one error per 10,000 base pairs. We actually found, on resequencing it, 30 errors. Had we used that original sequence, it never would have been able to be booted up. Part of the design is designing pieces that are 50 letters long that have to overlap with all the other 50-letter pieces to build smaller sub-units we have to design so they can go together. We design unique elements into this.

You may have read that we put watermarks in. Think of this: we have a four-letter genetic code: A, C, G and T. Triplets of that letter -- those letters code for roughly 20 amino acids -- that there's a single letter designation for each of the amino acids. So we can use the genetic code to write out words, sentences, thoughts. Initially, all we did was autograph it. Some people were disappointed there was not poetry. We designed these pieces so we can just chew back with enzymes. There's enzymes that repair them and put them together. And we started making pieces, starting with pieces that were five to 7,000 letters, fit those together to make 24,000-letter pieces, then put sets of those, going up to 72,000.

At each stage, we grew up these pieces in abundance so we could sequence them because we're trying to create a process that's extremely robust -- that you can see in a minute. We're trying to get to the point of automation. So, this looks like a basketball playoff. When we get into these really large pieces -- over 100,000 base pairs -- they won't any longer grow readily in E. coli. It exhausts all the modern tools of molecular biology. And so we turned to other mechanisms. We knew there's a mechanism called homologous recombination, that biology uses to repair DNA, that can put pieces together. Here's an example of it. There's an organism called Deinococcus radiodurans that can take three millions rads of radiation.

You can see in the top panel, its chromosome just gets blown apart. 12 to 24 hours later, it put it back together exactly as it was before. We have thousands of organisms that can do this. These organisms can be totally desiccated. They can live in a vacuum. I am absolutely certain that life can exist in outer space, move around, find a new aqueous environment. In fact, NASA has shown a lot of this is out there.

Here's an actual micrograph of the molecule we built using these processes -- actually just using yeast mechanisms with the right design of the pieces we put them in. Yeast puts them together automatically. This is not an electron micrograph; this is just a regular photomicrograph. It's such a large molecule we can see it with a light microscope. These are pictures over about a six-second period.

So this is the publication we had just a short while ago. This is over 580,000 letters of genetic code. It's the largest molecule ever made by humans of a defined structure. It's over 300 million molecular weight. If we printed out at a 10 font with no spacing, it takes 142 pages just to print this genetic code. Well, how do we boot up a chromosome? How do we activate this? Obviously, with a virus it's pretty simple. It's much more complicated dealing with bacteria. It's also simpler when you go into eukaryotes like ourselves: you can just pop out the nucleus and pop in another one, and that's what you've all heard about with cloning. With bacteria archaea, the chromosome is integrated into the cell, but we recently showed that we can do a complete transplant of a chromosome from one cell to another and activate it. We purified a chromosome from one microbial species. Roughly, these two are as distant as human and mice. We added a few extra genes so we could select for this chromosome. We digested it with enzymes to kill all the proteins. And it was pretty stunning when we put this in the cell -- and you'll appreciate our very sophisticated graphics here -- the new chromosome went into the cell. In fact, we thought this might be as far as it went, but we tried to design the process a little bit further.

This is a major mechanism of evolution right here. We find all kinds of species that have taken up a second chromosome or a third one from somewhere, adding thousands of new traits in a second to that species. So people who think of evolution as just one gene changing at a time have missed much of biology.

There's enzymes called restriction enzymes that actually digest DNA. The chromosome that was in the cell doesn't have one. The cell -- the chromosome we put in -- does. It got expressed, and it recognized the other chromosome as foreign material, chewed it up, and so we ended up just with the cell with the new chromosome. It turned blue because of the genes we put in it. And with a very short period of time, all the characteristics of one species were lost, and it converted totally into the new species, based on the new software that we put in the cell. All the proteins changed, the membranes changed -- when we read the genetic code, it's exactly what we had transferred in.

So this may sound like genomic alchemy, but we can, by moving the software DNA around, change things quite dramatically. Now, I've argued, this is not genesis -- this is building on three and a half billion years of evolution, and I've argued that we're about to perhaps create a new version of the Cambrian explosion where there's massive new speciation based on this digital design.

Why do this? I think this is pretty obvious in terms of some of the needs. We're about to go from six and a half to 9 billion people over the next 40 years. To put it in context for myself: I was born in 1946. There's now three people on the planet for every one of us that existed in 1946; within 40 years, there'll be four. We have trouble feeding, providing fresh, clean water, medicines, fuel for the six and a half billion. It's going to be a stretch to do it for nine. We use over 5 billion tons of coal, 30 billion-plus barrels of oil. That's a hundred million barrels a day. When we try to think of biological processes or any process to replace that, it's going to be a huge challenge. Then, of course, there's all that CO2 from this material that ends up in the atmosphere.

We now, from our discovery around the world, have a database with about 20 million genes, and I like to think of these as the design components of the future. The electronics industry only had a dozen or so components, and look at the diversity that came out of that. We're limited here primarily by a biological reality and our imagination. We now have techniques, because of these rapid methods of synthesis, to do what we're calling combinatorial genomics. We have the ability now to build a large robot that can make a million chromosomes a day. When you think of processing these 20 million different genes, or trying to optimize processes to produce octane or to produce pharmaceuticals, new vaccines, we can change, just with a small team, do more molecular biology than the last 20 years of all science. And it's just standard selection. We can select for viability, chemical or fuel production, vaccine production, et cetera.

This is a screen snapshot of some true design software that we're working on to actually be able to sit down and design species in the computer. You know, we don't know necessarily what it'll look like. We know exactly what their genetic code looks like. We're focusing on now fourth-generation fuels. You've seen recently corn to ethanol is just a bad experiment. We have second- and third-generation fuels that will be coming out relatively soon that are sugar, to much higher-value fuels like octane or different types of butanol.

But the only way we think that biology can have a major impact without further increasing the cost of food and limiting its availability is if we start with CO2 as its feedstock, and so we're working with designing cells to go down this road, and we think we'll have the first fourth-generation fuels in about 18 months. Sunlight and CO2 is one method -- (Applause) -- but in our discovery around the world, we have all kinds of other methods.

This is an organism we described in 1996. It lives in the deep ocean, about a mile and a half deep, almost at boiling-water temperatures. It takes CO2 to methane using molecular hydrogen as its energy source. We're looking to see if we can take captured CO2, which can easily be piped to sites, convert that CO2 back into fuel, to drive this process.

So in a short period of time, we think that we might be able to increase what the basic question is of "What is life?" We're truly, you know -- have modest goals of replacing the whole petrol-chemical industry.

(Laughter) (Applause)

Yeah. If you can't do that at TED, where can you?

(Laughter)

Become a major source of energy. But also, we're now working on using these same tools to come up with instant sets of vaccines. You've seen this year with flu, we're always a year behind and a dollar short when it comes to the right vaccine. I think that can be changed by building combinatorial vaccines in advance. Here's what the future may begin to look like with changing, now, the evolutionary tree, speeding up evolution with synthetic bacteria, archea, and eventually eukaryotes. We're a ways away from improving people. Our goal is just to make sure that we have a chance to survive long enough to maybe do that. Thank you very much.

(Applause)