Sounding off

Ever have the experience of getting into a car, closing the door, and accidentally shutting the seatbelt in the door?

What's interesting about this is that most of the time, we immediately realize it's happened, reopen the door, and pull the belt out.  It's barely even a conscious thought.  The sound is wrong, and that registers instantly.  We recognize when something "sounds off" about noises we're familiar with -- when latches don't seat properly, when the freezer door hasn't completely closed, even things like the difference between a batter's solid hit and a tip during a baseball game.

Turns out, scientists at New York University have just figured out that there's a brain structure that's devoted to that exact phenomenon.

A research team led by neuroscientist David Schneider trained mice to learn to associate a particular sound with pushing a lever for a treat.  After learning the sound, it became as habituated in their brains as our own expectation of what the car door closing is supposed to sound like.  If after that the tone was varied even a little, or the timing between the lever push and the sound was changed, a part of the mouse's brain began to fire rapidly.

The activated part of the brain is a cluster of neurons in the auditory cortex, but I think of it as the "What The Hell Just Happened?" module.

"We listen to the sounds our movements produce to determine whether or not we made a mistake," Schneider said.  "This is most obvious for a musician or when speaking, but our brains are actually doing this all the time, such as when a golfer listens for the sound of her club making contact with the ball.  Our brains are always registering whether a sound matches or deviates from expectations.  In our study, we discovered that the brain is able to make precise predictions about when a sound is supposed to happen and what it should sound like...  Because these were some of the same neurons that would have been active if the sound had actually been played, it was as if the brain was recalling a memory of the sound that it thought it was going to hear."

As a musician, I find myself wondering if this is why I had such a hard time unlearning my tendency to make a face when I hit a wrong note, when I first started performing on stage.  My bandmates said (rightly) that if it's not a real howler, most mistakes will just zoom right past the audience unnoticed -- unless the musician clues them in by wincing.  (My bandmate Kathy also added that if it is a real howler, just play it that way again the next time that bit of the tune comes around, and the audience will think it's a deliberate "blue note" and be really impressed about how avant-garde we are.) 

My band Crooked Sixpence, with whom I played for an awesome ten years -- l. to r., Kathy Selby (fiddle), me (flute), John Wobus (keyboard)

I found it a hard response to quell, though.  My awareness of having hit a wrong note was so instantaneous that it's almost like my ears are connected directly to my facial wince-muscles, bypassing my brain entirely.  I did eventually get better, both in the sense of making fewer mistakes and also responding less when I did hit a clam, but it definitely took a while for the flinch response to calm down.

It's interesting to speculate on why we have this sense, and evidently share it with other mammals.  The obvious explanation is that a spike of awareness about something sounding off could be a good clue to the presence of danger -- the time-honored trope in horror movies of one character saying something doesn't seem quite right.  (That character, however, is usually the first one to get eaten by the monster, so the response may be of dubious evolutionary utility, at least in horror movies.)

I find it endlessly fascinating how our brains have evolved independent little subunits for dealing with contingencies like this.  Our sensory processing systems are incredibly fine-tuned, and they can alert us to changes in our surroundings so quickly it hardly involves conscious thought.

Think about that the next time your car door doesn't close completely.

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Butterfly effect

Most of you probably know the basic story you were taught in high school biology; DNA has information-containing chunks called genes, which sit in specific places in packages called chromosomes.  Each of those genes is the instruction set for building a specific protein, and the instructions are read by creating an intermediary copy (called mRNA) of the specific gene in question, which then is transported to a structure in the cell called the ribosome, where the sequence is read and used to assemble the protein from smaller bits called amino acids.  The protein thus created -- it could be an enzyme, a structural protein, an energy carrier, a pigment, or any of dozens of other types -- goes on to do its specific job in the organism.

This pattern -- gene (DNA) to mRNA to protein -- was thought to be more or less the whole story by the people who unraveled the pattern, James Watson and Francis Crick, so in their typical self-congratulatory fashion they called it the "Central Dogma of Molecular Genetics."  (And if you know anything about their history, you'll understand why I'm calling it "typical.")  So it was a considerable shock when researchers found out that there was DNA in the genome of every species studied that didn't work this way.

It was a considerably bigger shock when it was found that the amount of DNA that did work this way was around one percent.

You read that right; between ninety-eight and ninety-nine percent of your genome is non-coding DNA.  It does not encode the instructions for building proteins.  Watson and Crick's "Central Dogma" only applies directly to less than two percent of an organism's DNA.  When this was discovered in the 1960s and 1970s, researchers (speaking of arrogance...) called it "junk DNA," following the apparent line of reasoning, "If we don't know what it does right now, it must be useless."

The whole "junk DNA" moniker never made sense to me, especially with the discovery of short tandem repeats, chunks of DNA between two and ten base pairs long that repeat over and over again (the average number of repeats is twenty-five).  Short tandem repeats are common in eukaryotic DNA, and their function is unknown.  That they do have a function -- and are not, in fact, "junk" -- is strongly supported by the fact that they're evolutionarily conserved.  Mutations happen, and if there really was no function at all for STRs, over time the pattern would get lost as mutations altered one base pair after another.  The fact that the pattern has been maintained argues that they have an important function of some kind, and mutations knock that function out and are heavily selected against.

We just don't know what it is yet.

The reason all this comes up is the discovery by a team right here in my neck of the woods, at Cornell University, that at least some of the patterns in butterfly wings are controlled by "genetic switches" in their non-coding DNA.  The team, led by Anyi Mazo-Vargas, looked at forty-six regions of non-coding DNA, and found out that a significant number of them, when disabled (a technique called gene knockout), cause huge changes in the butterfly's wing pattern.  Take, for example, the brightly-colored Heliconius butterflies:

[Image licensed under the Creative Commons Heliconius mimicry, CC BY 2.5]

Knock out a DNA sequence called WntA, and the stripes disappear; disable Optix, and the wings come out jet black.

Other than the obvious deduction -- that these non-coding sequences are acting as switches determining deposition of pigments and arrangements of the cells that generate iridescence -- not much is known about how these sequences work.  "We see that there's a very conserved group of switches that are working in different positions and are activated and driving the gene," Mazo-Vargas said.  

"We have progressively come to understand that most evolution occurs because of mutations in these non-coding regions," added Robert Reed, who co-authored the paper.  "What I hope is that this paper will be a case study that shows how people can use this combination of ATAC-seq and CRISPR [two techniques used in gene modification and knockout] to begin to interrogate these interesting regions in their own study systems, whether they work on birds or flies or worms."

So once again, as we look more closely at things, we find intricacies we never dreamed of.  What I love about research like this is that a seemingly small discovery -- that small stretches of non-coding DNA control macroscopic traits like coloration -- could have an impact on our understanding of how genetics works in general.

Truly -- a "butterfly effect."

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The palimpsest

Sophocles was a classical Greek playwright, whose beautiful and haunting tragedies Oedipus Rex, Antigone, and Oedipus at Colonus are standard fare in college literature classes.  Those three plays are his most famous, but there are four others still read and performed -- Ajax, The Women of Trachis, Electra, and Philoctetes.

Those seven plays are all that is left of the 120 plays he wrote.

Nineteen of Euripides's plays survive, out of nearly a hundred.  Seven of Aeschylus's plays still exist, from an estimated eighty.  Nothing is left of the work of the great scientists Anaxagoras, Eratosthenes, Aristarchus, and Thales except for fragments.

What we have from the classical Greek and Roman world is just what happened to survive, sometimes by design and sometimes by pure accident.  Fires claimed a great many ancient manuscripts, some of which were set deliberately.  The Great Library of Alexandria, which housed huge numbers of these works, endured loss after loss.  A fire set by the troops of Julius Caesar in 48 B.C.E. that was intended to destroy Egyptian ships at the port spread to the rest of the city and burned an estimated forty thousand scrolls in the Library.  Repeated sieges of the city under the Roman Emperors Aurelian and Diocletian three hundred years later destroyed a good percentage of what was left.  The rest of the surviving manuscripts met their end under two onslaughts from organized religion.  The first came in the early fifth century C.E. from the Christian Bishop Cyril, who not only worked to destroy the remnants of the Library, but had one of its leading scholars -- Hypatia -- brutally murdered by a mob.  (Cyril, on the other hand, went on to be canonized.)  The second came after the Muslim takeover of Egypt in the seventh century C.E., when the Caliph Omar ordered all of the remaining scrolls collected and burned for fuel.  Omar famously remarked, "If those books are in agreement with the Quran, we have no need of them; and if they are opposed to the Quran, destroy them."

What we know of pre-Dark-Ages European science and literature is so sparse that "fragmentary" seems a significant understatement.  It's as if we were trying to understand the works of William Shakespeare while having in hand Timon of Athens, Cymbeline, the last twenty pages of Coriolanus, and five randomly chosen sonnets.

There still remains some shred of hope for recovering some of this lost wealth of knowledge, however.  Researchers believe they have found pieces of the second century B.C.E. astronomer Hipparchus's lost manuscript Star Catalogue on a palimpsest -- a piece of parchment that had been erased for reuse.  Because parchment was expensive (it was made from specially tanned lamb or calf skin), used parchment was often scraped to remove the previous writing and then repurposed.  Using multispectral imaging, non-destructive technique for picking up faint traces of ink on manuscripts, a team from the Université Sorbonne and Cambridge University have uncovered what seems to be the beginning of Hipparchus's lost work in the background of the Codex Climaci Rescriptus, a Syriac Greek document from the eleventh century C.E.

You have to wonder what other gems from the ancient world lie hidden on palimpsests.

A piece of the document, showing the background writing that appears to be the introduction to Hipparchus's Star Catalogue

How amazing would that be to reclaim some of these windows into the past from manuscripts currently sitting in libraries and museums?  What would we learn about our forebears' history, science, and philosophy?  Until we can invent a time machine and go back to visit the Library of Alexandria -- the pipe-dream of many a scholar -- the best we can do is apply our modern technology to what we have.

And to judge by the recent discoveries, there may be more to find than we ever realized.

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The law of whatever works

One common misconception about the evolutionary model and natural selection is that it always leads to greater fitness.

It's fostered by the way the subject is taught; that evolution always works by "survival of the fittest," so over time organisms always get bigger, stronger, faster, and smarter.  There's a kernel of truth there, of course; natural selection does favor the organisms that survive longer and have more offspring.  But there are a number of complicating factors that make this oversimplified impression far wide of the truth.

First, evolution -- in the sense of changes in gene frequencies in populations -- can happen for other reasons besides fitness-based natural selection.  One common example is sexual selection, when a characteristic having little to nothing to do with fitness is the basis for mate choice, such as bright color in the males of many bird species.  This has led to sexual dimorphism -- males and females have dramatically different external appearance, as the females choose ornately-adorned mates who then pass those genes on to their offspring.

Second, the selecting factors can change when the environment does.  What is an advantage today can be a disadvantage tomorrow.  This can lead to what's called an evolutionary misfire -- when some characteristic that was beneficial turns deadly as the conditions change.  A particularly interesting example of this is the way moths navigate.  Moths, like most insects, have compound eyes, hemispherical structures with multiple radially-oriented facets.  They find their way around at night by using distant light sources (such as stars and the Moon), keeping the light from those objects shining into one facet of the eye.  If the light source is distant, this allows the moth to fly in a straight line.  The problem is, moths evolved in a context where there were no nearby light sources at night; and if you try this orientation trick on a close-up light source, you end up flying in circles.

And this is why moths spiral around, and eventually get fried by, candles, lanterns, and streetlights.

Third, many -- probably most -- genes have multiple effects, a phenomenon called pleiotropy.  A single gene that can provide a benefit in one way can provide a serious disadvantage in another.  This is, in fact, why this topic comes up today; scientists at the University of Chicago showed that a gene -- ERAP2 -- that gave people in the fourteenth century a better shot at surviving the bubonic plague also predisposes them (and their descendants) to Crohn's disease.

The link, of course, is the immune system; Crohn's is an autoimmune disease, one where the body's immune system starts fighting against its own tissue, in this case the lining of the digestive tract.  The improvement in survival during the Black Death was significant -- an estimated forty percent increase in the chances of fighting off the disease -- so during the pandemic, the increase in risk for Crohn's was an acceptable tradeoff for near certain death from the plague.

Evolution is, truly, "the law of whatever works at the time."  It's not forward-looking; the forces of selection act on whatever genes the population has currently got, and the set of genes which is able to make more copies of itself is the one that gets passed on to the next generation.  This can happen because of reasons of fitness, but for many other causes including pure random chance (what is called genetic drift).

And because of this, the genetic hand we were dealt can sometimes have untoward consequences -- in a world where the bubonic plague has in most places been eradicated, a gene that had a beneficial effect now turns out to be a significant disadvantage.

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Microborgs

One of the most terrifying alien species in the Star Trek universe is the Borg, a hive-mind collective of interlinked cyborgs that reproduce by assimilating individuals from other species, not the old-fashioned way (although they may do that, too, judging by how taken the Borg Queen was with Captain Picard in Star Trek: First Contact).  

Turns out the assimilate-your-neighbor approach isn't limited to the world of science fiction.  There are terrestrial species who seem to follow the Borg's mantra of "We will add your biological and technological distinctiveness to our own."  Bacteria are especially good at doing this; they have small, mobile pieces of DNA called plasmids that are capable of being exchanged between cells, allowing gene flow without (strictly speaking) sexual reproduction.  Unfortunately for us, these plasmids frequently contain such human-unfriendly gene constructs as antibiotic resistance sequences and "pathogenicity islands" -- genes that code for a virulent attack on the host, such as the ones in the nasty strains of E. coli that can land you in the hospital.

Recently, however, scientists discovered a species of bacteria that has an assemblage of chunks of assimilated DNA (they actually called these strands "Borgs" after the Star Trek villains) that might prove useful to humans rather than harmful.  A species of Archaea (an odd clade of bacteria relatively unrelated to other, more common species, which includes groups that specialize in living in acidic thermal springs, anaerobic mud, and extremely salty water) called Methanoperedens was discovered in lake mud in western North America, and it was found to consume methane -- and has Borgs that allow it to do so at a spectacular rate.

Methanoperedens is odd even without the superlatives.  Most of the Archaea that metabolize methane don't consume it, they create it.  Methanogens -- Archaea that live primarily in deep ocean sediments -- produce methane as a byproduct of their metabolism, secreting it in the form of methane clathrate (frozen methane hydrate) at such a rate that the abyssal plains are covered with the stuff.  (Some ecologists believe that methanogens are, individual for individual, the commonest organisms on Earth, outnumbering all other species put together.)  

Burning methane clathrate -- "flammable snow" [Image is in the Public Domain courtesy of the United States Geological Service]

Methanoperedens, though, is a different sort of beast.  It lives by breaking down methane.  More interesting still, this ability comes from the fact that it has Borgs almost a third the size of its ordinary complement of DNA, made up of gene fragments assimilated from a dozen different species.

What has sparked interest in this bizarre species is the potential for using it to combat climate change.  Methane is a powerful greenhouse gas -- it has thirty times the heat-trapping capacity that carbon dioxide does -- and there's a significant concern that as the Earth warms, decomposing organic matter in the tundra will trigger a positive feedback loop, releasing more methane and warming the planet further.  If this methane-eating bacteria could consume some of the excess methane, it's possible that it could be turned into a tool for bringing the climate back into equilibrium.

I'm a little dubious, however.  It seems unlikely that any kind of attempt to culture Methanoperedens would be possible on a big enough scale to make a difference.  It'd be nice if we'd just face up to the fact that there is, and always has been, one obvious solution; stop burning so damn much fossil fuel.  We're so desperate to cling to our conspicuous-consumption lifestyle that we can't face the reality of what we're doing to the long-term habitability of the Earth.  (It doesn't help, of course, that a great many of our politicians here in the United States are being funded by the fossil fuel industry.)

Whether or not this bacteria species turns out to have any practical applications, the whole phenomenon of evolution by assimilation of DNA from other species is absolutely fascinating.  We ourselves contain "foreign genes" -- most notably endogenous retroviruses, pieces of viral DNA that have taken up permanent residence in our DNA and which might comprise as much as five percent of our total genome.  (There is good evidence that the activation of certain endogenous retroviruses is connected to the development of multiple sclerosis and some forms of schizophrenia.)

Walt Whitman didn't know how true his words were when he said, "I contain multitudes."

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Mosquito magnets

My wife claims that I only bring her along on tropical vacations to lure the mosquitoes away from me.

She is, to put it bluntly, a mosquito magnet.  If there's an outdoor party, and there is a single lonely mosquito anywhere within a five-mile radius, it will find her.  Worse still, she has a bad allergic reaction to bites; being bitten leaves her itching for days.

Bad combo, that.

I, on the other hand, barely get bothered at all.  The same strange dichotomy got passed to our kids; our older son doesn't seem to get bitten much.  On the other hand, we took a family vacation to Belize when our boys were twelve and fifteen, and I saw our younger son was sitting on his bed one evening examining his legs.  I asked him what he was doing.

Turned out he was counting mosquito bites.  He lost count at around forty.

[Image licensed under the Creative Commons User:Ngari.norway, Mosquito bite4, CC BY-SA 3.0]

The contention that many have, of some people being more attractive to mosquitoes than others, was just demonstrated conclusively in a paper last week in the journal Cell, by a team led by Leslie Vosshall of the Howard Hughes Medical Institute.  What Vosshall and her team did was to have volunteers wear nylon stockings on their arms for six hours, allowing the fabric to pick up any chemicals the person was secreting in their sweat and skin oils.  The nylons were then cut up into squares, and the pieces presented to hungry Aedes aegyptii mosquitoes.

The results were unequivocal.  One subject, #33, had an attractiveness to mosquitoes over a hundred times greater than the least attractive subjects, #19 and #28.

What seems to set apart people like poor #33 is the particular cocktail of carboxylic acids in their skin oils.  Carboxylic acids are small organic molecules characterized by having a carboxyl group -- a carbon atom double-bonded to an oxygen atom and single-bonded to a hydroxyl (-OH) group -- and include such familiar compounds as amino acids and fatty acids.  It turns out that of the hundreds of different kinds of carboxylic acids, each person produces different ones in different amounts -- and this "scent" (not that you or I would notice the difference) is what determines who is a mosquito magnet, and who largely gets left alone.

A little discouraging, though, is their other finding; that this chemical signature is relatively resistant to changes in diet and grooming habits.  None of the contentions you might have heard -- eating foods rich in B vitamins, using unscented soaps and shampoos, and so on -- seemed to make any difference.  The people who were mosquito attractors stayed that way throughout the course of the experiment, regardless what they ate and what cosmetic products they used.

While this study might eventually lead to better repellents, at the moment, we're kind of stuck where we were.  The best mosquito repellent is DEET (diethyltoluamide), which has a pretty good track record for safety, although (as I found out when I was in Ecuador) dissolves plastics.  (Fortunately, the only thing damaged was a ball-point pen; I discovered this when I applied some mosquito repellent, picked up the pen, and it promptly stuck to my hand.)  Some other products, like Avon's "Skin So Soft," seem to have some effect but aren't nearly as reliable as DEET.  

Maybe if Vosshall and her team can pinpoint exactly which carboxylic acids are causing the problem, they could find some kind of repellent that would work by blocking them or breaking them down.  I know my wife would appreciate it.  It's late October in upstate New York, and the eight mosquitoes still left alive around here are still waiting by our back door for one last chance to bite her.

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The walk of life

There are countless different actions we take every day that we do so automatically we're hardly even aware of how complex they are.

Take, for example, walking.  Walking takes the coordination of dozens of muscles, each of which has to contract and relax in exactly the right sequence to propel us forward and adjust for irregularities of the terrain we're navigating.  To avoid falling, we need to keep our center of gravity over our base of support, which is aided by adjustments in posture and such counterbalancing movements as swinging the arms.  But in order to do that we have to keep track of proprioception -- our sense of where our bodies are -- which is accomplished by a whole array of sense organs, including vision, the tactile sensors in the skin, and the semicircular canals -- the balance organs in the inner ear, which work a little like a carpenter's level.

And all of those -- the sense organs that keep track of what's going on and the muscles that use that information to contract and relax at the right times -- are linked by an astonishingly complex set of nerve relays and circuits coordinated by our brains.

All of that, just to get up and walk across the room.

The reason the topic of locomotion comes up is a paper a couple of weeks ago in Current Biology describing a single-celled protist called Euplotes eurystomus that has fourteen leg-like appendages -- and is able to walk.

The scientists studying Euplotes found that the appendages had thirty-two different configurations, which they called"gait states," and that somehow, the little creature was keeping track of which sequence of gait states allowed for the most efficient walking.  It turned out that the internal scaffolding of the cell, made of hollow threads called microtubules, created cross-links from each appendage to the others.  The amount of tension in the microtubules allows the organism to coordinate the movement of all fourteen appendages.

"The fact that Euplotes' appendages are moving from one state to another in a non-random way means this system is like a rudimentary computer," said Wallace Marshall, of the University of California - San Francisco, who co-authored the paper.

Euplotes eurystomus [Image from Larson & Marshall, UCSF]

All of this puts me in mind of the idea of irreducible complexity -- that there are structures in living organisms that would not work if all the parts hadn't been created all at the same time.  It's a favorite salvo of the young-Earth creationists and proponents of intelligent design.  The battle cry usually goes something like, "One percent of an eye isn't good for anything."  Richard Dawkins does a brilliant takedown of this entire argument in his tour-de-force exposition of the evolutionary model The Blind Watchmaker, in which he demonstrates that "one percent of an eye" -- a simple, light-sensing patch -- is indeed better than nothing, and that once you have that one percent, incremental gains in acuity can lead to the complex eyes now found in the animal kingdom.  (More fascinating still, the ability to sense light is such a powerful evolutionary driver that this process may have occurred, independently, dozens of times in different lineages.  For a wonderful overview of the evolution of eyes, check out this article from 2017 in the journal Nature.)

So locomotion, like vision, isn't irreducibly complex at all.  It's complex, yes; but hardly irreducible, because a single-celled organism is able to use chemical reactions and a network of microtubules to accomplish something very much like walking.  Our ability to coordinate motion has a history going back billions of years, during which time it has evolved into an action so complicated and intricate it's a damn good thing we don't have to keep track of it consciously.

Think about that next time you move your muscles.

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