Since its beginnings over 400 years ago, microscopy has made leaps and bounds—even zeroing in on individual atoms. Now, as Nick Lunn reports for National Geographic, a new type of microscopy is taking the field another big step ahead, capturing high-resolution 3-D images of living cells as they move and operate within organisms.
Most microscopes are too slow to capture cellular movements in 3-D, according to a press release from the Howard Hughes Medical Institute, which collaborated on the new machine. And though researchers have imaged living cells, it's difficult to get high-resolution images of groups of cells. High-powered modern microscopy also bathes cells in powerful light, sometimes thousands or millions of times more intense than the sun, which may change their behavior or even damage the minute subjects.
“This raises the nagging doubt that we are not seeing cells in their native state, happily ensconced in the organism in which they evolved,” says Eric Betzig, chemistry Nobel Prize winner and project team leader at Howard Hughes. “It’s often said that seeing is believing, but when it comes to cell biology, I think the more appropriate question is, ‘When can we believe what we see?’”
One particular problem with peering at the insides of living organisms is that the surface of the subject tends to scatter light, distorting the image. And the deeper you look, the worse the problem. To overcome the issue, the new scope uses a technique from astrophysics called adaptive optics. Like new-age ground-based telescopes that are able to correct for image warping caused by Earth’s atmosphere, the scope can correct for the distortions caused by surface scattering.
“If you can measure how the light is warped, you can change the shape of the mirror to create an equal and opposite distortion that then cancels those aberrations,” Betzig tells Lunn.
Another cutting-edge technique that helps make this new scope work is called lattice light-sheet microscopy, a technique Betzig pioneered earlier this decade. Instead of bathing a sample in damaging, high intensity rays the microscope sweeps an ultra-thin sheet of light across the sample, generating lots of high-resolution 2-D images. Those are then stacked to create 3-D images without bleaching or damaging the sample. The result of the two techniques is a clear 3-D image of cells behaving naturally. A detailed description of the technique appears in the journal Science.
“Studying the cell on a coverslip is like watching a lion in the zoo—you’re not exactly seeing their native behaviors,” Betzig tells Lunn. “[Using the scope] is like watching the lion chase an antelope on the savanna. You’re finally seeing the true nature of cells.”
The images created so far are breathtaking. As Brandon Specktor at LiveScience reports, the researchers focused on transparent zebrafish, nematodes and cancer cells. Their first 3-D movies include cancer cells moving through blood vessels, immune cells swallowing sugar molecules and cells dividing in detail.
Even more exciting than the fine imagery is that the intensity of detail allows researchers to “explode” the tissues they are viewing to look at individual cells. “Every time we’ve done an experiment with this microscope, we’ve observed something novel — and generated new ideas and hypotheses to test,” Tomas Kirchhausen, a senior investigator at Boston Children’s Hospital says in a press release. “It can be used to study almost any problem in a biological system or organism I can think of.”
It will take a while for this microscopy revolution to make it out of the lab and into other universities and hospitals. As Specktor reports, the first microscope is a “Frankenstein’s monster” cobbled together with bits and pieces from other microscopes and machines. It currently occupies a ten-foot long table and requires customized software to operate.
But according to the press release, two second-generation scopes, which will be housed at cooperating labs, will only take up the space of one desk, and will be available to researchers from around the world who apply to use them. The team will also post the plans for the instrument so other institutions can try to build their own. Perhaps in ten years, Betzig tells Specktor, a smaller, affordable model will be available commercially.
Until then, the new images will have to tide us over. We agree with Betzig who tells Lunn that the first time he saw images from the scope “was f***ing awesome.” This, of course, is scientific jargon for “really neat-o.”