When I was little, I used to play with grow capsules, those little plastic pills that expand into a dinosaur or a turtle when you drop them in water. My brothers and I would try to guess what creature we would see before we dropped them into the bowl, and we watched excitedly as a menagerie of animals grew before our eyes. These toys, though mesmerizing, are not sophisticated.
Grow capsules are based on a simple concept: add water and an absorbent object will expand. Now scientists are using this principle to make it easier for us to see very tiny objects. It’s called expansion microscopy, and it’s built on the idea that instead of trying to see small things, why not make them bigger? It sounds like an idea dreamed up by a seven-year-old with an active imagination, but it actually works.
Let’s be clear: common microscopes are powerful, and they do a great job of letting us see into tissues and cells. Imagine you’re looking at patch of skin on your forearm under a microscope that magnifies your skin 100 times its normal size. Suddenly, your smooth skin looks more like an old leather couch, and your hair follicles are as big as trees. Now let’s go further, up to 500x magnification, to see individual cells. If we use special dyes and stains, we can see the nucleus, home of your DNA, and other large organelles that carry out different functions. If we go to 1,000x, we can start to make out groups of large proteins, like the structural ones that give our cells strength. But this is about as far as we can go with most microscopes, because physics won’t let us. Thanks, Einstein.
Bypassing microscope physics
Something called the diffraction barrier is what stops most microscopes around 1,000x. When light passes through most microscopes, it scatters too much, so we can only distinguish objects that are greater than 200 nanometers apart: enough to differentiate organelles, but not enough to differentiate most proteins. Many sub-cellular molecules that scientists want to study are packed so close together that we can’t tell them apart using common microscopes.
Scientists have a few tricks to get past the diffraction barrier, but none are easy. An electron microscope, for instance, beams electrons at a tissue rather than using light, which scatters more than the negatively charged particles. The problem with these microscopes is that we need to first embed the samples with expensive, radioactive, and very toxic compounds to make membranes and proteins visible. The other techniques are generally referred to as super-resolution microscopy, and they involve complex computer algorithms and expensive equipment to reconstruct the proteins of interest.
This is why expansion microscopy works so well. The objects are made larger, bypassing the diffraction barrier entirely.
Here’s how it works. You first find the tissue that you want to magnify: for example, a slice of brain tissue. You then infuse that brain tissue with a tiny compound called acrylamide, a molecule that’s tiny enough to squeeze into the cells. What makes the molecule so useful is that after it enters a cell, it starts forming chains and webs, entangling all the small molecules of the cell. Next we add a compound that anchors acrylamide to proteins, the relatively large molecules that do most of the work of the cell. Now you’re ready to expand.This is my favorite part. You may expect that enlarging a cell would be complicated, maybe requiring microwaves, a radioactive compound, or a large laser like the one in Honey, I Shrunk the Kids. But it’s far more simple than that: just add water. Within an hour, you have a piece of tissue that is over 100 times bigger than it was to start. That’s a huge difference. If you or I were to experience expansion of this scale, we would grow to the size of the Washington monument.
That this simple method works has astounded many scientists. Some worry that, because certain parts of the cell are more flexible than others, you may see some distortion in those areas as they expand faster. So far this is has not been the case. Instead all the cells and proteins have expanded at a similar rate, so scientists have observed very little distortion. However, this technology is still quite new. Most of the work has focused on brain tissue, so it remains unknown whether this technique can be applied to all types of tissue. More labs will need to experiment and report what they find.
What makes expansion really exciting to scientists is how cheap it is. Most biology labs already have most of the tools available to them – all you need are a few chemicals and a decent microscope. Other techniques that promise this kind of resolution require microscopes that, on the low end, cost around $500,000. This technique has the potential to revolutionize the field, giving all scientists the ability to view their samples at extraordinary resolution.
Perhaps expansion microscopy could even make a great teaching tool. When students first start studying biology, they often find it difficult to imagine what tiny structures look like, and most schools do not have the resources to buy advanced microscopes. But they can probably afford the materials for expansion microscopy. Medical school students could study what human tissues look like on a level of magnification never been taught before, and high school students could see brain synapses under a standard microscope, bringing an inspiring world into whole new classrooms. Pathologists who make diagnoses based on patient biopsies may have an easier time, after expansion, identifying the differences between normal and diseased tissues. The applications go far beyond the research lab.
Expansion microscopy is a great example of how thinking outside the box can revolutionize a part of science, and it’s easy to imagine the technique microscopy becoming common in labs everywhere. I, for one, am very excited to see all the tiny things that people will see, after they’ve been made a lot less tiny, especially viruses and single cell organisms. Speaking of making organisms bigger, a quick note to the science fiction fans: this technique cannot be performed on living organisms. So don’t expect titanic squirrels or monster hamsters to infest the world any time soon – at least not because of this research.
Peer Commentary
David Haggerty: I’ve tried using expansion techniques to enlarge neurons, which made them explode, but nonetheless I think this is going to be an amazing technique for studying other cell types and sub-cellular structures. This is a great overview of the limitations in imaging and how to overcome them.
Danbee Kim: When you call it cheap, are you thinking on the scale of a typical lab budget, or on the scale of a typical individual’s budget? This is an important detail that often gets forgotten: for a lab, something that costs $1,000 is cheap, but that price tag is completely inaccessible for individuals.
Gregory Logan-Graf responds: It’s basically the cost of pouring an acrylamide gel. I am trying it in the lab now, and it cost about $250 for me to get all the materials (granted, we had some general items in the lab already).
Michael Graw: You use brain tissue as an example, but is this something that could work in bacterial cells that don’t have nuclei or organelles but, rather, just a mess of cellular machinery floating around? They’re also a lot smaller than human cells to begin with, so if this expands them, but still not enough to resolve detail with a light microscope, is this technique compatible with electron microscopy on enlarged cells?
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