Inspired by the sea and the sky, a biologist invents a new kind of microscope

The device can achieve clear images using samples suspended in any kind of liquid

The Schmidt objektive produces detailed images of neurons in a mouse brain.
A mirror-based microscope can produce crisp, clear images, such as these mouse neurons.Anna Maria Reuss & Fabian Voigt

Anyone who’s ever owned a telescope has probably tried looking through the wrong end to see whether it works in reverse—that is, like a microscope. Spoiler alert: It doesn’t.

Now, a team of researchers inspired by the strange eyes of a sea creature has figured out a way to do it. By flipping the mirrors and lenses used in certain types of telescopes, they have created a new kind of microscope that can be used to image samples floating in any type of liquid—even the insides of transparent organs—while retaining enough light to allow for high magnification. The design could help scientists achieve high enough magnification to study tiny structures such as the long, skinny axons that connect neurons in the brain or individual proteins or RNA molecules inside cells.

“It’s nice to see even something as basic as a lens could still bring interest and there's still room there to do some work that would help a lot of people,” says Kimani Touissant, an electrical engineer at Brown University. He says the design could be useful in his work, in which he uses lasers to etch patterns into gels that mimic collagen and act as scaffolds for cells.

At very high magnification, light trained on a sample can scatter around it, blurring and dimming the image. To get around that problem, scientists using traditional, lens-based microscopes cover their sample with a thin layer of oil or water, then dip their device’s lens into the liquid, minimizing the degree of light scattering. But this technique requires instruments to have different lenses for different types of liquid, making it an expensive, finicky process and limiting the ways that samples can be prepared.

Enter Fabian Voigt, a molecular biologist at Harvard University and inventor of the new design. He was reading a book about animal vision when he encountered the odd case of scallops’ eyes. Unlike most animals, whose eyes feature retinas that send images to the brain, scallops have mantles covered with hundreds of tiny blue dots, each of which contains a curved mirror at its back. As light passes through each eye’s lens, its inner mirror reflects the light back onto the creature’s photoreceptors to create an image that then allows the scallop to respond to its environment.

An amateur astronomer since he was a teenager, Voigt realized the scallop’s eye design resembled a kind of telescope invented nearly 100 years ago called the Schmidt telescope. The Kepler Space Telescope, which orbits Earth, uses a similar curved mirror design to magnify far-away light from exoplanets. Voigt realized that by shrinking the mirror, using lasers for light, and filling the space between the mirror and the detector with liquid to minimize light scattering, the design could be adapted to fit inside a microscope.

So, Voigt and colleagues built a prototype based on those specs. Light enters from the top, passes through a curved plate that corrects for the mirror’s curvature, then bounces off a mirror to hit a sample and magnify it. The curved mirror can magnify the image much like a lens, Voigt says. It allows researchers to look at samples suspended in any kind of liquid, simplifying the process. Voigt says the design could be particularly useful for researchers who study organs or even entire organisms, such as mice or embryos, that have been made completely transparent by artificially removing their pigment.

The researchers tested their prototype by shining a laser onto transparent samples including the muscles in a tadpole’s tail, a mouse brain, and an entire chicken embryo. These images, the researchers reported last month in Nature Biotechnology, were as clear as those that could be achieved with conventional optical microscopes, despite using a simpler design, and providing more flexibility in the way researchers prepare samples.

The mirror design could prove useful to researchers aiming to trace the path of a mouse’s axons that wind throughout the brain, says Adam Glaser, an engineer at the Allen Institute for Neural Dynamics who is working on brain mapping. Axons can be dozens of millimeters in length but only nanometers in width, which makes mapping the entire mouse brain a herculean task. It’s also expensive to do using commercially available microscopes, which require numerous lenses and are finicky to operate. The new design, by contrast, could be easier to use because it requires only one mirror and, because it can image through any kind of liquid, allows researchers to be more flexible in how they prepare their brain samples.

Glaser adds that the new microscope could also aid researchers looking at RNA molecules within the neurons that could reveal what genes each cell is expressing. “Borrowing from astronomy is a wonderfully efficient and creative way to do science,” he says.

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