There’s an “Inverse Piano” in Your Head

Neuroscientist James Hudspeth has basically been living inside the human ear for close to 50 years.

In that time Hudspeth, head of the Laboratory of Sensory Neuroscience at The Rockefeller University, has dramatically advanced scientists’ understanding of how the ear and brain work together to process sound. Last week his decades of groundbreaking research were recognized by the Norwegian Academy of Science, which awarded him the million-dollar Kavli Prize in Neuroscience. Hudspeth shared the prize with two other hearing researchers: Robert Fettiplace from the University of Wisconsin–Madison and Christine Petit from the Pasteur Institute in Paris.

As Hudspeth explored the neural mechanisms of hearing over the years, he developed a special appreciation for the intricate anatomy of the inner ear—an appreciation that transcends the laboratory. “I think we as scientists tend to underemphasize the aesthetic aspect of science,” he says. “Yes, science is the disinterested investigation into the nature of things. But it is more like art than not. It’s something that one does for the beauty of it, and in the hope of understanding what has heretofore been hidden. Here’s something incredibly beautiful, like the inner ear, performing a really remarkable function. How can that be? How does it do it?” After learning of his Kavli Prize on Thursday, Hudspeth spoke with Scientific American about his work and how the brain transforms physical vibration into the experience of a symphony.

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[An edited transcript of the interview follows.]

How does the inner ear process sound?

In the 19th century there was one really important physiological insight from the German scientist Hermann von Hemholtz that endures today. He recognized that the cochlea—the receptive organ of the ear—is, in essence, an inverse piano. In the piano, each of the strings represents a single tone and the output is stirred together into a harmonious whole. The ear basically undoes that work. It takes the harmonious whole, separates out the individual tones and represents each of them at a different position along the spiral cochlea. Each of the 16,000 hair cells that line the cochlea is a receptor that responds to a specific frequency. And those hair cells are in a systematic order, just as the piano strings are.

“Transduction” is a word that comes up frequently in your work. What is its role in hearing?

The common currency of the nervous system is electrical. It is action potentials—streams of 1’s and 0’s, in effect—much like those in a computer. But the currency of the external sensory world is very different. We have photons—that is sight. We have pressure—that is touch. We have molecules—that is smell or taste. And finally we have vibrations in the air—that is the essence of sound. Each of those different types of physical stimulus must somehow be converted into the electrical signals that the brain is then capable of interpreting. That’s the transduction process. The thing that motivated me, and took the first 20 years of my 40-year career to really understand, is how that is accomplished. How the mechanical vibration, as it strikes the upper part of the hair cell—the so-called hair bundle—how that energy is converted into an electrical response.

What about the other 20 years?

The second half of my career was unexpected. It became apparent—from a number of lines of study by myself and others during the first 20 years—that the system was not just a passive transducer. The sound going in didn’t simply evoke a response. Instead, the ear has a so-called active process. The ear has a built-in amplifier, and that amplifier is unlike any of our other senses. It would be as if light going into the eye produced more light inside the eye, or smell going into the nose produced more smell molecules. In the case of our ears, the sound that goes into the ear is actually mechanically amplified by the ear, and the amplification is between 100- and 1,000-fold. It’s quite profound. And the active process also sharpens the tuning of hearing, so that we can distinguish frequencies that are only about 0.1 percent apart. By comparison, two keys on a piano are 6 percent apart.

Is amplification the current focus of your research?

It’s one of three specific things my group is investing a lot of effort in. One of the others is trying to understand how the hair bundle—the mechanically sensitive upper part of the hair cell—is assembled. It’s a real problem in developmental biology how you put something that complicated together. And another is the attempt to help regenerate hair cells. One of the biggest challenges in the field is that hair cells in mammals are not replaced when they die. That is why all of us tend to get progressively harder and harder of hearing, and eventually significantly deaf. One of the approaches we’re taking is to screen drugs to try to find a molecule that will allow hair cells to begin to regenerate again. We’ve screened 80,000 drugs so far and we have two compounds in particular that look promising. We’re now trying to learn in more detail how they operate, and whether they or related compounds could be used for regeneration in humans.

Do you see gene therapy as a potentially viable treatment for hearing loss?

I think hair cells are a very reasonable target for gene therapy—for a couple of reasons: First, there are a lot of different human hearing-loss conditions. There are approximately 100 that affect only hearing or hearing and balance, and about another 200 in which hearing loss accompanies a condition that affects the heart, the kidneys or other organs. So, particularly for the problems that are confined to the ear, gene therapy might be valuable. One of the people I shared this award with, Christine Petit from the Pasteur Institute in Paris, has really pioneered the genetic approach to identifying genes and proteins involved in the operation of human hearing. So we now have a repertoire of several dozen well-understood proteins, or genes that encode them, that are deficient in some forms of hearing loss and would be attractive targets for gene therapy.

The other thing that makes the ear particularly attractive is its geometry. Right now gene therapy usually means inserting genes by means of virus. And that can be problematic when you are talking about the entire body, because you may not want some of these genes to go places where they are not ordinarily operative. But the ear is what’s called a privileged compartment; it has spaces in it where the liquids are cut off from any other liquids in the body. And there is a potential to inject a gene-carrying virus there that will only be seen by the cells of the inner ear, and will not go to the liver or other organs and possibly cause harm.