Three scientists were awarded this year’s Nobel Prize in Chemistry for developing a new generation of optical microscopes that can peer at the processes inside living cells on the nanoscale. Their invention represents a huge leap over the optical microscopes that gave scientists their first glimpse of tiny living organisms starting in the 17th century.

The biological imaging techniques pioneered by Eric Betzig, Stefan Hell, and William Moerner succeeded in overcoming a physical limit defined by half the wavelength of light and first described by microscopist Ernst Abbe in 1873. That limit meant optical microscopy could not reveal biological objects smaller than 0.2 micrometers, such as viruses or proteins. Modern electron microscopes have the resolution to see at such small levels of detail, but their preparation is lethal for cells under observation and prevents scientists from peering at the inner workings of living cells.

Chemistry Nobel Laureates 2014

One of the first breakthroughs came from Stefan Hell, a physicist at the Max Planck Institute for Biophysical Chemistry, in Göttingen, Germany. In 1993, Hell had his eureka moment while working on fluorescence microscopy, a technique that involved using pulses of light to excite certain molecules in a way that allows scientists to see their glowing locations within cells. The problem was that the microscope resolutions were still too low to see objects such as individual DNA strands.

Hell bypassed the limitation by proposing a method called stimulated emission depletion. After using a laser beam’s pulse of light to excite the fluorescent molecule, a second laser quenches the fluorescent glow except for a nanometer-size volume in the middle. That allows scientists to build a very detailed image of the molecule by sweeping the “nano-flashlight” along the object and continuously measuring light levels, according to a Nobel Foundation explainer. Those small volume images were put together to form a detailed whole image.

By comparison, Eric Betzig and William Moerner, working independently, helped develop a second method called single-molecule microscopy. That method takes several images of the same area while turning the fluorescence of a few individual molecules on and off. Once all the images are superimposed on one another, they form a single “super-image” with details at the nanoscale level.

In 1989, Moerner, a chemist at Stanford University and an IEEE Senior Member, became the first scientist to ever measure the light absorption of a single molecule (he worked at the IBM research center in San Jose, Calif., at the time). He followed up that work eight years later by showing it was possible to control the fluorescence of single molecules, work he described in the journal Nature in 1997.

Such control over single-molecule fluorescence represented the practical solution to a theoretical concept envisioned by Eric Betzig two years earlier. Betzig, a physical chemist at the Janelia Research Campus of the Howard Hughes Medical Institute in Ashburn, Va., developed his ideas in the 1990s while working on a new type of optical microscopy called near-field microscopy.

After leaving his research career for a while (to work at his father’s machine tool company), Betzig returned and eventually demonstrated how the single-molecule fluorescence could help create the highly detailed “super-image” of a specialized cell organelle called a lysosome. His groundbreaking work appeared in the journal Science in 2006.

These advances in optical microscopy have allowed researchers to begin studying the inner workings of living cells in unprecedented detail. Hell has used the technique to peer inside living nerve cells to understand how brain synapses work. Moerner has examined proteins related to Huntington’s disease, an inherited genetic disorder that leads to the malfunction and breakdown of brain cells. Betzig has studied cell division within embryos.

All three researchers have published much of their work in IEEE journals such as IEEE Photonics Journal and through the IEEE Engineering in Medicine & Biology Society.

The Conversation (0)

Restoring Hearing With Beams of Light

Gene therapy and optoelectronics could radically upgrade hearing for millions of people

13 min read
A computer graphic shows a gray structure that’s curled like a snail’s shell. A big purple line runs through it. Many clusters of smaller red lines are scattered throughout the curled structure.

Human hearing depends on the cochlea, a snail-shaped structure in the inner ear. A new kind of cochlear implant for people with disabling hearing loss would use beams of light to stimulate the cochlear nerve.

Lakshay Khurana and Daniel Keppeler

There’s a popular misconception that cochlear implants restore natural hearing. In fact, these marvels of engineering give people a new kind of “electric hearing” that they must learn how to use.

Natural hearing results from vibrations hitting tiny structures called hair cells within the cochlea in the inner ear. A cochlear implant bypasses the damaged or dysfunctional parts of the ear and uses electrodes to directly stimulate the cochlear nerve, which sends signals to the brain. When my hearing-impaired patients have their cochlear implants turned on for the first time, they often report that voices sound flat and robotic and that background noises blur together and drown out voices. Although users can have many sessions with technicians to “tune” and adjust their implants’ settings to make sounds more pleasant and helpful, there’s a limit to what can be achieved with today’s technology.

8 channels

64 channels

Since optogenetic therapies are just beginning to be tested in clinical trials, there’s still some uncertainty about how best to make the technique work in humans. We’re still thinking about how to get the viral vector to deliver the necessary genes to the correct neurons in the cochlea. The viral vector we’ve used in experiments thus far, an adeno-associated virus, is a harmless virus that has already been approved for use in several gene therapies, and we’re using some genetic tricks and local administration to target cochlear neurons specifically. We’ve already begun gathering data about the stability of the optogenetically altered cells and whether they’ll need repeated injections of the channelrhodopsin genes to stay responsive to light.

Our roadmap to clinical trials is very ambitious. We’re working now to finalize and freeze the design of the device, and we have ongoing preclinical studies in animals to check for phototoxicity and prove the efficacy of the basic idea. We aim to begin our first-in-human study in 2026, in which we’ll find the safest dose for the gene therapy. We hope to launch a large phase 3 clinical trial in 2028 to collect data that we’ll use in submitting the device for regulatory approval, which we could win in the early 2030s.

We foresee a future in which beams of light can bring rich soundscapes to people with profound hearing loss or deafness. We hope that the optical cochlear implant will enable them to pick out voices in a busy meeting, appreciate the subtleties of their favorite songs, and take in the full spectrum of sound—from trilling birdsongs to booming bass notes. We think this technology has the potential to illuminate their auditory worlds.

Keep Reading ↓Show less