Sarah Vitak: This is Scientific American’s 60 Second Science. I’m Sarah Vitak. 


Modern medicine and bacterial pathogens are in an arms race. We use antibiotics to keep them at bay. And then they adapt to become immune to those antibiotics, evolving into superbugs.


The battle has been an asymmetric one—we just don’t have that many options in the fight. Most of our antibiotics come from bacteria—the vast majority from just a single genus: Streptomyces. And most antibiotics use the same handful of strategies to attack bacteria.


But there’s a reason that we use only a tiny fraction of the antibiotic chemicals that exist in nature.


Miriam Rosenbaum: This search for completely new substances was unsuccessful for the past 30 years. But it’s very difficult to make sure that we find an antibiotic—so a substance that’s produced by microorganisms and that’s toxic to other microorganisms but that is not toxic to humans.


Vitak: Miriam Rosenbaum is a professor of synthetic biotechnology at the Hans Knöll Institute in Germany.


But how then, if they are so hard to find, do scientists know that we have only found a tiny fraction of the antibiotic substances that exist in nature?


Rosenbaum: We do know that because for the past 20 years we were in this biological revolution of sequencing. 


Vitak: Researchers like Rosenbaum have taken that revolution underground—literally—like into the dirt.


Rosenbaum: And so with these environmental sequencing campaigns, we found out that actually, the microbial world is much, much bigger than we thought it is. And this is how we know that we only have 5 percent in the lab, because we see just looking at the DNA in the soil sample—we see there are 95 percent more. But where are they? We don’t have the cells. We can know more than their name—or more than that they exist there. We see what genes they have.


Vitak: They don’t have the cells because only about 1 to 15 percent of the species of bacteria in nature can currently be grown in the lab. It’s like dusting a room for fingerprints only to find that the place is totally covered—and in ones you don’t have IDs for. And also, that the party’s still going all around you, but you can’t see the guests.


What Rosenbaum can tell from the sequences is that these unseen bacteria do make more and different kinds of antibiotics.


So which bacteria are making them? And is it possible to keep them alive long enough to make the ID? Rosenbaum’s answer: microscopic bacterial pool parties.


Rosenbaum: Slowly over a long time we have been going smaller and smaller. And now we are at the picoliter-sized droplets, so way smaller than a milliliter that you can still see or a microliter that you can barely see. It’s a million times smaller than microliters. And so these, these picoliter droplets, now are the houses for these microorganisms. 


Vitak: So microscopic water houses.


Rosenbaum: And we put one cell in one of these droplets, so every cell gets their own house. And then, since these are so small, we can cultivate millions of these small droplet houses in one experiment. And so we take out of one soil sample of a few grams—we get millions of bacterial cells, and we put them all in their individual house. And then we see what grows.


Vitak: The work was published in the journal eLife. [Lisa Mahler et al., Highly parallelized droplet cultivation and prioritization of antibiotic producers from natural microbial communities]


And what they found is that they were able to grow a completely different set of bacteria than what would normally grow using traditional cell culturing techniques.


Rosenbaum: So typically, we put them either in a shake flask, that’s like the size of a hand, and then we have a few microbial cells in there that are basically lost in an ocean. Or we put them on an agar plate on the solid media when they don’t normally grow in this type of environment.


Vitak: Giving them their own private space to grow separately also probably helps ...


Rosenbaum: To take them out of the competition to give them a chance to actually grow up and to grow without competition and without somebody producing antibiotics and fighting against them, and so on.


Vitak: And the micro water houses are proving to be very flexible incubators. They are tiny, so millions can be grown together in one test tube, and they can be manipulated. So they can be put onto agar plates individually, giving the bacteria a better shot at growing there. Or they can be used to do experiments with different conditions inside each individual droplet.


But the goal has always been to turn them into tiny antibiotic factories.


Rosenbaum: So we took all the droplets that had growth in it, and then we added an indicator bacterium that has a light label, a fluorescent label. If these indicator bacteria are able to grow when they are added to the droplet, then we get a light signal—a green or red signal of this droplet.


Vitak: So red or green light coming from a droplet means the wild bacteria isn’t producing an antibiotic—which would kill the indicator bacteria in the drop. The color of the light conveniently tells them what type of bacteria is still alive.


But a dark droplet—so one without any light coming from it—means if the wild bacteria is killing the indicator bacteria stopping it from growing and stopping it from producing the light. So it must be producing an antibiotic.


Rosenbaum: So we can select all the dark droplets and then deposit them. Now we want to get these cultures; we want to get whoever is producing the antibiotic. And now we want to get those out of the droplet.


Vitak: This means that they can screen millions of bacteria for antibiotic properties pretty quickly and easily.


Inside these microscopic bacterial pool parties, humans might just find an upper hand in the arms race against the superbugs.


Thanks for listening. For Scientific American’s 60 Second Science, I’m Sarah Vitak.

【参考译文】

Sarah Vitak：这里是《科学美国人》的《60秒科学》。我是莎拉-维塔克。


现代医学和细菌病原体正在进行一场军备竞赛。我们使用抗生素来阻止它们。然后它们适应性地对这些抗生素产生免疫力，进化成超级病菌。


这场战斗是一场不对称的战斗，我们在这场战斗中没有那么多选择。我们的大多数抗生素来自细菌--绝大多数只来自一个单一的属。链霉菌（Streptomyces）。而且大多数抗生素使用相同的少数策略来攻击细菌。


但是，我们只使用自然界中存在的极少数抗生素化学品是有原因的。


米里亚姆-罗森鲍姆：在过去的30年里，这种寻找全新物质的努力是不成功的。但要确保我们找到一种抗生素--即一种由微生物产生的、对其他微生物有毒但对人类无毒的物质，是非常困难的。


维塔克：米莉亚-罗森鲍姆是德国汉斯-克诺尔研究所的合成生物技术教授。


但是，如果它们如此难以找到，那么科学家们如何知道我们只找到了自然界中存在的抗生素物质的极小部分？


罗森鲍姆：我们确实知道，因为在过去的20年里，我们一直处于这场测序的生物革命中。


维塔克。像罗森鲍姆这样的研究人员把这场革命带到了地下--从字面上讲--就像进入了泥土。


罗森鲍姆：所以通过这些环境测序活动，我们发现实际上，微生物世界比我们想象的要大得多。这就是我们如何知道我们在实验室里只有5%的微生物，因为我们看到只是看土壤样本中的DNA，我们看到还有95%的微生物。但它们在哪里？我们没有这些细胞。我们能知道的不仅仅是它们的名字--或者说不仅仅是它们存在于那里。我们看到他们有什么基因。


维塔克：他们没有细胞，因为目前只有自然界中大约1%到15%的细菌种类可以在实验室中生长。这就像在一个房间里清除指纹，却发现这个地方被完全覆盖，而且是那些你没有身份证的指纹。还有，你周围的聚会仍在进行，但你看不到客人。


罗森鲍姆从这些序列中可以看出，这些看不见的细菌确实在制造更多不同种类的抗生素。


那么是哪些细菌在制造它们？是否有可能让它们保持足够长的时间来制造ID？罗森鲍姆的答案是：显微镜下的细菌池聚会。


罗森鲍姆：在很长一段时间里，我们一直在慢慢地变得越来越小。现在我们已经达到了皮升大小的液滴，比你还能看到的一毫升或你几乎看不到的一微升小得多。它比微升要小一百万倍。因此这些，这些皮升水滴，现在是这些微生物的房子。


维塔克：所以微型的水屋。


罗森鲍姆：我们把一个细胞放在这些液滴中，所以每个细胞都有自己的房子。然后，由于这些水滴非常小，我们可以在一个实验中培养出数百万个这样的小水滴房子。因此，我们从一个几克的土壤样本中，得到了数百万个细菌细胞，我们把它们都放在各自的房子里。然后我们看看什么会生长。


维塔克：这项工作发表在eLife杂志上。[丽莎-马勒（Lisa Mahler）等人，高度并行的液滴培养和自然微生物群落中抗生素生产者的优先排序] 。


他们的发现是，他们能够培养出与使用传统细胞培养技术通常生长的细菌完全不同的细菌。


罗森鲍姆：所以通常情况下，我们要么把它们放在一个像手掌大小的摇瓶中，然后我们在里面有一些微生物细胞，这些细胞基本上在海洋中迷失了。或者我们把它们放在固体培养基的琼脂板上，当它们通常不在这种环境中生长。


维塔克：给它们自己的私人空间，让它们单独生长，可能也有助于......


罗森鲍姆：让它们脱离竞争，让它们有机会真正成长起来，在没有竞争、没有人生产抗生素和对抗它们的情况下成长，等等。


维塔克：而且事实证明，微型水屋是非常灵活的孵化器。它们很小，因此可以在一个试管中生长出数百万个，而且可以对它们进行操作。所以它们可以被单独放到琼脂板上，让细菌在那里有更好的生长机会。或者它们可以被用来在每个单独的液滴内做不同条件的实验。


但我们的目标一直是将它们变成微小的抗生素工厂。


罗森鲍姆：所以我们把所有有生长的液滴拿出来，然后加入一种指示菌，这种指示菌有一个光标签，一个荧光标签。如果这些指示菌被添加到液滴中时能够生长，那么我们就得到一个光信号--这个液滴的绿色或红色信号。


维塔克：所以从液滴中发出的红光或绿光意味着野生细菌没有产生抗生素--这将杀死液滴中的指示细菌。光的颜色可以方便地告诉他们哪种类型的细菌仍然活着。


但是，一个黑暗的液滴--即没有任何光线的液滴--意味着如果野生细菌正在杀死指示细菌，阻止它生长，并阻止它产生光线。所以它一定是在生产抗生素。


罗森鲍姆：所以我们可以选择所有的黑暗液滴，然后将它们存入。现在我们想得到这些培养物；我们想得到谁在产生抗生素。而现在我们想把这些东西从液滴中弄出来。


维塔克：这意味着他们可以相当迅速和容易地筛选出数百万个细菌的抗生素特性。


在这些微观的细菌池聚会中，人类可能只是在与超级细菌的军备竞赛中找到一个上风。


感谢您的收听。在《科学美国人》的60秒科学节目中，我是Sarah Vitak。