Prestin: Purveyor of Pianissimo

How hearing happens in the inner ear.

Why are mammals so soft and unprotected, ourselves most of all, being naked? One answer, evolutionarily, is that we are high instrumented, with exquisite senses of vision, touch, smell, position, and hearing, which project our defenses outward, from a hard exoskeleton to an over-the-horizon system, to put it in modern military parlance. Mammals have, for example, far better hearing than reptiles or other preceeding animals, both in frequency range and sensitivity. What is a lawnmower to us would be softly audible to a lizard, while what is pianissimo to us would not be audible at all. This was one of the super-powers that kept small insectivorous mammals going through the age of dinosaurs, both on the hunt and on defense against the velociraptors. High frequency hearing has been taken to particular extremes by cetaceans and bats.

A recent paper described the atomic structure of prestin, the key protein of the power-amplifier of mammalian hearing. But to understand its role, one needs some appreciation of the ornate engineering of our hearing apparatus, particularly the cochlea. The cochlea is the small snail-shaped organ that sits inside the hardest bone of our bodies. It is tonotopic, meaning that sound pitch is interpreted in order along its coiled length, as though it were an inverse piano keyboard. The highest frequency sounds are picked up at the beginning, near the oval window where the stapes connects with the cochlea, while lower-pitch sounds are detected at the tiny apex. 

Schematic of the outer, middle, and inner ear. Note the direction of sound flow, first through the scala vestibuli of the cochlea, then around the apex, back through through the scala tympani, and to the pressure reliever of the round window. The basilar membrane sits in the middle, allowing excitation of itself when the frequency of the sound matches its intrinsic stiffness, which varies continuously along its length.

Sound comes in via the eardrum and the small bones of the middle ear. Waves then propagate from the oval window through the fluid passages of the cochlea, (scala vestibuli), around the apex, and back out through the scala tympani to the round window, which is the final pressure reliever. Sound receptors are arranged along the central organ of Corti, (green), where the various frequencies are separately mapped and detected by the inner hair cells.

A Nobel prize was awarded in 1961 for the first viable explanation of how the cochlea works. At the core of the organ of Corti is the basilar membrane, whose width and stiffness varies continuously as its ribbon furls through the cochlea.

"When flattened and straightened, the basilar membrane appears wedge shaped, with its width gradually increasing from the cochlea’s “input” end (its base) toward the far end (its apex). The change in width results in a 1e4-to 1e5-fold reduction in the membrane’s stiffness from base to apex. This stiffness is conferred by the membrane’s dense strands of collagen fibers running perpendicular to the long dimension and making the membrane highly anisotropic"

An exaggerated standing wave excites its frequency-dependent point along the basilar membrane of the cochlea, here notionally stretched out for illustration. Lower frequencies are detected farther from the base.

It is this stiffness that acts as a frequency selector, with each frequency exciting a standing wave at its own characteristic point along this basilar membrane, and thus along the length of the cochlea. The standing wave is detected by inner hair cells, which convert motion to electrical signals that go to the brain for processing and perception.

Cross-section of the basilar membrane, scala media, and associated cells, including especially the inner hair cells (IHC) which perceive sound and conduct resulting electrical signals to the brain, and the outer hair cells (O), which perceive sounds and set up a sympathetic positive feedback vibration, amplifying soft sounds thousands-fold, to assist the function of the inner hair cells.

So far so good. But the cochlea also harbors outer hair cells, which are specific to mammals, and amplify our hearing by roughly 50 decibels. Yet these hair cells have far fewer nerve connections to the brain, and those connections do not map to the same auditory decoding areas as those from the inner hair cells. What gives? Well, it took till the 1970s to realize that the cochlea is not a passive organ, it is an active organ, one interesting sign of which are cochlear emissions. These are sounds coming out of the cochlea as a sort of amplified echo based on incoming lower amplitude sounds. It turns out that outer hair cells (which outnumber the inner hair cells on the basilar membrane) are not sensing nerve cells in the usual sense. Rather, they sense incoming sound and rapidly compress / decompress themselves, thus amplifying the signal vibration for the benefit of the inner hair cells, which then can relay a signal at far higher sensitivity than they could unassisted. This behavior is called electromotility.

Scanning electron micrograph (left) of outer hair cells with their cili at the top.  DC are helper cells. At right is a dissected outer hair cells, with the stereocilia at top, cuticular plate, and nucleus at bottom.

And how to outer hair cells perform this feat? Aside from a complex set of cilia at their tops, connecting to each other and to the tectorial membrane, plus alot of other intricate ionic physiology, they are covered (75% of their membranes along one side) with the protein prestin, which functions as a piezioelectric transducer. This protein is evolutionarily derived from a large family of anion transporters, so has 14 helical transmembrane protein segments that anchor it in the membrane, and has a sort-of-pore, which binds to anions like sulfate, chloride, and an inhibitor, salicylate. But this pore does not conduct any ions through the membrane. Instead, the change of local membrane voltage, which is induced by the firing of ion channels in the tips of the cilia, causes only a shape change, calculated via this new structure, of ~740 square angstroms reduction when electrically excited, which is about 10% of its total area. This is why the outer hair cell can contract extremely rapidly in reponse to the incoming frequency-discriminated sound signal. The energy for all this does not come (immediately) from ATP, as would be typical (but far to slow). No, it comes from an ionic environment that is specially tuned within the organ of Corti vs the neighboring fluid-fillled sound conduction channels (the scala vestibuli and the scala tympani directly underneath the basilar membrane), which create a potassium and charge gradient that allow the outer hair cells to fire without draining their own energy reserves.

Structures of prestin in activated (left) and relaxed (right) conformations. The overall area change of the protein induced by membrane charge changes leads to the contraction of the entire outer hair cell, in synchrony with the sound being perceived.

Our hearing system is magnificent. One would tempted to call it a miracle of senstivity and discrimination, except that its long and painful evolution is clear, and its current incarnation remains subject to various deficiencies, like the various maladies of loss of hearing in old age, or the gain of tinnitus.

"The efficiency of conversion from mechanical force to electrical charge is estimated to be ~20 fC nN−1, four orders of magnitude greater than the efficiency of the best man-made piezoelectric material"

"The action of prestin is also orders of magnitude faster than that of any other cellular motor proteins."

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We Can be Heroes, Just for One Day

Activating the archetypes through fantasy and magic, in science fiction.

Why is science fiction so full of magic? The Force, warp drive, transporters, replicators, spider-spinning webs, other Marvel super-powers ... a genre that supposes itself to be science-based is anything but. Sure, we may hope for some of these technologies. The tablet computer was prefigured on Star Trek. But most of this magic violates basic physics- it is never going to be realized. I am running through some of the Star Wars ouvre, and it has been striking to watch this fantastical conjunction of the hero tale with magic and archetypal elements and characters. Why?

The hero tale forms a classic template, not just dramatically, but psychologically. It conveys a series of (usually male-centric) value judgements on what and who is important, and more significantly conveys hope to the unformed youngster that she or he too can unearth such powers within, can find such friends and helpers, and can do such important tasks. Heroes enact a drama to which we relate empathically, and thus adopt as a possibility for ourselves. Thus the need for a rousing climax where good triumphs over evil, just deserts are meted out, and all the other apparatus of the genre. The cultural significance and importance of such dramas is hard to overstate. And likewise, the impact of our more jaded and cynical media landscape of today is significant and bodes ill for our dreams of the future.

People need templates on how to live, what to strive for, what is important, what unimportant. Without inspiring stories, we are left with a diminished existence. The archetypal stories need to be told for their archetypal images to activate our  archetypal instincts in sympathy, to encourage and raise our vision of what is possible and socially significant. While fragments of these images may arise in dreams, they do not generally cohere and encourage in a dream setting as they do in a purposefully composed heroic story. Our dreams, frankly, beat us down more often than they raise us up. Good story tellers mediate in this space between the inchoate internal world that is neither consistently positive nor very socially conscious, and conscious reality, which is where the great deeds need to be done.

But how about all the magic? One can take that is simply hopeful, positive thinking, totally in line with the rest of the hero fantasy. Humans have wanted to fly forever, and our dreams are full of it. Yet never in a million years has that fantasy involved baggage checks, shoe removal, and flimsy tray tables. The real dreamers take to hang gliding. Would I like to use a transporter? Absolutely! Science or not, the fantasy / hero tale can make it so. Magical elements express in particularly clear fashion the positive-thinking aspect of the fantasy genre, which is meant, as above, to be encouraging to we ... who are otherwise generally stuck and oppressed in our battle with day to day existence, including whatever frustrations the ambient technology presents.

Children generally lack confidence, being on the losing end of power struggles with others most of the time. Encouraging tales, templates, and examples are essential to unlock coherent and socially positive dreams about the future. Whether as cowboys and Indians, or as rebels with the Force of love and good intentions, or as crime fighters, healers, wizards, etc., the roles that we present to children through the media are immensely influential for our future cultural health. 

The hero tale has a special place for friends and helpers as well, who may arise in unlikely guises. The encouragement to seek help and be alert to help and sympathy from unlikely sources is another great strength of this genre. Like the hopefulness of magic, which may be an unanticipated power from within or without, the appearance of tricksters, helpers, and friends is an encouraging aspect that prepares the young viewer to integrate that heroic dream into a constructive social setting, encouraging maturity as well as heroism.

One more angle of fantasy magic is the spiritual or religious aspect- dramatic powers that reach beyond the human, whether from gods, or in other cultural settings, super-advanced beings, usual forces, etc. The hero may possess some magical powers and have magical friends, but there clearly are limits. One task is to find out what they are- to explore this odd world the hero finds her or himself in, a task which mirrors that of growing up and coming to terms with the complexity of adulthood. The greater powers may be mysterious and perhaps need to be respected, since the wellsprings of reality are beyond the hero's comprehension, as they are beyond ours. But where we generally take them for granted and ignore them, the hero drama can personify them and make us think about their strangeness and wonder.

So, nothing science about it, just the oldest trick in the book in making up a great story that is full of hopeful elements at all levels, personally, physically, socially, and morally.

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The Hunt for Enemy RNA

How our cells tell foreign RNA from friendly RNA, in a truly baroque process.

RNA is hot these days. It is the active ingredient of the leading and innovative coronavirus vaccines, it appears to be the primordial molecule at the origin of life, and it keeps cropping up in new permutations in molecular biology, with every year bringing new acronyms for novel roles it plays in our cells. Half of viruses use RNA for their genomes, making it an important target of the immune system as well. We have several mechanisms that sense viral RNAs, and likewise several mechanisms to differentiate self-RNA from foreign RNA. It is evident that an arms race of military intelligence has been taking place over the evolutionary eons. 

Among the common ways we have to tell friendly RNA from foe are special "caps" chemically attached to the front end of message RNAs, further methylation modifications of the front end of RNAs, and the existence of double-stranded RNA, which is generally rare in our cells. Most RNA viruses have single-standed genomes, but they usually have a double-stranded RNA intermediate in their replication process. Eukaryotic cells focus intently on recognizing that double-stranded RNA, doing so with proteins named RIG1 and MDA5. RIG1 is an RNA helicase that binds and recognizes double-stranded RNA, and then triggers the production of interferons, the primary signaling molecules telling cells that there is a viral infection, and which induce production of a wide range of other antiviral proteins.

But with our own RNA all over the place, it naturally happens that some double-stranded RNA forms accidentally, from our own sequences. What to do about that? One mechanism is RNA editing, where selected "A" residues are chemically switched to "I" or inosine, which base pairs differently from A, and destabilizes double-stranded RNA. This editing is performed by an enzyme called ADAR1. For coding mRNAs, these edits can alter their meaning, so it is also called RNA recoding, and  routinely affects the sequences of several important proteins. 

ADAR gene products and isoforms (left) all perform RNA editing of A (adenine) to I (inosine) in double-standed RNA regions of self-RNAs, (right), to prevent them from causing false alarms of our internal antiviral surveillance systems.

Another mechanism to protect friendly RNA is the attachment of methyl groups to A residues, (m6A), which also shields them directly from RIG1 surveillance. The m6A modifications are applied by enzymes METTL3 and METTL14, and are detected by YTHDF1, which binds them and can increase their expression by speeding up translation, or destabilize them, or have other effects on their expression. The logic of the various proteins that recognize m6A modifications is diverse and remains rather unclear, actually, though the general trend is one of increasing expression of recognized messages. 

One has to suppose that these editing and modification systems are relatively slow, so that incoming viral RNAs can be recognized before they themselves are modified and turned into invisible infiltrators. So there must be some very careful tuning involved, and great incentives for viruses to encode such modification systems for themselves. For example, coronaviruses encode in their tiny genomes several proteins that put "friendly" chemical caps on the front ends of their own RNAs.

Getting back to the editing and m6A systems, genetic mutations generating defective ADAR1 cause severe auto-immune disorders, where the anti-viral interferon system is over-activated. What recent researchers found curious, however, was that defects in YTHDF1 cause similar effects, over-activating antiviral immune systems, even though YTHDF1 is not inherently part of the core systems of protecting self-RNA from recognition by all these antiviral detectors. It turns out that YTHDF1's effect is mediated by just one of its gene targets- ADAR1. Translation of the ADAR1 mRNA is enhanced by YTHDF1 after it binds to m6A modifications on that mRNA. This in turn promotes the ADAR1- catalyzed edits of other cellular RNAs, especially double-stranded ones, preventing them from getting caught up in the RIG1-activated red alert system of interferons and viral response.

In this way, one system of self-identification and protection is tied into another system, for reasons that are truly hard to fathom, and are only a tiny part of a far more elaborate system. I think it is an example of evolution run amok, developing one bureaucracy on top of other ones, on top of yet other ones, in a gerry-rigged system that has had billions of years to accumulate. Yes, it is all very finely tuned, thanks to the necessities of natural selection and the struggle against predation by invaders. But it is the farthest thing from being designed.

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Being American

With apologies to those outside the US, throughout the Americas, naturally.

The meaning of being an American is obviously a bit fraught right now. The US had a heyday in the post-WW2 era, when we ruled the world and enjoyed breakneck technological and economic growth. Many seem to think that the conditions of that era are some kind of birth-right, that a lifestyle of mainline Christianity, hamburgers, and trucks is a cultural patrimony worth fighting for, against the existential changes wraught by demography, immigration, climate change, and education. We have come a quite a way from the days of the Civil War, when a similar fight revolved around the right to keep Black people in bondage, but the current historical predicament does rhyme, as they say.

The US is still an incredibly rich country, and a technological leader in countless fields. But at the same time, other countries with lower military budgets and fewer world policing duties show us up in better living conditions, and more progressive political systems. But that is obviously not what grates on the right wing base- that other countries may be more liberal, prosperous, and happy. (Though in fairness, such competing countries are typically also less diverse, and thus have higher social solidarity, from a tribal / ethnic perspective, which does seem to be striking a chord with the right wing). No, what grates is that their god-given right to the American way is dissolving, for all kinds of reasons, but none that completely irresponsible policy, cynical politics, and general greed and obtuseness can't make go away, at least for a little while.

During the Civil War, Lincoln through his Gettysburg address and other writings tried to forge a new vision of what America was about, one with world-wide significance that left behind the stasis and meanness of slavery for the promise of equal opportunity and human development in an abundant and growing land. It was that vision that propelled the US through the next century, through railroads, flight, military might, the oil age, and to our current age of computer and biomedical technological frontiers.

It is clear that we again need a new vision, now that our peak of relative military and economic power is waning. There is no going back. Climate change is making sure of that, even if the Chinese don't follow it up with other unpleasant facts on the ground. The US of old is irrevocably gone, and pining for it isn't going to bring it back, especially if destroying our democracy is the method chosen to get there. What is worse, our moral authority is even more imperiled than those harder forms of power and influence.

Atlanta Olympics opening ceremonies, featuring lots of Stetson hats and pickup trucks.

Remember the 1996 Atlanta Olympics? Dreadful generally, but what sticks in my mind is the fleet of pickup trucks that were featured in the opening ceremony. How incredibly tone-deaf, and what an homage to greed and planetary destruction. But now, a quarter century on, we are still fighting that same fight, between those looking to the past, and those looking to the future. The past was one of abundance, thanks to the bountiful nature that the US was endowed with (or stole brutally from its occupants). The future looks a bit less abundant, because of the damage we ourselves have wrought on the way to all these technological wonders. Also because our population is itself unsustainable, and needs to be smaller, even after we adhere to more sustainable lifestyles and technologies. The future is going to be difficult, no question, and it will require us to think harder, and feel more keenly about others and the environment around us. Merely raping the environment will no longer do (just as chaining and whipping other humans no longer did a century and a half ago). We will have to work with it and in many cases, make sacrifices to heal it. Even pay reparations.

Land-grant colleges endowed throughout the US, courtesy of far-thinking Republicans of the Civil War era.

That is pretty clearly where the new vision of America should be going. To a prosperous future that is sustainable at the same time that it is abundant and equitable. This is a hard task, politically as well as technically, far more difficult than the great things we have accomplished in the past, like the Manhattan project or the Apollo program. And one can sense that the younger generations are ready for this task- they just need a little encouragement and vision to get us there.

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