Listening to tomographic tales

Listen up, researchers in the Netherlands and the USA have pieced together a picture of the most exquisite of molecular machines using electron-microscopic tomography. The team has obtained the first detailed three-dimensional structure of the gossamer-like filaments of proteins found within the inner ear that gives us our sense of hearing and balance.

The research, undertaken by Manfred Auer of Lawrence Berkeley National Laboratory and colleagues could lead to a clearer understanding of how hearing works and perhaps one day help with the development of new treatments for particular forms hearing loss affecting many people.

"It's one of the most beautifully deigned systems in the body," says Auer, "But how it really works remains a mystery. Our goal is to determine what the system looks like, so we can determine how it functions."

The protein filaments help to convert the mechanical vibrations produced by sound waves entering the ear into the electrical signals that are then interpreted as sounds by the brain. Astoundingly, these filaments can function over a sensory range spanning six orders of magnitude allowing our hearing to cope with the dropping of a pin, but also the sound of a Motorhead concert.

There is no other sensory system in biology nor in electrical engineering that is capable of such a range of sensing. Nevertheless, the filaments are a mere four nanometres across and just 160 nanometers long and so are, in one sense, incredibly fragile. If these filaments break, the world can fall silent.

Auer and his colleagues A. J. Hudspeth of the Howard Hughes Medical Institute and Laboratory of Sensory Neuroscience, The Rockefeller University, Da Neng Wang of the Skirball Institute of Biomolecular Medicine, New York University Medical Center, Abrahram Koster and Ulrike Ziese of the department of Molecular Cell Biology, at Utrecht University, The Netherlands, Chandrajit Bajaj of the Center for Computational Visualization, University of Texas-Austin, and Niels Volkmann of The Burnham Institute, La Jolla, California used electron tomography in their study. They acquired hundreds of images of the hearing structure at different angles, and then reconstructed these to form a single composite three-dimensional image. The technique, the researchers say, yields highly detailed images of structures at the molecular scale.

This electron tomography approach to investigating the electromechanics of hearing was begun almost a decade ago by Auer's team when they set out to learn more about this the last unmapped component of the auditory system. The key to understanding hearing lies in zooming in ever close on the sprouting bundles of hair-like, cilia that line the inner ear. These bundles of cilia sway in the fluid, like underway reeds oscillating in the current, as the eardrum resonates to the sound entering the ear, so these cilia are buffeted by the waves.

At high resolution one can see that each bundle of cilia is composed of individual hairs, stereocilia. Adjacent stereocilia are linked together by protein filaments, also known as tip links. When the stereocilia sway, the tip links stretch. This mechanical process opens a channel in the system so that positively charged ions can stream into the hair cell. This ion stream, modulated by the sound waves, initiates the release of neurotransmitters, which ultimately reach the nervous system converting mechanical sound waves into an electrical signal.

"The system is incredible, says Auer, "But we still don't really know what constitutes the links, and we don't know how the hair bundle operates at the molecular level." With this work, that is beginning to change.

"One of the holy grails in structural cell biology is obtaining a molecular inventory of complex systems, and showing how the proteins work together to achieve their marvellous function," says Auer, "We're striving to develop such an inventory for the hair bundle." He adds that, "Ultimately, we will get a molecular representation of this entire bundle, with all of its machinery, which will give us a fundamental insight into how the bundle works and how hearing really works."