她助力永久改变疫苗技术 | 盖茨笔记

For most people, the highly effective mRNA COVID vaccines made by Moderna and Pfizer-BioNTech seemed to come out of the blue. But these new vaccines, which were essential to end this pandemic and will likely play a critical role in preventing future pandemics, are the product of decades of painstaking work by researchers.

在大多数人眼中，由莫德纳和辉瑞/BioNTech等公司生产的高效的mRNA新冠疫苗似乎是横空出世。但实际上，这种新型疫苗是研究人员数十年艰苦工作的成果，它们对结束这次大流行病至关重要，并且可能在预防未来的大流行病方面发挥关键作用。

One of those researchers is Dr. Katalin Karikó, a Hungarian biochemist who long ago saw the potential of mRNA to save lives when few others did.

匈牙利生物化学家卡塔琳·考里科博士就是这些研究人员中的一员。她独具慧眼，在很久以前mRNA技术还鲜为人知的时候，便已发现了其挽救生命的潜力。

The daughter of a small-town butcher in Hungary, Karikó knew from a young age that she wanted to become a scientist. She was drawn to biochemistry and developed a particular fascination with messenger RNA, or mRNA, molecules that (among other things) direct the creation of proteins in your body.

考里科来自匈牙利的一个小镇，是屠户的女儿，她从小就立志成为一名科学家。她被生物化学深深吸引，并对信使RNA（mRNA）产生了特别的兴趣。mRNA是一种分子，（除其他外）指导人体内蛋白质的合成。

Messenger RNA functions as a kind of middleman—it carries the directions for making proteins from your DNA to the factories in your cells where the proteins will be assembled. It’s a bit like the waiter in a restaurant who writes down your order and takes it to the kitchen, where the cooks will make your meal.

mRNA的功能像是一种“中间人”——它将DNA发出的制造蛋白质的指令传达到细胞中的“工厂”，在那里蛋白质将被组装起来。这有点像餐厅的侍者，记下你点的菜，然后传达给厨房，在那里厨师会为你制作菜肴。

In the 1980s, while working on her PhD in her native Hungary, Karikó became convinced that tiny strands of mRNA could be injected into cells to send instructions to the body to make its own medicines. She was interested in developing mRNA treatments for stroke, cancer, and other diseases.

20世纪80年代，考里科在她的祖国匈牙利攻读博士学位时，确信可将微小的mRNA片段注入到细胞中，让其向身体发出指令来自己制造药物。她对开发中风、癌症和其他疾病的mRNA疗法很感兴趣。

Although vaccines were not the focus of Karikó’s work, other researchers saw that it would be possible to use mRNA to make those as well—for flu, coronaviruses, and maybe even various forms of cancer.

虽然疫苗并非考里科研究的重点，但也有其他研究人员意识到了利用mRNA制造疫苗的可能性——用于流感、冠状病毒，甚至可能是各种癌症。

Using mRNA to make vaccines would be a major departure from the way most vaccines work. Many conventional vaccines operate by injecting a weakened or dead form of the virus you’re trying to stop. Your immune system sees the new shapes on the virus, kicks into gear, and builds up immunity. While conventional vaccines have been very effective, it takes years of lab work and clinical studies to make sure that they are safe and will produce a good immune response.

利用mRNA制造的疫苗将与大多数疫苗的工作原理截然不同。许多传统疫苗通过注射特定病毒的减毒或灭活形式来发挥作用。你的免疫系统看到病毒的新形态，就会针对性地发动攻击，从而建立免疫反应。虽然传统疫苗已展示出其高效性，但需要多年的实验室工作和临床研究才能确保其安全性以及产生良好的免疫反应。

The idea behind mRNA vaccines was quite clever. Since mRNA takes the orders for proteins from the DNA and delivers them to the cooks in your cells’ kitchen, what if we could change those orders in a very targeted way? By teaching your cells to make shapes that match shapes on the actual virus, the vaccine would trigger your immune system without having to introduce the virus itself.

mRNA疫苗背后的想法相当巧妙：既然mRNA会从DNA中获取制造蛋白质的指令，并将其传递给“细胞厨房”中的“厨师”，如果我们能够以一种非常有针对性的方式改变这些指令会怎么样？通过教会你的细胞制造与实际病毒相匹配的形状，这样不必引入病毒本身，疫苗也会触发你的免疫系统。

If they could be made, mRNA vaccines would be a huge advance over conventional vaccines. Once you had mapped out all the proteins that make up the virus you wanted to target, you’d identify the one that you want antibodies to grab. Then you’d study the virus’s genetic code to find the instructions for making that protein, and you’d put that code into the vaccine using mRNA. If, later, you wanted to attack a different protein, you’d just change the mRNA. This design process would take at most a few weeks. You would ask the waiter for fries instead of a side salad, and your immune system would do the rest.

如果mRNA疫苗能被成功制造出来，那将比传统疫苗前进一大步。一旦你厘清构成想要针对的目标病毒的所有蛋白质类型，你就会很容易确定那个想让抗体抓住的蛋白质。然后你要研究病毒的基因编码，找到制造这种蛋白质的指令，接着利用mRNA将编码导入疫苗。如果以后你想要攻击另一种蛋白质，只需改变mRNA就可实现。这个设计过程最多只需要几周时间。你只需要向侍者点薯条而不是沙拉，剩下的事情就交由免疫系统来完成。

There was just one problem: It was only a theory. No one had ever actually made an mRNA vaccine. What’s more, most people in the field thought it was crazy to even try, not least because mRNA is inherently unstable and prone to degrading quickly. Also, cells have evolved to avoid being hijacked by foreign mRNA, and there would need to be a way of getting around this defense system.

只有一个问题：该想法还停留在理论阶段。此前还从来没有人真正制造出mRNA疫苗。更重要的是，该领域的大多数人甚至认为就连尝试都是疯狂且不现实的，尤其是考虑到mRNA本身极不稳定，容易迅速降解。此外，细胞已经进化到可以避免被外来mRNA“劫持”，因此，需要找到一种绕过这个防御系统的方法。

Karikó’s interest in mRNA eventually brought her to the U.S. And in 1993, while doing research at the University of Pennsylvania, Karikó and her boss managed a feat that told them they were on to something: They got a human cell to produce a tiny amount of new proteins using a modified version of mRNA that had been altered so it could get past the cell’s defense system. This was a breakthrough, because it meant that if they could expand the production dramatically, they would be able to make a cancer treatment using mRNA.

考里科对mRNA的兴趣指引她最终去往美国。1993年，在宾夕法尼亚大学做研究时，考里科和她的导师完成了一项壮举，这将他们引向了一个新方向：他们利用一种修饰过的mRNA（通过改造使其能够穿越细胞的防御系统）成功让一个人类细胞制造出极少量的新蛋白质。这是一个突破，因为这意味着如果能够大幅度地增加蛋白质产量，他们就能够利用mRNA来治疗癌症。

卡塔琳·考里科博士从小就立志成为一位科学家。照片摄于1985年，考里科在她的实验室里工作。(图源：个人照片/卡塔琳·考里科)

Stories of medical discoveries often don’t travel in straight line from breakthrough to lifesaving impact. And Karikó’s story is no different. Karikó’s work lost momentum when her boss left academia for a biotech firm. She no longer had a lab or financial support for her work; although she applied for grant after grant, every application was rejected. In 1995, she he had a cancer scare, she was taken off the tenure track at work, and her husband was stuck in Hungary because of a problem with his visa. But Karikó was undeterred.

医学发现的故事往往并非一帆风顺，取得突破到产生拯救生命的影响之间的过程漫长而曲折。考里科的故事也不例外。在她的导师离开学术界，进入一家生物科技公司工作后，考里科的工作失去了动力。她不再拥有实验室，也失去了资金支持；尽管她一次又一次地申请资助，但每次都被拒绝。1995年，她患上了癌症，并被取消了终身教职资格，她的丈夫也因为签证问题而滞留在匈牙利。但考里科并没有被生活击垮。

Then in 1997, she began working with Drew Weissman, a new colleague who came to the University of Pennsylvania with a promising background: He had done a fellowship at NIH under the supervision of Tony Fauci, and he was interested in using Karikó’s work on mRNA to develop vaccines.

在1997年，她开始与德鲁·魏斯曼合作，这是一位刚来到宾夕法尼亚大学的新同事，有着良好的背景：他曾在托尼·福奇的指导下，在美国国立卫生研究院担任研究员。他很有兴趣利用考里科的mRNA研究来研发疫苗。

Together Karikó and Weissman kept pursuing the idea of working with mRNA that had been engineered in a lab. But they still had to get more mRNA past the cell’s defense systems, a problem that other scientists helped solve. In 1999, a cancer researcher named Pieter Cullis and his colleagues proposed that lipids—basically, tiny bits of fat—could be used to encase and protect a more delicate molecule, such as mRNA. Six years later, working with Cullis, biochemist Ian MacLachlan did it for the first time. The lipid nanoparticles he developed paved the way for the first mRNA vaccines.

考里科和魏斯曼一起合作，继续研究实验室中被设计改造过的mRNA。但他们仍需尽可能让更多的mRNA穿越细胞的防御系统，这一问题在其他科学家的帮助下得以解决。1999年，一位名为皮耶特·库里斯的癌症研究人员和他的同事提出，脂质（简单来说就是微小的脂肪）可以用来包裹和保护更脆弱的分子，比如mRNA。六年后，生物化学家伊恩·麦克拉克兰与库里斯合作，首次取得了成功。他开发的脂质纳米颗粒为第一批mRNA疫苗的诞生铺平了道路。

在宾夕法尼亚大学的实验室，卡塔琳·考里科博士和她的同事德鲁·魏斯曼博士帮助开发了使mRNA疫苗成为可能的新技术。（图源：宾夕法尼亚大学医学院)

As late as 2010, hardly anyone in the federal government or private industry was interested in trying to make vaccines using mRNA. Major pharmaceutical companies had tried and failed, and some scientists felt that mRNA would never trigger enough of a response in the body. But an official at DARPA, the little-known research program for the U.S. military, saw enough promise in the technology that he started funding mRNA vaccines for infectious diseases.

到了2010年，联邦政府或私营企业中已经几乎没有人有兴趣再尝试用mRNA制造疫苗。一些大型制药公司曾经尝试过，但都失败了，一些科学家认为mRNA永远不会在人体内引发足够的反应。但美国国防部高级研究计划局（美国军方一个鲜为人知的研究项目）的一位官员看到了这项技术的光明前景，于是他开始资助研发作用于传染病的mRNA疫苗。

As pioneering as this work was, it didn’t lead immediately to new vaccines. Accomplishing that would be the task of companies dedicated to translating the breakthrough into a product that could be approved and sold; the U.S.-based Moderna and Germany-based CureVac and BioNTech were founded to do just that.

尽管这项工作具有开创性，但这并没有立即引发新疫苗的出现。实现这一目标的任务落在了那些致力于将这一突破转化为一种上市产品的公司肩上；总部设在美国的莫德纳公司和总部设在德国的CureVac和BioNTech公司正是为了实现这一目标而创立的。

In 2014, Karikó joined BioNTech, which was working on an mRNA vaccine for cancer. Early efforts didn’t work, although a test of a rabies vaccine showed promise. Still, Karikó and her BioNTech colleagues persevered, as did scientists at Moderna. When COVID hit, they immediately set out to make a vaccine for the new virus. It was a good bet.

2014年，考里科加入了BioNTech公司，当时该公司正在研究一种针对癌症的mRNA疫苗。尽管一种针对狂犬病的疫苗在试验后展示出了前景，但癌症疫苗的早期努力并未取得成果。尽管如此，考里科和BioNTech的同事们仍然坚持不懈，莫德纳的科学家也从未放弃。新冠疫情暴发时，他们立即着手研发针对新病毒的疫苗。他们选对了。

The notion that mapping a virus’s genome would allow you to create an mRNA vaccine in a matter of weeks proved to be exactly right. In March 2020, just six weeks after scientists sequenced the COVID virus’s genome, Moderna announced that it had identified an mRNA-based candidate and begun making it for clinical trials. On December 31, the mRNA vaccine made by BioNTech in partnership with Pfizer was approved for emergency use by the World Health Organization. When Karikó received the first dose of the vaccine she had done so much to create—a few days before it was officially approved—she wept.

事实证明，绘制病毒的基因组图谱可以在几周内开发出一种mRNA疫苗的想法是完全正确的。2020年3月，在科学家对新冠病毒的基因组进行测序后仅六个星期，莫德纳就宣布已经研发出一种基于mRNA技术的候选疫苗，并准备开始临床试验。12月31日，BioNTech与辉瑞公司联合研发的mRNA疫苗获得了世界卫生组织的紧急使用授权。在接种她耗费心力研制的疫苗的第一针时（在该疫苗正式获批的前几天），考里科流泪了。

卡塔琳·考里科博士接种她耗费心力研制的疫苗的第一针时流泪了。(图源：宾夕法尼亚大学医学院)

2021年，德国柏林，BioNTech的高级副总裁卡塔琳·考里科博士与BioNTech的联合创始人庆祝他们被授予德国未来奖，该奖项用以表彰他们为新冠疫苗做出的贡献。(图源：Picture Aliiance/盖蒂图片社)

For all her amazing foresight, I doubt even Dr. Karikó imagined that mRNA vaccines would one day play an essential role in ending a pandemic – and giving us a tool to prevent the next one. And to me, that’s the important lesson of her story: It’s impossible to predict exactly how breakthroughs will shape the future. That’s why it’s critical, if the science makes sense, that we should be willing to bet on crazy sounding ideas and the researchers like Dr. Kariko willing to fight tooth and nail to pursue them. They just might change the world.

即使拥有令人赞叹的远见，我猜测考里科博士也没有想到mRNA疫苗有一天会在结束大流行病方面发挥重要作用——并为我们提供了一种预防下一次大流行病的工具。对我来说，她的故事带来了重要启示：我们不可能准确预测出科学突破将如何塑造未来。因此，如果科学上是合理的，我们应当为听起来疯狂的想法投资，并支持像考里科博士这样愿意竭尽全力探索它们的研究人员，这至关重要。他们很可能会改变世界。