All life, every living thing ever, has been built according to the information in DNA. What does that mean? Well, it means that just as the English language is made up of alphabetic letters that, when combined into words, allow me to tell you the story I'm going to tell you today, DNA is made up of genetic letters that, when combined into genes, allow cells to produce proteins, strings of amino acids that fold up into complex structures that perform the functions that allow a cell to do what it does, to tell its stories. The English alphabet has 26 letters, and the genetic alphabet has four. They're pretty famous. Maybe you've heard of them. They are often just referred to as G, C, A and T. But it's remarkable that all the diversity of life is the result of four genetic letters. Imagine what it would be like if the English alphabet had four letters. What sort of stories would you be able to tell? What if the genetic alphabet had more letters? Would life with more letters be able to tell different stories, maybe even more interesting ones?
所有的生命, 历史上所有的生物, 都是根据 DNA 中的 信息创造出来的。 那是什么意思? 意思是,就如同英语这门语言, 生命也是用字母组成的, 字母再拼成词汇, 今天我要给大家讲个故事。 DNA 是用基因字母组成的, 当它们拼成基因之后, 细胞就能够产出蛋白质, 这些蛋白质是一串串氨基酸 折叠而成的复杂结构, 它可以实现一些功能, 让细胞正常工作, 说出它的故事。 英文字母表有二十六个字母, 基因字母表则有四个字母。 它们很有名,你们可能听过, 通常直接用 G、C、A和 T 来表示。 但惊人的是,各式各样的生命 都是由四个基因字母产生出来的。 想像一下,如果英文字母表 只有四个字,会是怎样的状况? 你能讲出什么样的故事? 如果基因字母表 有更多字,又会如何? 有更多基因字母的生命 会不会说出不同的故事, 或是更有趣的故事?
In 1999, my lab at the Scripps Research Institute in La Jolla, California started working on this question with the goal of creating living organisms with DNA made up of a six-letter genetic alphabet, the four natural letters plus two additional new man-made letters. Such an organism would be the first radically altered form of life ever created. It would be a semisynthetic form of life that stores more information than life ever has before. It would be able to make new proteins, proteins built from more than the 20 normal amino acids that are usually used to build proteins. What sort of stories could that life tell?
1999 年,我在加州拉霍亚的 斯克里普斯研究所中的一间实验室 开始探究这个问题, 目标是要创造出活的有机体, 它们的DNA由六个基因字母组成, 包括四个天然的字母, 再加上两个人造的新字母。 这种有机体从根本上 改变了的生命形式,且史无前例。 它会是半合成的生命形式, 至今没有任何生命 能像它储存那么多信息。 它能够制造出新的蛋白质, 不单单只用那二十种 通常用来制造蛋白质的 常见氨基酸。 那样的生命能说出什么样的故事?
With the power of synthetic chemistry and molecular biology and just under 20 years of work, we created bacteria with six-letter DNA. Let me tell you how we did it.
靠着合成化学和分子 生物学的强大帮助, 只花了不到二十年, 我们就创造出 DNA 有六个字母的细菌。 让我说一下怎么做到的吧。
All you have to remember from your high school biology is that the four natural letters pair together to form two base pairs. G pairs with C and A pairs with T, so to create our new letters, we synthesized hundreds of new candidates, new candidate letters, and examined their abilities to selectively pair with each other. And after about 15 years of work, we found two that paired together really well, at least in a test tube. They have complicated names, but let's just call them X and Y.
你只需要记住高中 生物学中的一样东西, 那就是:四个天然基因字母 配对形成两组基础配对。 G 和 C 配对,A 和 T 配对, 所以,为了创造新字母, 我们合成了数百种新候选字母, 研究它们和彼此 做选择性配对的能力。 经过约十五年的努力, 我们发现两个字母 配对起来的状况非常好, 至少在试管中是如此。 它们的名字很复杂, 就姑且称它们为 X 和 Y。
The next thing we needed to do was find a way to get X and Y into cells, and eventually we found that a protein that does something similar in algae worked in our bacteria. So the final thing that we needed to do was to show that with X and Y provided, cells could grow and divide and hold on to X and Y in their DNA. Everything we had done up to then took longer than I had hoped -- I am actually a really impatient person -- but this, the most important step, worked faster than I dreamed, basically immediately.
接着我们需要做的事, 是要想办法把 X 和 Y 放入细胞中, 终于,我们发现我们的细菌中 有一种蛋白质和 海藻的蛋白质性能类似。 所以,我们需要做的最后一件事, 就是要证明在有 X 和 Y 的前提下, 细胞仍然能够生长和分裂, 且它们的 DNA 中保有 X 和 Y。 在那之前我们做的一切, 花的时间都比我期望的还长—— 我其实是个很没耐心的人—— 但这个最重要的步骤, 成功的速度比我梦想的还快, 基本上是一蹴而就。
On a weekend in 2014, a graduate student in my lab grew bacteria with six-letter DNA. Let me take the opportunity to introduce you to them right now. This is an actual picture of them. These are the first semisynthetic organisms.
在 2014 年的一个周末, 我实验室里的研究生栽培出了 有六个字母 DNA 的细菌。 让我利用这个机会 把它们介绍给各位。 这是它们的真实照片。 这些是最早的半合成有机体。
So bacteria with six-letter DNA, that's really cool, right? Well, maybe some of you are still wondering why. So let me tell you a little bit more about some of our motivations, both conceptual and practical. Conceptually, people have thought about life, what it is, what makes it different from things that are not alive, since people have had thoughts. Many have interpreted life as being perfect, and this was taken as evidence of a creator. Living things are different because a god breathed life into them. Others have sought a more scientific explanation, but I think it's fair to say that they still consider the molecules of life to be special. I mean, evolution has been optimizing them for billions of years, right? Whatever perspective you take, it would seem pretty impossible for chemists to come in and build new parts that function within and alongside the natural molecules of life without somehow really screwing everything up. But just how perfectly created or evolved are we? Just how special are the molecules of life? These questions have been impossible to even ask, because we've had nothing to compare life to. Now for the first time, our work suggests that maybe the molecules of life aren't that special. Maybe life as we know it isn't the only way it could be. Maybe we're not the only solution, maybe not even the best solution, just a solution.
DNA 有六个字母的细菌, 真的很酷,对吧? 也许在座有些人 仍然很纳闷为什么要这样做。 让我跟各位简略说明 我们的一部分动机, 包括概念上和实际上的动机。 概念上,人们会思考生命是什么、 生命和非生命的差别在哪里, 人类从会思考时就在想这些了。 许多人对于生命的诠释就是完美, 甚至被视为造物主存在的证据。 生物之所以不同, 是因为神赋予它们生命。 其他人则用比较科学的解释, 但我认为,可以说 他们仍然认为生命的分子是特别的。 我的意思是,数十亿年来, 演化已经把它们最优化了,对吧? 不论你采用哪一种观点, 似乎化学家都不可能 创造出能在生命的自然分子中运作 或与之一起运作的新部位, 而且还不会把事情搞砸。 但我们到底被创造或演化得多完美? 生命的分子到底有多特别? 这些问题,连要被问出来都不可能, 因为我们没有任何东西 可以拿来和生命做比较。 史上第一次,我们的研究指出 也许生命的分子并没有那么特别, 也许我们所知道的生命 并不是唯一的生命形式。 也许我们不是唯一的解决方案, 甚至不是最好的解决方案, 也许只是一种解决方案。
These questions address fundamental issues about life, but maybe they seem a little esoteric. So what about practical motivations? Well, we want to explore what sort of new stories life with an expanded vocabulary could tell, and remember, stories here are the proteins that a cell produces and the functions they have. So what sort of new proteins with new types of functions could our semisynthetic organisms make and maybe even use? Well, we have a couple of things in mind.
这些问题在谈的 是生命的根本议题, 但它们看似有些深奥。 那实用的动机呢? 事实上,我们想要探究 基本单位扩大之后的 生命能够讲述怎样的新故事, 别忘了,这里的故事 指的是细胞能产生的蛋白质 及它们的功能。 所以,我们的半合成 有机体能够制造出 怎样的新功能蛋白质, 甚至能为我们所用呢? 我们对此有一些想法。
The first is to get the cells to make proteins for us, for our use. Proteins are being used today for an increasingly broad range of different applications, from materials that protect soldiers from injury to devices that detect dangerous compounds, but at least to me, the most exciting application is protein drugs. Despite being relatively new, protein drugs have already revolutionized medicine, and, for example, insulin is a protein. You've probably heard of it, and it's manufactured as a drug that has completely changed how we treat diabetes. But the problem is that proteins are really hard to make and the only practical way to get them is to get cells to make them for you. So of course, with natural cells, you can only get them to make proteins with the natural amino acids, and so the properties those proteins can have, the applications they could be developed for, must be limited by the nature of those amino acids that the protein's built from. So here they are, the 20 normal amino acids that are strung together to make a protein, and I think you can see, they're not that different-looking. They don't bring that many different functions. They don't make that many different functions available. Compare that with the small molecules that synthetic chemists make as drugs. Now, they're much simpler than proteins, but they're routinely built from a much broader range of diverse things. Don't worry about the molecular details, but I think you can see how different they are. And in fact, it's their differences that make them great drugs to treat different diseases. So it's really provocative to wonder what sort of new protein drugs you could develop if you could build proteins from more diverse things.
首先是要让细胞为我们 制造蛋白质,让我们使用。 现今,蛋白质 被用在很广泛的应用领域中, 从保护士兵不受伤的材料, 到检测危险化合物的装置, 但至少对我来说, 最让人兴奋的应用是蛋白质药物。 虽然相对比较新, 但蛋白质药物已经改革了医学, 比如,胰岛素是一种蛋白质。 你们可能听过它,被作为 药物源源不断的生产, 完全改变了我们 对糖尿病的治疗方式。 但问题是,蛋白质很难生产, 取得蛋白质的唯一实际方式, 就是叫细胞产生蛋白质。 所以,你只能让自然细胞 利用天然氨基酸制造蛋白质, 所以那些蛋白质能拥有的特性、 能够开发出来的用途, 都会被那些用来制造 蛋白质的氨基酸的 天然性质所限制。 这就是它们, 二十种常见氨基酸,它们通过 相互结合来制造蛋白质, 它们看起来差别不大。 它们并没有带来 创造出供许多不同的功能, 相对于合成化学家所制造的 药物小分子来说。 这些小分子比蛋白质更简单, 但它们是由更多不同形式的 东西创造出来的。 不需要关注那些细节 你们就能看出它们之间的差别。 事实上,正是它们的差异, 让它们成为很棒的药物, 用来治疗不同的疾病。 所以,令人兴奋的地方在于, 以更多样化的蛋白质作为来源, 我们可以开发出 什么样的新蛋白质药物。
So can we get our semisynthetic organism to make proteins that include new and different amino acids, maybe amino acids selected to confer the protein with some desired property or function? For example, many proteins just aren't stable when you inject them into people. They are rapidly degraded or eliminated, and this stops them from being drugs. What if we could make proteins with new amino acids with things attached to them that protect them from their environment, that protect them from being degraded or eliminated, so that they could be better drugs? Could we make proteins with little fingers attached that specifically grab on to other molecules? Many small molecules failed during development as drugs because they just weren't specific enough to find their target in the complex environment of the human body. So could we take those molecules and make them parts of new amino acids that, when incorporated into a protein, are guided by that protein to their target?
那么,我们能否用 我们的半合成有机体 来制造出蛋白质, 且包含不同的新氨基酸, 也许是精选的氨基酸, 来赋予蛋白质 某些我们想要的特性或功能呢? 比如, 许多蛋白质被注射到 人体内就会失去稳定性, 它们很快就会被降解,消失, 因此它们无法成为药物。 如果我们能用新的 氨基酸来制造蛋白质, 在它们上面附加一些功能, 可以保护它们不受环境影响, 可以保护它们不被降解, 让它们能成为更好的药物会如何? 我们能不能在蛋白质上 附加一些小触手, 用来准确地紧抓其它的分子? 许多小分子被用来 开发药物时会失败, 是因为它们的特异性 比较低,无法在人体的 复杂环境中找到它们的目标。 那么,我们能不能用这些分子 来当作新氨基酸的一些部分, 当把它们整合到蛋白质中时, 该蛋白质就会引导它们找到目标呢?
I started a biotech company called Synthorx. Synthorx stands for synthetic organism with an X added at the end because that's what you do with biotech companies.
我创立了一家叫做 Synthorx的生物科技公司。 Synthorx 代表“合成有机体”, 在最后加上“X”是因为 生物科技公司都会这样做。
(Laughter)
(笑声)
Synthorx is working closely with my lab, and they're interested in a protein that recognizes a certain receptor on the surface of human cells. But the problem is that it also recognizes another receptor on the surface of those same cells, and that makes it toxic. So could we produce a variant of that protein where the part that interacts with that second bad receptor is shielded, blocked by something like a big umbrella so that the protein only interacts with that first good receptor? Doing that would be really difficult or impossible to do with the normal amino acids, but not with amino acids that are specifically designed for that purpose.
Synthorx 和我的实验室密切合作, 他们对能够识别人体细胞 表面上的某种受体的蛋白质 非常感兴趣。 但问题是,它也会识别 同样细胞表面上的另一种受体, 而这样则会带来毒性。 那么,我们能否制造出 那种蛋白质的变体, 把会和第二种不良受体 发生作用的那部分给掩盖起来, 用像大伞样的东西把它屏蔽掉, 让蛋白质只会和第一种 好的受体发生作用? 用常见的氨基酸很难 或根本不可能做到这一点, 但若用专门为此目的而设计的 氨基酸就不用担心了。
So getting our semisynthetic cells to act as little factories to produce better protein drugs isn't the only potentially really interesting application, because remember, it's the proteins that allow cells to do what they do. So if we have cells that make new proteins with new functions, could we get them to do things that natural cells can't do? For example, could we develop semisynthetic organisms that when injected into a person, seek out cancer cells and only when they find them, secrete a toxic protein that kills them? Could we create bacteria that eat different kinds of oil, maybe to clean up an oil spill? These are just a couple of the types of stories that we're going to see if life with an expanded vocabulary can tell.
然而,把我们的半合成 细胞当成小工厂 制造出比较好的蛋白质药物, 并非唯一有趣的应用, 因为要记住,是蛋白质 让细胞实现它们的功能。 所以,如果有细胞能够制造出 具有新功能的新蛋白质, 我们是否能让它们做到 自然细胞无法做到的事? 比如,我们能否开发出 一种半合成有机体, 注射到人体中,去寻找癌细胞, 只有找到癌细胞时,才会 分泌有毒蛋白质来杀死癌细胞? 我们能否创造出一种细菌, 能吃掉不同类的油, 也许能用来清理原油泄漏? 上述这些,只是当词汇量增加时 生命能诉说的其中几种故事。
So, sounds great, right? Injecting semisynthetic organisms into people, dumping millions and millions of gallons of our bacteria into the ocean or out on your favorite beach? Oh, wait a minute, actually it sounds really scary. This dinosaur is really scary. But here's the catch: our semisynthetic organisms in order to survive, need to be fed the chemical precursors of X and Y. X and Y are completely different than anything that exists in nature. Cells just don't have them or the ability to make them. So when we prepare them, when we grow them up in the controlled environment of the lab, we can feed them lots of the unnatural food. Then, when we deploy them in a person or out on a beach where they no longer have access that special food, they can grow for a little bit, they can survive for a little, maybe just long enough to perform some intended function, but then they start to run out of the food. They start to starve. They starve to death and they just disappear. So not only could we get life to tell new stories, we get to tell life when and where to tell those stories.
听起来很棒,对吧? 将半合成有机体注射到人体中, 将数百万加仑这种细菌倒入海洋中 或倒在你最爱的海滩上? 喔,等等,这听起来 其实挺吓人的。 这只恐龙的确挺吓人的。 但有个困难之处: 我们的半合成有机体为了要生存, 会需要被喂食 X 和 Y的化学前体。 X 和 Y 和大自然中存在的 任何东西都完全不同。 细胞没有它们, 也没有能力制造它们。 所以,当我们在实验室 受控环境中制造出它们时, 我们可以喂食它们 很多非天然的食物。 接着,当我们把它们散布到 人体中或外面的海滩上, 在那些地方,它们无法 取得特别的食物, 它们可以成长一点点, 它们可以生存一会儿, 也许刚好长到足以实现 一些我们希望的功能, 但接着,它们就没有食物可吃了。 它们会开始挨饿。 它们会饿死,然后消失。 所以,我们不但能 让生命说新的故事, 也能控制生命在特定地点 与时间说新故事。
At the beginning of this talk I told you that we reported in 2014 the creation of semisynthetic organisms that store more information, X and Y, in their DNA. But all the motivations that we just talked about require cells to use X and Y to make proteins, so we started working on that. Within a couple years, we showed that the cells could take DNA with X and Y and copy it into RNA, the working copy of DNA. And late last year, we showed that they could then use X and Y to make proteins. Here they are, the stars of the show, the first fully-functional semisynthetic organisms.
在这场演讲的一开始, 我告诉各位我们在 2014 年 创造出了半合成有机体, 能储存更多信息, 将 X 和 Y 存在它们的 DNA 中。 但我们刚刚谈到的所有动机, 需要细胞能够使用 X 和 Y 来制造蛋白质, 所以我们开始处理这一点。 在几年内,我们证明了 细胞能够把有 X 和 Y 的 DNA 复制到 RNA,也就是 DNA 的工作拷贝。 去年年底, 我们证明了它们还可以 用 X 和 Y 来制造蛋白质。 这就是相关研究的主角, 史上第一个全功能半合成有机体。
(Applause)
(掌声)
These cells are green because they're making a protein that glows green. It's a pretty famous protein, actually, from jellyfish that a lot of people use in its natural form because it's easy to see that you made it. But within every one of these proteins, there's a new amino acid that natural life can't build proteins with.
这些细胞是绿色的,因为它们会 制造出一种发绿光的蛋白质。 事实上,这种蛋白质 很有名,来自水母, 很多人会使用它的天然形式, 因为这样可以很容易 看出你造出來了。 然而,在所有这些蛋白质中, 有一种新的氨基酸,自然生命 无法用它来制造蛋白质。
Every living cell, every living cell ever, has made every one of its proteins using a four-letter genetic alphabet. These cells are living and growing and making protein with a six-letter alphabet. These are a new form of life. This is a semisynthetic form of life.
史上所有的活细胞, 不论是制造哪一种蛋白质, 都是使用了四个特定的基因字母。 而这些细胞是活的, 会成长,还会制造出 六个字母的蛋白质。 它们是新的生命形式。 这是一种半合成的生命形式。
So what about the future? My lab is already working on expanding the genetic alphabet of other cells, including human cells, and we're getting ready to start working on more complex organisms. Think semisynthetic worms.
那么未来呢? 我的实验室已经在努力扩展 其它细胞的基因字母, 包括人类细胞, 且我们已经准备好要开始 创造更复杂的有机体。 想想半合成的蠕虫。
The last thing I want to say to you, the most important thing that I want to say to you, is that the time of semisynthetic life is here.
我想要告诉各位的最后一件事, 也是最重要的: 半合成生命的时代已经到来。
Thank you.
谢谢。
(Applause)
(掌声)
Chris Anderson: I mean, Floyd, this is so remarkable. I just wanted to ask you, what are the implications of your work for how we should think about the possibilities for life, like, in the universe, elsewhere? It just seems like so much of life, or so much of our assumptions are based on the fact that of course, it's got to be DNA, but is the possibility space of self-replicating molecules much bigger than DNA, even just DNA with six letters?
克里斯·安德森: 弗洛伊德,这真是了不起。 我想问问你, 你的研究究竟意味着什么? 我们该如何看待生命的可能性, 比如,在宇宙中,或者其它地方? 感觉就是,生命有大一部分, 或是说我们的很大一部分假设 是基于这个事实:一切都跟 DNA有关, 但自我复制分子出现的可能性 是否比 DNA 大很多, 甚至只是六个字母的 DNA?
Floyd Romesberg: Absolutely, I think that's right, and I think what our work has shown, as I mentioned, is that there's been always this prejudice that sort of we're perfect, we're optimal, God created us this way, evolution perfected us this way. We've made molecules that work right alongside the natural ones, and I think that suggests that any molecules that obey the fundamental laws of chemistry and physics and you can optimize them could do the things that the natural molecules of life do. There's nothing magic there. And I think that it suggests that life could evolve many different ways, maybe similar to us with other types of DNA, maybe things without DNA at all.
弗洛伊德:是的,没错。 我们的研究显示, 正如我先前提过的, 一直以来都有一种偏见存在, 认为人类就是完美的, 我们是最理想化的, 神把我们创造成这样, 演化把我们变得这么完美。 我们做出的分子能够 和天然分子并存, 我认为那意味着任何分子 只要能遵守化学 和物理的基本原理, 且能被最优化, 那它们就能够做到生命的 天然分子能做到的事。 这不是什么魔法。 我认为,那意味着, 生命演化的方式有很多种, 也许有与我们拥有 类似 DNA 的生命体, 或也许完全不含 DNA 的东西。
CA: I mean, in your mind, how big might that possibility space be? Do we even know? Are most things going to look something like a DNA molecule, or something radically different that can still self-reproduce and potentially create living organisms?
克里斯蒂安:在你心中, 那种可能性有多大? 我们认得出来吗?大部分的东西 都会看起来像 DNA 分子吗? 或是极度不同的生命体 也能够自我繁殖, 且有可能创造出活的有机体?
FR: My personal opinion is that if we found new life, we might not even recognize it.
弗洛伊德:我个人的意见是, 如果我们找到了新生命, 我们可能也不会认出它。
CA: So this obsession with the search for Goldilocks planets in exactly the right place with water and whatever, that's a very parochial assumption, perhaps.
克里斯蒂安:那么我们对 寻找宜居行星的迷恋, 一定要找到有水 和其它生命的地方, 这样的假设是不是显得太狭隘了?
FR: Well, if you want to find someone you can talk to, then maybe not, but I think that if you're just looking for any form of life, I think that's right, I think that you're looking for life under the light post.
弗洛伊德:如果你能找人 谈谈这件事,那答案也许是否定的。 但如果你只是想找到 其它任何形式的生命, 那么没错,我想其它 生命形式就近在眼前。
CA: Thank you for boggling all our minds. Thank so much, Floyd.
克里斯蒂安:谢谢你带来这些惊喜。 非常谢谢,弗洛伊德。
(Applause)
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