Nobel Laureate Decodes Answers about Life’s Beginning, Medicine’s Future

作为诺贝尔奖得主和newbb电子平台校友 Venki Ramakrishnan 描绘了他从雅典研究生院到英国分子实验室的历程, 他还展示了最微小的生命图景.

这项发现获得了诺贝尔奖, 有助于解开生命起源之谜, and now can help pharmaceutical companies build better antibiotics.

And that tiny picture of the ribosome at work is both language and machine, combined with a beautiful waltz of dancers looking for the just right pairing.

如果你是左脑分析专家, 你可能会欣赏一段遗传密码——由三个字母组成的四个字母组合而成——它可以组合制造20多种蛋白质，这些蛋白质是构建和运行人体所必需的.

如果你是右脑可视化专家, 你可能会看到一个舞者在寻找一个恰好带着构建蛋白质链所需的氨基酸的伴侣——拒绝求婚者，直到合适的人出现, and then stepping aside to let the next pair of dancers form.

但是Ramakrishnan脑海中的画面是生物学中最大的问题——核糖体, a molecule made up RNA and protein foundational to life. He knew it needed to be seen in order to be understood.

Ramakrishnan用通俗易懂的语言描述了核糖体和他的旅程，他的听众有几百人，他们冒着雷雨聚集在沃尔特·罗通达(Walter Rotunda)，聆听这位获得博士学位的人的演讲.D. 来自俄亥俄州的物理学博士说，为了跟上生物学研究人员的步伐，必须上本科课程, 然后赢得 2009年诺贝尔化学奖.

他的故事的副本， Gene Machine: The Race to Decipher the Secrets of the Ribosome很快就卖光了.

身体的基因食谱

Ramakrishnan指出，人们大约有25个,000个基因, 但蠕虫或植物可能有这么多, too.

“Genes are essential information about how to make proteins,他说. Just as amino acids are the building blocks of proteins, proteins are the building blocks and fuel of the human body.

“Each gene has information to make a particular kind of protein. You can think of a gene as a page in a cook book…. And proteins go off and carry out all sorts of functions. 它们进行化学反应. 它们给出结构. 它们构成了你的头发、皮肤等.”

人体中的蛋白质是由大约20种不同氨基酸的不同组合组成的长链. “所以你可以有不同的链，这些链有这20种氨基酸的不同排列. 所以你可以把蛋白质想象成一个句子其中的字母代表氨基酸.”

就像自动驾驶的折纸, 这些蛋白质链会自动折叠成不同的形状，比如皮肤组织中的胶原蛋白, 血红蛋白在血液中携带氧气, 或者视网膜中的视紫红质来感知光线.

“我给你这三种蛋白质的原因是它们的形状和功能完全不同,他说, 这样的例子有成千上万, 每个都有自己的形状和功能. And every one of them is made somehow by reading instructions in our genes.”

只有四个字母的基础语言

基因由DNA组成, 而DNA是两条交织在一起的链，由四个碱基以不同的顺序和数量组成.

但是形式并不能说明功能. “从DNA结构中不清楚的是，DNA中碱基的顺序如何以某种方式指定如何制造蛋白质? 这是怎么做到的呢?罗摩克里希南说.

“A molecule of DNA in us contains thousands of genes. We have 23 chromosomes, so our 25,000个基因 are distributed among our 23 chromosomes. You can think of DNA as a library with lots of books, or a cookbook with lots of recipes.”

他拿存档的书作了类比, where the library doesn’t let you check out the original book, 但他们会给你一份复印件.

“细胞的作用非常相似. When it needs a particular protein, it makes a copy of the gene for that protein. And that copy is like a copy of one of the strands of DNA, and it’s called 信使核糖核酸.”

DNA是双螺旋结构, 或者两条线, 信使核糖核酸 is a single strand carrying the same information. 仍然只有4个碱基.e. four letters—in various orders and amount that carry the recipe for a specific protein.

“这是怎么读的?他接着说. 大自然是如何解读密码——一种由碱基序列构成的语言——并将其转化为氨基酸序列以形成蛋白质的呢?

In the RNA, researchers label the four bases G, C, A and U. But since it’s hard to spell many words—or the 20 proteins needed—with just four letters, “大自然使用三个字母的代码. 它将把这三个字母作为一个单元来读. That unit is called a ‘codon’ because it’s a unit of the genetic code.”

翻译代码

但还是少了点什么. 想象一台发动机运转，车轮转动——是什么将能量从发动机传递到车轮?

氨基酸不能直接识别DNA, 因此，科学家们开始寻找一种适配分子——一种可以在一端与三个碱基配对的分子(就像三叉的延长线插头一样)。, and at the other end carry an amino acid building block (like a bindle on a hobo’s stick).

一旦被发现，这些被称为 转移核糖核酸 分子.

“它们被称为转移，因为它们将氨基酸转移到正在生长的蛋白质链上,罗摩克里希南说.

蛋白质工厂——核糖体

所有这些蛋白质制造活动都发生在一个叫做核糖体的微小制造中心. Ribosomes are specialized 分子 made of about one-third proteins and two-thirds RNA.

• 注意: 如果你没有时间 watch Ramakrishnan’s May 2 entire talk in 雅典, 跳到视频的1点8分40秒，观看他的电影《newbb电子平台》——现在你已经了解了信使RNA, 转移核糖核酸, 氨基酸和蛋白质.

下面是Ramakrishnan对核糖体装配线的描述，你也可以在他的视频中看到:

细胞中有很多TRNA, and they can come in at random … and if they don’t match the code, 他们拒绝了. But if they match the code, the ribosome joins the first two amino acids. 然后整个物体要移动. 然后一旦它移动, 第一个TRNA被踢出, 新的TRNA变成旧的TRNA, 但是注意现在它连上了两个氨基酸. 然后第三个TRNA进来, 如果它是正确的, 它被接受，然后(它的蛋白质)被结合……. The ribosome is only choosing the TRNAs that correspond to the code on the message, and those TRNAs have the right amino acids attached to them, 所以当它把氨基酸拼接在一起时, they are in the order specified by the code on the gene.”

“这就是美妙之处,他说, 这就是为什么它被称为翻译, because it’s translating from the language of genes to the language of proteins.

“So all of this was known when I entered the field.“但要了解这样一台机器，你必须看到细节，仔细观察，”他指出. “You’ve gotta be able to see things to get to that next level of understanding.”

寻找合适的工具

So Ramakrishnan began his work on the ribosome using X-ray crystallography.

“你所做的就是形成晶体. And crystals are regular, three-dimensional stacks of 分子…. 然后你拿起晶体，用一束x射线照射它，然后收集散射光线.” And then the computer becomes the lens, refocusing the data into an image.

“If  you were able to collect these scattered rays, 然后如果你能在计算机上用数学方法重新组合这些散射光线, you would be able to regenerate an image of the object.”

但理论上需要很长时间才能付诸实践.

And he would have to learn X-ray crystallography.

Ramakrishnan在布鲁克海文国家实验室使用中子散射——而不是x射线晶体学——来观察生物结构, “但我意识到我无法用中子散射来解决任何关于核糖体的有趣问题。. 所以他休了一年假, 获得古根海姆奖学金, to the  MRC Laboratory of Molecular Biology in Cambridge, England—to learn how to use X-ray crystallography to get the pictures he wanted.

小图像没有大画面

他有很多小照片.

他看着小块的核糖体，就像一辆没有组装手册的汽车的未组装部件.

That was the state of play in the mid-1990s, he said.

“我在休假期间有了一些想法，关于如何解决像整个核糖体那么大的问题, in terms of getting enough signal in the diffraction experiment.“首先，他需要高质量的晶体.

But now he was a professor with a small lab and an NIH grant at the University of Utah. And he was not alone in pursuing answers to the structure of the ribosome.

他和他的两名研究生团队正在与世界各地的研究团队竞争.

“我发现我将与资金雄厚的团队进行正面竞争，这些团队已经做了很长时间了, and I had my two first-year graduate students in Utah…. I was thinking of giving up the whole thing altogether,他说.

但我又想, ‘看, 水晶已经存在很长时间了, 还没有人知道如何解决它, 我有一些想法.我还想, ‘This is the most important problem in this field, and one of the most important problems in biology—how a gene is read to make proteins.'”

所以我们回到了剑桥的实验室, and 1999 found him with expert colleagues in crystallography and stable funding.

The ribosome has two parts—called the large subunit and 小亚单位.

由于其他人已经很好地掌握了大的亚单元，Ramakrishnan的团队解决了小的亚单元.

RNA主宰的世界成为焦点

“Now, when you do the experiment, it doesn’t tell you the structure of the molecule. 它给你一个三维图像……. So how do you get an atomic structure from this sort of image? 这有点像把一个巨大的三维拼图拼在一起，”Ramakrishnan说.

Within about a month of each other in the year 2000, a group at Yale solved the large subunit picture, and the Ramakrishnan group solved the other half of the puzzle, 小亚单位.

核糖体的结构和功能很快就成为人们关注的焦点.

“其中一件事是(在大亚基中)氨基酸连接在一起开始制造蛋白质的地方——在这个完全由RNA组成的口袋里……. 同样，与遗传信息结合并读取信息的部分(在小亚基中)几乎完全是RNA.

“为什么这很有趣? It’s because there was a long-standing chicken or egg puzzle. 核糖体是制造蛋白质的物质, but if the ribosome itself is made of both RNA and proteins, 核糖体是如何产生的呢?他问.

“我们现在相信，生命开始于一个由RNA主导的世界，因为RNA可以进行化学反应，但它也可以携带信息, 像DNA一样. 然后它被用来制造蛋白质, 然后最终蛋白质接管了很多化学反应和其他原本可能只由RNA扮演的角色. DNA可能是后来才出现的.

“And so RNA probably is the oldest information molecule in the world. 结构表明.

“然后六年之后, we solve the entire ribosome”—with 信使核糖核酸, 翻译RNA和超过50万个原子.

“如果你解决了核糖体的结构, you can now solve the structure of antibiotics bound to the ribosome,罗摩克里希南说. “So we were able to solve lots of different antibiotics bound to the ribosome, 制药公司现在正试图利用这些结构来设计更好的抗生素.

当他在雅典时, Ramakrishnan获得了母校的荣誉博士学位，并发表了题为“细菌和真核生物翻译的终止”的技术演讲.” (If you remember a codon from earlier in this story, 他的离职演讲涉及“终止密码子”,” i.e. 到达消息的末尾.)