Expansion Microscopy Has Transformed How We See the Cellular World

Expansion microscopy images of the dinoflagellate Karenia papiloniacea .

甲藻 Karenia papiloniacea 的放大显微镜图像。

Centrin is in green, nucleus in blue, and in red what appear to be intracellular crystals that could be compartments for metabolite storage.

中心蛋白为绿色，细胞核为蓝色，红色为细胞内晶体，可能是代谢物储存的隔间。

W hen you slip a slide under a microscope, a system of glass lenses magnifies the object of your attention — a microbe, for example.

当您将载玻片放在显微镜下时，玻璃镜片系统会放大您关注的物体（例如微生物）。

But even with the largest zoom on a classic compound optical system, scientists struggle to make sense of finer details, which can be further obscured when tough cell walls make it difficult to inject dyes that help identify structures.

但即使使用经典复合光学系统的最大变焦，科学家们仍难以理解更精细的细节，当坚韧的细胞壁使得难以注入有助于识别结构的染料时，这些细节可能会进一步模糊。

Now, rather than invest in more powerful and more expensive technologies, some scientists are using an alternative technique called expansion microscopy, which inflates the subject using the same moisture-absorbing material found in diapers.

现在，一些科学家没有投资更强大、更昂贵的技术，而是使用一种称为膨胀显微镜的替代技术，该技术使用与尿布中相同的吸湿材料来使物体膨胀。

“It’s cheap, it’s easy to learn, and indeed, on a cheap microscope, it gives you better images,” said Omaya Dudin , a cell biologist at the University of Geneva who studies multicellularity.

“它很便宜，很容易学习，而且事实上，在便宜的显微镜上，它可以给你带来更好的图像，”日内瓦大学研究多细胞的细胞生物学家 Omaya Dudin 说。

Expansion microscopy was developed by Ed Boyden at the McGovern Institute for Brain Research at the Massachusetts Institute of Technology in 2015.

膨胀显微镜是由麻省理工学院麦戈文脑研究所的 Ed Boyden 于 2015 年开发的。

Boyden and colleagues successfully expanded a biological sample by infusing it with a hydrogel made of sodium acrylate.

博伊登和同事通过向生物样本注入由丙烯酸钠制成的水凝胶，成功地扩展了生物样本。

A key ingredient layered in diapers to keep babies dry, the compound can absorb hundreds of times its weight in water while retaining its overall structure.

这种化合物是尿布中保持婴儿干燥的关键成分，可以吸收其重量数百倍的水，同时保持其整体结构。

Omaya Dudin (top) and Gautam Dey

奥玛亚·杜丁（上）和高塔姆·戴伊

In expansion microscopy, specific biomolecules such as proteins are anchored to the gel.

在膨胀显微镜中，特定的生物分子（例如蛋白质）固定在凝胶上。

As the gel absorbs added water, its weblike matrix swells, and the space between the web’s anchor points dilates.

当凝胶吸收添加的水时，其网状基质膨胀，并且网锚点之间的空间膨胀。

Ideally, the overall structure remains, allowing researchers to visualize extra-tiny anatomy or see inside cells with tough barriers.

理想情况下，整体结构保持不变，使研究人员能够可视化超微小的解剖结构或看到具有坚固屏障的细胞内部。

Dudin had spent six frustrating years trying to force antibodies through his target cells’ sturdy walls to bind to specific proteins and visualize their internal structures, and he was only able to do so through a complex freeze-and-thaw protocol that destroyed most of the final product.

杜丁花了六年令人沮丧的时间试图迫使抗体穿过靶细胞坚固的细胞壁与特定蛋白质结合并可视化其内部结构，而他只能通过复杂的冷冻和解冻方案来做到这一点，该方案破坏了大部分最终产品。

Desperate, he struck up a Covid-era collaboration with the lab next door that was using expansion microscopy.

绝望之下，他与隔壁使用膨胀显微镜的实验室建立了新冠时代的合作。

“That moment was just magical.

“那一刻真是太神奇了。

All the cells were expanded, everything stained, we could see,” Dudin said.

我们可以看到所有的细胞都扩增了，所有的东西都被染色了，”杜丁说。

“It very rapidly became clear that we should aim for the sky with this one.”

“很快我们就清楚了，我们应该用这个瞄准天空。”

Gautam Dey , a cell biologist at the European Molecular Biology Laboratory in Heidelberg who studies mitosis, found that the method worked just as well in his lab.

海德堡欧洲分子生物学实验室研究有丝分裂的细胞生物学家高塔姆·戴伊 (Gautam Dey) 发现这种方法在他的实验室中同样有效。

The samples were clearer, and the dyes and antibodies penetrated cells more effectively, so the two labs struck up a collaboration to visualize species they had never studied before.

样本更清晰，染料和抗体更有效地渗透细胞，因此两个实验室展开合作，以可视化他们以前从未研究过的物种。

They are working to chart the landscape of cytoskeletal diversity , visualizing complex cytoskeletal structures that have never been seen in such detail.

他们正在努力绘制细胞骨架多样性的图景，以可视化从未如此详细地观察过的复杂细胞骨架结构。

Perhaps most importantly, expansion microscopy is possible for any lab with a basic microscope and the hydrogel.

也许最重要的是，任何拥有基本显微镜和水凝胶的实验室都可以使用膨胀显微镜。

“People have talked about democratizing microscopy before.

“人们以前曾谈论过显微镜的民主化。

This is it, it’s happening,” Dey said.

就是这样，它正在发生，”戴伊说。

“I think it’s just a matter of time before any cell biology lab in the world is doing it.

“我认为世界上任何细胞生物学实验室这样做只是时间问题。

A basic fluorescence microscope is never too far away.”

基本的荧光显微镜永远不会太遥远。”

T he first species that Dudin’s lab imaged using expansion microscopy was the unicellular eukaryote Sphaeroforma arctica , a protist that has multiple nuclei in a single cell.

杜丁实验室使用膨胀显微镜成像的第一个物种是单细胞真核生物 Sphaeroforma arctica，这是一种在单个细胞中具有多个细胞核的原生生物。

This image shows cells at different stages of their life cycle.

该图显示了处于生命周期不同阶段的细胞。

Nuclei in the two upper cells are undergoing mitosis, or nuclear division.

两个上部细胞中的细胞核正在进行有丝分裂或核分裂。

The lower cells are in late mitosis, with the nuclei switching back to a growth stage.

下部细胞处于有丝分裂后期，细胞核转回到生长阶段。

T he predatory ciliate Lacrymaria is a Dudin lab favorite and has a feeding structure formed from a vortex of microtubules.

捕食性纤毛虫泪腺是杜丁实验室的最爱，它的进食结构是由微管涡流形成的。

Although it is retracted here, Lacrymaria can rapidly extend the tubule structure to capture escaping prey.

虽然在这里缩回，但泪玛丽亚可以迅速伸展小管结构以捕获逃跑的猎物。

E xpansion microscopy has allowed Dudin and Dey to see all sorts of unexpected structures.

膨胀显微镜使杜丁和戴伊能够看到各种意想不到的结构。

For instance, Rhinomonas is a unicellular photosynthetic alga with two flagella, found predominantly in marine environments.

例如，犀单胞菌是一种具有两个鞭毛的单细胞光合藻类，主要存在于海洋环境中。

The appearance of the specialized protein centrin (green) decorating regularly spaced arrays was previously unreported for this lineage.

以前没有报道过该谱系中装饰规则间隔阵列的特殊蛋白质中心蛋白（绿色）的出现。

D iatoms are particularly difficult to image through their protective glass shells, called frustules.

硅藻特别难以通过其保护性玻璃壳（称为硅藻壳）成像。

Dey’s lab decided to use an alternative expansion microscopy protocol, in which the sample is expanded and its proteins tagged with fluorescent antibodies; rapid freezing then locks everything in place.

Dey 的实验室决定使用另一种扩展显微镜方案，其中样品被扩展并用荧光抗体标记其蛋白质；快速冷冻然后将所有东西锁定到位。

C entrin is a small calcium-binding protein that co-polymerizes with larger proteins to produce networks of structural filaments in a cell.

C entrin 是一种小型钙结合蛋白，可与较大的蛋白质共聚，在细胞中产生结构丝网络。

Centrin-containing fibers are especially abundant in ciliates; this intricate mesh (yellow) is located just below the cell membrane in this expanded Vorticella cell.

纤毛虫中含有中心蛋白的纤维尤其丰富；这个复杂的网格（黄色）位于这个扩展的涡细胞中细胞膜的正下方。

I n freshwater ciliates known as Vorticella , the researchers spotted “an amazing centrin cage, dotted tubulin flagellar components, and an insane mouth apparatus [at far left, green],” Dudin said.

杜丁说，在被称为涡虫的淡水纤毛虫中，研究人员发现了“一个令人惊叹的中心蛋白笼、点状微管蛋白鞭毛成分和一个疯狂的口器（最左边，绿色）”。

In the middle, a spindle (green) appears to be organizing as cells prepare for division.

在中间，当细胞准备分裂时，纺锤体（绿色）似乎正在组织。

Green dots of the structural protein tubulin are visible throughout the protist’s distinctive stalk (at right).

结构蛋白微管蛋白的绿点在原生生物独特的茎中可见（右图）。

A dinoflagellate identified in Antarctica’s Ross Sea is known to steal organelles called plastids from the microalga Phaeocystis antarctica .

已知在南极洲罗斯海发现的一种甲藻可以从微藻南极棕囊藻中窃取称为质体的细胞器。

Expansion microscopy of the engulfing process revealed that the host microbe retained more than just plastids.

吞噬过程的放大显微镜显示，宿主微生物保留的不仅仅是质体。

The alga’s nucleus (blue) and other features such as a protein complex crucial for photosynthesis (green) were also observed inside the host.

在宿主体内还观察到了藻类的细胞核（蓝色）和其他特征，例如对光合作用至关重要的蛋白质复合物（绿色）。

These interactions offer insight into early evolutionary steps of eukaryotes but are still not fully understood.

这些相互作用提供了对真核生物早期进化步骤的深入了解，但仍不完全清楚。

E xpansion microscopy of the dinoflagellate Lingulodinium polyedra reveals the chromosomal organization (DNA in blue) and internal axostyle (center, green) — a microtubule structure that helps the cell move.

甲藻 Lingulodinium polyedra 的扩张显微镜揭示了染色体组织（蓝色 DNA）和内部轴杆（中心，绿色）——一种帮助细胞移动的微管结构。

“We have imaged more than 60 species across the dinoflagellate tree, allowing us to map cytoskeletal diversity within the whole lineage,” Dudin said.

“我们对甲藻树上 60 多个物种进行了成像，使我们能够绘制整个谱系内的细胞骨架多样性图，”Dudin 说。

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