How a Microscope has revolutionized our view of cells

Researchers have created a microscope capable of observing cells in 3-D. With this new technology scientists can watch videos of cells and their natural environments without needing to extract them. Eric Betzig, group leader at Howard Hughes Medical Institute joins Hari via Google Hangout to discuss the implications of this new technology.

TRANSCRIPT

Researchers have created a microscope capable of observing cells in 3-D.

With this new technology, scientists can watch videos of cells in their natural environments without needing to extract them.

Eric Betzig, group leader at Howard Hughes Medical Institute, joins us via Google Hangout to discuss the implications of this new technology.

So, Eric, I, probably like most people in, you know, middle-school biology class remember looking at everything on a flat slide through this little microscope, and I never really thought about the fact that I was just looking at them in 2-D.

What's the importance, what's the leap forward in being able to see a cell in 3-D?

Well, if you want to understand how the cell works, you can make an analogy to understanding how a car works or how the engine of a car works, and if all you had was a two-dimensional picture of it, it's pretty difficult to puzzle out how it works, but if you can see it in three dimensions and furthermore kind of take it apart or explode it apart, then you can get a better idea of what's going on.

All right.

So how did you do it?

How are you being able to... How are able to see something that is so tiny?

It's not like you're getting a telescope to shrink down and looking from the side.

So it's... think of it like a deli slicer but which doesn't actually physically cut the cells.

So it's a very, very thin sheet of light, which just scans one plane at a time as it goes through the cell, but it does it very rapidly, and from that, we computationally put together a 3-D image.

So that's one part of the problem, but the other part is to get it away from that glass slide that you talked about, which is like looking at cells in the Sahara, okay?

They're not exactly exhibiting their native behaviors, so what you'd like to be able to do is look at cells in the environment in which they evolved because that's the only way you're going to get the real picture, and so that's where another technology, borrowed from astronomy, comes in -- adaptive optics.

Because as you look into multicellular organisms, the light gets scrambled by the other cells on top of the cell you want to see, and the adaptive optics unscrambles it so you can then use this deli slicer to get your 3-D image of any cell inside of the organism.

You're literally talking about some of the same techniques that we're using in high-power telescopes that help us look out across space...

Absolutely.

...to try and look inside a single cell.

Yes.

Correct.

Now, the advantage of looking at a cell in the Sahara, as you say, was the fact that we could put these cells into middle-school classrooms, and we could make them portable and whatever.

I'm assuming that your microscope is not that small.

That would be correct.

So in the original prototype in our paper, it fills a 10-foot table.

We are hard at work on actually producing one that will fit on a small coffee table that we would like to make accessible to other labs so that...You know, if you have one microscope in the world that can do this thing, it's like having one Hubble Space Telescope.

You know, it's a pretty narrow bottleneck to get results, and so the path to success is replication and getting other people to be able to do it as well.

Now, you've also called your microscope a three-in-one microscope.

Explain.

Well, in the sense that it is this deli slicer in the center, but the way it works is, you have to create this thin sheet of light, which is the knife, so to speak, but then you have to look at the light which is generated in the cell, actually perpendicular to that knife, to see what's going on, and the trouble is, is the light that goes in gets warped, and the light that gets out gets warped, so it's two adaptive optic microscopes and one deli slicer, so that's the three-in-one.

Got it.

How long until you can actually replicate this microscope and get it to a scale and an affordability level where there could be a hundred or a thousand or a hundred thousand of them?

Yeah, well, I'd be happy with a hundred to begin with, but the goal for us is to have this new version ready sometime late this fall, and the deli slicer part actually has been replicated in probably over a hundred labs now, and again, we have a pretty well-working model about how to document these things, so it becomes easy for others to replicate.

We're going to replicate that model for this new microscope, so it's hopefully as successful as the last one.

So in this pursuit of science, you're basically giving away the ingredients and the how-to kit on how someone can do this for themselves, or I should say, labs can do this for themselves.

How much time and energy went into making that first one, and then how much time and energy now that the blueprint exists to make the second one?

Yeah, so time and energy on the first one, you're probably looking at the culmination of about 4 years of effort by maybe two or three people.

The new one is at least as much effort.

What are some of the things that you think you see being impacted just by shifting the perspective and the view?

I mean, because when you look at cellular, our understanding of how cells work, it's always been in a two- dimensional level unless there's computational models.

Even worse, I mean, it isn't even so much thinking two-dimensionally.

It's thinking statically, so if you open a college textbook on biology, and you look at the picture, the drawing they have of a cell in there and its internal organelles, to me, I view that of a caricature of what the cell really is.

It isn't even a representation.

It's a caricature.

Cells are... I think the picture which is coming out of microscopes, which I really consider a 4-D microscope because it's 3-D plus the time, and the time is a critical element of it because the thing that defines life is that it's animate, and it's moving.

Again, you would never understand the engine in your car if the pistons were all frozen together in the view you got, right?

So I think what these new microscopes are showing is how incredibly dynamic and, by chance, how things bump together even at the molecular level, which is actually what drives everything that makes you and me.

So really we're talking how we understand, for example, how drugs work, usually on receptors and binding areas of specific cells, that's all been with an understanding of a plane and a fixed point in time.

Well, not even so much a plane, but, for example, typical drug discovery works in terms of a lock and key.

Yeah.

Pocket in one protein, and you try to have a drug that fits in that pocket so the other protein can't get there.

But that's only one way of looking at it.

There are other types of interactions between proteins that are much more transient and sort of just a kiss-and-run kind of thing, and so I think these new microscopes are revealing that and actually will therefore offer different types of strategies for drug discovery than the traditional ones.

All right.

Eric Betzig, from the Howard Hughes Medical Institute, thanks so much for joining us.

Thank you, Hari.