一种被遗忘已久的病毒将如何帮我们解决抗生素危机 – Alexander Belcredi

TED 精选 2018-12-27

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一种被遗忘已久的病毒将如何帮我们解决抗生素危机 - Alexander Belcredi

病毒的名声一直都不好——但有些病毒将来某天也许能够拯救我们的生命，生物科技企业家亚历山大 · 贝尔克雷迪如是说。在这个引人入胜的演讲中，他向我们介绍了噬菌体——一种自然产生的病毒，能精准猎杀对人体有害的细菌；同时他也展示了在对抗耐抗生素超级细菌日益增长的威胁中，这些曾被遗忘的生命体会如何给我们带来新希望。

00:12
Take a moment and think about a virus. What comes to your mind? An illness? A fear? Probably something really unpleasant. And yet, viruses are not all the same. It's true, some of them cause devastating disease. But others can do the exact opposite -- they can cure disease. These viruses are called "phages."
大家花一点时间，想一想病毒（是什么）。你脑海里浮现的是什么呢？是疾病？还是恐惧？多半是非常不愉快的感觉吧。然而，病毒的影响并非都是负面的。的确，有些病毒能引发致命疾病；但另一些病毒则截然相反——它们能治愈疾病，这类病毒被称为“噬菌体”。

00:36
Now, the first time I heard about phages was back in 2013. My father-in-law, who's a surgeon, was telling me about a woman he was treating. The woman had a knee injury, required multiple surgeries, and over the course of these, developed a chronic bacterial infection in her leg. Unfortunately for her, the bacteria causing the infection also did not respond to any antibiotic that was available. So at this point, typically, the only option left is to amputate the leg to stop the infection from spreading further. Now, my father-in-law was desperate for a different kind of solution, and he applied for an experimental, last-resort treatment using phages. And guess what? It worked. Within three weeks of applying the phages, the chronic infection had healed up, where before, no antibiotic was working. I was fascinated by this weird conception: viruses curing an infection. To this day, I am fascinated by the medical potential of phages. And I actually quit my job last year to build a company in this space.
我第一次听说噬菌体病毒要追溯到2013年，我身为外科医生的岳父向我介绍了他当时的一名女性患者的治疗情况。该女性患者膝盖受伤，需要进行多次手术，在进行这些手术的过程中，她的腿部出现了慢性细菌感染的症状。不幸的是，所有当时的抗生素对引发她感染的细菌都不起作用。一般来说，在这种情况下，唯一的选择就是截肢，以阻止感染进一步扩大。我的岳父急需一种不同的治疗方案，他请求实施尚处于实验阶段的唯一可能有效的噬菌体方案，你猜怎么着？那个治疗方案生效了。使用噬菌体之后不到三周，慢性感染就得到了治愈，而在此之前，所有抗生素无一有效。我被这个奇特的概念深深迷住了: 病毒竟然能够治愈细菌感染。直至今日，我依然为噬菌体的医疗潜能所着迷。于是，我去年辞掉工作，在这个领域创立了一家公司。

01:38
Now, what is a phage? The image that you see here was taken by an electron microscope. And that means what we see on the screen is in reality extremely tiny. The grainy thing in the middle with the head, the long body and a number of feet -- this is the image of a prototypical phage. It's kind of cute.
那么，究竟什么是噬菌体呢？你们看到的这个影像是用电子显微镜拍的，也就是说，实际上我们在屏幕上看到的东西极其微小。中间粒状的东西有头、长长的身体、还有很多脚——这就是一个典型噬菌体的形貌，看上去还有点可爱呢。

02:00
Now, take a look at your hand. In our team, we've estimated that you have more than 10 billion phages on each of your hands. What are they doing there?
现在，看看你的手，据我们团队的估计，人的每只手上有100多亿个噬菌体。它们在你手上干什么呢？

02:12
Well, viruses are good at infecting cells. And phages are great at infecting bacteria. And your hand, just like so much of our body, is a hotbed of bacterial activity, making it an ideal hunting ground for phages. Because after all, phages hunt bacteria. It's also important to know that phages are extremely selective hunters. Typically, a phage will only infect a single bacterial species. So in this rendering here, the phage that you see hunts for a bacterium called Staphylococcus aureus, which is known as MRSA in its drug-resistant form. It causes skin or wound infections.
事实上，病毒擅长感染细胞；而噬菌体则擅长感染细菌。和我们的身体一样，你的手就是细菌活动的温床，是噬菌体的理想狩猎场，因为终究噬菌体会猎杀细菌。还有重要的一点需要了解，即噬菌体都是挑剔的猎手；通常，一个噬菌体只会感染一种细菌。所以，在这张渲染图中的噬菌体，只会猎杀一种叫做金黄色葡萄球菌的细菌，在耐药状态下它被称为MRSA，它会导致皮肤和伤口感染。

02:51
The way the phage hunts is with its feet. The feet are actually extremely sensitive receptors, on the lookout for the right surface on a bacterial cell. Once it finds it, the phage will latch on to the bacterial cell wall and then inject its DNA. DNA sits in the head of the phage and travels into the bacteria through the long body. At this point, the phage reprograms the bacteria into producing lots of new phages. The bacteria, in effect, becomes a phage factory. Once around 50-100 phages have accumulated within the bacteria cell, the phages are then able to release a protein that disrupts the bacteria cell wall. As the bacteria bursts, the phages move out and go on the hunt again for a new bacteria to infect.
噬菌体猎杀所用的工具是它的脚，这些脚其实是超级灵敏的感受器官，用于准确探测细菌细胞的表面。噬菌体一旦探测到细菌表面，就会锁定住细菌的细胞壁，接着将自己的DNA 注射进入细菌体内。位于噬菌体头部的DNA，通过它那长长的身躯进入细菌体内。这时，噬菌体会对细菌重新编码，以生产出大量新的噬菌体。事实上，细菌已变成了噬菌体工厂。一旦细菌体内积累了约50-100个噬菌体后，这些噬菌体就会释放一种破坏细菌细胞壁的蛋白质。当细菌破裂时，噬菌体就跑出来，继续搜寻新的细菌进行感染。

03:35
Now, I'm sorry, this probably sounded like a scary virus again. But it's exactly this ability of phages -- to multiply within the bacteria and then kill them -- that make them so interesting from a medical point of view. The other part that I find extremely interesting is the scale at which this is going on. Now, just five years ago, I really had no clue about phages. And yet, today I would tell you they are part of a natural principle. Phages and bacteria go back to the earliest days of evolution. They have always existed in tandem, keeping each other in check. So this is really the story of yin and yang, of the hunter and the prey, at a microscopic level. Some scientists have even estimated that phages are the most abundant organism on our planet. So even before we continue talking about their medical potential, I think everybody should know about phages and their role on earth: they hunt, infect and kill bacteria.
很抱歉，这可能听起来又像一种可怕的病毒了。但这正是噬菌体所拥有的能力—— 在细菌内部繁殖，然后杀死细菌—— 从医学的角度来看，这让噬菌体显得很有趣。另外一个让我十分感兴趣的方面，是这件事的发展规模。就在五年前，我对噬菌体还一窍不通；然而，今天我会告诉你们，它们是自然法则的一部分。噬菌体和细菌又回到了进化早期，它们总是成双存在，并且彼此相互制约；这跟阴和阳，或是猎人与猎物的关系别无二致，只不过它们的关系存在于微观世界。有些科学家甚至估计，噬菌体可能是地球上数量最多的生命体。所以，在我们继续讨论它们的医疗潜能之前，我想每人都该了解噬菌体，和它们在地球上扮演的角色：它们搜寻、感染，进而杀死细菌。

04:30
Now, how come we have something that works so well in nature, every day, everywhere around us, and yet, in most parts of the world, we do not have a single drug on the market that uses this principle to combat bacterial infections? The simple answer is: no one has developed this kind of a drug yet, at least not one that conforms to the Western regulatory standards that set the norm for so much of the world. To understand why, we need to move back in time.
那么，大自然中怎么会有如此运作完美的生物，无处不在，时时刻刻伴随着我们；然而在世界上大多数地方，在我们的医药市场上，却没有一种能利用这种机制去对抗细菌感染的药物呢？答案其实很简单：还没人发明这种药，至少还没有这样一种药品能够符合为世界多数东西制定标准的西方监管准则，想知道其中的原因，就要往前追溯一下。

04:57
This is a picture of Félix d'Herelle. He is one of the two scientists credited with discovering phages. Except, when he discovered them back in 1917, he had no clue what he had discovered. He was interested in a disease called bacillary dysentery, which is a bacterial infection that causes severe diarrhea, and back then, was actually killing a lot of people, because after all, no cure for bacterial infections had been invented. He was looking at samples from patients who had survived this illness. And he found that something weird was going on. Something in the sample was killing the bacteria that were supposed to cause the disease.
照片中的这位是菲利克斯 · 德雷尔，他是发现噬菌体的两位科学家之一。只不过当1917年他发现噬菌体时，他对于自己的发现还一无所知。当时，他对一种叫做菌痢的疾病很感兴趣，这是一种由细菌感染引发的严重腹泻疾病，那个年代，这种疾病的致死率很高，毕竟那会儿治疗细菌感染的药物还没有问世。当时他正在观察从疾病幸存者身上提取的样本，他发现了一些奇怪的事情，样本中的某种东西正在杀死那些致病的细菌。

05:31
To find out what was going on, he did an ingenious experiment. He took the sample, filtered it until he was sure that only something very small could have remained, and then took a tiny drop and added it to freshly cultivated bacteria. And he observed that within a number of hours, the bacteria had been killed. He then repeated this, again filtering, taking a tiny drop, adding it to the next batch of fresh bacteria. He did this in sequence 50 times, always observing the same effect. And at this point, he made two conclusions. First of all, the obvious one: yes, something was killing the bacteria, and it was in that liquid. The other one: it had to be biologic in nature, because a tiny drop was sufficient to have a huge impact. He called the agent he had found an "invisible microbe" and gave it the name "bacteriophage," which, literally translated, means "bacteria eater." And by the way, this is one of the most fundamental discoveries of modern microbiology. So many modern techniques go back to our understanding of how phages work -- in genomic editing, but also in other fields. And just today, the Nobel Prize in chemistry was announced for two scientists who work with phages and develop drugs based on that.
为了查明原因，他做了一个非常巧妙的实验。他取出样本，进行过滤，直到确定样本中只保留了极微小的生物，接着，他从中取出一小滴，滴入刚培养好的细菌中。他观察到，在接下来的几个小时之内，细菌统统被杀死了。于是他重复进行这个实验，再次过滤、从中取一小滴，滴入下一批最新培养出的细菌中；他接连将这组实验做了50次，每次都观察到了相同的效果。于是，他得出了两个结论。首先，最明显的一个结论就是：没错，有样东西正在杀死细菌，它就存在于那些液体中。另外一个结论是：它本质上一定是生物，因为一小滴竟足以产生如此大的影响。他把刚发现的这种试剂叫做“看不见的微生物”，并将其命名为“噬菌体”，其字面意思就是“细菌吞噬者”。顺便提一句，这是现代微生物学上最基础性的发现之一，许多现代科技又回到我们对噬菌体运作机制的理解—— 不仅是基因编辑技术，在其他领域也是如此。而就在今天，两名研究噬菌体、并开发基于噬菌体药物的科学家获得了诺贝尔化学奖。

06:41
Now, back in the 1920s and 1930s, people also immediately saw the medical potential of phages. After all, albeit invisible, you had something that reliably was killing bacteria. Companies that still exist today, such as Abbott, Squibb or Lilly, sold phage preparations. But the reality is, if you're starting with an invisible microbe, it's very difficult to get to a reliable drug. Just imagine going to the FDA today and telling them all about that invisible virus you want to give to patients. So when chemical antibiotics emerged in the 1940s, they completely changed the game. And this guy played a major role.
追溯到二十世纪二十年代和三十年代，人们也立刻看到了噬菌体的医学潜能。即使看不见噬菌体，我们毕竟拥有了能杀死细菌的可靠物质。像雅培、百时美施贵宝或礼来这些今天依然存在的公司，开始销售噬菌体制剂。但问题在于，如果用一种不可见的微生物做基础，是很难生产出可靠药物的。试想一下，你今天就去FDA，向他们介绍你要给病人用的这种不可见的病毒，他们会作何反应。所以当上世纪四十年代化学抗生素问世的时候，它们彻底改变了游戏规则。这主要得归功于图上的这个人。

07:16
This is Alexander Fleming. He won the Nobel Prize in medicine for his work contributing to the development of the first antibiotic, penicillin. And antibiotics really work very differently than phages. For the most part, they inhibit the growth of the bacteria, and they don't care so much which kind of bacteria are present. The ones that we call broad-spectrum will even work against a whole bunch of bacteria out there. Compare that to phages, which work extremely narrowly against one bacterial species, and you can see the obvious advantage.
他是亚历山大 · 弗莱明，因为他对世界上第一种抗生素青霉素的开发做出了巨大贡献，而获得了诺贝尔医学奖。抗生素与噬菌体的作用原理截然不同。最大的不同就是，抗生素会抑制细菌生长，不管是哪种细菌。我们称之为广谱抗菌的抗生素，它们甚至会抑制人体内所有细菌。与之相比，噬菌体的作用面则很有限，只对一类细菌有效，因此，抗生素的优势显而易见。

07:47
Now, back then, this must have felt like a dream come true. You had a patient with a suspected bacterial infection, you gave him the antibiotic, and without really needing to know anything else about the bacteria causing the disease, many of the patients recovered. And so as we developed more and more antibiotics, they, rightly so, became the first-line therapy for bacterial infections. And by the way, they have contributed tremendously to our life expectancy. We are only able to do complex medical interventions and medical surgeries today because we have antibiotics, and we don't risk the patient dying the very next day from the bacterial infection that he might contract during the operation.
那时，抗生素的出现让人们觉得梦想成真。你有一名患者疑似患上了细菌感染，你给他开了抗生素，而你不需要真正对引发疾病的细菌有更多了解，很多患者的病就治好了。因此，随着我们开发出越来越多的抗生素，新抗生素立刻就会成为治疗细菌感染的首选。顺便一提，抗生素为我们寿命的延长做出了巨大贡献。今天，我们能够进行复杂的医疗干预和外科手术，是因为我们有抗生素，所以，我们不再冒着患者可能因为手术中细菌感染而在术后第二天死去的危险。

08:24
So we started to forget about phages, especially in Western medicine. And to a certain extent, even when I was growing up, the notion was: we have solved bacterial infections; we have antibiotics. Of course, today, we know that this is wrong. Today, most of you will have heard about superbugs. Those are bacteria that have become resistant to many, if not all, of the antibiotics that we have developed to treat this infection.
因此，我们开始忘记噬菌体的存在，尤其是在西药中。更确切的说，甚至在我成长过程中，大家的观念都是：我们已解决了细菌感染问题；因为我们有了抗生素。当然，今天我们都知道，这种观念是大错特错的。现在，多数人都听说过超级细菌吧。那是一种即便不是对所有抗生素，也是对很多我们开发的、治疗细菌感染的抗生素有抗药性的细菌。

08:51
How did we get here? Well, we weren't as smart as we thought we were. As we started using antibiotics everywhere -- in hospitals, to treat and prevent; at home, for simple colds; on farms, to keep animals healthy -- the bacteria evolved. In the onslaught of antibiotics that were all around them, those bacteria survived that were best able to adapt. Today, we call these "multidrug-resistant bacteria." And let me put a scary number out there. In a recent study commissioned by the UK government, it was estimated that by 2050, ten million people could die every year from multidrug-resistant infections. Compare that to eight million deaths from cancer per year today, and you can see that this is a scary number.
这一切是如何发生的呢？事实上，我们并非像我们想的那样聪明。从我们开始在所有地方都使用抗生素—— 在医院用于治疗和预防；在家里对付小感冒；在农场用，为使动物保持健康—— 细菌进化了。在抗生素的围攻之下，活下来的细菌都是适应力最强的。今天，我们称之为“多药耐药性细菌”。我要向大家展示一组可怕的数据，在最近一项由英国政府委托的研究中，预计直至2050年，每年大约会有一千万人死于多药耐药性细菌感染。和目前每年死于癌症的八百万人相比，这个数字显然非常可怕。

09:35
But the good news is, phages have stuck around. And let me tell you, they are not impressed by multidrug resistance.
但好消息是，噬菌体的应用离我们不远了。而且，我得告诉你们，它们可不在乎多药耐药性。

09:43
They are just as happily killing and hunting bacteria all around us. And they've also stayed selective, which today is really a good thing. Today, we are able to reliably identify a bacterial pathogen that's causing an infection in many settings. And their selectivity will help us avoid some of the side effects that are commonly associated with broad-spectrum antibiotics. But maybe the best news of all is: they are no longer an invisible microbe. We can look at them. And we did so together before. We can sequence their DNA. We understand how they replicate. And we understand the limitations. We are in a great place to now develop strong and reliable phage-based pharmaceuticals.

它们只是喜欢猎杀我们周围的细菌。而且，它们仍然保持着选择性，在今天看来依然是一件好事。今天，我们能可靠地识别在多种情况下造成感染的细菌病原体，而噬菌体的选择性会帮助我们避免通常由广谱抗生素所造成的副作用。也许这才是最好的消息：噬菌体不再是不可见微生物。我们可以看到它们，之前我们已经看过了。我们能对它们的基因进行测序，了解它们的复制机制。我们也明白它们的局限性。我们正处在一个能够开发强力而可靠的基于噬菌体的药物新时代。

10:24
And that's what's happening around the globe. More than 10 biotech companies, including our own company, are developing human-phage applications to treat bacterial infections. A number of clinical trials are getting underway in Europe and the US. So I'm convinced that we're standing on the verge of a renaissance of phage therapy. And to me, the correct way to depict the phage is something like this.
世界各地都已经开始行动了。包括我们公司在内，超过10家生物科技公司正开发人类噬菌体应用以治疗细菌性感染，数个临床试验正在欧洲和美国进行。所以，我确信我们正站在噬菌体疗法复兴的边缘。依我看，描画噬菌体的正确方式应该像这样。

10:49
To me, phages are the superheroes that we have been waiting for in our fight against multidrug-resistant infections.
在我看来，在与多药耐药性细菌感染的战斗中，噬菌体就是我们一直期待的超级英雄。

10:56
So the next time you think about a virus, keep this image in mind. After all, a phage might one day save your life.
所以，下次你想到病毒的时候，请记住这个噬菌体超人形象！毕竟，噬菌体也许会在某一天挽救你的生命。