鑽石舞台

基因編輯細菌：腫瘤你好，腫瘤再見

如今，許多可交互對象都建立在程序之上，這些程序的設計往往帶有明確的目的。我們通常認為有生命的東西不在這個範疇內，但越來越多的科學家正對活細胞甚至整個生物體進行編程和設計。

這個研究領域被稱為合成生物學，其中一個研究方向就是基因編輯出能受人指揮和控制的細胞大軍：用於尋找患病組織的「受訓細胞」、用於探查環境的「武裝細胞」、能夠攻擊其他細胞的「刺客細胞」。

聽起來很酷，對嗎？但實際上，基因編輯的針對性和準確性並沒有那麼強。

「基因編輯仍有一定局限性，暫時不能賦予細胞們真正的空間意識，它們並不知道自己在人體中身處何處——是在腫瘤中？肝臟中？還是在胰腺或是大腦中？它們可能會根據分子線索來找到答案，但並沒有像 GPS 一樣的系統直接告訴它們是否身處執行任務的正確位置。」美國加州理工學院（Caltech）化工教授米哈伊爾·夏皮羅（Mikhail Shapiro）說道，他的實驗室最近利用氣泡解決了這一問題。

在編程細胞以創建微小的氣囊（gas vesicle）結構上，他們的實驗室已經進行了大量工作。氣囊本質上是漂浮在細胞內的小氣泡，被一層堅硬的蛋白質外殼包裹着，就像是納米級的乒乓球。

「它們的起源十分有趣。在演化歷程中，氣囊是令光合微生物能夠在漂浮在水上的結構，這些生活在水中的微生物需要浮出水面才能獲得充足的陽光。」

夏皮羅和他的團隊此前就已能為哺乳動物細胞或其他細菌插入製造氣囊的基因，他們當時這樣做是為了把氣囊用作成像工具。

他們的靈感來自水母——準確來講，來自綠色熒光蛋白（GFP）。GFP 的一項用途是通過基因編碼附着在天然蛋白質上，這能幫助科學家跟蹤看到活體細胞或動物體內的蛋白質，並追蹤它們。

將 GFP 作為示蹤劑徹底改變了顯微成像的遊戲規則，GFP 的發現和研發也因此獲得了 2008 年的諾貝爾獎。

「這讓我們對探尋一種類似於熒光蛋白的新物質開始着迷——它類似熒光蛋白，但它並不與光，而是與聲波產生相互作用。這樣一來，我們就能用超聲波對其成像。遇到材料密度或剛性與周圍環境不同時，聲波會發生散射或反射，而空氣的密度和剛性特徵與生物組織和水這樣的環境相比，有着很大的差別。」

而最近他們有了新的想法——或許這些氣體囊泡可以有其他用法，例如，用超聲波有意將其引爆。「我們只要稍稍加強超聲波，就會像大力擊打乒乓球一樣讓氣囊破裂開來。」與此同時，其中的氣體會釋出，在細胞內形成一個氣泡。氣泡本不會變化，但在持續作用的超聲波下，它會不斷膨脹收縮。「隨着時間的推移，一些氣泡會聚集在一起形成更大的氣泡，直到氣泡大到能在超聲波的作用下發生強烈的內爆……[查看全文]

Engineered Bacteria Use Air Bubbles

as Acoustically Detonated Tumor TNT

You read that right. Researchers have taken the chemical defenses of some insects and turned them into sounds, which, it turns out, repel people just as well.

So many of the objects we interact with nowadays run on programming and are designed with an exact purpose in mind. 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.

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…[full tra‍n‍scri‍pt]

封面圖片來源：Pixabay

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