Hudspeth 10/28/2014 9:26 AM Page 1

The Energetic

A. J. Hudspeth

Abstract: As the gateway to human communication, the sense of is of enormous importance in our lives. Research on hearing has recently been revolutionized by the demonstration that the ear is not simply a passive receiver for sound, but also an ampli½er that augments, ½lters, and compresses its inputs. Hair cells, the ear’s sensory receptors, use two distinct methods to implement an active process that endows our hearing with these remarkable properties. First, the vibration-sensitive structures of the ear, called hair bundles, display a mechanical instability that allows them to oscillate in response to stimulation. And second, the membranes of hair cells are replete with proteins that contract in response to electrical stimuli, thus enabling the cells to act like tiny muscles. The activity of these two motile processes can be so exuberant as to cause normal to emit sounds.

Most of us use hearing aids. Electronic devices amplify sound for the bene½t of those with com- promised hearing, whereas the ears of people with normal hearing contain biological structures that serve an identical function. This so-called active process can amplify sounds by more than a hundred - fold. The ear’s intrinsic ampli½er additionally tunes our responsiveness to speci½c frequencies of sound, thus facilitating the recognition of sound sources and the discrimination of speech. The ac - tive process also allows us to analyze acoustic sig- nals over a million-fold range of magnitudes, com- A. J. HUDSPETH, a Fellow of the pressing responses so that we can appreciate both American Academy since 2002, is soloist and orchestra. Most remarkably, the ear’s the F. M. Kirby Professor and Head of the Laboratory of Sensory Neu- native hearing aid can, like an electronic device, be - roscience at the Rockefeller Uni- come unstable, leading to the emission of sounds versity. He is also an Investigator at from the ear. Hearing is a highly adaptive sensory the Howard Hughes Medical Insti- modality, for it provides an early warning of poten- tute and a member of the National tial adversaries or predators and a foretaste of pos- Academy of Sciences. His research sible prey while they are still distant. In these en - has been published in journals deavors, there is a clear advantage in having the most such as The Journal of Neuroscience, Nature Reviews Neuroscience, Nature, sensitive and discriminating auditory apparatus. and Neuron; he recently coedited Evolution has accordingly fostered an active process the ½fth edition of the textbook whose performance approaches the limits set by the Principles of Neural Science (2013). physics of sound.

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The Because hearing is the key sense in The basic outline of the hearing process Energetic human communication, its importance is is familiar to us from high school biology.3 Ear most apparent in persons whose hearing Sound waves–the alternate compres- is de½cient. Hearing is ordinarily the sions and rarefactions of the air associated means by which children acquire language with a sound–are captured by the external and thus their avenue to other forms of ear, traverse the , and strike the symbolic communication. One child in a thin, elastic . The ensuing vibra- thousand is born deaf, however, and a tions propagate through the three minis- comparable percentage will become deaf cule bones of the –the hammer, before maturity, largely a result of the anvil, and stirrup–to the . Named several hundred forms of genetic hearing for its resemblance to a spiraled snail shell loss.1 Before the advent of a simple and (κόχλος in Greek), the cochlea encom- effective test to identify these children passes three helical turns in an organ the within days of birth, many suffered years size of a chickpea. Abutting the cochlea of retarded development owing to their within the temporal bone of the skull are unrecognized condition. the ½ve receptor organs of the vestibular Verbal exchanges not only facilitate the labyrinth, our source of information transmission of information but also sit- about rotatory movements and linear ac - uate us in our social milieux, yet forty mil- celerations including gravity. lion Americans–an eighth of the popu- The cochlea comprises three tiny, liquid- lace–have hearing loss severe enough to ½lled tubes that spiral in parallel from the mar their daily lives, for example by im- organ’s base to its apex. Vibration of the peding conversation on the telephone or in stirrup bone applies an alternating pres- a noisy environment. Age-related hear- sure to the contents of one chamber, set- ing loss, or presbycusis, affects 25 percent ting in motion the elastic boundaries be - of our population at age sixty-½ve and 50 tween the tubes. One of these boundaries, percent by age eighty, distancing many the , supports the me- individuals from friends and family and chanically sensitive structure of the ear, greatly diminishing their quality of life. the . Here the vibration oc - Finally, abrupt hearing loss–whether from casioned by the incoming sound is rein- overloud sounds, infections, or certain terpreted as an electrical signal, the com- medications–may afflict individuals of mon currency of signaling throughout the any age. Deafness can be psychologically nervous system. This process, the analog of devastating, leading to depression and detecting light in the eye or an odorant in even suicide as a result of the isolation that the nose, constitutes auditory transduction. it imposes. As Helen Keller remarked in a The receptors responsible for transduc- letter: tion are termed hair cells, for each bears on its top surface a mechanically sensitive or- I am just as deaf as I am blind. The problems ganelle called the hair bundle, which com - of deafness are deeper and more complex, prises between ten and three hundred reg- if not more important, than those of blind- ularly spaced, erect, cylindrical protrusions ness. Deafness is a much worse misfortune. called (Figure 1). This name, For it means the loss of the most vital stim- which means “stiff hairs,” characterizes an ulus–the sound of the voice that brings important feature: each stereocilium con- language, sets thoughts astir and keeps us in tains a rigid fascicle of cross-linked ½la- the intellectual company of man.2 ments of the protein actin. When a me - chanical force is applied at the top of the

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Figure 1 A. J. The Process of Hair Cells Hudspeth

The scanning electron micrograph at the upper left shows the surface of the sacculus, a sensory organ in the of a frog. Conical hair bundles extend about three ten-thousandths of an inch, from the smooth tops of the mechanically sensitive hair cells. The hair cells are separated by supporting cells marked by a stubble of ½ne protrusions called microvilli. The enlargement at the upper right portrays a single hair bundle comprising about sixty stereocilia and a lone with a bulbous tip at the tall edge of the bundle. Note the progressive increase in stereociliary length from left to right; deflecting the bundle in the same direction excites the cell.

The diagram of two adjacent stereocilia schematizes the mechanism of transduction. When the hair bundle stands at rest, the ½lamentous tip link interconnecting the stereocilia bears little tension and the channel at its lower end is usually closed. An excitatory stimulus (thick arrow) deflects the bundle toward its tall edge, causing a sliding motion between the stereocilia and consequently increasing the tension in the link. This tension opens the channel, allowing positively charged ions to carry electrical current into the cell (curved arrow). If the stimulus persists for more than a few hundredths of a second, the adapts: the upper insertion of the tip link slides down the longer stereocilium (arrowhead), relaxing the tip link and allowing the channel to reclose. Note that the relative proportions in the diagram have been exaggerated in the interest of clarity. In reality, the loudest tolerable stimulus would deflect the hair bundle by only one-quarter of a stereociliary diameter and the channel would be smaller than the line thickness. Source: Figure prepared by the author.

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The hair bundle, each constituent stereocilium Stimuli are conveyed to the mechano- Energetic pivots at its tapered base, with minimal electrical-transduction channels by tip Ear flex ing along its shaft. This movement en- links, which are molecular threads consis t - tails a sliding motion between adjacent ste- ing of four molecules of extracellular pro- reocilia that is central to the transduction teins called cadherins that run obliquely process. from the tip of each stereocilium to the The stereocilia in a hair bundle are not flank of the longest adjacent stereocilium of uniform length. A poorly understood (Figure 1). Each of these tip links is likely developmental process causes one row of connected to two ion channels at its lower these stereocilia to grow longest, while also end. When the top of a hair bundle is rendering each successive row progres- pushed toward its tall edge, the sliding sively shorter. Every hair bundle is accord- between adjacent stereocilia increases ingly beveled like the tip of a hypodermic the tension in the obliquely mounted link, needle. This characteristic is of importance which pulls the channels open. Movement in transduction, for the bundle is most sen- in the opposite direction allows a small sitive to deflection along the direction of fraction of the channels that are open at its bevel. Displacement of the hair bun- rest to close. Because the tip links are ori- dle’s top toward its tall edge excites the ented parallel to a bundle’s bevel, they do hair cell, whereas motion in the opposite not sense perpendicular stimuli. direction has an inhibitory effect. Move- The direct linkage of channel opening ment at a right angle, perpendicular to the to hair-bundle movement has three im- bundle’s plane of mirror symmetry, elic- portant consequences for our hearing. its no response. The hair bundle can thus First, because there are no chemical in - be considered a biological strain gauge that termediates in the transduction process, is excited or inhibited by appropriately hearing is rapid. We are able to detect oriented mechanical stimuli. sounds at frequencies as great as twenty thousand oscillations per second, and bats Like other excitable cells, the hair cell and whales can respond to stimulation at produces electrical signals across its sur- frequencies ½ve times that great. By com- face membrane through the action of ion parison, we process visual stimuli at only channels, which are proteins that traverse one-thousandth of that speed: in motion the membrane and offer tiny pores through pictures and television, images presented which electrically charged ions can flow. twenty or thirty times per second are con - Most channels are equipped with some strued as continuous because they exceed form of molecular gate that can open or the eye’s rate of transduction. close to regulate the flux of ions. The chan- The direct opening of channels next ex - nels responsible for signaling in the ner- plains why hearing is so sensitive. The vous system, for example, include those re- faintest sounds that we can perceive vi - sponsive to membrane voltage, which un- brate hair bundles by ten billionths of an derlie the propagating signals called action inch, which is an atomic dimension. This potentials, and those sensitive to neuro- movement is analogous to the apex of the transmitter chemicals, which mediate the Washington Monument budging by less synaptic interactions between neurons. than an inch. The sensitivity of hearing is The ion channels of the hair bundle in - limited by noise produced by the water stead have mechanically sensitive gates molecules of the inner ear’s fluids that, that open and close in response to bundle excited by heat, continually buffet hair displacements. bundles.

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The third and most important conse- mensions and material properties. Doing A. J. quence of the direct mechanical gating of this would present a challenge, however, Hudspeth transduction channels is the mechanical because a hair bundle, like other cellular instability of the hair bundle. Applying a components, requires a liquid environ- small force to a hair bundle tenses the tip ment. Movement through the extracellular links, which may in turn activate several fluid causes a sound wave to dissipate, los - transduction channels. Because opening ing power due to viscosity, which reflects the channels’ molecular gates relaxes the the friction between a hair bundle and the attached tip links, the links associated with surrounding water molecules. The active the remaining channels must bear more process represents evolution’s reconcili- of the stimulus force. If these channels ation of these issues. By continually sup- then open as a consequence, an avalanche plying energy to the vibrating hair bundles, ensues: the activation of a few channels the active process counters the energy- triggers the opening of the rest. Similar dissipating effects of hydrodynamic fric- behavior occurs when more than a certain tion and allows our hearing to exploit res- number of channels have been shut by onance. stimulation in the opposite direction; now As its name suggests, the active process the remaining channels close in concert. must work to overcome viscosity and am - The consequence is that a hair bundle be- plify a hair bundle’s mechanical inputs.4 comes bistable, adopting either a con- The law of conservation of energy im - ½guration with open channels upon stim- plies that a hair cell must draw on some ulation toward its tall edge or a state with source of biochemical energy to power its closed channels in response to force in the active process. At least in the ears of land- opposite direction. The bundle cannot, dwelling, non-mammalian vertebrates, a however, remain stably in a position be- form of myosin–the type of protein that tween the two extremes. This behavior re- animates our muscles–does the work sembles that of a child’s click toy, a metal that underlies the active process. Rather strip that snaps between two shapes with like the participants in a tug o’ war, myosin an audible pop. As we shall see, the insta- molecules consume cellular energy to pull bility of the hair bundle has been har- against intracellular strands of the pro- nessed by evolution to implement the ac- tein actin. Through such exertions, a clus- tive process. ter of myosin molecules at the upper end of each tip link continually tightens the Sounds can be captured effectively link and thus ensures that some transduc- through the phenomenon of resonance, in tion channels remain open. If movement which each cycle of a stimulus tone adds of the hair bundle toward its tall edge fur- a tiny increment of energy to a vibrating ther tenses the link and activates more structure. This is how an opera singer’s channels, then the myosin molecules work voice can shatter a champagne glass: pro- less and allow the link to relax and some longed vocalization of the note to which channels to reclose. Conversely, when a the glass is tuned causes an oscillation that negative hair-bundle movement slackens grows in amplitude until the material fails. the link and closes the channels, the my - Hearing would be most sensitive if the osin molecules ascend, restoring tension ear’s structures were free to accumulate and thereby reopening the channels. This sound energy through resonance; each in- process is called adaptation: whenever a dividual hair bundle would vibrate at a protracted displacement is applied to the speci½c frequency determined by its di - bundle, transduction channels transiently

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The open or close, after which the myosin titatively for the active process. Bun dle Energetic move ments restore the status quo ante with- motility contributes to the active pro cess Ear in a few hundredths of a second. The adap- in mammals as well, but, as discussed be - tation process ensures that the machinery low, in these animals it is supplemented by of transduction is always poised where it an additional mechanism. is most effective: on the brink of channel opening. Among the most striking and useful Imagine that a hair bundle is somehow features of hearing is our ability to distin- deflected toward its tall edge, perhaps by guish tones of different frequencies. Al - collision with an energetic water molecule, though a semitone, the narrowest interval such that most of the channels snap open. on a piano, represents a frequency differ- The myosin molecules react by lowering ence of about 6 percent, a trained listener the tip-link tension in an effort to restore can readily detect an interval of only 0.2 the probability of channel opening to an percent–in musical parlance, three cents, equilibrium value of one-half. Before that or hundredths of a semitone. Frequency point is reached, however, the closure of discrimination is of obvious importance some channels triggers an avalanche in in the performance and appreciation of the opposite direction and most of the music. However, this faculty is also used remaining channels snap shut as well. In continually in daily life in our recogni- response, the myosin molecules begin to tion of sound sources and our interpreta- ascend in a renewed effort to achieve equi- tion of speech. The distinctions between librium. But again they are thwarted, for various phonemes, or speech sounds, rest as the rising tip-link tension opens some upon the frequencies present in each (Fig- channels, the remainders stampede in the ure 2). To identify a speaker and, more same direction. As the system jumps back particularly, to determine what she has and forth in a futile attempt to achieve said, the cochlea must somehow parse equilibrium, the hair bundle oscillates complex sounds into their constituent from side to side. Me chanical recordings frequencies. from hair bundles have demonstrated In 1863, German physician and physicist these spontaneous movements in vitro.5 Hermann von Helmholtz ½rst appreciated A mechanical stimulus applied to an that the cochlea works like an inverse oscillatory hair bundle harnesses this ac- piano. A piano blends the sounds from sev - tivity. If the frequency of stimulation is sig- eral independent resonators–the oscil- ni½cantly greater or less than that at which lating strings–into a harmonious whole. the hair bundle oscillates spontaneously, The cochlea undoes this effort, separating then the ensuing response is small. If the from a complex sound the various pure stimulus accords with the bundle’s natu- tonal constituents. Every component is ral frequency of oscillation, however, the then analyzed independently so that the adaptation process can pump an incre- brain receives a description of each succes- ment of energy into each cycle of move- sive phoneme in terms of its constituent ment. Just as the motion of a child’s swing frequencies. From this information, the gradually increases with each pa rental central nervous system can calculate what push, the response grows over a few cycles word was spoken while also abstracting to a peak amplitude at least a hundred such nuances as accent and emotional in- times larger than that of a passive sys tem. flection. In the extensively studied ear of the frog, How are the different components of a active hair-bundle motility accounts quan- complex sound separated? This operation

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Figure 2 A. J. The Operation of the Mammalian Cochlea Hudspeth

The sonogram in the upper panel analyzes my voice declaiming the ½nal line of Dylan Thomas’s poem “Fern Hill.”6 Time (in seconds) is represented on the horizontal axis and frequency (in thousands of cycles per second) on the vertical; loudness is signi½ed by brightness. The prominent vowels in “though,” “sang,” “my,” “chains,” and “sea” involve multiple low frequencies–the formants–whereas the consonants are represented by high frequencies. When responding to speech such as this, the cochlea rapidly and continuously deconstructs phonemes into their constituent frequencies; the brain then uses the resultant information to infer what has been heard.

The schematic drawings in the lower panel show how the snail-shaped cochlea would look if unrolled: a long, bone-enclosed tube bisected by the elastic basilar membrane. Sound striking the eardrum sets it and the three tiny bones of the middle ear into oscillation, which is communicated to the liquid contents of the cochlea. Each frequency component of the sound elicits a traveling wave that propagates along the basilar membrane and peaks at a speci½c position corresponding to that frequency. By this means, the cochlea separates complex sounds into vibrations that stimulate certain of the sixteen thousand hair cells arrayed along the basilar membrane. Note that the vertical motion of the membrane has been exaggerated three hundred thousand–fold with respect to the cochlea’s length. Source: Figure prepared by the author.

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The is performed by the basilar membrane, Because the basilar membrane oscillates Energetic one of the elastic boundaries of the within the liquids that ½ll the cochlear Ear cochlear chambers that are deflected by chambers, it too loses energy to viscosity. sound pressure. The basilar membrane Research conducted during the past two ex tends about one and one-third inches decades has demonstrated how the active along the cochlear spiral and varies con- process counters this problem. In the tinuously in its physical attributes. At the mammalian cochlea, the active process is base of the cochlea the membrane is nar- facilitated by twelve thousand outer hair row, light, and taut; like the thinnest string cells that spiral along the basilar mem- on a violin, it oscillates at a high frequen- brane in three parallel rows adjacent to cy. The basilar membrane at the cochlear the single row of inner hair cells. The outer apex, which like the coarsest string on a hair cells transmit a negligible amount of contrabass is broad, massive, and floppy, information to the brain; instead, they instead resonates upon stimulation at a low serve as dedicated ampli½ers that enhance frequency. Each intermediate position is the mechanical stimuli delivered to the in- most responsive to stimulation at a speci½c ner hair cells. When sound displaces the frequency that grows incrementally from basilar membrane, side-to-side move- the apex, which responds to twenty vibra- ments of the tweak the tions per second, to the base, which is sen- underlying hair bundles, exciting active sitive to twenty thousand cycles a second. hair-bundle motility like that of other hair When a particular tone is sounded, the cells. In addition, transduction of the me - basilar membrane begins to vibrate at the chanical input elicits in outer hair cells an same frequency. The membrane does not electrical response that drives a unique move as a unit, though; instead, the oscil- phenomenon called somatic motility. When lation propagates from the base toward the the cell’s voltage becomes more negative, apex as a traveling wave (Figure 2). The the millions of prestin molecules studding motion is small at the membrane’s base the membrane of each outer hair cell ex - but grows progressively larger as the wave pand; a more positive voltage causes con- approaches the place that responds to that traction. The entire cell consequently speci½c frequency. There the wave achieves changes in length, respectively elongating its peak amplitude before rapidly dissipat- or shortening like a tiny muscle. And like ing like a comber breaking upon a beach. a muscular contraction, somatic motility A complex sound engenders overlapping delivers energy, accentuating the basilar but largely independent traveling waves membrane’s vibrations. This activity con- for each of its components. The position at stitutes an example of positive feedback which each wave peaks speci½es its frquen- in which sound-induced vibrations beget cy; the magnitude of each peak indicates still larger oscillations. And in the active the wave’s loudness. Arrayed in single ½le process, as in a public-address system, pos- along the basilar membrane, four thou- itive feedback can lead to instability. sand receptors called inner hair cells de- tect these vibrations and produce electrical For decades after the ½rst proposal that responses that are then conveyed to the the ear employs an active process, there was brain by thirty thousand nerve ½bers. The little evidence to support the hypothesis. cochlea thus acts as a frequency analyzer, This changed when careful measurements providing the central nervous system with showed that, in a very quiet sound cham- a nearly instantaneous report of the tones ber, the ears of at least 70 percent of normal present in any acoustic stimulus. humans emit one or more tones. In other

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words, the ear not only takes sound in, but Spontaneous otoacoustic emissions are A. J. also puts sound out! These spontaneous not the only unexpected emanations of a Hudspeth otoacoustic emissions are not pathologi- normal human ear. The instability in hair- cal, but on the contrary are a hallmark of cell transduction also generates combi- healthy ears whose hair cells are capable nation tones, sounds that are heard and of exuberant activity. even emitted from ears though they are As discussed above, the active process is absent from acoustic stimuli. Suppose one an example of positive feedback. More- listens to simultaneous, moderately loud over, like many man-made feedback sys- sounds of two distinct but nearby pitches: tems, the active process exhibits gain con- a higher frequency f2 and a lower one f1. trol: it can be turned up or down as cir- In addition to these two tones, a normal cumstances dictate. When ampli½cation listener then hears the prominent combi- is unnecessary in a loud environment, the nation tone 2·f1–f2, twice the lower fre- feedback largely vanishes and the ear is quency minus the higher. This tone is essentially passive. Under the conditions somewhat fainter than the two that are that prevail through most of daily life, actually sounded, but is nevertheless loud corresponding to sound-pressure levels enough to be perceived clearly. In fact, of approximately sixty decibels, ampli - composers have created music in which ½cation makes only a modest contribu- no instrument actually plays the audible tion to the ear’s responsiveness. Near the melody. Two streams of tones are played threshold of hearing around zero decibels, instead, and the listener’s ear synthesizes however, we feel that we can hear a pin the melody from the successive tone pairs. drop: indeed, our acoustic sensitivity is Composers György Ligeti and Karlheinz enhanced more than a hundredfold by the Stockhausen are among those who have active process operating at its highest gain. experimented with this effect, which was An individual who lacks the active pro - ½rst discovered in the eighteenth century cess as a consequence of hair-cell damage by violinist and composer Giuseppe Tar- loses this ampli½cation and therefore be- tini.7 comes hard of hearing. Because combination tones originate What happens if the strength of feed- from the instability of normally function - back increases still further? The result is ing hair bundles, they provide a useful called a bifurcation: an abrupt, qualitative assay for normal hearing. Most newborn change in the behavior of the auditory ap - children in the United States are now sub- paratus. Just as slowly turning up a public- jected to a simple test in which two tones address system suddenly elicits a howling are played into each ear while a sensitive noise, the ear can reach the point at which microphone records the sounds in the ear some hair cells begin to oscillate sponta- canal. If the measured intensity of the com- neously. The vibrations are transmitted bination tone exceeds a certain threshold, back out of the cochlea, resulting in spon- hearing in that ear is almost certainly nor - taneous otoacoustic emissions that can be mal. If the response is diminished, how- measured in the ear canal. In rare cases, ever, other tests can con½rm whether a these sounds can be heard by nearby peo- hearing defect is present and how it might ple, even at a distance of several inches. be remedied. There can be no doubt in such instances that the cochlear ampli½er is active, for Hearing loss is a growing problem in a the ear radiates energy into the surround- society characterized by increases in both ing air. lifespan and noise pollution. Although cell

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The division continually replenishes most cells The most enticing avenue for a long- Energetic in the human body, a few critical types of term solution to deafness is through the Ear cell–including hair cells in the ear as well regeneration of hair cells. Although ½shes, as nerve cells in the brain and muscle cells amphibians, and reptiles (including birds) in the heart–are unfortunately not re - can readily replace these receptors, mam- placed by this means. As we lose hair cells, mals for unknown reasons cannot. Nu - we also forfeit the advantages afforded by merous researchers are now attacking this the cochlea’s active process. The ear’s problem, trying to understand how regen - sensitivity thereby declines, rendering us eration naturally occurs and why it is de - hard of hearing. A diminished capacity to ½cient in mammals. Although the pace of distinguish frequencies impairs our ability research is painfully slow for those with to recognize the subtle nuances of speech. impaired hearing, recent results are en - And loss of the cochlea’s compressive couraging. Various treatments have cre- qual ity means that weak sounds become ated mammalian hair cells in vitro and even inaudibly soft and strong sounds offen- in the damaged ears of animals, and in - sively loud. It is for this reason that a hear - vestigators have begun to identify the mo - ing aid is so often unsatisfactory: the de- lecular signals that underlie the decision of vice intensi½es the sounds reaching the ear precursor cells in the ear to multiply and but cannot restore the normal sharpness assume the role of hair cells. and dynamic range of hearing. American Sign Language (asl) provides The active process provides a striking one successful means of communication example of the opportunistic nature of for the hearing-impaired. Used by half a evo lution. The direct mechanical gating million people in the United States and of transduction channels–the simplest Canada, this form of signing represents a mechanism that might be envisioned– highly evolved language quite distinct inevitably inflicts the distortion respon- from spoken English. Regional derivatives sible for combination tones. This mode of asl and other distinctive sign languages of action additionally imposes mechani- are used throughout the world. During the cal instability on the hair bundle. Despite last few decades, the deaf have also ben- these flaws, direct channel gating has ap - e½tted from the introduction and evolu- parently persisted by virtue of its great tion of the cochlear prosthesis. Surgically speed. The necessity of maintaining the implanted into a damaged ear, this array transduction machinery within its narrow of electrodes restores a degree of hearing working range likely supported the evo- by directly stimulating the nerve ½bers that lution of adaptation. This process too has run from the cochlea into the brain. A been implemented in a simple manner, receiver worn outside the head replaces through the activity of a common form of the lost hair cells by deconstructing myosin, the workhorse of force production sounds into their component frequencies in cells. Yet most remarkably, combining and sending electrical signals to the cor- the phenomena of direct transduction and responding electrodes. As the most suc- adaptation has yielded the fundamental cessful neural prosthesis to date, with near- features of the active process: a tuned am- ly three hundred thousand users world- pli½er with a broad dynamic range, the wide, the cochlear implant has raised foundation of our extraordinary hearing. hopes for progress with future electrode systems that might be used to restore vi- sion or overcome spinal injuries.

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endnotes A. J. Hudspeth Author’s Note: The author thanks Ms. Christina Black, Mr. Jeff Robinson, and Dr. Maurine Packard for comments on the manuscript. 1 Guy P. Richardson, Jacques Boutet de Monvel, and Christine Petit, “How the Genetics of Deafness Illuminates Auditory Physiology,” Annual Review of Physiology 73 (2011): 311–334. 2 James Kerr Love, ed., Helen Keller in Scotland: A Personal Record Written by Herself (London: Methuen & Company Ltd., 1933), 68. 3 A. J. Hudspeth, “The Inner Ear,” in Principles of Neural Science, 5th ed., ed. Eric R. Kandel, James H. Schwartz, Thomas M. Jessell, Steven A. Siegelbaum, and A. J. Hudspeth (New York: McGraw-Hill, 2013), 654–681. 4 A. J. Hudspeth, Frank Jülicher, and Pascal Martin, “A Critique of the Critical Cochlea: Hopf– a Bifurcation–is Better than None,” Journal of Neurophysiology 104 (2010): 1219–1229. 5 A. J. Hudspeth, “Integrating the Active Process of Hair Cells with Cochlear Function,” Nature Reviews Neuroscience 15 (2014): 600–614. 6 Dylan Thomas, The Poems of Dylan Thomas, ed. Daniel Jones (New York: New Directions, 1971), 195–196. 7 Daniel P. Walker, Studies in Musical Science in the Late Renaissance (London: London University Press, 1978), 123–170.

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