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You can get a $100 60-day credit on a new Linode account at linode.com/scishow. If you love watching videos of single-celled critters wriggling around under a microscope, you’re not alone.

But you may wonder if there’s footage of even tinier biology. Well, here’s an image of just that. This string of beads is actually DNA wrapped around some proteins.

Looks pretty cool, right? But snapshots like these come with a dark secret. A death sentence.

In order to take a picture of something this small, you have to kill your sample. And that’s a bummer, because biology doesn’t necessarily look or act the same when it’s dead. But over the past few decades, scientists have developed a new technology that can see really tiny things without killing them.

It’s called atomic force microscopy, and its real-time, small-scale footage is helping scientists study some pretty important stuff, like how to treat cancer. [♪ INTRO] In 1538, the Italian physician Girolamo Fracastoro noted that if he put one of his eyeglass lenses on top of another, the object beneath them would look a lot larger. Fast forward to the end of the century, and you’ve got the first compound microscopes. Today, their descendents can use visible light to see things as small as 200 nanometers in size.

Or roughly 1/500th of the diameter of a human hair. That scale is perfectly fine if you’re studying things like blood cells or bacteria, but if your target is a virus, or molecules like DNA and proteins, you can forget about that. Below 200 nanometers, you can run up against a problem called the Limit of Diffraction.

Light is a wave, and when waves interact with the edges of things, say a teeny bacterium or parts of your microscope, they diffract. They spread out and blur your image.

And because the shortest wavelengths of light that your typical human eye can see hover around 400 nanometers, diffraction prevents us from resolving any details smaller than half that wavelength. So on the scale of, say, a 2.5-nanometer thick strand of DNA, diffraction turns the whole thing into a giant blurry mess. And it wouldn’t matter if you stacked doctor Girolamo’s glasses up to outer space. So long as you’re trying to look at DNA with visible light waves, you can’t unblur the image.

So back in 1933, scientists decided to get around that limitation entirely, not by switching to a different wavelength of light, but to electrons. Electron microscopes shoot a beam of electrons through a specimen to detect where they slam into atomic nuclei, and exactly how they scatter in the process.

Using this technique, researchers can see things as small as 0.1 nanometer. That’s two thousand times better than traditional optical microscopes. So if you want an up close look at, oh, say, how a novel coronavirus infects human cells, you’re good to go.

Well, at least after you kill everything. Because in order for electron microscopy to work, your sample has to conduct electricity, and it needs to be placed in a vacuum. That means a specimen must be dehydrated, frozen, sliced up and covered with something conductive, like gold.

Not only is it dead, all that prep work and the electricity you’re pumping through these teeny tiny corpses can damage them. And putting your sample through a proverbial meat grinder probably isn’t the best way to figure out how fundamental biology works in the real world. But luckily, in the mid-1980s, scientists developed a nano-scale microscope that was a lot more merciful.

The Atomic Force Microscope, or AFM, doesn’t need its samples to conduct electricity, so you don’t have to coat them in some conductive metal. You don’t have to freeze them, slice them up, or dehydrate them, either. AFM's also don’t have to operate in a vacuum, so they can look at samples while they’re in liquid, which is where a lot of life likes to hang out.

Here’s how they let us look at life in all its living, gooey glory. Heads up, it’s kind of an “I’m not touching you” game on atom-scale steroids. The AFM's that researchers use to study live biological samples have a super tiny probe that wiggles up and down at a very specific frequency, and moves along the sample, hovering just above the surface.

When the tip of the probe is 10 nanometers away from the sample, it gets pulled toward the sample because of a phenomenon called van der Waals forces, which famously allows geckos to stick to seemingly anything. But when the tip gets too close, within a few tenths of a nanometer, it gets pushed away because all of the electrons in the tip and the sample’s surface really hate being too close to one another. Well, as much as subatomic particles are capable of experiencing hate.

By tracking all of this pushing and pulling, and how those forces affect the probe’s wiggling, scientists can figure out where the tip runs into any grooves or bumps. That builds up a 3D map of a sample, down to the atomic level. And if you use the right kind of probe, AFM's can do more than map.

They can also measure the mechanical properties of your sample, like surface friction or stiffness. It turns out, some cancerous cells are stiffer than their healthy counterparts, so scientists are currently investigating how to use atomic force microscopy to help diagnose cancer. Which, is pretty sweet!

But for all its bio-scanning power, the original atomic force microscopes came with one huge flaw. They needed minutes to complete a single image. That’s plenty of time for camera-shy proteins and viruses to scurry away, so those early pictures could have missed a lot of important details.

But by 2001, researchers had miniaturized the scanning machinery and made other improvements to kick AFM's into high gear. Today’s high-speed AFM's can show us how nanobiology works in real time. I’m talking actual video, capturing up to 50 frames per second!

This allows scientists to film everything, from DNA strands coming together to form the double helix, to cell membranes opening up to let in foreign invaders, to proteins folding up to change what they can do in your body. And there’s more! Atomic force microscopy doesn’t just let us watch molecular processes happen live, it lets us manipulate them, too.

For example, you can stick the molecule of a drug onto the tip of the scanning probe, use the AFM to locate the receptor you want the molecule to interact with, plop it in, and see what happens. Scientists are using this technique to study how existing breast and prostate cancer drugs work, to get them to do their job even better.

So yeah, we’ve come a long way since Girolamo Fracastoro’s eyeglasses. But we’ve also come back around to creating a technology that lets us study teeny tiny things while they’re still kicking. And I am off to watch some of those awesome videos now, but right after I talk about our sponsor for this episode.

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