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Microscopes are great for studying tiny things, but they have limits. Luckily, scientists have found a way to make tiny things larger, and it involves a chemical you can find in diapers.

Hosted by: Olivia Gordon

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Sources:

https://www.ruf.rice.edu/~bioslabs/methods/microscopy/microscopy.html
https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-017-0393-3
https://www.sciencedirect.com/science/article/pii/S0959438817302921
https://www.nature.com/articles/nmeth.4113
https://www.nature.com/articles/nbt.3641
https://www.nature.com/articles/nbt.3625
https://www.nature.com/articles/nphoton.2009.100
https://onlinelibrary.wiley.com/doi/epdf/10.1111/jmi.12712
[ INTRO].

Tiny things make up the whole universe — from bacteria on your skin, to cells in your body, and quantum particles if you want to get even smaller. But even under ideal conditions, the human eye can only make out things that are at least 0.1 millimeters apart.

That’s about the thickness of one piece of paper. Microscopes have made studying tiny things a lot easier, but they have limits, too. So, wouldn’t it be nice if we could just make things... bigger?

Turns out, scientists have done that with tissue samples, using a chemical you can find in diapers. If you were asked to picture a microscope, you’d probably think of a light microscope. They’re one of the most common types.

And while there are variations, all of them basically work by shining light onto an object, and magnifying the image using lenses. Light microscopes let us observe things that are at least 250 nanometers apart, which is about the thickness of a human hair. Some of the smallest objects you can see are red blood cells and bacteria.

If you try to zoom in more than that, the image will get blurry because of how light diffracts, or spreads out, when it hits an object. So you wouldn’t be able to visualize DNA or an atom, for example. This physical limit to light microscopes is called the Abbe diffraction limit, named after the German physicist who worked it out in 1873.

But since then, scientists have figured out how to get higher resolution images using other techniques, like electron microscopy. Electron microscopes use magnetic lenses to magnify the image. And they use electron beams instead of light beams to visualize the image, which diffract a lot less.

So we can even see atoms with them! But they come at a price — most of them cost upwards of a million dollars. And they’re not good for everything.

Many biologists use microscopy to look for proteins and other molecules in tissues, like to study diseases. These things are in the nanometer range, so they need a high-resolution microscope. But because electron microscopes work by passing electrons through an object, tissue slices usually have to be very thin.

So it’s tricky to work with sections of tumors and brains. That’s where expansion microscopy comes in. It almost sounds too simple to be true, but scientists have found that you can stretch biological tissues by embedding a chemical that can swell into them.

As it happens, the most well-characterized one is used to make diapers spongy. It’s called sodium polyacrylate. Sodium polyacrylate has two main properties, which you’ve maybe seen in action on a baby’s bottom.

First, these molecules bind to each other and form a sturdy mesh-like structure. And second, this polyacrylate mesh can sort of open up so that water molecules fill in the gaps. That’s how diapers absorb liquids, and swell up.

So, say you’re interested in looking at some proteins in liver tissue and want to use expansion microscopy. First, you have to chemically fix the tissue — basically stopping all biological activity, like a snapshot in time. Next, you add fluorescent molecules that are designed to bind to the proteins you want to study.

These molecules also have a chemical anchor that lets them stick to the polyacrylate mesh after it forms. Fluorescent molecules are a fairly common tool in cell biology. They let scientists use a kind of light microscopy called fluorescent microscopy to study specific parts of a sample.

Anyway, then you add some sodium acrylate molecules, which evenly make their way around the proteins and other stuff inside the tissue. Before you can add water and expand the tissue, you need to make sure everything doesn’t just burst. Because that would ruin your experiment.

So you need to use chemicals to degrade structural proteins , while leaving everything else intact. And then you can add water. As the tissue expands, proteins and other molecules that were originally very close to each other move farther apart.

This makes them more easily visible under a light microscope, and scientists can overcome the Abbe diffraction limit. So expansion microscopy lets researchers visualize small things like proteins, RNA, or even connections between neurons called synapses. In fact, this technique has been used in brain samples to map synapses and cells in fruit flies, mice, non-human primates, and even humans.

Cataloging how different neurons make connections can help scientists learn what information is sent and received in various brain regions. Eventually, this could help us identify things that go wrong in disordered brains too. Overall, expansion microscopy is cheap and promising, and it can be used on most biological samples — from brain to lung tissues.

But like every technique, there are also limitations. For instance, buying specialized fluorescent molecules can get pricey, because synthesizing and mass producing them is expensive. And because you need to remove structural proteins to let the tissue expand, you can’t study any of them.

Also, since tissue samples after expansion are 99% water, they can be nearly transparent and tricky to see. Plus, scientists have to be careful with the samples because they’re more fragile. But, with improvements, expansion microscopy could help us study the mysteries of the brain.

Only time will tell! Thanks for watching this episode of SciShow, and thanks especially to our patrons on Patreon. Without their support, we wouldn’t be able to make all these videos about weird and cool science.

So if you want to join the SciShow community, you can go to patreon.com/scishow. [OUTRO].