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嘿，大家好。
Hey, everyone.
欢迎收听《Drive》播客。
Welcome to the Drive podcast.
我是你们的主持人，阿提亚。
I'm your host, Attia.
这个播客、我的网站，还有我的每周通讯，都专注于把长寿科学转化为每个人都能理解的内容。
This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone.
我们的目标是提供健康与保健领域最好的内容，为此我们组建了一支优秀的分析师团队。
Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen.
对我来说，不依赖付费广告来提供所有这些内容，这一点极其重要。
It is extremely important to me to provide all of this content without relying on paid ads.
为了实现这一点，我们的工作完全依靠会员的支持。
To do this, our work is made entirely possible by our members.
作为回报，我们为会员提供专属内容和福利，远超免费内容。
And in return, we offer exclusive member only content and benefits above and beyond what is available for free.
如果你想把这个领域的知识提升到一个新的层次，我们的目标就是确保会员获得的回报远超订阅费用。
If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of the subscription.
如果你想了解更多高级会员的福利，请访问 peterattiamd.com/订阅。
If you want to learn more about the benefits of our premium membership, head over to peterattiamd.com forward slash subscribe.
欢迎收听《The Drive》特别节目。
Welcome to a special episode of The Drive.
今天，我们要回顾现代医学科学中一些关键的历史片段。
Today, we're going to take a look at some critical pieces of history in modern medical science.
通常，这个播客关注的是医学研究的发现和应用。
Now, we normally focus on this podcast on the findings and applications of medical research.
但这一集，我们要换个角度，看看那些看似无关紧要的基础研究，如何成为医学革命的基石。
But in this episode, we're going to instead look at that process with an emphasis on how apparently and at times seemingly irrelevant basic research, can be the stepping stone upon which medical revolutions are built.
我们本可以把它作为一系列发现来呈现，但我觉得，如果你亲眼看到这些科学家是谁，他们真正想做什么，以及在任何人意识到他们发现了什么之前的那一刻是什么样子，这个论点会更有说服力。
Now, we could have presented this as a series of findings, but I think the argument works best if you actually see it play out, to see who these scientists were, what they were genuinely trying to do, and what it looked like in the moment before anyone understood what they stumbled into.
所以，与其争论这个论点，我更想通过一个个故事来展示给你看。
So rather than argue the thesis, I want to show it to you story by story.
等我们讲完，你应该就能明白，过去五十年里最重要的几类药物到底是怎么来的。
By the time we're done, you should hopefully understand where several of the most consequential drug classes of the last fifty years actually came from.
而且我希望不止如此，你还会有一个新的视角，去思考医学进步究竟从哪里来，以及这如何影响我们整个社会应该如何重视那些推动医学创新的基础科学研究。
And hopefully more than that, you'll have a different framework for thinking about where medical progress actually comes from, and how that informs how we, as a society, should value the basic science research that fuels medical innovation.
好了，话不多说，希望你喜欢这期特别节目。
So, without further delay, I hope you enjoy this special episode of The Drive.
1961年夏天，一位年轻的日本生物化学家下村修，和他的妻子秋实，还有他的导师弗兰克·约翰逊，在新泽西州普林斯顿上了一辆旅行车，开了三千英里，来到华盛顿州的西北角。
In the summer of nineteen sixty one, a young Japanese biochemist named Osamu Shimamuru and his wife, Akemi, and his mentor Frank Johnson loaded into a station wagon in Princeton, New Jersey, and drove 3,000 miles to the Northwest corner of Washington State.
他们的目的地是圣胡安岛上一个叫星期五港的地方。
Their destination was a place called Friday Harbor on San Juan Island.
他们去那里是为了水母。
They went there for jellyfish.
具体来说，是一种叫维多利亚多管发光水母的小水母，它几乎透明，在太平洋西北部的冷水里漂浮。
Specifically, Acoria victoria, a small, mostly transparent jellyfish that drifts in the cold waters of the Pacific Northwest.
它的伞状体边缘有一圈微小的器官，会发出淡淡的绿光。
Its umbrella is rimmed with tiny organs that emit a faint green light.
下村当时正在研究生化发光，并以此作为自己的职业方向。
Shimomura was building a career studying the chemistry of bioluminescence.
他们用浅网兜一只一只地把水母捞起来，带上岸，然后用剪刀手工剪下水母伞盖上的发光环，一只一只地处理。
They scooped them up one at a time with shallow dip nets, brought them ashore, and cut the luminous rings off the umbrellas with scissors by hand, one jellyfish at a time.
第一个夏天的目标是五万只。
The goal that first summer was 50,000.
第二年夏天他们又来了，第三年也来了。
They came back the next summer, and the next.
连续十九年，下村和他的家人，还有一批批轮换的学生，每年都回到星期五港。
For nineteen consecutive years, Shimomura and his family and a rotating cast of students returned to Friday Harbor.
到1988年他们最终停止时，他们已经剪了大约八十五万只水母的伞盖，而这些水母是从海湾里捞上来的大约一百万只中取出的。
By the time they finally stopped in 1988, they had cut the bells off approximately 850,000 jellyfish, drawn from a population of about 1,000,000 pulled from the bay.
十九个夏天，一百万只水母。
Nineteen summers, a million jellyfish.
如果你在1965年走到码头上下村面前，问他正在做什么，他会诚实地告诉你，他在试图弄清水母是如何发光的。
If you had walked up to Shammamura on a dock in 1965 and asked him what he was doing, he would have told you honestly that he was trying to understand how a jellyfish produces light.
这就是整个项目。
That was the whole project.
他并不是想治病。
He wasn't trying to cure a disease.
他不是在设计药物，也没打算要彻底改变科学发现的过程。
He wasn't designing a drug, and he wasn't setting out to revolutionize the very process of scientific discovery.
他就是一个拿着剪刀切水母环的人，因为他想知道这种动物为什么会发光。
He was a man with scissors cutting rings off jellyfish because he wanted to know how the animal glowed.
下面是他发现的。
Here's what he found.
当他碾碎水母环并纯化蛋白质时，他首先分离出一种发出蓝光而非绿光的蛋白质，而且只有在钙离子存在时才会发光。
When he ground up the jellyfish rings and purified the proteins, the first thing he isolated was a protein that emitted blue light, not green, and only emitted that light in the presence of calcium ions.
他称之为水母素。
He called it aquarine.
这本身就是一项漂亮的生物化学成果。
That, by itself, was a beautiful piece of biochemistry.
以前从来没有人见过由钙触发产生光的蛋白质。
Nobody had ever seen a calcium triggered light producing protein before.
但在纯化水母素的过程中，他一直注意到背景里有一种微量污染物，另一种不会自己发光的蛋白质。
But while he was purifying aquarium, he kept noticing in the background a trace contaminant, a second protein that didn't glow on its own.
但是当你用正确波长的蓝光照射它时，它会发出明亮的绿色荧光。
But when you shone the right wavelength of blue light on it, it fluoresced bright green.
他把它纯化出来，并简单地命名为绿色荧光蛋白，也就是GFP。
He purified it, and he named it plainly green fluorescent protein or GFP.
结果发现，水母运行的是一套双蛋白质光学系统。
The jellyfish, it turned out, was running a two protein optical system.
水母素从钙信号中产生蓝光。
Aquarine generated blue light from a calcium signal.
然后，蓝光激发紧挨着的GFP，GFP吸收蓝光，并将能量重新发射为绿光。
That blue light then excited GFP sitting right next to it which absorbed the blue light and re emitted the energy as green.
这就是你在水中看到的光芒，是水母生物学中一个精巧的杰作。
And that s the glow you see in the water, an elegant piece of jellyfish biology.
下村修发表了这项研究，然后他和家人又回去抓更多水母，主要是为了研究水母素。
Shimomura published it and he and his family went back to catching more jellyfish, mostly to study aquarium.
而GFP，也就是那种绿色蛋白，在文献里就那么放着，基本上被忽略了将近三十年。
GFP, the green protein, sat there, in the literature, basically ignored, for almost thirty years.
而接下来，这个故事就变得非同寻常了。
And here's where the story becomes extraordinary.
因为GFP，最终发现，具有三个特性，而这三个特性是任何人都没理由从一种随机的水母蛋白身上预料到的。
Because GFP, it eventually turned out, has three properties that nobody had any reason to expect from a random jellyfish protein.
第一，它能自行折叠。
First, it folds itself.
你不需要任何辅助机制就能让它发挥作用。
You don't need any helper machinery to make it work.
第二，它能仅凭自身的三个氨基酸，并且只利用氧气，就自己构建出发光核心。
Second, it builds its own fluorescent core all by itself from three of its own amino acids and using nothing but oxygen.
第三，也是改变生物学的一点，GFP在地球上几乎所有生物体的几乎所有细胞中都能发挥作用。
And third, and this is the part that changes biology, GFP works in almost any cell in almost any organism on Earth.
因为GFP是一种蛋白质，这意味着我们可以把它的基因植入生物体内，生物体就会制造出GFP。
Because it's a protein, that means we can put the gene into an organism and the organism will make GFP.
由于GFP能自行折叠并形成自己的荧光核心，它不依赖任何水母特有的信号。
Because GFP folds itself and creates its own fluorescent core, it doesn't rely on any jellyfish specific signal.
所以我们可以把GFP的基因放进细菌里，细菌就会发光。
So we can put the gene for GFP into a bacterium and it glows.
放进蠕虫里，蠕虫也会发光。
Put it in a worm, the worm glows.
放进老鼠、植物，或者培养皿中的人类细胞里，它们在蓝光照射下都会发光。
Put it into a mouse, into a plant, into a human cell in a dish, they all glow under the presence of blue light.
想想这意味着什么。
Think about what that means.
我们可以让生物体内的特定部分发光。
We can make specific parts of biology glow.
如果你能把GFP的基因连接到任何你感兴趣的基因上，那么那个基因制造的蛋白质就会在活细胞内到处携带一个小绿光手电筒。
And if you can attach the gene for GFP to any other gene you care about, the protein made from that gene will carry a little green flashlight with it everywhere it goes inside a living cell.
这是历史上第一次，你能在活体组织中实时观察生物过程。
For the first time in history, you could watch biology happen in real time in living tissue.
你能看到单个蛋白质在细胞里从一处移动到另一处。
You could watch a single protein move from one part of a cell to another.
你能在显微镜下看到癌细胞在活老鼠体内爬行并转移。
You could watch a cancer cell crawl through tissue and metastasize in a living mouse under a microscope.
你能看到透明斑马鱼胚胎一个细胞一个细胞地发育。
You could watch an embryo develop, cell by cell, in a transparent zebrafish.
你可以标记一个干细胞，然后追踪它所有的后代，直到这个生物体的一生结束。
You could mark a stem cell and follow every one of its descendants for the lifetime of an organism.
在GFP出现之前，这些都不可能实现。
None of this was possible before GFP.
完全不可能。
None of it.
现在这已经太常见了，大一实验课上就能培养出表达GFP的转基因细菌。
Now, it s so routine, you develop GFP transgenic bacteria in a freshman lab class.
到了90年代，生物学家们搞清楚他们手里有什么之后，生物学研究就爆发了。
Once biologists figure out what they had, in the 1990s, the biology research exploded.
哥伦比亚大学一位叫马丁·谢尔菲的研究员把GFP表达在细菌和线虫里。
A researcher at Columbia named Martin Shelfi expressed GFP in bacteria and worms.
它们就发光了。
They glowed.
加州大学圣地亚哥分校一位叫罗杰·陈的化学家花了接下来十年时间改造出各种变体：青色、黄色、橙色，最后还有红色。
A chemist at UCSD named Roger Chen spent the next decade engineering variants: cyan, yellow, orange, eventually red.
另一个团队开发了GCaMP，把GFP和钙结合蛋白融合在一起，这样GCaMP只有在有钙信号的时候才会发出绿光。
Another team developed GCaMP fusing GFP to a calcium binding protein so GCaMP would only grow green light in the presence of calcium signals.
我们现在能看着神经元放电，看着精子让卵子受精。
We could now watch neurons fire and watch sperm fertilize an egg.
现代生物学里有一整套荧光报告蛋白，颜色齐全。
We have an entire palette of fluorescent reporters used in modern biology.
它们全都是下村修在华盛顿州一个码头上从水母里提取出来的那个蛋白的后代，只是经过各种改造。
All of them are descendants in one way or another from the protein Shimomura pulled out of the jellyfish on a dock in Washington State.
我怎么说都不为过，现代生物学有多少都靠这个。
I cannot overstate how much of modern biology runs on this.
今天你走进世界上任何一家大型生物学或生物医学研究实验室，工作台上某个地方肯定在用GFP或者它的某个衍生版本。
If you walk into any major biology or biomedical research lab in the world today, GFP or one of its descendants is in use somewhere on the bench.
药物研发流程依赖它。
Drug development pipelines depend on it.
癌症研究依赖它。
Cancer research depends on it.
神经科学依赖它。
Neuroscience depends on it.
分子生物学、细胞生物学、系统生物学。
Molecular, cellular, systems biology.
GFP几乎在每个实验室里都有。
GFP is in virtually every lab.
现代生物学基本上没有一个重要领域，其工具箱里没有受到一种来自水母的蛋白质的影响。
There is essentially no significant area of modern biology that isn't touched somewhere in its toolkit by a protein that came out of a jellyfish.
因为下村修有一种看似与医学无关的纯粹好奇心，他想知道水母为什么会发光。
Because Shimomura had a seemingly medically irrelevant simple basic curiosity, he wanted to know what makes jellyfish glow.
2008年，诺贝尔化学奖颁给了下村修、马丁·查尔菲和罗杰·钱恩，以表彰他们在绿色荧光蛋白的发现和开发方面的贡献。
In 2008, the Nobel Prize in Chemistry was awarded to Oshamu, Shimomura, Martin, Chalfi, and Roger Chen for the discovery and development of green fluorescent protein.
所有这些进步——基因疗法、癌症筛查、神经科学——全都源于一个男人和他的家人，在华盛顿州的一个小海湾度过了十九个夏天，切下了一百万只水母的伞盖，弄清楚了水母是怎么发光的。
And every single one of those advances, the gene therapies, the cancer screens, the neuroscience, all of it, exists because a man and his family spent nineteen summers in a small bay in Washington State cutting the bells off a million jellyfish, figuring out how jellyfish glow.
我想从这里开始讲，是因为我觉得水母的故事揭示了一个在现代医学中一直被低估的事实。
I want to start there because I think the jellyfish story makes a point about a persistently underappreciated truth in modern medicine.
我们现在认为是现代医学的很大一部分——你药柜里的药、你验血时做的诊断测试、现在开始治愈那些曾经被视为死刑判决的疾病的基因疗法，甚至那些支撑这些发现的实验室每天使用的基础工具——其中很大一部分都源于那些在开始时看起来与治疗人类疾病毫无关系的研究。
A staggering fraction of what we now consider modern medicine, the drugs in your medicine cabinet, the diagnostic tests you had run on your blood, the gene therapies that are now starting to cure diseases we used to consider death sentences, or even the foundational tools used every day by the laboratories that fuel these discoveries, so much of it traces back to research that at the moment it began looked like it had nothing to do with treating human disease.
有人在研究水母，研究某种蛇或蜥蜴的毒液，研究长在稻米上的真菌，研究温泉里的微生物，或者研究某种单细胞生物DNA中的重复模式。
Somebody was studying a jellyfish, studying this snake or that lizard's venom, studying fungus growing on rice, a microbe in a hot spring, a repeating pattern in some single celled organism's DNA.
后来，有时是几十年后，这些研究成了改善甚至拯救了数百万人生命的工作的基础。
And later, sometimes decades later, that research turned out to be the foundation of work that has improved or even saved millions of lives.
我觉得这一点值得停下来想一想。
I think this is worth pausing on.
我们通常谈论医学进步时，总是习惯从意图和医学目标的角度出发。
The reflexive way we typically talk about medical progress is in terms of intent, in terms of medical goals.
我们会说，比如‘我们在研究治疗阿尔茨海默症的方法’，或者‘他们在开发治疗肥胖的药物’。
We say things like, We're working on a cure for Alzheimer's, or They're developing a drug for obesity.
当然，科学中也有大量重要的、有明确目标的问题解决型研究。
And of course, there is enormous, important, intentional problem solving science.
事实上，现代医学中一些最重要的进展都来自高度定向的努力：放疗、检查点抑制剂、单克隆抗体、激酶抑制剂、抗病毒疗法、mRNA疫苗。
In fact, some of the most important advances in modern medicine have come from highly directed efforts: RT therapy, checkpoint inhibitors, monoclonal antibodies, kinase inhibitors, antiviral therapies, mRNA vaccines.
这些都需要非凡的、有目的的工程优化、临床开发和坚持不懈。
These required extraordinary intentional engineering optimization, clinical development, and persistence.
重点不是说定向科学没用。
The point isn't that directed science doesn't work.
它显然有用。
It obviously does.
关键在于，许多这样的成功最终都建立在先前的生物学发现基础之上。
The point is that many of those successes ultimately rest on a foundation of biological discoveries that came first.
但今天我想让大家思考的是，很多最具影响力的医学进步，并不是来自一群人坐在房间里想着怎么治病。
But what I want us to think about today is that an enormous amount of the most consequential medical progress does not come from people sitting in a room asking how to cure a disease.
而是来自人们坐在房间里，或者到实地去，问这样一个问题：自然界里的这个东西到底是怎么运作的？
It comes from people sitting in a room or going out in the field and asking, how does this thing in nature actually work?
这种方法之所以能如此有效，原因让我感到由衷的谦卑。
The reason this can be so productive is something I find to be genuinely humbling.
大自然并没有解决我们在医学上关心的问题。
Nature hasn't solved the problems we care about in medicine.
进化并不是为了延长寿命，更不是为了预防阿尔茨海默病、动脉粥样硬化、骨质疏松，或者任何那些在生育之后很久才出现的慢性病。
Evolution is not optimizing for longevity, and it certainly isn't optimizing for preventing Alzheimer's disease, atherosclerosis, osteoporosis, or any of the chronic diseases that emerge long after reproduction.
但进化产生了别的东西——一个几乎难以想象的庞大工具箱，里面有分子、信号通路、防御系统、代谢适应和生物策略。
But evolution has generated something else, an almost unimaginably vast toolkit of molecules, signaling pathways, defense systems, metabolic adaptations, and biological strategies.
大自然在数百万个物种中进行了大约四十亿年的实验。
Nature has been running experiments across millions of species for roughly four billion years.
虽然它没有替我们解决问题，但它往往已经创造出了我们正在寻找的解决方案中的一些组成部分。
And while it hasn't solved our problems for us, it has often already created some of the components of the solutions we're looking for.
挑战在于，当我们看到它们时，要能认出来。
The challenge is recognizing them when we see them.
现代医学可能只有几百年历史，但大自然已经在数百万个物种身上并行进行了数十亿年的实验。
While modern medicine is perhaps a few 100 years old, nature has been running experiments across millions of species in parallel for billions of years.
我们常常发现，我们需要的机制其实早就存在了。
We often find that the mechanisms we need already exist.
我们需要的分子可能早就有了。
The molecule we need may already exist.
有时候我们甚至还没意识到问题是什么，大自然就已经有了应对的办法。
Sometimes we don't even know what the problem is and nature already has a trick up its sleeve.
我们只需要足够留心，观察得足够久、足够仔细，才能发现它。
We just have to be paying attention long enough and close enough to notice it.
一旦你真正理解了这一点，很多医学史看起来就不一样了。
And once you internalize that, a lot of medical history starts to look different.
研究方法看起来也不一样了。
The methods look different.
方法应该有所不同。
The methods should look different.
因为如果大自然已经解决了这么多问题，那么有时候科学家能做的最有成效的事情不是发明新东西，而是找到那个已经发明了它的生物。
Because if nature has already touched so many of these problems, then sometimes the most productive thing a scientist can do is not invent something new, it's to find the organism that already invented it.
我们今天就要围绕这个原则来展开。
That principle is where we're going to spend our time today.
自然界已经解决了很多问题。
The natural world has solved a lot of problems.
一旦我们找到这些解决方案，真正认识到它们的价值，我们就可以在此基础上发展，并将它们转化为研究和临床工具。
Once we find those solutions and really recognize them for what they are, we can build on them and translate them into research and clinical tools.
我觉得接下来的故事可能是这个理念最清晰的例证之一：找到大自然开发的工具，直接应用到医疗实践中。
And I think the next story is perhaps one of the cleanest illustrations of that idea: finding a tool developed by nature and directly putting it into medical practice.
在20世纪60年代末，一位名叫远藤章（Akiro Endo）的日本生物化学家在三共制药公司工作，他当时在研究胆固醇。
In the late 1960s, a Japanese biochemist named Akiro Endo was working at the Sunkyo Drug Company in Tokyo, and he was thinking about cholesterol.
那时，胆固醇合成的基本生化机制已经为人所知。
By that point, the basic biochemistry of cholesterol synthesis was understood.
康拉德·布洛赫和西奥多·莱南在1964年因解开这个机制而获得了诺贝尔奖。
Conrad Bloch and Theodor Leinen had won the Nobel Prize for working it out in 1964.
这个领域的每个生物化学家都知道，胆固醇合成中的限速步骤是一种叫做HMG辅酶A还原酶的单一酶。
Every biochemist in the field knew that the rate limiting step in cholesterol synthesis was a single enzyme called HMG CoA reductase.
而且原则上大家都明白，只要能抑制这种酶，就应该能降低体内的胆固醇水平。
And everyone understood, in principle, that if you could just inhibit that enzyme, you should be able to lower the body's cholesterol levels.
问题是，没人知道怎么找到这样的抑制剂。
The problem was nobody had any idea how to find such an inhibitor.
那个时代的药物化学还无法从头设计出这样的分子。
The medicinal chemistry of the era was not capable of designing one from scratch.
所以，远藤问了一个不同的问题。
So, Endo asked a different question.
他没有问，我该怎么设计一个抑制HMG辅酶A还原酶的分子。
He didn't ask how do I design a molecule that inhibits HMG CoA reductase.
他问的是，自然界里谁已经在做这件事了？
He asked, Who in nature is already working on one?
他的推理大概是这样的：真菌和霉菌一生都在和细菌打仗。
His reasoning went something like this: Fungi and molds spend their entire existence at war with bacteria.
它们生活在同样潮湿、腐烂、营养丰富的环境里，为了争夺资源，一直在进行化学层面的竞争。
They live in the same wet, decaying, nutrient rich environments, and they're in constant chemical competition for resources.
经过数亿年的竞争，真菌进化出了庞大的武器库，也就是各种小分子，用来毒杀、瘫痪或者饿死它们的细菌对手。
Over hundreds of millions of years of that competition, fungi have evolved an enormous arsenal of weapons, small molecules designed to poison, disable, or starve their bacterial competitors.
我们早就有一个著名的例子。
We already had one famous example.
亚历山大·弗莱明发现的青霉素，正是这样一种武器，是真菌用来杀死细菌的化学物质。
Penicillin, discovered by Alexander Fleming, is exactly that kind of weapon, a chemical that a fungus uses to kill bacteria.
远藤的洞察在于：很多细菌要生长，就需要甾醇，也就是类似固醇的分子，来构建它们的细胞膜。
Endo's insight was this: many bacteria, in order to grow, need sterols, or sterile like molecules, to build their cell membranes.
如果你是一种真菌，想饿死周围的细菌，一个极其有效的武器就是能阻断细菌甾醇合成的分子。
And if you were a fungus trying to starve out your bacterial neighbors, one extremely effective weapon would be a molecule that blocks bacterial sterile synthesis.
也就是说，在真菌花了数亿年创造出的近乎无穷无尽的化合物库中，应该存在一种能抑制胆固醇合成通路的分子。
Which means somewhere out there in the near endless catalog of compounds that fungi have spent hundreds of millions of years inventing, there ought to be a molecule that inhibits the cholesterol synthesis pathway.
具体来说，应该有一种分子能抑制HMG辅酶A还原酶。
Specifically, there ought to be a molecule that inhibits HMG CoA reductase.
某个地方的某种真菌，早就设计出了解决这个问题的药物。
Some fungus, somewhere, had already designed the drug to solve this problem.
远藤决定去寻找它。
Endo sought out to find it.
于是他和同事黑田正雄开始进行筛选。
So he and his colleague, Massiao Kuroda, started screening.
在接下来的两年里，他们测试了超过6000种微生物菌株，其中大部分是真菌，看它们是否能抑制HMG辅酶A还原酶。
Over the next two years, they tested more than 6,000 microbial strains, most of them fungal, for the ability to inhibit HMG CoA reductase.
两年过去了，一无所获。
For two years, nothing.
终于，在1972年3月，他们有了发现。
Finally, in March 1972, they got a hit.
一种从京都一家粮店的大米样本中分离出的桔青霉菌株，产生了一种对酶有强抑制作用的提取物。
A strain of Penicillium citronum, growing on a rice sample from a grain shop in Kyoto, produced an extract with potent inhibitory activity against the enzyme.
远藤将他的研究结果分享给了制药公司默克，默克也自己开始寻找真菌，希望能找到一种相关的化合物，最终将其推向临床。
Endo shared his results with the pharmaceutical company Merck, who went searching for fungi on their own for a related compound they could in turn bring to the clinic.
不久之后，他们从一种不同的真菌——土曲霉中分离出了一种密切相关的化合物，命名为洛伐他汀，并于1987年在美国获得批准。
Shortly thereafter, they isolated a closely related compound from Aspergillus teres, a different fungus, called it lovastatin and got it approved in The United States in 1987.
从洛伐他汀出发，最终衍生出了辛伐他汀、普伐他汀、阿托伐他汀、瑞舒伐他汀。
From lovastatin, you eventually get simvastatin, pravastatin, atorvastatin, rizuvastatin.
这一整类药物，按照任何合理的估计，已经预防了数百万起心血管事件和数百万例过早死亡。
The entire class of drugs that by any reasonable estimate has prevented millions of cardiovascular events and millions of premature deaths.
我希望你们注意到刚才发生的事情的结构，因为这是我之前提出的论点最清晰的体现。
I want you to notice the structure of what just happened because it's the cleanest possible version of the argument I made a few moments ago.
远藤并没有发明他汀类药物的起点。
Acuroendo did not invent the starting point for statins.
是橘青霉发明的。
Penicillium citronum invented it.
是土曲霉发明的。
Aspergillus teres invented it.
远藤和后来几代药物化学家所做的，就是把那个起点转化成一种安全、可规模化、临床上实用的药物类别。
What Endo and the generations of medical chemists who followed did was transform that starting point into a safe, scalable, clinically useful class of medications.
这些真菌需要一种抑制甾醇合成的方法来生存，当然原因和预防动脉粥样硬化性心血管疾病不同，但抑制甾醇合成的需求是一样的。
These fungi needed a way to inhibit sterile synthesis in order to survive, for a different reason than ASCVD prevention to be sure, but a need to inhibit sterile synthesis all the same.
所以远藤向大自然提出了正确的问题。
So Endo asked the right question of nature.
谁已经解决了这个问题？
Who has already solved this problem?
而大自然，在京都的一家粮店里，把答案递给了他。
And nature, sitting in a grain shop in Kyoto, handed him the answer.
一块米上长的霉菌，在远藤开始寻找答案之前，已经处理胆固醇问题几亿年了。
A mold growing on a piece of rice that had been working on the cholesterol problem for a few hundred million years before IKiro Endo started looking for the answer.
他只需要成为那个想到去问的人。
He just had to be the one who thought to ask.
我说这是最清晰的案例，因为远藤是有意去寻找的。
Now, I say this as the cleanest case because Endo went looking on purpose.
他有一个假设，认为大自然可能已经解决了这个问题，结果证明他是对的。
He had a hypothesis about where nature might have already solved the problem, and he turned out to be right.
但我接下来要讲的多数故事并不是这样的。
But most of the stories I want to tell you next are not like that.
在大多数故事里，那些找到颠覆性答案的人，其实根本没在找答案。
In most of them, people who found a paradigm shifting answer were not even looking for it at all.
他们看的是完全不同的东西。
They were looking at something else entirely.
一条蛇、一个温泉、一个盐池、一只沙漠蜥蜴。
A snake, a hot spring, a salt pond, a desert lizard.
而他们在那里发现的东西，事后看来，改变了一切。
And what they found there turned out in retrospect to change everything.
这就把我们带到了南美洲。
Which takes us to South America.
在巴西，二十世纪上半叶，巴西矛头蝮，也就是巴西枪头蛇，是一个严重的公共卫生问题。
In Brazil, in the first half of the twentieth century, Bathrops jararaca, the Brazilian lancehead pit viper, was a serious public health problem.
现在依然是。
It still is.
这种矛头蝮蛇很漂亮，但脾气暴躁，身上有锯齿状花纹，大约三到五英尺长，它的毒液会导致血压突然急剧下降。
The jararaca lancehead is a beautiful, irritable, zigzag patterned pit viper about three to five feet long and its venom causes a sudden catastrophic drop in blood pressure.
1901年，巴西的布坦坦研究所成立，很大程度上就是为了研究毒蛇咬伤。
In 1901, the Butantan Institute in Brazil was founded, in no small part to understand venomous snake bites.
他们开始收集、研究并储存矛头蝮蛇的毒液。
They began collecting, studying, and stockpiling pit viper venom.
后来，毒液逐渐被用作研究材料。
Eventually, venom began to be leveraged as a research material.
冻干的、量足、当地就能获取。
Liophilized, abundant, locally available.
它不再仅仅是研究的对象。
And it stopped being just an object of study itself.
药理学家可以用它作为试剂来探索哺乳动物的生理机制。
Pharmacologists could use it as a reagent to probe mammalian physiology.
在20世纪40年代末，巴西药理学家毛里西奥·罗查·席尔瓦正在研究循环性休克。
In the late 1940s, the Brazilian pharmacologist Mauricio Rocha de Silva was working on circulatory shock.
当时，人们认为循环性休克是由组胺介导的。
At the time, circulatory shock was thought to be mediated by histamine.
他想知道蛋白水解酶，比如常见的胰蛋白酶或贾拉里卡毒液中的蛋白酶，是否会从血浆中释放组胺。
He wanted to know whether proteolytic enzymes, common ones like trypsin or proteases in Jurarika venom, released histamine from plasma.
于是，他将血液暴露于贾拉里卡毒液。
So, he exposed blood to Jurarika venom.
毒液并没有从血液样本中释放组胺。
The venom did not release histamine from blood samples.
它释放了别的东西。
It released something else.
这发现了一种新的肽，一种强效的血管扩张剂，它还能引起豚鼠小肠的缓慢收缩。
This was the discovery of a new peptide, a potent vasodilator, which also produced a slow contraction in the small intestines of guinea pigs.
他将这种肽命名为缓激肽，源自希腊语，意为“缓慢运动”。
He named this peptide bradykinin, from the Greek for slow movement.
这是一个重大的发现。
This was a massive discovery.
在随后的几十年里，缓激肽被证明是哺乳动物心血管生物学中的一个关键角色，是血压、血管通透性和炎症的内源性调节因子。
In the decades since, bradykinin has turned out to be a fundamental player in mammalian cardiovascular biology, an endogenous regulator of blood pressure, vascular permeability, and inflammation.
但我们的故事并没有就此结束。
But our story doesn't stop here.
十五年后，罗查·伊西尔瓦有一个叫塞尔吉奥·费雷拉的研究生，他交给费雷拉一个难题。
A decade and a half later, Rocha Isilva had a graduate student named Sergio Ferreira, and he handed Ferreira a puzzle.
由毒液在血浆中生成的缓激肽比在试管中合成的缓激肽活性更强。
Bradykinin generated in plasma by venom was more active than a synthetic bradykinin produced in a test tube.
为什么？
Why?
费雷拉在1965年发表的答案是，毒液还含有另一类肽，它们通过阻断缓激肽的分解来增强其作用，这就是缓激肽增强因子（BPF）。
Ferreira's answer, published in 1965, was that the venom also contained a separate family of peptides that potentiated bradykinin's effects: bradykinin potentiating factor or BPF, by blocking the breakdown of bradykinin.
毒液中的蛋白酶导致缓激肽在血浆中释放，而毒液中的BPF则保护这些缓激肽不被降解。
The venom proteases caused bradykinin to be released in the plasma and BPFs in the venom protected that bradykinin from degeneration.
BPF的研究让费雷拉在伦敦的皇家外科医师学会的维恩实验室获得了一个博士后职位。
The BPF work landed Ferreira a postdoctoral position in London, in the Vein lab at the Royal College of Surgeons.
在实验室里，另一位博士后叫凯文·恩格。
In the lab, another postdoc named Kevin Inc.
他正在研究肺循环中的血管紧张素，发现血管紧张素I在肺部被转化为血管紧张素II，这是一种血管收缩剂。
Was studying angiotensin in pulmonary circulation, having found that angiotensin I is converted to angiotensin II, a vasoconstrictor, in the lungs.
费雷拉从巴西带了粉末状的BPF到伦敦，他和凯文·恩格的研究得出了一个意外的发现。
Ferrara brought powdered BPF with him to London from Brazil, And his work with Kevin Ng converged on an unexpected finding.
通过在凯文的实验准备中加入BPF，结果发现，降解缓激肽的酶同时也是将血管紧张素I转化为血管紧张素II的酶。
By adding BPF to Kevin's preparations, it turned out that the same enzyme that was degrading bradykinin was also converting angiotensin I to angiotensin II.
这两个过程都被BPF抑制了。
Both jobs were inhibited by BPFs.
这种酶显然有两个协同作用：破坏血管扩张剂缓激肽，并产生血管收缩的血管紧张素II。
This enzyme apparently had two synergistic jobs: destroy the vasodilator, bradykinin, and produce the vasoconstricting angiotensin II.
他们发现这种酶就是血管紧张素转换酶，也就是ACE。
They found that this enzyme was angiotensin converting enzyme, or ACE.
ACE之前已经被发现了，但发现一种强效的ACE抑制剂引起了施贵宝公司化学家的注意。
Now, ACE had previously been discovered, but the identification of a potent ACE inhibitor caught the attention of chemists at squib.
蛇毒肽本身并不是可行的药物。
The venom peptides themselves were not viable drugs.
它们口服无效，半衰期也很短。
They're not orally active and they have a short half life.
施贵宝的化学家从雅拉里卡蛇毒中提取了最小的活性BPF肽，以此为结构先导，设计了一种小分子口服活性药物，以与蛇毒肽相同的方式抑制ACE。
Squibb's chemists took the smallest active BPF peptide from the Jurarika venom and used it as their structural lead and designed a small orally active molecule that inhibited ACE in the same way that venom peptide did.
这通常被认为是基于机制的理性药物设计最早期的例子之一。
This is conventionally remembered as one of the earliest examples of rational, mechanism based drug design.
他们把这个分子叫做卡托普利，并于1981年获得FDA批准，成为临床上首个口服ACE抑制剂。
They called the molecule captopril and it was approved by the FDA in 1981 as the first oral ACE inhibitor in clinical use.
卡托普利催生了依那普利、赖诺普利、雷米普利等ACE抑制剂类药物，并在概念上开启了血管紧张素受体阻滞剂，如氯沙坦、缬沙坦等。
And captopril begat enalapril, lisinopril, ramipril and the rest of the ACE inhibitor class and conceptually began the angiotensin receptor blockers losartan, valsartan, and so on.
肾素-血管紧张素-醛固酮系统如今是整个医学中药物干预最多的通路之一。
The renin angiotensin aldosterone system is now one of the most heavily drugged pathways in all of medicine.
这些药物是治疗高血压、心力衰竭、慢性肾病、心肌梗死后重构和糖尿病肾病的基础药物。
These drugs are foundational in the treatment of hypertension, heart failure, chronic kidney disease, post MI remodeling, and diabetic nephropathy.
它们很可能是有史以来最重要的药物类别之一。
They are plausibly among the most consequential drug classes ever developed.
那么，让我们稍微停下来，仔细想想这条因果链。
So, let's sit with the causal chain for a moment.
数百万人的生命得以挽救或延长，是因为布坦坦研究所一直在储备当地的蛇毒。
Millions of lives saved or extended because the Butantan Institute was stockpiling local snake venom.
一个临床问题：这种蛇毒是如何致人死亡的？
A clinical question, how does this venom kill people?
由此产生了一种研究试剂。
Produced a research reagent.
这种试剂原本是用来验证一个关于休克的错误假说，却意外发现了缓激肽——一种在心血管和炎症生物学中至关重要的信号分子。
The reagent used to probe a wrong hypothesis about shock produced the accidental discovery of bradykinin, a fundamental signaling molecule in cardiovascular and inflammation biology.
在缓激肽生物测定中出现的一个差异，导致了BPF的发现。
A discrepancy in a bradykinin bioassay produced BPFs.
这些BPF被带到了伦敦一个研究肺血管的实验室，结果发现有一种酶同时控制着两个相互对立的血压系统。这个发现交到两位药物化学家手里，最终催生了一类改变世界的药物。
BPFs carried to a London lab studying lung vasculature produced the recognition that one enzyme sat at the center of two opposing blood pressure systems, and that recognition handed to two medicinal chemists produced a world changing drug class.
在二十世纪的前七十年里，根本没人想过要研发降压药。
For the first seventy years of the twentieth century, nobody was trying to develop a hypertension drug.
这个分子是七十年野外工作和基础生物学研究的产物，每一步都是在回答前一步没有预料到的问题。
The molecule fell out of seventy years of fieldwork and basic biology, each step asking a question the previous step hadn't anticipated.
研究巴西矛头蝮蛇毒液如何杀死猎物，本来可能拯救巴西成千上万的生命。
The question of how a Brazilian pit viper venom kills its prey could have saved thousands of lives in Brazil.
但结果，通过基础医学科学家的好奇心，全世界数千万人的生命得以挽救或延长。
Instead, through the curiosity of basic medicinal scientists, tens of millions of lives around the world have been saved or extended.
对于更专业的听众来说，你们已经知道接下来这个故事的重要性，所以再怎么强调也不为过。
For a more technical audience, you already know the importance of the next story, and it's therefore somewhat impossible to overstate.
任何在生物实验室待过的人，哪怕只是大学一年级上过生物实验课，都知道这项工作如何彻底改变了生物学和医学。
Anyone who has spent any time in a biology lab, including simply taking a freshman year biology lab class at university, knows how fundamentally this work has changed biology and medicine forever.
正是这项技术打开了通往过去几十年生物学研究黄金时代的大门。
It is the technique that opened the door to the last few decades, the golden age of biology research.
而这一切，始于一个温泉。
And it begins at a hot spring.
上世纪60年代中期，印第安纳大学的一位微生物学家，名叫托马斯·布洛克，开始每年夏天去黄石国家公园。
In the mid-1960s, a microbiologist at Indiana University named Thomas Brock started taking summer trips to Yellowstone National Park.
他可不是普通的徒步爱好者。
He wasn't a typical hiker.
他是一位微生物生态学家，对极端微生物很感兴趣，也就是那些生活在极端环境里的生物。
He was a microbial ecologist who became interested in extremophiles, organisms that live in extreme environments.
黄石公园有数百处地热景观，那里能接触到的耐高温水生环境，比地球上其他地方都要密集。
Yellowstone, with its hundreds of geothermal features, has a higher concentration of accessible high temperature aquatic habitats than just about anywhere else on Earth.
当时，微生物学界的普遍看法是，细菌能在最高大约55摄氏度的环境下生长，超过这个温度，它们或许能存活，但高温会阻碍它们的分子机制，使其无法成功繁殖。
At the time, the prevailing belief in microbiology was that bacteria could grow in conditions up to about 55 degrees Celsius, after which they might survive, but the heat prevented their molecular machinery from successful reproduction.
随着温度继续升高，人们认为蛋白质会变性，细胞膜会溶解，整个体系会陷入混乱和热力学的无序。
As temperatures keep rising, the belief was that proteins may be denaturing, membranes dissolving, and the whole thing a mess of chaos and thermodynamics.
没有什么能活下来。
Nothing could survive.
因此，接近沸点的温泉被认为必然是无菌的。
Hot springs near boiling temperatures were therefore assumed to be necessarily sterile.
布罗克并不相信这一点。
Brock didn't believe it.
他开始在黄石公园的温泉中寻找，结果证明他是对的。
He started looking through Yellowstone's hot springs, and he was right.
在一个叫章鱼泉的地方，他观察到粉红色的丝状细菌在88摄氏度的水中生长，这远高于当时认为的生命上限。
At a place called Octopus Spring, he observed pink, filamentous bacteria growing in water at 88 degrees Celsius, well above the supposed ceiling for life.
在接下来的几年里，他和一位名叫哈德森·弗里兹的本科生一起开发了分离和培养这些生物的技术，考虑到它们偏好的生存温度，这可不是件容易的事。
Over the next several years, he and an undergraduate student named Hudson Freeze worked out the technique to isolate and culture these organisms, no small task given their preferred resting temperature.
1969年，他们发表了一篇论文，成功描述了一种从黄石下间歇泉盆地的蘑菇泉中分离出的嗜热细菌。
And in 1969, they published a paper successfully characterizing a species of thermophilic bacteria they'd isolated from mushroom spring in Yellowstone's Lower Geyser Basin.
他们恰如其分地将其命名为Thermus aquaticus，拉丁语意为“热的”和“水的”。
They fittingly named it Thermus aquaticus, Latin for hot and of the water.
这就是他们的项目。
And that was their project.
两位科学家想知道，在接近沸腾的水里是否还有生命存在。
Two scientists asking whether anything was alive in nearly boiling water.
答案是有的。
The answer was yes.
他们发表了论文。
They published the paper.
然后继续前行。
They moved on.
现在我们把时间快进十五年。
Now we jump forward fifteen years.
1983年，一位名叫凯利·穆利斯的生物化学家在加州一家名为Cetus的生物技术公司工作。
In 1983, a biochemist named Carey Mullis was working at a biotech company in California called Cetus.
他当时在想如何在试管里复制DNA。
And he was thinking about how to copy DNA in a test tube.
他在开车去门多西托的路上灵光一现，这个想法非常巧妙。
The conceptual idea which he famously had on a drive up to Mendocito was beautiful.
把DNA双螺旋的两条链通过加热到接近沸腾来分开，实际上就是熔断让姐妹链保持在一起的氢键。
You separate the two strands of DNA double helix by heating it near boiling, effectively melting the hydrogen bonds that keep the sister strands together.
然后冷却溶液，当温度恢复正常时，短的特定DNA序列，也就是引物，会结合到你想要复制的区域。
You then cool the solution which allows short specific DNA sequences called primers to bind to the regions you want to copy as the temperature returns to normal.
接着，用聚合酶来延伸DNA，从结合到目标序列的引物开始，这样就在你感兴趣的区域内复制出了母链的副本。
Then, you have a polymerase enzyme extend the DNA which will start at those primers bound to their target sequence, thus creating copies of the parent strand in your region of interest.
现在，从一条双链DNA母链开始，你得到了你选择的DNA序列的两条双链副本。
You now have two copies of double stranded DNA sequence of your choosing, having started with a single double stranded parent.
然后重复这个过程。
And then you repeat the process.
每个循环都会让DNA数量翻倍。
Each cycle doubles your DNA.
经过30个循环，你就能把一个分子变成十亿个副本。
After 30 cycles, you have turned one molecule into a billion copies.
这项技术叫做聚合酶链式反应，也就是PCR。
This technique is known as polymerase chain reaction or PCR.
但这里有一个问题。
But there was just one problem.
当时人们使用的DNA聚合酶来自大肠杆菌。
The DNA polymerases people used at the time were derived from E.
而且它们一加热就会分解。
Coli and they fell apart when you heated them.
所以，每当PCR循环需要在接近沸腾的温度下使DNA变性时，聚合酶无法在过程中存活，这意味着每个循环都必须手动添加新的酶。
So when every cycle of PCR required denaturing the DNA at near boiling temperatures, the polymerases could not survive the process, which meant you had to add fresh enzyme manually at every cycle.
虽然这个方法有效，但既繁琐又昂贵，还容易出错，基本上无法大规模实际应用。
It worked, but it was tedious, expensive, error prone, and basically not practical at any meaningful scale.
CTAS的科学家们著名地开发了一个机器人，在热循环仪中每轮PCR后自动添加新的聚合酶，他们称之为“循环先生”。
The scientists at CTAS famously developed a robot to add fresh polymerase after each round of PCR in its thermocycler, dubbed Mr.
循环先生。
Cycle.
但这仍然远未达到高通量、高保真、经济高效的DNA扩增方法。
But this was still nowhere near a high throughput, high fidelity, cost effective means for amplifying DNA.
CTAS团队需要一种聚合酶，能够反复承受95摄氏度的高温而不分解。
The team at CTAS needed a polymerase that could survive being heated to 95 degrees Celsius over and over without falling apart.
他们需要一种能在接近沸水温度下存活的酶。
They needed an enzyme that could survive in near boiling water.
他们转向了水生栖热菌。
They turned to Thermus aquaticus.
聚合酶对于生命的延续是根本必需的。
Polymerase is fundamentally necessary for life to continue.
每个生物体都必须具备复制自身DNA的能力，以便将DNA传递给新细胞或新世代。
Every organism necessarily requires a means of copying their own DNA in order to pass that DNA onto new cells or new generations.
水生栖热菌显然能在至少88摄氏度的温度下完成这一过程。
Thermus aquaticus could apparently do this at temperatures of at least 88 degrees Celsius.
在20世纪70年代中期，水生栖热菌聚合酶，通常称为Taq聚合酶，已经被分离并部分表征，部分原因是该物种在布洛克的工作后被保存在公共培养物收藏中。
In the mid-1970s, the Thermus aquaticus polymerase, commonly referred to as TAQ or Taq polymerase, had been isolated and partially characterized, in part because the species had been deposited in public culture collections after Brock's work.
CETIS团队在此基础上，在实验室中纯化了Taq聚合酶，并将其整合到他们的PCR方案中。
The CETIS team built on this, purified Taq polymerase in their lab, and plugged it into their PCR protocols.
这样一来，整个技术以及所有生物科学都发生了翻天覆地的变化。
With this, the entire technique and all of biological sciences transformed.
现在，你可以把反应体系装好，设定好热循环仪，然后走开，回来时就能得到你序列的十亿份拷贝。
Now, you could load the reaction, set the thermocycler, walk away, and come back to a billion copies of your sequence.
我们几乎可以无限量地获得任何我们想要的DNA序列，来自任何物种，只需在循环加热模块上孵育几个小时就能准备好。
We had a near endless supply of any DNA sequence we desired, from any species we desired, ready to go after a few hours of incubation on a cycling heating block.
穆利斯因发明PCR在1993年获得了诺贝尔化学奖，这是实至名归的。
Mullis won the Nobel Prize in chemistry in 1993 for inventing PCR, and deservedly so.
但这之所以成为可能，是因为布罗克和弗里斯在几十年前就曾问过，极端温度下是否有生命存在。
But it was only possible because Brock and Fries had asked, decades earlier, whether anything lived in extreme temperatures.
他们在88摄氏度的温泉中发现了生命。
They found life in an 88 degrees Celsius hot spring.
他们找到了收集和培养这些物种的方法，并将这些物种分享给了世界各地的科学家，供他们自行观察、研究和利用。
They found a way to collect and culture those species, and they shared that species with scientists everywhere to see, study, and utilize on their own.
我想让大家思考一下，这带来了怎样的影响。
And I want us to think about what that unleashed.
PCR不是一种药物。
PCR is not a drug.
PCR比药物更基础。
PCR is something more fundamental than a drug.
PCR是现代分子生物学几乎所有领域的基石技术。
PCR is the enabling technology for essentially all of modern molecular biology.
抱歉，这个列表有点长。
I'm sorry, this list is long.
长到足以说明问题，但还远远不够详尽。
It's long enough to make the point, but it's not long enough to be nearly exhaustive.
DNA是所有生命的编码，而PCR是我们与这个编码互动的工具。
DNA is the code upon which all of life is programmed, and PCR is the tool we use to interact with that code.
PCR无处不在。
PCR is everywhere.
它是基因检测、法医DNA分析、癌症突变筛查、产前筛查、疫苗开发、祖源检测、转基因实验动物、GFP等荧光标记、重组治疗性蛋白的克隆、整个基因组学领域、所有基因疗法的开发以及病毒感染检测的基础。
It's the basis of genetic testing, forensic DNA analysis, cancer mutation panels, prenatal screening, vaccine development, ancestry testing, transgenic lab animals, fluorescent reporters like GFP, the cloning of any recombinant therapeutic protein, the entire field of genomics, the development of every gene therapy, and viral infection testing.
所有这些都依赖于PCR。
All of it depends on PCR.
所以，这些都依赖于Taq聚合酶。
So, of it depends on Taq polymerase.
而这一切都追溯到一位微生物学家，他在思考热水中是否可能有生命存在。
And all of it traces back to a microbiologist wondering whether anything could live in hot water.
没有那篇1969年的论文，现代生物学根本不可能像今天这样存在。
Without that 1969 paper, modern biology as it exists today simply could not exist.
如果没有人在某个地方去沸水中寻找生命，我们就不可能达到现在的水平，这是无法想象的。
There's no plausible alternative history in which we get to where we are without somebody somewhere going to look in the boiling water for life.
我们很幸运，那个人是汤姆·布洛克。
We just got lucky that that somebody was Tom Brock.
也许更幸运的是，他提前做了这件事，没有人问他打算治愈什么疾病。
And perhaps we got especially lucky that he got to do it in advance without anybody asking what disease he was trying to cure.
然而，这一发现如此基础，与现代生物学和医学紧密相连，以至于很难想象在过去三十年里，没有他的工作，任何疾病能被治愈。
And yet, the discovery is so fundamental, so irrevocably intertwined with modern biology and medicine, that it's hard to imagine how any disease at all could have been cured in the last thirty years without his work.
他的好奇心驱使他去黄石温泉寻找微生物生命的迹象。
His curiosity leading him to search for signs of microbial life inside of Yellowstone Hot Springs.
接下来的这个故事，在我看来，特别生动地说明了这个道理，因为它的影响直到最近才被理解，我们其实正亲眼看着这段历史在眼前展开。
This next story is, to me, a particularly exciting illustration of the principle because its ramifications were understood so recently that we are really in the midst of watching the timeline play out.
故事始于1980年代末，在西班牙地中海沿岸阿利坎特附近的一个小镇圣保拉。
The story begins in the late 1980s in the small Spanish coastal town of Santa Paula near Alicante on the Mediterranean.
圣保拉以盐田闻名，那里有大片浅浅的蒸发池，海水在其中浓缩，形成盐度极高的水池。
Santa Paula is famous for its salt flats, vast shallow evaporative ponds where seawater concentrates, creating dramatically saline pools of water.
这些盐池支持着一个奇特的生物群落，即耐盐甚至需要盐分的微生物，称为嗜盐菌，其中许多是古菌，它们适应了在几乎能杀死其他一切生物的盐度下茁壮生长。
These salt ponds support a strange community of organisms, salt tolerant or even salt requiring microbes called halophiles, many of them archaea that have adapted to thrive at salinity levels that would kill virtually anything else.
一位名叫弗朗西斯科·莫希卡的年轻西班牙微生物学家，在阿利坎特大学攻读博士学位，研究对象就是这些古菌中的一种——地中海盐盒菌。
A young Spanish microbiologist named Francisco Mojica was doing his PhD on one of these archaea's, Holophyrex mediterinae, at the University of Alicante.
实际上，他最初的研究课题几乎完全是另一回事。
His original project, in fact, was almost a different project entirely.
他当时研究的是这种生物如何应对盐度的变化。
He was studying how this organism responds to changes in salinity.
但有人抢先一步，先发表了。
But someone beat him to the punch and published it first.
所以在这个过程中，他不断碰到其基因组的一个奇怪特征。
So along the way, he kept stumbling over a weird feature of its genome.
那里有一簇簇短的、规律间隔的回文重复序列，大约30个碱基对的序列反复出现，中间被长度一致的非重复间隔序列隔开。
There were these clusters of short, regularly spaced palindromic repeats, sequences of about 30 base pairs that repeated over and over, separated by unique non repeating spacer sequences of regular length.
顺便说一下，对于那些可能不熟悉回文的人来说，回文就是从左往右读和从右往左读都一样的东西。
Just parenthetically, for those of you who might not be familiar with a palindrome, a palindrome is something that when read left to right and right to left is the same.
所以“race car”这个词就是回文，因为不管你怎么读，它都是一样的。
So the word race car is a palindrome because regardless of which way you read it, it's the same way.
当然，我最喜欢的回文，是我最近从我们的一位研究分析师那里学到的，就是“Go hang a salami”这句话。
And of course, my favorite palindrome, which I just learned of recently from one of our research analysts, is the phrase, Go hang a salami.
我是个意大利香肠吃货。
I'm a lasagna hog.
我建议你自己验证一下，这确实是个回文。
I encourage you to prove to yourself that that is indeed a palindrome.
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总之，这些序列在基因组里到处都是，但他不知道它们是什么。
Anyway, these were everywhere in the genome, but he didn't know what they were.
事实上，没人知道它们是什么。
In fact, nobody knew what they were.
他并不是第一个看到这些序列的人。
He wasn't the first to see them exactly.
一个由石野良纯领导的日本团队曾在E. coli中注意到类似的重复模式。
A Japanese group led by Yoshizumi Ishino had noted similar repeating patterns in E.
那是在1987年，但只是作为他们论文讨论部分的一个脚注被提及。
Coli in 1987, left as effectively a footnote in the discussion section of their paper.
莫希卡是第一个明确把它们当作研究对象的人。
Mojica was the first to identify them explicitly as a feature to investigate.
这些序列的功能完全是个谜，大多数分子生物学家遇到它们时只是耸耸肩，然后继续做自己的事。
The function was a complete mystery, and most molecular biologists who came across these sequences shrugged and moved on.
但莫希卡没有就此罢休。
Mojica didn't move on.
他花了将近十年的时间，整个九十年代一直到二十一世纪初，都在试图弄清楚这些重复序列到底在做什么。
He spent the better part of a decade, the entire 1990s and into the early 2000s, trying to figure out what these repeats were doing.
突破出现在2003年。
The breakthrough came in 2003.
那时候，基因组学革命正如火如荼，公共数据库里已经有足够多的已测序基因组，莫希卡可以做一些以前做不到的事情。
By that point, the genomics revolution was in full swing, and there were enough sequenced genomes in the public databases that Mojica could do something he couldn't do before.
他可以取出那些独特的间隔序列，也就是重复序列之间的部分，然后去问测序数据库：你们以前见过这个序列吗？
He could take the unique spacer sequences, the bits between the repeats, and ask the sequencing database, Have you seen this sequence before?
他把序列提交到美国国立卫生研究院的BLAST数据库，结果回来了：见过。
He sent it through the NIH database known as BLAST, and the answer came back, yes.
其中一些间隔序列与噬菌体的DNA完全匹配，噬菌体就是感染细菌和古菌的病毒。
Some of those spacer sequences exactly matched DNA from bacteriophages, viruses that infect bacteria and archaea.
这就是关键所在。
That was the key.
莫希卡意识到，这些重复序列并不是随机的垃圾。
Mojica realized that the repeats weren't random junk.
它们是一种记录。
They were a record.
每个间隔序列都是一段DNA，是生物体从过去的噬菌体感染中捕获的。
Each spacer was a snippet of DNA that the organism had captured from a past bacteriophage infection.
重复序列的簇就是索引。
The clusters of repeats were the index.
重复序列之间是过去感染记忆的编码。
Between the repeats were the codes for memories of past infections.
这看起来像是一个免疫系统，具体来说是适应性免疫系统。
This looked like an immune system, specifically an adaptive immune system.
细菌或古菌实际上是在给自己接种疫苗，通过保留噬菌体基因组的片段，并利用这些信息在未来的遭遇中识别并摧毁它们。
The bacterium, or archaean, was in effect vaccinating itself against viruses by holding onto fragments of the phage's genomes and using that information to recognize and destroy them on future encounters.
这是一个惊人的发现。
This was a stunning insight.
这意味着细菌和古菌，生物学中最简单的生物，拥有一个具有记忆的复杂适应性免疫系统。
It implied that bacteria and archaea, the simplest organisms in biology, had a sophisticated adaptive immune system with memory.
我们现在把这个系统叫做CRISPR，也就是成簇规律间隔短回文重复序列。
We now call that system CRISPR, clustered regularly interspaced short palindromic repeats.
而附近的那些蛋白质就被称为Cas，是CRISPR相关蛋白的缩写。
And the nearby proteins were deemed Cas, short for CRISPR associated.
莫希卡把论文写了出来。
Mojica wrote up the paper.
他在2003年把它投给了《自然》杂志。
He submitted it to Nature in 2003.
结果连外审都没送就被拒了。
It was rejected without external review.
他又投给了《美国国家科学院院刊》。
He sent that to the proceedings of the National Academy of Science.
还是被拒，理由是缺乏新颖性和重要性。
Rejected, lacking novelty and importance.
他又投给了《分子微生物学》杂志。
He sent it to molecular microbiology.
被拒了。
Rejected.
《核酸研究》也拒了。
Nucleic acids research.
又被拒了。
Rejected.
他越来越绝望，还担心别人抢先发表，最后投给了一个较小的期刊《分子进化杂志》，经过十二个月的审稿和修改，终于在2005年2月发表了。
Increasingly desperate and now afraid he was going to be scooped, he eventually submitted it to a smaller journal called the Journal of Molecular Evolution, which after twelve months of review and revision, finally published it in February 2005.
这里我们又看到，革命性的科学不仅仅是资金不足的问题。
This is another place where we see that revolutionary science isn't simply underfunded.
即使革命性的发现被看到并记录下来，领域内的人仍然可能看不出它的意义。
Once the revolutionary insight is seen and documented, even then the field can still miss what it's looking at.
细菌拥有适应性免疫系统这一发现，可以说是过去五十年分子生物学最重要的发现之一，却被该领域四大顶级期刊拒之门外。
The discovery that bacteria have an adaptive immune system, arguably one of the most important findings in molecular biology over the past fifty years, was rejected by four of the top journals in the field.
审稿人和编辑都没有看出他们眼前发现的重要性。
The reviewers and editors did not see the significance of what they were looking at.
莫希卡当时在研究盐池古菌。
Mojica was studying salt pond archaea.
他是一位西班牙微生物学家，实验室规模不大，他的发现听起来像是冷门的微生物学内容。
He was a Spanish microbiologist with a small lab and his findings sounded like esoteric microbial biology.
最终是一个不太知名的期刊发表了这篇论文，现在看来，这绝对是一篇里程碑式的文章。
It took a lesser journal to publish what is, in retrospect, an absolute landmark paper.
从那以后，时间线就变得很短了。
From there, the timeline is short.
世界各地的实验室开始跟进，或者自己发现了其他相关特征。
Labs around the world began to catch on or discover other features on their own.
丹尼斯克，对，就是那家酸奶公司，提供了直接实验证据，证明CRISPR确实在细菌中作为适应性免疫系统起作用。
Danisco, yeah, the yogurt company, provided direct experimental evidence that CRISPR really does work as an adaptive immune system in bacteria.
细菌是乳制品发酵所必需的。
Bacteria are necessary for dairy fermentation.
细菌容易受到噬菌体感染的爆发。
Bacteria are susceptible to outbreaks of phage infections.
这对工业乳制品来说是个巨大的实际问题。
This is an enormous practical problem for industrial dairy.
丹尼斯克2007年发表在《科学》杂志上的论文验证了莫希卡的假说，并确认了Cas9是识别CRISPR编码序列、切割并摧毁噬菌体DNA的蛋白质。
Danisco's 2007 paper in the journal Science validated Mojica's hypothesis and identified Cas9 as the protein that recognizes CRISPR encoded sequences to cut and destroy bacteriophage DNA.
2012年，詹妮弗·杜德纳和埃马纽埃尔·沙尔庞捷，以及差不多同一时间，由我们之前播客采访过的冯峥领导的博德研究所和麻省理工学院的一个团队，展示了你可以利用这种细菌免疫系统，用定制的引导RNA进行编程，然后在任何基因组的任何特定位置进行DNA切割。
In 2012, Jennifer Doudna and Emmanuelle Charpoutier, and around the same time, a group at the Broad Institute and MIT led by Feng Zheng, who we've previously had on the podcast, showed that you could take this bacterial immune system, program it with a custom guide RNA, and use it to cut DNA at any specific location in any genome you wanted.
在细菌中，切割的目的是破坏噬菌体的繁殖能力。
In bacteria, the goal of the cut was to destroy the phage's ability to reproduce.
杜德纳和沙尔庞捷展示了你可以同时提供一个新的DNA模板与CRISPR系统一起使用，这样不是破坏基因组，而是将新DNA整合到切割位点。
Doudna and Charpoutier showed that you could instead provide a new template of DNA alongside the CRISPR system, and instead of destroying the genome, you could incorporate new DNA into the cut site.
你可以修改活生物体基因组中的基因。
You could modify genes within the genome of a living organism.
杜德纳和沙尔庞捷因此获得了2020年诺贝尔化学奖。
Doudna and Charpoutier won the 2020 Nobel Prize in Chemistry for this.
这里的影响是巨大的。
The implications here are enormous.
大多数基因治疗试验都已经被叫停了。
Most gene therapy trials have been discontinued.
它们通常的目标是给患有遗传疾病的人添加一个新基因。
Their typical goal was to add a new gene to people with genetic disorders.
这些额外的基因不一定能长期存在，所以持久性可能是个问题。
These extra genes don't always stick around for long, so durability could be a concern.
而且如果基因本身是有毒的，就像亨廷顿病那样不只是功能丧失，正常版本的疗效可能会受到宿主自身致病基因竞争的制约。
And if the gene itself was toxic, not just losing function like in Huntington's disease, the normal variant's efficacy could be limited by the competition with the host's own pathological gene.
我们以前没有办法真正修改导致疾病的基因变异。
We had no way to actually modify the gene variant that led to a disease.
但现在我们可以了。
But now we do.
2023年12月，FDA批准了Cascovy，这是首个进入临床的CRISPR疗法。
And in December 2023, the FDA approved Cascovy, the first CRISPR based therapy ever brought to clinic.
它是用来治疗镰状细胞病的。
It's the treatment for sickle cell disease.
镰状细胞病，直到最近，还是一种治疗选择有限、寿命缩短的疾病。
Sickle cell disease, until very recently, was a disease with limited options and shortened lifespans.
CRISPR疗法并不是简单意义上的治愈。
CRISPR therapy isn't a cure in the simple sense.
它复杂、昂贵，而且需要骨髓预处理。
It's complex, expensive, and requires bone marrow conditioning.
但对于能够接受治疗的患者来说，效果非常显著。
But for the patients who can access it, the results are extraordinary.
曾经定义他们生活的血管闭塞性危机基本上停止了。
The vaso occlusive crisis that defined their lives essentially stop.
从西班牙盐池古菌中一个奇怪的DNA模式，到一种能持久治疗镰状细胞病的疗法。
From a strange DNA pattern in a Spanish salt pond archaea to a therapy that durably treats sickle cell disease.
而且最近，一项1b期试验公布了一项非常有前景的结果，针对家族性高胆固醇血症的CRISPR衍生治疗。
And even recently, a phase 1b trial posted incredibly promising results for a CRISPR derived treatment of familial hypercholesterolemia.
自盐池发现以来三十年，CRISPR正在治愈疾病。
Thirty years since the salt ponds, CRISPR is curing diseases.
再说，看看整个事情的来龙去脉。
And again, look at the structure of what happened.
弗朗西斯科·莫希卡并不是为了治愈镰状细胞病才开始研究的。
Francisco Mojica did not set out to cure sickle cell disease.
他最初是想搞清楚，一种不起眼的嗜盐古菌的基因组里，为什么会有重复的序列。
He set out to understand why the genome of an obscure salt loving archaeon had repeated sequences in it.
结果他发现的那个系统，竟然成了一种功能强大到惊人的可编程分子工具。
The system he uncovered turned out to be a programmable molecular tool of staggering power.
我们人类，作为创造技术的物种，其实并没有发明CRISPR。
We humans, the species that builds the technologies, didn't invent CRISPR.
CRISPR是细菌在大概三十亿年前发明的，用来防御那些在生命诞生后不久就开始攻击它们的病毒。
Bacteria invented CRISPR somewhere around three billion years ago as a defense against viruses that have been trying to exploit them since shortly after life began.
莫希卡只是注意到了这一点。
Mohica just noticed it.
我们并不是为了寻找编辑基因组的工具才去研究的。
We didn't go looking for a tool to edit the genome.
我们是在盐滩上闲逛时发现它的。
We found it when wandering through salt flats.
我想讲的最后一个故事，可能是与疾病负担关系最大的一个。
The last story I want to tell is perhaps the most relevant story in terms of disease burden.
它比之前的一些例子少了一些基础探索的色彩，但也是最直接相关的。
It's a little less basic exploration than some of our previous examples, but it's also the most tangibly relevant.
这个播客的每一位听众，甚至可以说现在每个说英语的人，都知道这些药，但很少有人知道它们是怎么来的。
Every listener to this podcast, hell, probably every person in the English speaking world at this point knows these drugs, but very few may know where they came from.
在1980年代末，一位名叫约翰·吴的临床内分泌科医生在纽约布朗克斯退伍军人医疗中心工作。
In the late 1980s, a clinical endocrinologist named John Ng was working at the Bronx VA Medical Center in New York.
他是一位亲力亲为的初级保健内分泌科医生，大部分时间都在照顾患有糖尿病的退伍军人。
He was a hands on primary care endocrinologist who spent most of his time taking care of veterans with diabetes.
但他还有一个副业。
But he had a side project.
他在诺贝尔奖得主、物理学家和生物化学家罗斯林·亚洛的实验室里做实验，亚洛几十年前发明了放射免疫测定技术。
He worked on the bench in the laboratory of Roslyn Yallo, the Nobel Prize winning physicist and biochemist who, decades earlier, had invented the radioimmunoassay technique.
黄石实验室开发出了特别灵敏的方法，用来检测和识别肽类激素。
Yellowstone lab had developed unusually sensitive methods for detecting and characterizing peptide hormones.
作为一名治疗糖尿病患者的内分泌科医生，Eng想用这些工具来寻找影响胰腺的新型肽类物质。
And as an endocrinologist working with diabetic patients, Eng wanted to use the tools to hunt for novel peptides that affected the pancreas.
他在文献里读到了一些有意思的东西。
He'd read something interesting in the literature.
美国国立卫生研究院的研究人员报告说，某些有毒爬行动物的咬伤——特别是希拉毒蜥，一种生活在美洲西南部沙漠里的、体型粗壮、行动缓慢、皮肤带珠状鳞片的蜥蜴——会导致被咬动物出现严重的胰腺炎症和肿大。
Researchers at NIH had reported that the bite of certain venomous reptiles, including notably the Gila monster, a stocky, slow moving, beaded skinned lizard native to the deserts of the American Southwest caused dramatic inflammation and enlargement of the pancreas in bitten animals.
毒液里的某种成分对胰腺影响很大。
Something in the venom was hitting the pancreas hard.
为什么一种沙漠蜥蜴的毒液会专门针对胰腺呢？
Why would a desert lizard have a venom that targets the pancreas?
Ng不知道答案，但他觉得值得研究一下。
Ng didn t know, but he thought it was worth investigating.
希拉毒蜥还有一个生物学上有趣的特点：它很少进食，有时一年只吃三四顿。
The Gila monster also had another biologically interesting property: it eats very rarely, sometimes only three or four meals a year.
然而，在进食之间，它似乎能在长时间禁食中保持非常稳定的血糖水平。
And yet, between meals, it appears to maintain remarkably stable blood glucose levels through long stretches of fasting.
不管这只蜥蜴的胰腺在做什么，它运作的方式和我们不一样。
Whatever the lizard's pancreas was doing, it was doing it differently from ours.
于是，昂订购了一些干燥的吉拉毒蜥毒液，开始用他从耶洛实验室继承的检测方法来分析这些毒液。
So, Eng ordered some dried Gila monster venom and started running it through the assays he's inherited from Yellow's lab.
他和同事让-皮埃尔·罗斯曼一起合作，罗斯曼开着他的丰田凯美瑞在布鲁克林和布朗克斯之间来回运送样本。昂系统地分离了毒液中的肽类成分。
Working with his colleague, Jean Pierre Rothman, who would shuttle samples back and forth from Brooklyn to The Bronx in his Toyota Camry, Eng systematically separated the peptide components of the venom.
他发现了两种肽。
He found two peptides.
其中一种之前已经被描述过。
One had been described before.
第二种是全新的。
The second was new.
1993年发表时，他将其命名为艾塞那肽-4。
Published in 1993, he named it Excendin-four.
当他测序艾塞那肽-4时，结果非常惊人。
When he sequenced Excendin-four, the result was remarkable.
这种肽与一种叫做GLP-1的人类激素，即胰高血糖素样肽-1，有大约53%的氨基酸序列相似性。GLP-1是一种肠道激素，在进食后刺激胰岛素分泌。
The peptide showed about 53% amino acid sequence similarity to a human hormone called GLP-one, glucagon like peptide-one, a gut hormone produced in the intestine that stimulates insulin secretion in response to a meal.
奇怪的是，这种蜥蜴的毒液肽在被咬的哺乳动物体内，激活的受体竟然和我们自己进食后刺激胰岛素分泌的激素所激活的受体相同。
Oddly, the lizard had a venom peptide that activated in a mammal that it had bitten the same receptor as our own meal induced insulin stimulating hormone.
这就解释了胰腺发炎的原因。
That explained the pancreatic inflammation.
咬一口就像用锤子猛击GLP-1受体一样。
The bite was hitting GLP-one receptors like a hammer.
艾塞那肽-4有一个GLP-1没有的关键特性。
Excedin-four had a key property that GLP-one does not.
天然的GLP-1在血液中的半衰期大约只有两分钟。
Native GLP-one has a half life in the bloodstream of about two minutes.
一种叫做DPP-4的酶几乎在肠道产生它的同时就把它分解掉了。
An enzyme called DPP-four chews it up almost as fast as the gut makes it.
这其实对GLP-1的正常功能来说没问题，但作为药物，这种天然激素就没法用了。
That's actually fine for what GLP-one normally does, But it makes the native hormone useless as a drug.
你得不停地给它输液才行。
You'd have to be infusing it in constantly.
相比之下，Exendin-4对DPP-4有抵抗力。
Excedin-four, by contrast, is resistant to DPP-four.
它的半衰期是几小时，而不是几分钟。
Its half life is on the order of hours, not minutes.
它作用于GLP-1受体，持久性比GLP-1本身要强。
It acts on the GLP-one receptor with a durability that GLP-one itself lacks.
Eng在沙漠蜥蜴的唾液里发现了一种长效GLP-1受体激动剂，可以直接使用。
Eng had found a long acting GLP-one receptor agonist sitting in the saliva of a desert lizard ready to use.
Eng试图让退伍军人事务部为这一发现申请专利。
Eng tried to get the VA to patent the discovery.
但退伍军人事务部拒绝了。
The VA declined.
最后他自己申请了专利，授权给了一家小型生物技术公司，后来这些权利辗转到了礼来和Amylin手里。
Eventually patented it himself, licensed it to a small biotech and the rights eventually made their way to Eli Lilly and Amylin.
2005年，美国食品药品监督管理局批准了合成的Exenin-four，商品名为Byetta，通用名为Exenatide，用于治疗2型糖尿病。
In 2005, the FDA approved synthetic Exenin-four under the trade name Byetta, generic name Exenatide, for the treatment of type two diabetes.
这是首个推向市场的GLP-1受体激动剂。
It was the first GLP-one receptor agonist ever brought to market.
然后，闸门就打开了。
And then the floodgates opened.
Excedin-four是一种外来的“海拉”怪物肽，所以很多患者对这种疗法产生了免疫反应。
Excedin-four was a foreign HeLa monster peptide, so many patients developed immune responses to the therapy.
这种疗法需要每天注射两次，并且要精心安排在用餐时间附近，还伴有肾脏负担和恶心等副作用。
The therapy required twice daily injections, provided carefully around meal windows, and included side effects like kidney strain and nausea.
不过，对于能耐受的患者来说，它确实有效。
That said, in patients who tolerated it, it worked.
诺和诺德、礼来等公司意识到，这不仅仅是一个改善糖尿病血糖控制的生物杠杆，更是一个减肥的非凡工具。
Novo Nordisk, Lilly, and others realized that this was an enormous biological lever, not just a way to improve glycemic control in diabetes, but as it turned out, extraordinary tool for weight loss.
我们之前详细聊过，GLP-1信号还能抑制食欲、减缓胃排空，并改变大脑对食物奖励信号的评估方式。
As we've talked about at length, GLP-one signaling also suppresses appetite, slows gastric emptying, and changes how the brain weighs reward signals around food.
后来的药物并不是直接的艾塞那肽类似物，而是对天然人GLP-1序列进行改造，以降低免疫原性、延长半衰期，有些还增加了GLP-1之外的其他靶点。
Subsequent drugs were not direct extendin-four analogs, but modifications of the native human GLP-one sequence engineered to reduce immunogenicity, increase half life, and in some cases, add alternative targets in addition to GLP-one.
现在我们有利拉鲁肽、司美格鲁肽，还有替尔泊肽，后者在GLP-1的基础上还增加了GIP激动作用。
We now have liraglutide and semaglutide along with tirzepatide, which adds GIP agonism in addition to GLP-one.
这些药物我们已经聊了很多，随着科学的发展，我们还会继续讨论。
We've talked about these drugs at length, and we'll continue to talk about them as the science develops.
可以说，这些药物正在实时重塑医学。
Suffice it to say, these drugs are reshaping medicine in real time.
它们正在改变2型糖尿病和肥胖症的治疗方式。
They're reshaping the treatment of type two diabetes, and they're reshaping the treatment of obesity.
心血管结局数据让我们重新思考代谢疾病作为动脉粥样硬化风险驱动因素的作用，目前还有针对心力衰竭、肾病、睡眠呼吸暂停、酒精使用障碍、更广泛的成瘾问题，甚至可能包括阿尔茨海默病的临床试验正在进行中。
The cardiovascular outcome data is changing how we think about metabolic disease as a driver of atherosclerotic risk, and there are ongoing trials in heart failure, kidney disease, sleep apnea, alcohol use disorder, addiction more broadly, and possibly Alzheimer's disease.
我们还不清楚适应症范围最终会有多广。
We don't yet know how broad the indication space will turn out to be.
我们知道这是过去五十年里最重要的药物类别之一。
We do know that this is one of the most consequential drug classes of the last fifty years.
而它的直接起源是一位布朗克斯退伍军人医院的临床医生，他想知道研究沙漠蜥蜴的咬伤如何导致胰腺炎症，能从中了解内分泌学的什么。
And the proximate origin was a clinician at a Bronx VA hospital wondering what he might learn about endocrinology by studying how a desert lizard's bite caused pancreatic inflammation.
我觉得这些故事本身就非常有趣，也许我只是对研究特别着迷。
Now, these stories are, I think, incredibly interesting in their own right, and maybe I'm just a sucker for research.
在我看来，每一个都是科学过程的精彩例证。
They are each, in my opinion, fascinating illustrations of the scientific process.
但我也想把这个话题拉回到更大的论点上来，因为我觉得这一点很重要。
But I also want to bring this back to the larger argument because I think that point matters.
我们来看看刚才讲的内容。
Let's look at what we just walked through.
现代细胞生物学依赖一种来自水母的蛋白质。
Modern cell biology runs on a protein from a jellyfish.
他汀类药物来自一种长在米上的真菌。
Statins come from a fungus growing on rice.
ACE抑制剂这类药物来自一种蛇，它的毒液通过降低血压来致命。
The ACE inhibitor class came from a snake whose venom kills by dropping blood pressure.
PCR技术，以及由此衍生出的几乎所有现代分子生物学，都来自黄石公园温泉中的一种微生物。
PCR, and by extension, essentially all modern molecular biology, came from a microbe in a Yellowstone hot spring.
CRISPR，现代基因编辑的基础，来自一个盐池生物的基因组，而GLP-1类药物则来自一种除了冷知识外几乎不为人知的沙漠蜥蜴。
CRISPR, the foundation of modern gene editing, came from the genome of a salt pond organism, and the GLP-one class of drugs came from a desert lizard that's hardly known outside of trivia.
除了他汀类药物，最初的科学家并不是为了治疗疾病。
With the exception of statins, the original scientist was not trying to cure a disease.
下村脩并不是为了革新细胞生物学。
Shimomura wasn't trying to revolutionize cell biology.
费雷拉是在研究蛇毒中的蛋白质。
Ferreira was studying proteins in snake venom.
布罗克是在研究温泉中的生命。
Brock was studying life in hot springs.
莫希卡是在研究盐池。
Mojica was studying salt ponds.
Eng对胰腺功能感到好奇。
Eng was curious about pancreatic function.
如果你把这些项目中的任何一个放在它开始的那一年，放在一个转化影响评审小组面前，一个会问这个能治什么病、什么时候能治好的小组，其中很多项目可能都很难获得资助。
If you had taken any one of these projects in the year it started and put it in front of a translational impact review panel, a panel that asks what disease will this cure and on what timeline, many of them would have struggled to get funded.
有些几乎肯定会直接失败。
Some almost certainly would have failed outright.
“我想研究水母为什么会发光”在这种框架下并不是一个值得资助的提议。
I want to study how a jellyfish glows is not a fundable proposal in that framework.
事实上，克隆了GFP基因的道格拉斯·普拉舍尔，无法让NIH继续资助他的研究。
In fact, Douglas Prasher, who cloned the GFP gene, could not get NIH to fund him to continue.
这个体系正是以我描述的方式失败了。
The system failed in exactly the way I'm describing.
然而，总的来说，这些看似无关紧要、由好奇心驱动的“自然界到底发生了什么”类型的科学研究，共同产生了基础性的工具和疗法，如今正在改善或挽救着保守估计数亿人的生命。
And yet collectively, this body of work, this catalog of seemingly irrelevant curiosity driven, what is going on in nature type of science produces foundational tools and therapies that are now improving or saving the lives of conservatively hundreds of millions of people.
现代医学中几乎没有什么操作，在其供应链的某个环节，不依赖于我刚才描述的至少一项发现。
There's almost nothing you can do in modern medicine that doesn't, at some step in its supply chain, depend on at least one of the discoveries I just described.
我觉得我们在预测哪些好奇心驱动的研究会有用这方面，系统性地做得不好，但我不确定是否真的有办法让我们系统性地擅长这件事。
I think we are systematically bad at predicting which curiosity driven work is going to matter, but I'm not convinced there is actually a way to become systematically good at it.
我觉得这是关于科学进步实际如何发生的最重要、最被低估的事实之一。
I think this is just one of the most important and most underappreciated facts about how scientific progress actually happens.
而且我认为这对我们如何看待科学资助、科学政策，以及把研究框定为需要以接近治愈来证明自身价值的文化，都有实际的影响。
And I think it has real consequences for how we should think about science funding, science policy, and the cultural framing of research as something that needs to justify itself by proximity to a cure.
不过，这里我得小心一点。
Now, want to be careful here.
我不是说所有基础科学都是好的，也不是说我们应该资助每一份递交上来的资助申请，不管它质量如何。
I am not arguing that all basic science is good or that we should fund every grant proposal that comes through the door regardless of merit.
这里显然有幸存者偏差的成分。
There is an obvious element of survivorship bias here.
我们今天讨论的基础科学，是今天值得讨论的基础科学。
The basic science that we are talking about today is the basic science that is worth talking about today.
今天几乎没有一个好奇心驱动的项目会变成GFP或CRISPR。
Almost none of today's curiosity driven projects will become GFP or CRISPR.
但这正是关键所在。
But that's actually the point.
教训不是说每个探索性项目都会带来变革。
The lesson is not that every exploratory project will become transformative.
教训是我们很难提前预测哪些项目会带来变革。
The lesson is that we are extraordinarily bad at predicting ahead of time which ones will.
确实存在糟糕的基础科学。
There is bad basic science.
也有无趣的基础科学。
There is uninteresting basic science.
还有严谨、负责任的同行评审，我们绝对应该保留。
And there is rigorous, accountable peer review that we should absolutely preserve.
我要说的是更具体的一点：以近期转化影响为标准的评判，即要求每个项目回答“这能治愈什么疾病”的标准，并不总是适用的筛选标准。
What I'm arguing is something more specific, that the criterion of near term translational obvious impact, the criterion that asks of every project what disease will this cure is not always the right filter to apply.
一旦退一步看，这似乎显而易见。
It seems obvious once you take a step back.
大自然做实验的时间比我们长得多。
Nature has been doing experiments for longer than we have.
大约四十亿年，差不多吧。
Four billion years, give or take.
我们在医学上要解决的每一个问题：胆固醇调节、血压调节、葡萄糖代谢、免疫记忆、修复受损DNA、应对极端压力。
Every problem we're trying to solve in medicine: cholesterol regulation, blood pressure regulation, glucose metabolism, immune memory, repairing damaged DNA, surviving extreme stress.
这些问题中的每一个，在进化史上，都有某种生物以某种形式遇到过，要么是利用这些通路，比如蛇毒，要么是为了在极端环境中生存下来。
Every single one of these problems has been encountered in some form by some organism at some point in evolutionary history, either to exploit these pathways in the case of things like snake venoms or to survive them in the case of extreme environments.
在很多情况下，经过数百万年或数十亿年的进化，大自然已经形成了合理的解决方案。
And in many cases, through millions or billions of years, evolution has shaped a reasonable solution.
至少可以说，大自然已经发展出了一套了不起的工具箱。
Nature has, at a minimum, developed a remarkable toolkit.
医学史上有很多例子，我们并没有发明底层的机制。
The history of medicine is full of examples where we didn't invent the underlying mechanism.
我们只是发现了它，理解了它，然后把它改造成有用的东西。
We discovered it, understood it, and then engineered it into something useful.
很多分子就摆在那里，机制也早就铺好了。
Many of the molecules are just sitting out there, the mechanisms already laid out.
我们只需要愿意去找，包括——甚至尤其是——去那些乍一看跟医学没什么关系的地方找。
We just have to be willing to go look, including, and perhaps especially, in places that don't at first look medically relevant.
回过头来看，真正重要的研究几乎总是始于一个关于疾病、但当时还不明显的问题。
In retrospect, the work that turns out to matter almost always begins as a question that is not yet obvious about a disease.
它始于某个人想弄清楚自然界某个东西到底是怎么运作的。
It begins with somebody who wants to understand how some piece of nature actually works.
是好奇心在驱动。
It's driven by curiosity.
我想确保这不会被误解为贬低后面那大量的工作。
And I want to make sure this is not interpreted as discounting the enormous amount of work that follows.
好奇心可能推动最初的发现，但有意识的转化显然也是过程中至关重要的一环。
Curiosity may drive an initial discovery, but intentional translation is obviously a pivotal part of the process too.
盐池古菌的免疫系统治不了镰状细胞病。
An immune system in salt pond archaea cannot cure sickle cell disease.
我们需要科学家直接研究人类疾病，操作CRISPR系统，经过多年专注的实验，基础发现才能变成人类疗法。
We need scientists directly characterizing the human disease, manipulating the CRISPR system, and going through years of dedicated focused experimentation before the basic discovery becomes a human therapeutic.
所以我认为，把生物医学科学看作一个连续体是值得的，链条上的每一步都需要投入必要的时间、精力和资源。
So I do think it's worth seeing biomedical science as existing on a continuum, with necessary time, attention, and resources devoted to each step in the chain.
看近期的医学进展，很容易觉得这是人类主导、人类设计、有意图的成果。
It is easy to look at recent medical advances and see something human driven, human designed, and intentional.
人类制造了CAR T细胞和检查点抑制剂用于癌症治疗，还有单克隆抗体、激酶抑制剂、mRNA疫苗。
Humans made CAR T cells and checkpoint inhibitors for cancer therapy, monoclonal antibodies, kinase inhibitors, mRNA vaccines.
更难看到的是，如果没有科学家先剖析自然世界，这些人类智慧的产物是不可能存在的。
What can be more difficult to see is that these products of human ingenuity would be impossible without scientists dissecting the natural world first.
如果不先理解T细胞的基本生物学，嵌合T细胞就不可能存在。
Chimeric T cells cannot exist without understanding fundamental T cell biology first.
如果我们不知道哪些检查点和激酶值得抑制，就无法开发检查点和激酶抑制剂。
Checkpoint and kinase inhibitors can't be developed if we don't know the checkpoints and kinases worth inhibiting.
如果不先理解天然的多克隆抗体表达，单克隆抗体就毫无意义。
Monoclonal antibodies make no sense without first understanding natural polyclonal antibody expression.
你明白我的意思了吧。
And you get the point.
虽然很多基础问题确实是从明显与疾病相关的系统开始的，但这仍然是为了这个论点服务的。
While it's true that many of these basic questions begin in obviously disease relevant systems, it still is in service of this thesis.
基础科学，也就是知识的基础，是治愈人类疾病过程中不可或缺的一部分。
The basic science, the foundational base of knowledge, is an irrevocably necessary part of the process of curing human disease.
有人，其实是有成千上万的人，必须对自然世界在基本层面如何运作感到好奇。
Someone, hundreds of thousands of someones really, had to be curious about how the natural world worked at its fundamental level.
只有在那之后，凭借他们获得的知识，我们才能有效地用我们自己创造的设计分子来补充我们的实验室和身体。
Only then, with the knowledge they gained, can we effectively supplement our labs and our bodies with designer molecules of our own creation.
我希望你今天离开时能对这个想法有所体会。
What I hope you'll leave with today is an appreciation for this idea.
你药柜里的药并不是仅仅来自实验室里的一个干净的想法。
The drugs in your medicine cabinet did not just come from a clean idea in a lab.
它们始于对世界如何运作的无数小小的好奇之举。
They started with a million small acts of curiosity about how the world works.
对我来说，这里关于谦逊的教训，我真正从中领悟到的，是我们作为一个文化和资助体系，应该对那些提出那些微小、奇怪、有时看似无关问题的人更加慷慨。
And the lesson in humility here, for me, the thing I genuinely take from all of this, is that we should be much more generous as a culture and as a funding apparatus with the people who are out there asking those small, strange, sometimes apparently irrelevant questions.
因为我们已经被证明非常不擅长预测哪一个会改变一切。
Because we are demonstrably terrible at predicting which one of them is going to change everything.
我们需要那些能把好奇心转化为人类成果的人。
We need people who translate curiosity into human outcomes.
但我忍不住被这样一个事实所打动：那些看似不切实际的问题，有时恰恰是最重要的。
But I can't help but be struck by the fact that the apparently impractical question is, sometimes, the one that matters most.
感谢收听本周的《The Drive》节目。
Thank you for listening to this week's episode of The Drive.
如果你想深入了解本期内容，请访问 peterattiamd.com 的节目笔记页面。
Head over to peterattia,md.com forward slash show notes if you want to dig deeper into this episode.
你也可以在 YouTube、Instagram 和 Twitter 上找到我，账号都是 Peter Attia, MD。
You can also find me on YouTube, Instagram, and Twitter, all with the handle Peter Attia, MD.
你也可以在 Apple Podcasts 或你使用的任何播客播放器上给我们留下评论。
You can also leave us review on Apple Podcasts or whatever podcast player you use.
这个播客仅供一般信息参考，不构成医疗、护理或其他专业医疗服务的实践，包括提供医疗建议。
This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice.
不构成医患关系。
No doctor patient relationship is formed.
使用这些信息和本播客链接的材料，风险自负。
The use of this information and the materials linked to this podcast is at the user's own risk.
本播客的内容不旨在替代专业医疗建议、诊断或治疗。
The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment.
用户不应因任何医疗状况而忽视或延迟获取医疗建议，如有此类情况，应寻求其医疗保健专业人员的帮助。
Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions.
最后，我非常重视所有利益冲突。
Finally, I take all conflicts of interest very seriously.
关于我的所有披露以及我投资或提供建议的公司，请访问 peterattiamd.com/About，那里有我保持最新和活跃的披露列表。
For all of my disclosures and the companies I invest in or advise, please visit peterattiamd.com slash About where I keep an up to date and active list of all disclosures.
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