The Ears Have It

The jobs also gave Hudspeth a sneak peek at medicine in action. During his lunch break, he would surreptitiously sneak up into the observation dome above the hospital’s surgical theater and watch open-heart surgery while he ate his lunch. “It was so grand. This was the hospital where open-heart surgery techniques were pioneered,” says Hudspeth. “There were four surgical theaters, and surgeon Michael DeBakey would go clockwise from room to room doing the critical parts of surgeries. I would tag along with my sandwich. Fourteen-year-olds were not supposed to be there, and especially not eating a tuna sandwich!”

“The hope is that we can restore hearing in humans by regenerating hair cells in our own ears, basically by hijacking the molecular program that made the hair cells in the first place.”

This kind of zealous interest and curiosity is what has kept Hudspeth in the laboratory for more than 40 years. Despite an inauspicious beginning that included a string of difficult situations—expulsion from high school, the Vietnam War, and an aborted postdoc—Hudspeth has since devoted his career to understanding how hair cells in the inner ear translate sound into electrical signals transmitted to the brain. His laboratory was the first to show directly that mechanical stimulation of the hair cells causes an electrical response that results in sound perception. More recently, his team built a microscope that takes one million measurements per second, with subnanometer resolution, allowing an assessment of the mechanical properties of molecular constituents in the hair bundle—an organelle made up of about 60 stereocilia that project from the apical surface of a single hair cell.

Here, Hudspeth talks about how he made his decision to leave an unfortunate work situation after falling into a fjord during an early morning jog in the pitch-black Stockholm winter; how the dean of one university moved him to the basement adjacent to the morgue; and how the structures in our ears are analogous to a public-address system.

Hudspeth Hatches

A born naturalist. By the time Hudspeth finished high school, he and his younger brother had amassed a veritable zoo—more than 200 animals, including poisonous snakes, a raccoon, opossums, armadillos, and a colony of breeding box turtles. To maintain the impressive turtle colony, the brothers arranged to receive produce discarded by the local supermarket. “We would bring home a bushel of rotting produce. After a while, more turtles would turn up and try to get into our fenced backyard—it was such a good feed,” he says.

Good and bad vibrations. “My high school experience was mostly distinguished by being expelled,” says Hudspeth. “The school was an oppressive Episcopal day school.” To rebel, Hudspeth says, he ran a modest crime ring. He became very good at counterfeiting a key by memorizing its imprint and applied this skill to the school’s master key, giving him and his friends access to rooms off-limits to students. Hudspeth also tapped faculty phone lines and hijacked the school’s PA system to play Beach Boys songs. Thinking phosphorus was analogous to sodium, which is submerged in kerosene to prevent it from bursting into flames, he discovered that mixing kerosene and phosphorus creates “a monstrous liquid that couldn’t be exposed without risk of life.” Although he disposed of the experimental jar in the river, this shenanigan, on top of the others, got him expelled. He was readmitted to school, but as punishment had to remain in study hall after school and was not allowed to participate in extracurricular activities. “My grades went up to the top of the class as a result,” he says.

Peer pressure. Hudspeth entered Harvard University as a freshman in 1963, majoring in biochemistry. But the transition was difficult. “I was always very shy. In second grade, because I wouldn’t talk, the teacher thought I was learning-impaired and wanted to send me back a grade. But fortunately, I was tested and got sent a grade ahead instead. I had not been paying attention because I was bored, so the pressure helped me work harder. It was similar in college. I was suddenly terrified. I was with these students from prep schools who could read the Iliad in Greek and I didn’t know where Greece was!” Hudspeth worked hard and by his junior year realized he was doing better than a lot of other students.

Hudspeth Hums Along

An accidental dual degree. When Hudspeth graduated from Harvard in 1967, men could avoid being drafted for the Vietnam War by going to graduate school. So he applied and was admitted both to Harvard’s neurobiology graduate program and to its medical school. He chose graduate school, but a year into the program, the deferment policy changed and he switched to medical school to continue to avoid the draft. He toggled back and forth between the two programs as the policy changed between 1968 and 1974, finally earning both a PhD and an MD.

Sparking an interest. Neuroscience as a field was just gearing up in the late 1960s, and Harvard had one of three graduate programs in the U.S. Hudspeth was one of three students admitted to the new program in 1967. “There were no courses, no rotations; there was no nothing,” he says. “We initially took medical school courses, but then demanded that someone teach us, and this was the origin of my interest in hearing.” Instead of providing courses, the advisors decided that giving lectures to the medical students would be a way for the grad students to learn neuroscience. The lecture on hearing was assigned to Hudspeth. “There was good work being done on the visual system, and I wondered why no one was working on the auditory system. That is how I got hooked.”

Absentee advisors. Hudspeth’s advisors, Torsten Wiesel and David Hubel, who shared the 1981 Nobel Prize in Physiology or Medicine for their work on how visual information is interpreted by the brain, were not very good at directing him, he says. “They were good scientific role models but were not interested in helping students find their way.” But Hudspeth found a hands-on role model in anatomy professor Jean-Paul Revel, who taught him how to do electron microscopy and how to think like a cell. “He taught me to ask, ‘What is the cell doing? Why are things this way, and what is the basis of the phenomenon you are seeing?’” Hudspeth started 13 different projects. Eight of these turned into publications, including one on the role of gap junctions between cells, and another on the reestablishment of tight junctions in epithelial cells within 30 minutes after cell damage. “I was out of control, banging around in the lab and not getting much advice. It was only sex, drugs, and rock-and-roll that got me through it all.”

Caught in the middle. Hudspeth chose to do a postdoc with Åke Flock at a research institute associated with the Karolinska University Hospital in Stockholm, both because Flock was using electron microscopy to study hair cells, and because Sweden could potentially provide a safe haven from the draft situation in the U.S. But upon his arrival, researchers with whom Hudspeth shared lab space were surprisingly cold to him. He subsequently learned that their behavior stemmed from disapproval of Flock’s planned career move to the Karolinska Institute. Any horizontal move to a new position did not follow the hierarchical Swedish professorship system. Although Hudspeth conducted three months of library research on the auditory system, he performed almost no actual experiments over ten months in Stockholm. In December 1974, while out jogging, he slipped and fell into a fjord. “As I went underwater I reasoned that if I didn’t drown, I would leave the next day. I didn’t drown—and I left.”

Mysterious supporters. Despite his fruitless postdoc, Hudspeth returned to the U.S. to faculty position offers from Rockefeller University and Caltech. Clearly, Hudspeth had supporters who thought he could do research, but he says he doesn’t know who recommended him for the positions.

Mechanical stimuli. After joining Caltech, Hudspeth began to execute the research plan he had mapped out in Stockholm. With David Corey, his first graduate student, he directly manipulated hair cells in vitro to show, for the first time, that physical pushing of the hair bundle stimulates hair cells to produce an electrical response. The two then showed that the response originates from mechanically sensitive channels that pass potassium ions but are also permeable to other cations. Hudspeth’s lab chose the hearing organ of the bullfrog for the experiments because it was large and easy to work with. “I had assumed from the beginning that hair cells of vertebrates all worked similarly. And by and large, the discoveries made in frog and turtle systems have been shown to also apply as well in mammals, and presumably, in humans.”

Hair removal. In 1983, Hudspeth moved to the University of California, San Francisco. “This was a very exciting institution at that point, nearing its peak as the best place for biomedical research, with extremely collaborative professors and students and minimal departmental boundaries.” Then, in 1989, he accepted an opportunity to build a neuroscience program at the University of Texas Southwestern Medical Center. After almost three years of work to set up the program, which included recruiting new professors, Hudspeth was told that the program was not needed. Coinciding with Hudpseth’s acceptance into the National Academy of Sciences, the dean of the university moved him to a basement office next door to the morgue. “It was a cruel act, but the dean was subsequently removed, and the president [of the university] was placed under investigation for deflection of university funds for private use.” Despite the drama, his research continued to go well. Hudspeth and postdoc Peter Gillespie developed a way to isolate all of the 3,000 hair bundles from the inner ear of the frog at once, for biochemical work. Inspired by the age-old practice of using wax as a depilatory, the two put molten agarose over the inner ear hairs, let it set, and then briskly twisted and pulled the agarose, ripping out the hair bundles. The technique has since become standard and has been adapted for use in other vertebrate systems.

Hudspeth Homes In

Public-address system. In 1995, when Hudspeth moved to Rockefeller University, his research also took a new turn. “I thought by this time I had exhausted what I wanted to do with hair cells, but then a new idea came to the fore. It turns out that the ear is not just a passive recipient of sound but has a built-in amplifier, something like a biological hearing aid that is part of the hair cell apparatus,” he says. This amplifier has a profound effect on hearing—making it 100- to 1,000-fold more sensitive. When this amplifier wears out or is damaged, we become hard of hearing. There were hints of this amplification, called the active process, for more than 50 years, and in 1999, along with postdoc Pascal Martin, Hudspeth showed that in amphibians the hair bundle itself is the source of this amplification. “This amplifier is based on a particular kind of instability that has interesting math properties. If you turn up a public-address system too far, it finally goes unstable and begins to howl and whine, oscillating spontaneously. And that is just what happens in our own ears. Each of the sensory hair cells has in it an amplifier that can go unstable so that sound actually comes out of the ear.”

Restoring hearing. Hudspeth’s lab is now working on zebrafish, which, unlike mammals, are able to regenerate their hair cells. Understanding which genes are activated in cells during regeneration may provide clues about how to turn on this process in mammals. The lab recently identified a spectrum of genes that may be involved in the differentiation of progenitor cells to hair cells in zebrafish. “The hope is that we can restore hearing in humans by regenerating hair cells in our own ears, basically by hijacking the molecular program that made the hair cells in the first place.”

Mentorship philosophy. “I try, particularly with postdocs, to give them a start on what they are going to do independently. Peter Gillespie and I started the twist-off biochemistry work on hair bundles, but when he took that direction in his own lab I quit doing the biochemistry as a major effort. And when Joe Howard pursued single-molecule work, I gave up the reins on that to him.”

Common theme. While Hudspeth says he found most of his Harvard courses uninspiring, his physical chemistry professor, George Kistiakowsky, was very committed to undergraduate teaching. “This turned out to be the most important thread in my scientific career, applying rigorous physical and chemical principles to biological systems. This course was an inspiration for that and what the rest of [my career] has been about.”

Greatest Hits

• Discovered by direct mechanical stimulation that hair bundles in the inner ear transduce an auditory stimulus to an electrical signal that results from the opening of ion channels in hair cells
• Devised an agarose-based method to remove intact hair bundles for biochemical study
• Determined that the tension of hair bundles, required for sensing sound, is reset by myosin motor proteins
• Showed that hair cells operate near an instability that confers important properties on our hearing