Harvard Medical School
Dr. Corey is also the Bertarelli Professor of Translational Medical Science at Harvard Medical School.
Force-Gated Ion Channels
When David Corey entered Amherst College he had one focus: physics. Entranced by what he saw as its elegant simplicity, Corey marveled at the power of physics to describe complex phenomena with a few equations. With a special interest in electronics, Corey was preparing himself for a career as a physicist.
Amherst's decision to hire biophysicist Stephen George to create an undergraduate neuroscience major changed all that in Corey's senior year. George convinced Corey that understanding how the brain is wired could have its own elegance.
Too late to apply for graduate school to study neuroscience, Corey landed a job as a technician in Ann Stuart's laboratory at Harvard Medical School. There he discovered sensory neurobiology, and there he also met James Hudspeth, who later became his graduate mentor at Caltech and introduced him to the hair cells of the inner ear. As a result, Corey has spent his scientific career trying to tease apart how these sensory receptor cells use hair-like projections – called stereocilia – to convert sound waves into the neural signals that allow us to enjoy music and maintain balance. Over the years, there has been tremendous progress on how hair cells operate, but some of their innermost workings remain a mystery.
"It's been both deeply satisfying and frustrating," Corey admits. "For many other sensory systems we know at a molecular level how a sensory signal becomes a neurological signal. When it comes to hearing, we now know the structures, and we know the biophysics, but we really don't know most of the molecules that make it happen."
As a graduate student at the California Institute of Technology in the late 1970s, Corey worked on some of the basic questions framed by Hudspeth: How does deflection of the stereocilia by sound change the hair cell's voltage? What kind of conductance is activated? How does the cell respond to sustained stimuli? His work suggested that there are specific "transduction" channels in the stereocilia that are directly activated by mechanical force, that they can open in microseconds when stimulated, and that they permit the influx of positively charged ions such as potassium and calcium.
To learn more about the biophysics of ion channels, Corey completed postdoctoral training at Yale with former HHMI investigator Charles Stevens. However, he soon went back to his first love, the hair cell.
"At least I was smart enough to recognize a good question!" Corey laughs. It's really a question with two parts. One addresses the biomechanics of how forces generated by sound waves hitting the eardrum open these ion channels. The second attempts to identify the proteins that compose the transduction channel itself or connect to it.
On the biomechanical level, researchers understand that transduction channels in hair cells are directly opened by force rather than a biochemical stimulus. Various kinds of ion channels, present throughout the body, open and close at drastically different speeds. Ion channels regulated by voltage in nerve cells, for example, open and close in the 2- to 10-millisecond range. However, the hair-cell transduction channels are so fast – a thousand times faster than the ion channels on nerve cells – that researchers studying them had to develop new tools and instruments.
"We do have the coolest equipment," Corey says, "because so much of what we do requires making new electronics, optics, and mechanical probes to work at a level of nanometers and microseconds."
On a molecular level, however, attempts to identify the proteins that make up the transduction apparatus have had mixed success. One success was work by Corey, Hudspeth, and Peter Gillespie of the Vollum Institute, which identified a small myosin motor protein that sets the resting tension on transduction channels, so they can open with the smallest additional force. In the process Corey also discovered two other myosins that function in structures similar to stereocilia.
Work from other labs identified two proteins that together make up the string-like "tip link" that pulls channel open. Corey and his colleagues went on to solve the atomic structure of these proteins and used molecular dynamics stimulations to understand how they hold together and how they break with excessive noise – a satisfying combination of molecular biology and biophysics.
To find more components of the transduction apparatus, Corey has used high-throughput sequencing to identify all the genes that hair cells use, at developmental points before and after they become mechanically sensitive. Some will be components of the transduction apparatus. And many of these are known deafness genes, raising hope that more deafness genes will emerge from the screen.
His work has also uncovered genes important in development of the ear, including a gene that inhibits hair cells from regrowing. Damage to hair cells is now usually permanent. For instance, the basis for much age-related hearing loss is the loss of hair cells that are never replaced. A treatment that temporarily blocked this inhibitor gene could one day be used to restore hair cells.
"It's rewarding to know that in the process of doing this research, we make discoveries that will have implications for treating hearing loss and for human health," Corey says.
However frustrating the search for the identity of the transduction apparatus has been, Corey hasn't considered changing course.
"I haven't finished yet. It's a pretty fundamental question," says Corey, who maintains that the joy of discovery is his greatest motivation. "If I could answer it, I would be able to tell one complete story. I think that would be a pretty satisfying accomplishment."