Sarah Vitak: This is Scientific American’s 60 Second Science. I’m Sarah Vitak.
Sarah Vitak：这里是《科学美国人》的 60 秒科学。我是Sarah Vitak。
So many of the objects we interact with nowadays run on programming and are designed for an exact purpose. We don’t typically think of living things as falling into this category, but more and more scientists are programming and designing living cells and even whole organisms.
如今，许多可交互对象都建立在程序之上，这些程序的设计往往带有明确的目的。我们通常认为有生命的东西不在这个范畴内，但越来越多的科学家正对活细胞甚至整个生物体进行编程和设计。
This area of research is called synthetic biology, and there is a whole subsection of this field that is all about figuring out how to engineer cellular armies that can be commanded and controlled: cells trained to search out diseased tissues; cells equipped for environmental reconnaissance; cell assassins that put out hits on other cells.
这个研究领域被称为合成生物学，其中一个研究方向就是基因编辑出能受人指挥和控制的细胞大军：用于寻找患病组织的“受训细胞”、用于探查环境的“武装细胞”、能够攻击其他细胞的“刺客细胞”。
Sounds cool, right? But in reality, nothing is that targeted and exact.
听起来很酷，对吗?但实际上，基因编辑的针对性和准确性并没有那么强。
Mikhail Shapiro: It’s somewhat limited, because those cells, to date, don’t really have spatial awareness, they don’t know, spatially, where they are in the body: Are they in a tumor? Are they in the liver? Are they in the pancreas? Are they in the brain? So, you know, they might try to figure that out based on molecular clues. But they don’t have this kind of GPS that’s telling them that they’re in the right place to carry out their actions.
Mikhail Shapiro：基因编辑仍有一定局限性，暂时不能赋予细胞们真正的空间意识，它们并不知道自己在人体中身处何处——是在肿瘤中?肝脏中?还是在胰腺或是大脑中?它们可能会根据分子线索来找到答案，但并没有像GPS一样的系统直接告诉它们是否身处执行任务的正确位置。
Vitak: That is Dr. Mikhail Shapiro, a professor of chemical engineering at Caltech. His lab recently tackled this problem head on using the power of air bubbles. [Avinoam Bar-Zion et al., Acoustically triggered mechanotherapy using genetically encoded gas vesicles]
Vitak：Mikhail Shapiro是加州理工学院化工教授。他的实验室最近利用气泡的力量解决了这个问题。[Avinoam Bar-Zion 等人， 使用基因编码气体囊的声学触发机械疗法]
Their lab had already been doing a lot of work with programming cells to create tiny structures called gas vesicles. They are basically just little air bubbles surrounded by a hard shell of protein that then float around inside the cell. You can think of them like nanoscale Ping-Pong balls.
在编程细胞以创建微小的气囊(gas vesicle)结构上，他们的实验室已经进行了大量工作。气囊本质上是漂浮在细胞内的小气泡，被一层坚硬的蛋白质外壳包裹着，就像是纳米级的乒乓球。
Shapiro: They have a fascinating origin. They basically evolved as flotation devices for photosynthetic microbes that live in water and need to float to the top of the water so they can get enough sunlight.
Shapiro：它们的起源十分有趣。在演化历程中，气囊是令光合微生物能够在漂浮在水上的结构，这些生活在水中的微生物需要浮出水面才能获得充足的阳光。
Vitak: Dr. Shapiro and his team had previously been able to put the genes for making gas vesicles into mammalian cells or other bacteria. At the time, they were doing this because they wanted to use it as a tool for imaging.
Vitak：Shapiro博士和他的团队此前就已能为哺乳动物细胞或其他细菌插入制造气囊的基因，他们当时这样做是为了把气囊用作成像工具。
They were inspired by jellyfish—more specifically, something that they make called green fluorescent protein, or GFP. The good thing about this protein is: it can be genetically encoded to be attached to naturally occurring proteins, allowing scientists to view them and track where they go in living cells or animals.
他们的灵感来自水母——准确来讲，来自绿色荧光蛋白(GFP)。GFP的一项用途是通过基因编码附着在天然蛋白质上，这能帮助科学家跟踪看到活体细胞或动物体内的蛋白质，并追踪它们。
Using GFP as an imaging tool totally changed the game in microscopy, so much so that its discovery and development was awarded a Nobel Prize in 2008.
将GFP作为示踪剂彻底改变了显微成像的游戏规则，GFP的发现和研发也因此获得了2008年的诺贝尔奖。
Shapiro: So we were kind of obsessed about finding something similar to a fluorescent protein but that, instead of being fluorescent, meaning interacting with light, would interact with sound waves and allow us to image it with ultrasound. And sound waves get scattered, or reflected, off of materials that have a different density, or stiffness, relative to their surroundings. And air, you know, is very different in its density and its compressibility, sort of, compared to tissue and water, and so on.
Shapiro：这让我们对探寻一种类似于荧光蛋白的新物质开始着迷——它类似荧光蛋白，但它并不与光，而是与声波产生相互作用。这样一来，我们就能用超声波对其成像。遇到材料密度或刚性与周围环境不同时，声波会发生散射或反射，而空气的密度和刚性特征与生物组织和水这样的环境相比，有着很大的差别。
Vitak: But recently they had the idea that maybe they could use these vesicles for other purposes—namely, by using ultrasound to intentionally burst the bubbles.
Vitak：但最近他们有新想法，或许这些气体囊泡可以有其他用法——即通过使用超声波来故意使气泡破裂。
Shapiro: If we just crank up the ultrasound a little bit, then we’re hitting that Ping-Pong ball hard enough that it cracks and opens.
Shapiro：我们只要稍稍加强超声波，就会像大力击打乒乓球一样让气囊破裂开来。
Vitak: When it does, the air is released, and so you have a little bubble inside the cell. Alone, it wouldn’t do anything. But as the ultrasound continues, the bubbles expand and contract.
Vitak：与此同时，其中的气体会释出，在细胞内形成一个气泡。气泡本不会变化，但在持续作用的超声波下，它会不断膨胀收缩。
Shapiro: And over time, several of these bubbles of air will come together and join up to form a larger bubble until it’s big enough that the ultrasound causes it to undergo a strong mechanical implosion.
Shapiro：随着时间的推移，一些气泡会聚集在一起形成更大的气泡，直到气泡大到能在超声波的作用下发生强烈的内爆。
Vitak: They started by getting this to work on the gas vesicles alone. They pulled a bunch of gas vesicles out of cells (an easy procedure because they just float to the top) and hit them with ultrasound. Then they listened in with an ultrasound mic and, sure enough, they could pick up the vesicles popping.
Vitak：他们首先单独对气囊施加超声波：从细胞中取出一堆气囊(气囊都漂浮在最上层，所以很容易取出)，然后用超声波轰击。果不其然，他们从超声波麦克风采集到的音频中听到了气囊爆裂的声音。
Shapiro: It’s ultrasound, so humans can’t hear it. But the spectrum of it looks like broadband noise. So when you turn on your TV, and it’s showing this like ...
Shapiro：我们施加的是超声波，人耳无法听到，但它的频谱看起来像是宽频带的噪声，就像是你打开电视时出现的——
[CLIP: White noise]
[剪辑：白噪声]
Shaprio: And I think that’s you would expect to hear if it were in the audible range.
Shapiro：如果它在声波范围内，你应该就能听到了。
Vitak: They wanted to see it as well.
Vitak：他们也想看看。
Shapiro: So we borrowed a five-million-frame-per-second camera from our aeronautics department and connected it to a microscope ...
Shapiro：所以我们从学校的航空系借来了一台每秒500万帧的摄像机，连接到了显微镜上……
Vitak: ... which sounds excessive, but actually it wasn’t. Sure enough, they could see the vesicles breaking and forming the bubbles, which would then pop. And all of this would happen in a matter of microseconds.
Vitak：这听起来有点过了，但其实恰到好处。他们果然看到了气囊破裂形成气泡、气泡又在随后破裂的过程，而这一切都发生在几微秒之中。
Next they wanted to try to apply it, so they made gas vesicles that had proteins on the surface that would bind to cancer cells. Then they mixed them with cancer cells in a dish and hit it with ultrasound.
接下来，他们想尝试实际应用这些气囊。他们为此制造了表面具有可与癌细胞结合的蛋白质的气囊，并在培养皿中将它们与癌细胞混合，再用超声波轰击。
It worked.
结果很成功。
Shapiro: Think of it as you’re punching the cancer cells. So these bubbles are expanding and contracting, and they’re punching and sending shockwaves very locally. And so that was pretty cool because, you know, we kind of converted our innocent little imaging agent into a little bomb that we put on a cancer cell and blow it up. But we thought it would be even cooler if we could get cells to be the bomb and have those cells go into the body and infiltrate a tumor to get inside.
Shapiro：就好像是你在对癌细胞拳打脚踢，这些气泡的膨胀和收缩会在局部产生冲击，发出冲击波。这非常酷，我们实际上把‘人畜无害’的小小显像剂变成了小炸弹，安在癌细胞上然后引爆。我们还在想，要是能让细胞变成炸弹后进入人体，潜入肿瘤组织，那就更酷了。
Vitak: So they tried the same experiments again, but this time they used bacteria that were engineered not only to make gas vesicles but also to home in on tumors.
Vitak：于是，他们用基因编辑过的细菌重复了相同的实验，这些细菌不仅能够产生气囊，还可以导向肿瘤。
In the petri dish, it worked.
在培养皿中，它起作用了。
Their next step was to try it inside an animal. This is where the ultrasound aspect really pays off because ultrasound can be used and targeted to a very specific location in the body. It basically makes up for that lack of cellular GPS I mentioned earlier.
他们的下一步计划是在动物体内进行测试。由于超声波能够定位到体内特定的精确位置，气囊的超声波特性体现出了真正的价值，这基本上解决了前文所说“缺乏GPS定位”的问题。
So they injected some of these bacteria into the bloodstream of mice with tumors. And they saw ...
因此，他们将其中一些细菌注入患有肿瘤的小鼠的血液中。他们看到...
Shapiro: ... the bacterial cells kind of go different places around the body. But in most of the body, they get eliminated by the immune system—except in the core of the tumor because the tumor is an immunosuppressive environment.
Shapiro： ......细菌细胞去到了全身的不同部位。在大部分区域，它们会被免疫系统清除，但在肿瘤的核心区域不会，因为这是一个免疫抑制的环境。
Vitak: So basically using one of cancer’s key traits—and adaptations against it.
Vitak：他们正是利用癌症的这一关键特性，进行了针对性的改良。
Shapiro: And what’s cool is that because the gas vesicles can serve as both an imaging agents and now a therapeutic agent. We could see, with ultrasound imaging, that the cells were in the tumor and could confirm that our little therapeutic agent got there and established a little colony inside the tumor center.
Shapiro：妙就妙在，气囊既可以作为显像剂，也能作为治疗剂。通过超声成像，我们看到细胞在肿瘤之中，确认了我们的小治疗剂已经抵达肿瘤中心，并在那里建立了一个小型‘殖民地’。
Vitak: Then they targeted ultrasound at the tumor. They did this in combination with a new class of cancer drugs that allow immune cells to find and kill cancer cells, known as immune checkpoint inhibitors. On average, the mice who received the bacteria and ultrasound treatment lived twice as long as the mice that only got the new cancer drugs.
Vitak：然后他们将超声波对准肿瘤。这一过程还结合了一类能让免疫细胞发现并杀死癌细胞的抗癌药物——免疫检查点抑制剂(immune checkpoint inhibitors)，结果发现，同时接受细菌和超声波治疗的小鼠寿命是仅接受抗癌新药治疗小鼠的两倍。
This is maybe just the beginning for what we can do with these little targeted missile bacteria. They might also be promising for other disease treatments. Especially because you can have the bacteria carry a payload like a drug and then burst them open to release it in a particular location.
这可能只是这些小小“细菌追踪导弹”的一个开始，更大的潜力仍待探索。它们或许也能在其他疾病的治疗上发挥作用，你可以利用细菌携带药物等载荷，将其运抵特定位置后炸裂并释放。
Shapiro: It’s a great example of Mother Nature giving us this, you know, precious gift. And it’s something that actually was discovered more than 100 years ago: the first paper noticing that there are these air-filled pockets in bacteria was published in 1895.
Shapiro：这是自然母亲赠予我们一份珍贵礼物。实际上，细菌内的气囊早在一百多年前就被发现了：第一个注意到这一点的论文发表于1895年。
So I just think it's a neat story of going all the way from, you know, a couple billion years of evolution to then 100 years of basic biologists, you know, poking around at them—and now these proteins finding a whole new life.
我真的觉得这是个很有意思的故事：从几十亿年的演化历程，到一百多年来的基础生物学家，都在围绕它们兜兜转转，而这些蛋白质如今获得了全新的生命。
Vitak: Thanks for listening. For Scientific American’s 60 Second Science, I’m Sarah Vitak.
Vitak：感谢收听。这里是《科学美国人》的 60 秒科学，我是 Sarah Vitak。
Sarah Vitak: This is Scientific American’s 60 Second Science. I’m Sarah Vitak.
So many of the objects we interact with nowadays run on programming and are designed for an exact purpose. We don’t typically think of living things as falling into this category, but more and more scientists are programming and designing living cells and even whole organisms.
This area of research is called synthetic biology, and there is a whole subsection of this field that is all about figuring out how to engineer cellular armies that can be commanded and controlled: cells trained to search out diseased tissues; cells equipped for environmental reconnaissance; cell assassins that put out hits on other cells.
Sounds cool, right? But in reality, nothing is that targeted and exact.
Mikhail Shapiro: It’s somewhat limited, because those cells, to date, don’t really have spatial awareness, they don’t know, spatially, where they are in the body: Are they in a tumor? Are they in the liver? Are they in the pancreas? Are they in the brain? So, you know, they might try to figure that out based on molecular clues. But they don’t have this kind of GPS that’s telling them that they’re in the right place to carry out their actions.
Vitak: That is Dr. Mikhail Shapiro, a professor of chemical engineering at Caltech. His lab recently tackled this problem head on using the power of air bubbles. [Avinoam Bar-Zion et al., Acoustically triggered mechanotherapy using genetically encoded gas vesicles]
Their lab had already been doing a lot of work with programming cells to create tiny structures called gas vesicles. They are basically just little air bubbles surrounded by a hard shell of protein that then float around inside the cell. You can think of them like nanoscale Ping-Pong balls.
Shapiro: They have a fascinating origin. They basically evolved as flotation devices for photosynthetic microbes that live in water and need to float to the top of the water so they can get enough sunlight.
Vitak: Dr. Shapiro and his team had previously been able to put the genes for making gas vesicles into mammalian cells or other bacteria. At the time, they were doing this because they wanted to use it as a tool for imaging.
They were inspired by jellyfish—more specifically, something that they make called green fluorescent protein, or GFP. The good thing about this protein is: it can be genetically encoded to be attached to naturally occurring proteins, allowing scientists to view them and track where they go in living cells or animals.
Using GFP as an imaging tool totally changed the game in microscopy, so much so that its discovery and development was awarded a Nobel Prize in 2008.
Shapiro: So we were kind of obsessed about finding something similar to a fluorescent protein but that, instead of being fluorescent, meaning interacting with light, would interact with sound waves and allow us to image it with ultrasound. And sound waves get scattered, or reflected, off of materials that have a different density, or stiffness, relative to their surroundings. And air, you know, is very different in its density and its compressibility, sort of, compared to tissue and water, and so on.
Vitak: But recently they had the idea that maybe they could use these vesicles for other purposes—namely, by using ultrasound to intentionally burst the bubbles.
Shapiro: If we just crank up the ultrasound a little bit, then we’re hitting that Ping-Pong ball hard enough that it cracks and opens.
Vitak: When it does, the air is released, and so you have a little bubble inside the cell. Alone, it wouldn’t do anything. But as the ultrasound continues, the bubbles expand and contract.
Shapiro: And over time, several of these bubbles of air will come together and join up to form a larger bubble until it’s big enough that the ultrasound causes it to undergo a strong mechanical implosion.
Vitak: They started by getting this to work on the gas vesicles alone. They pulled a bunch of gas vesicles out of cells (an easy procedure because they just float to the top) and hit them with ultrasound. Then they listened in with an ultrasound mic and, sure enough, they could pick up the vesicles popping.
Shapiro: It’s ultrasound, so humans can’t hear it. But the spectrum of it looks like broadband noise. So when you turn on your TV, and it’s showing this like ...
[CLIP: White noise]
Shaprio: And I think that’s you would expect to hear if it were in the audible range.
Vitak: They wanted to see it as well.
Shapiro: So we borrowed a five-million-frame-per-second camera from our aeronautics department and connected it to a microscope ...
Vitak: ... which sounds excessive, but actually it wasn’t. Sure enough, they could see the vesicles breaking and forming the bubbles, which would then pop. And all of this would happen in a matter of microseconds.
Next they wanted to try to apply it, so they made gas vesicles that had proteins on the surface that would bind to cancer cells. Then they mixed them with cancer cells in a dish and hit it with ultrasound.
It worked.
Shapiro: Think of it as you’re punching the cancer cells. So these bubbles are expanding and contracting, and they’re punching and sending shockwaves very locally. And so that was pretty cool because, you know, we kind of converted our innocent little imaging agent into a little bomb that we put on a cancer cell and blow it up. But we thought it would be even cooler if we could get cells to be the bomb and have those cells go into the body and infiltrate a tumor to get inside.
Vitak: So they tried the same experiments again, but this time they used bacteria that were engineered not only to make gas vesicles but also to home in on tumors.
In the petri dish, it worked.
Their next step was to try it inside an animal. This is where the ultrasound aspect really pays off because ultrasound can be used and targeted to a very specific location in the body. It basically makes up for that lack of cellular GPS I mentioned earlier.
So they injected some of these bacteria into the bloodstream of mice with tumors. And they saw ...
Shapiro: ... the bacterial cells kind of go different places around the body. But in most of the body, they get eliminated by the immune system—except in the core of the tumor because the tumor is an immunosuppressive environment.
Vitak: So basically using one of cancer’s key traits—and adaptations against it.
Shapiro: And what’s cool is that because the gas vesicles can serve as both an imaging agents and now a therapeutic agent. We could see, with ultrasound imaging, that the cells were in the tumor and could confirm that our little therapeutic agent got there and established a little colony inside the tumor center.
Vitak: Then they targeted ultrasound at the tumor. They did this in combination with a new class of cancer drugs that allow immune cells to find and kill cancer cells, known as immune checkpoint inhibitors. On average, the mice who received the bacteria and ultrasound treatment lived twice as long as the mice that only got the new cancer drugs.
This is maybe just the beginning for what we can do with these little targeted missile bacteria. They might also be promising for other disease treatments. Especially because you can have the bacteria carry a payload like a drug and then burst them open to release it in a particular location.
Shapiro: It’s a great example of Mother Nature giving us this, you know, precious gift. And it’s something that actually was discovered more than 100 years ago: the first paper noticing that there are these air-filled pockets in bacteria was published in 1895.
So I just think it's a neat story of going all the way from, you know, a couple billion years of evolution to then 100 years of basic biologists, you know, poking around at them—and now these proteins finding a whole new life.
Vitak: Thanks for listening. For Scientific American’s 60 Second Science, I’m Sarah Vitak.
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