(Intro)

The smallest things can teach you a lot about life. Cells, proteins, tiny hamsters eating tiny burritos, they're all fascinating, especially to scientists. Well I don't know if the tiny hamster thing is especially fascinating to scientists, I think that's fascinating to everyone. But the point of this episode is microscopes which have opened up a whole new world for science.

And over time, microscopes have gotten better and better at revealing the tiniest things as scientists have come up with new ways to hack the physics of light. Because when it comes to traditional microscopes there’s a problem.

Usually they work by passing light though the thing that you're looking at and then collecting that light with a lens. And that’s a great system except for once that light hits your specimen the light spreads out. Light travels in waves and if you blow something up big enough, those waves start to overlap effectively cancelling each other out, resulting in a blurry image.

So you can't use a traditional visible-light microscope to pick out anything smaller than about 200 nanometers or billionths of a meter.

And that’s an issue for any scientist who wants to see something really tiny. A biologist, for instance, wouldn’t be able to see anything much smaller than the largest structures in a human cell, and biologists, well they really want to know what's going on in there.

So scientists started thinking up some creative ways to get around the blurry light problem and they’ve come up with some pretty fascinating and in at least one case, potentially deadly, new techniques.

To give a sense of how game-changing the first two techniques are, their inventors were awarded the 2014 Nobel prize in chemistry and they don’t hand those things out to just anybody. First, a group of researchers invented a technique that’s called STimulated Emission Depletion or STED, basically its like microscopic laser tag.

With STED, you mark the sample you want to study by attached strange little modules called fluorophores. Fluorophores have three states: ground, excited and dark and you can control those states using lasers.

So if you tag your sample with some the fluorophores then aim a laser at it, the extra energy knocks them up into the excited state and then they light up on the way back down to the ground state. Then you use a second laser to surround the beam of the first one, concentrating the energy on the very center of your target so the surrounding fluorophores stay in the dark state and only your target lights up. Then you just snap a picture.

A similar technique called Single Molecule Imaging uses Fluorophores too, but it excites only a few molecules of the sample at a time. This allows scientists to get a clear look at a smaller part of the sample, and then after lighting up an taking pictures of a few molecules at a time, they can then put together all of those images into a bigger picture, just like a Pointillist painting.

These techniques can let scientists see things down to about 20 nanometers, which is only about 10 times the width of DNA, and ten times smaller than what you would see with a traditional microscope. So for the first time we can now see tiny details of a cell with visible light. But there are things that are still too small for us to see.

And preparing samples for traditional microscopes has another drawback; it usually kills them. Sometimes that's fine, but sometimes, well, biology is the study of living things, not fixed, mounted and treated with chemicals things. So if you wanna check out a living sample, you can use X-Rays.

The LCLS at Stanford University relies on cells being alive only in the most technical sense of the term. By blasting the sample with X-Rays it can image live bacterial cells fresh from the bottle.

Now you might be thinking that huge pulses of X-Rays might be dangerous, even deadly and yes, they are. The beams coming from the LCLS are actually powerful enough to literally tear your sample to shreds, and if you weren't behind a nice thick layer of lead, it would probably kill you.

But the X-Rays are moving at the speed of light, which is faster than the sample can disintegrate. So after the X-Rays hit but before the sample blasts apart, you grab your data.

That data gives you the original shape of the objects at the instant the X-Rays hit. But one thing, you gotta make sure that you're not anywhere in the room when this thing goes off because those pulsing X-Rays will just rip your cells to pieces.

On the plus side this technique can see down to about 75 nanometers. And researchers are working on building an even better instrument that can shoot more X-Rays at the sample in less time, which should be able to get resolution of just a nanometer or two. Which means in the future we'll probably be learning things about the tiniest parts of living things by just exploding them with X-Rays!

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