On the study of naked mole-rats.

On the study of naked mole-rats.

This is a riff on an essay from several years ago.

In 1974, evolutionary biologist Richard Alexander gave a lecture describing the conditions that might spawn eusocial vertebrates. 

Alexander was a bug guy – “eusocial” refers to extremely cooperative animals like bees, ants, and termites. Individuals sacrifice themselves for others.  Non-breeders help with childcare.  The colony seems more intelligent than its members.

Alexander proposed that a eusocial mammal could evolve if the animals were small compared to their food sources, and if they lived in underground burrows that could be expanded easily and defended by a small percentage of the colony.

After the lecture, an audience member mentioned that this “hypothetical eusocial mammal” sounded a lot like the naked mole-rat.  Alexander was introduced to Jennifer Jarvis, who had studied individual naked mole-rats but not their social lives.  Alexander and Jarvis collaborated to write The Biology of the Naked Mole-Rat.

Eliot Weinberger condensed this 500-page textbook into his 3-page essay, “Naked Mole-Rats.”

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Like us, naked mole-rats are both good and bad.  They are cooperative.  They are affectionate.  They are always touching.  When they meet strangers, they fight to the death.  When a breeding female dies, many other females regain fertility and the colony erupts into civil war.

Weinberger wrote that naked mole-rats “are continually cruel in small ways.”  But they are outdone by naked apes. 

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For a research paper published in 2008, Thomas Park and colleagues found that being pinched by tweezers causes naked mole-rats pain, but injection with caustic acid does not.

“We tested naked mole-rats in standard behavioral models of acute pain including tests for mechanical, thermal, and chemical pain.  We found that after noxious pinch or heat, the mole-rats responded similarly to mice.”

“In contrast to the results using mechanical and thermal stimuli, there was a striking difference in responses to strong chemical irritants.  Two chemicals were used – capsaicin from hot peppers and hydrochloric acid – which normally evoke very intense pain in humans and other animals.  Injection of either rapidly evoked intense licking and guarding behaviors in mice.”

“In contrast, naked mole-rats showed virtually no response.”

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Perhaps you worry that acid-resistant naked mole-rats could conquer the world.  Fear not.  A form of kryptonite exists.  Injection of an 11-amino-acid signaling peptide allows acid to hurt naked mole-rats just as much as it hurts mice.  Or us.

Half a dozen animals were subjected to each treatment.

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Naked mole-rats don’t die from cancer. 

They should.  Their cells, like ours, are copied from copies of copies.  Errors compound.

Some errors are particularly deadly.  Our cells are supposed to stop growing when they touch.  They are supposed to commit suicide when old.  But the instructions telling a cell when and how to kill itself can be lost, just like any other information.

This is cancer.

In cancer, a single cell proliferates at the expense of others.  A cancer cell claims more than its fair share of space.  It commandeers nutrients.  This cell, and its progeny, and its progeny’s progeny, will flourish. 

Then the scaffolding creature dies.  Then the cancer cells die, too. 

But every cell that isn’t an egg or sperm is terminal anyway.  In the colony of our body, most cells are non-breeding members.  From a cancer cell’s perspective, it has nothing to lose.

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We develop cancer often.  With each passing day, we produce about 100 billion new cells.  Each time we produce a new cell, all 3 billion letters of our genome must be copied. 

The enzymes that copy our genome make one mistake every billion letters.  Each cell division: three new mutations.  Each day: three hundred billion new mutations.

Some mutants are trouble. 

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Our bodies kill cancer.  Your immune system – the same mess of mucous, inflammation, and goo that goes haywire during the flu – seeks and destroys renegade cells.  Your body is a fascist enterprise; white blood cells, its militarized police.

Chemotherapy does not kill cancer.  Chemotherapy means flooding the body with poisons that stop all cells from reproducing.  With luck, if the spread of cancer is slowed, your immune system can kill it before it kills you.

In naked mole-rats, cancers always grow as slowly as if the rodents were receiving chemo, allowing their immune systems to squelch cancers at a leisurely pace.  Their cancers are slowed by a heavy sugar called “hyaluronan,” which is packed so tightly into the space between cells that there is no room to grow.

In 2013, biologist Xiao Tian and colleagues wrote that “naked mole-rats may have evolved a higher concentration of hyaluronan to provide the skin elasticity needed for life in underground tunnels.  This trait may have then been co-opted to provide cancer resistance and longevity.”

They became impervious to cancer almost by mistake.

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The record lifespan for a naked mole-rat in captivity is 28 years, 4 months.  The record-holder was nicknamed James Bond.  He was senior consort to his queen and continued rutting – and siring pups – up until the day he died.

Bond was dissected.  His cells showed extensive oxidative damage in their lipids, proteins, and DNA.  Bond should have been hobbled by age.  But time did not slow him down.

Science writer David Stipp described him as “a little buck-toothed burrower who ages like a demigod.”

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Humans typically cease breeding long before we die.  From an evolutionary perspective, as soon as we stop having children, our fitness drops to zero.

And yet, we have long lifespans.  The dominant theory is an offshoot of “the grandmother hypothesis” – because we often care for grandchildren, there may have been evolutionary pressure to maintain good health until our grandchildren also reach reproductive age. 

With twenty-year generations, there’d be an incentive to survive until our sixties.

After that, perhaps our ancestors were no longer helpful.  And so we’ve inherited a propensity to decay.  Expensive medical interventions can preserve us longer, but once we pass our natural lifespans, brains and bodies weaken.

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When scientists starve animals in the lab, it’s called “caloric restriction.”  This protocol extends lifespan in a wide variety of species.  Monkeys, mice, flies, and worms.  Ten-fold increases in lifespan have been observed.

Caloric restriction should extend the lives of humans, too.

There are unpleasant side effects.  Caloric-restricted mice spend their time staring at empty food bowls.  They are listless: barely moving, barely sleeping.  They live longer, but worse – and if they are fed slightly less, they die of malnutrition.

Frequent starvation in the wild may have caused naked mole-rats to evolve their prodigious longevity.

Naked mole-rats expand their colonies outward, searching for edible roots.  When they find a good root, they gnaw it carefully, attempting to keep the plant alive as long as possible.  But a colony of naked mole-rats eats faster than any plant can grow.  When the plant dies, the colony plunges into famine. 

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Most eusocial animals carefully ventilate their homes.  Termites build giant pylons in the desert.  Although temperatures outside careen from 35 degrees at night to over 100 during the day, the interior of the mound remains a constant 87 degrees.  And the termites do not asphyxiate.  Their exhalations are swept away by circulating air.

Naked mole-rats burrow with less care.  They sleep in piles, hundreds of bodies lumped together underground.  Those near the center soon run out of oxygen.

We would die.

Most animals, deprived of oxygen, can’t fuel their brains.  Thoughts are expensive.  Even at rest, our brains demand a constant influx of energy or else the neurons “depolarize” – we fall apart.

Since the death penalty was reintroduced in the United States in 1976, we have killed eleven prisoners in gas chambers.  During the 1983 execution of Jimmy Lee Gray in Mississippi, officials cleared the observation room after eight minutes.  Gray was still alive, gasping for breath.  His attorney said, “Jimmy Lee Gray died banging his head against a steel pole in the gas chamber while reporters counted his moans.”

Gas chambers are pumped full of cyanide gas, carbon monoxide, or carbon dioxide.  Carbon dioxide is cheapest. 

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With each breath, we inhale oxygen, burn sugar, and exhale carbon dioxide.  When we drive, our cars intake oxygen, burn gasoline, and exhaust carbon dioxide. 

In small amounts, carbon dioxide is beneficial.  Carbon dioxide allows plants to grow.  But when you put too much inside a chamber, somebody dies.  Put too much in the air worldwide and we all die.

The planet Venus was habitable, once.  Humans could have lived there.  Venus had a deep ocean and mild weather.

Through some fluke, Venus experienced a temporary bump in the amount of carbon dioxide in the air.  Carbon dioxide traps heat, which caused water to evaporate.  Clouds formed, which trapped more heat.  The cycle continued. 

Venus is now a fiery inferno.  The ground is bare rock.  Sulfuric acid rains from the sky.

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Lab mice die in gas chambers.  Sometimes one mouse is set inside the plexiglass box; sometimes several mice inside a Chinese-food takeout container are gassed together.  A valve for carbon dioxide is opened; the mice lose consciousness; they shit; they die.

A naked mole-rat would live.  Unless a very determined researcher left the gas flowing for half an hour.  Or so found Thomas Park and colleagues – the same team that discovered that naked mole-rats dislike being pinched.  As they reported in 2017:

Human brains drink sugar.  We are like hummingbirds that way.  And our brains are very fussy eaters.  We are fueled exclusively by glucose.

Naked mole-rats are less particular.  Their minds slurp fructose to keep from dying.

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Naked mole-rats are the most cooperative of mammals.  They are resistant to cancer.  Unperturbed by acid.  They age with the libidinous gracelessness of Hugh Hefner. 

They are able to withstand the horrors of a gas chamber.

And yet, for all these talents, naked mole-rats are easily tormented by human scientists.

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Featured image from Wikimedia Commons.

On psychedelic drugs as medicine.

On psychedelic drugs as medicine.

We are creatures of habit.

learning_to_walk_by_pushing_wheeled_toyLife would be excruciating if we were not.  Can you imagine: consciously remembering to breathe every few seconds?  Concentrating with the intensity of a toddler each time you stand and walk across a room?  Carefully considering the rules of grammar and conjugation when you stop to ask someone for directions?

Our brains zip through so much unconsciously.  Most of us can drift into reverie while driving and still go through all the motions correctly, stopping at red lights, making the appropriate turns, our mind set on autopilot.

We live, and we learn, and our brains constantly change – neurons reach out to form synaptic connections to one another.  Other connections wilt away.  The resultant network determines who we are.  More precisely, the pattern of connections determines which thoughts we are good at having.  Thoughts we’ve thunk before come easily.

But our propensity for habit can hijack our lives.  In David Foster Wallace’s Infinite Jest, viewers of the highly-addictive titular film are unable to think of anything but watching it again.  One taste and you’re hooked!

otto_wegener_vers_1895_2Or, in an example closer to most humans’ experience, Marcel Proust writes of the way our shared experience with a lost love causes the brain to ache each time a similar experience must be forded alone.  Over and over we hurt: going to sleep alongside her was a habit.  Chatting in the evening was a habit.  Walking to the store hand in hand was a habit.  The brain is still wired such that it could effortlessly zip through these tasks, but… she is gone.

In an example that is – unfortunately! – increasingly relevant today, William Burroughs writes that powerful opiates do not hook users right away.  It takes many recurrent episodes to rewire the brain.  In his (overly cavelier) words:

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Painting by Christiaan Tonnis.

The question is frequently asked: Why does a man become a drug addict?

The answer is that he usually does not intend to become an addict.  You don’t wake up one morning and decide to be a drug addict.  It takes at least three months’ shooting twice a day to get any habit at all.  And you don’t really know that junk sickness is until you have had several habits.  It took me almost six months to get my first habit, and then the withdrawal symptoms were mild.  I think it no exaggeration to say it takes about a year and several hundred injections to make an addict.

. . .

You don’t decide to be an addict.  One morning you wake up sick and you’re an addict.

And then, depression.  To perceive the world a shade darker than it ought to be comes easily… to someone who is depressed.  A depressed person’s brain has been rewired through perhaps a lifetime of rumination and pain.  Suicidal ideation gets easier and easier and easier… unless it goes too far, and then it becomes impossible.  Dead matter doesn’t think.

thenightmare
The Nightmare by John Henry Fuseli.

Cognitive behavioral therapy attempts to use the brain’s own habit-forming capabilities to battle depression.  Because today’s depressed thoughts enable tomorrow’s depression, a conscious effort to find joy and beauty today could ease tomorrow’s struggle.  Phrases like “virtuous cycle” are bandied about.

My wife, each evening, asks me to list four good things that happened during the day; if we forget the ritual through a harried week or two, it’s difficult to start again.  I lay in bed, pondering, “What was good about the day?”  Which should always be easy.  I have two loving children whom I am graced to spend time with.  I am not in jail.  I have a warm, safe place to sleep.  I have enough to eat.  I live near phenomenal libraries.

But the habit of depression digs the mind into a rut.

lsd-clinical-trial-bottleWhich has caused several researchers to wonder, “Would cognitive behavioral therapy work better if a patient could be jolted out of the rut first, then trained in a new virtuous cycle?”  We have access to several potent chemicals that wrest the brain out of its routines.  Psychedelic drugs like lysergic acid diethyl amide, dimethyl tryptamine, and psilocin are powerful beasts.

Which is not to say that, if you’re feeling sad, you should go find that raver dude you know and ask what he’s holding.  For one thing, most psychedelics are illegal in the United States.  This contributes to the dearth of high-quality clinical information about their uses – obtaining permission to run clinical trials with Schedule I compounds is difficult, and drugs can’t be downgraded from Schedule I status without reams of data from clinical trials.  Nonsensical bureaucracy at its best!

Plus, high-quality clinical trials must control for the placebo effect – neither patients nor doctors should know whether an individual is receiving the treatment or a control.  But I’m guessing most recipients recognize the difference between an injection of DMT or saline.  Did your visual field suddenly fragment into geometric patterns?  Did you feel an out-of-body sensation akin to alien abduction?  Did your memories begin to unfold like interlocking matryoshka-doll puzzle boxes?  Those are sensations I rarely experience from salt water.

LauretaAnd the sheer power of psychedelic drugs also makes them dangerous.  Dr. Lauretta Bender, whose least harmful contribution to science was the idea that emotional disturbances could be diagnosed by asking a child to reproduce pictures of geometric shapes, assumed that LSD would cure autism.  If she’d been right, this sort of baseless cognitive leap would’ve been heralded as brilliance.  She injected large doses into the muscles of children as young as five.  Daily.  When that “cure” proved insufficient, she combined it with electroconvulsive therapy: high currents to overwhelm their little brains.

Enforced acid trips in nightmarish environs of total control can ruin lives.

Especially since Dr. Bender was diagnosing autism in routinely-abused orphans based on symptoms like “avoids eye contacts” and “difficulty forming trusting relationships.”

5009548522_6701801dcb_oAcid trips can end lives, too.  At least one involuntary research subject ensnared in the CIA’s efforts to use LSD as mind-control reagent committed suicide.  And there are innumerable horror stories of murders committed by people mired in psychedelic trips.  Then again, most murders are committed by people who haven’t taken psychedelics.  In Ronald Siegel’s Intoxication he writes that:

Many bad trips are a function of personality; not everybody is a good subject for a mind-altering experience.  And even experienced users can have a bad day.  … Harold, a veteran of one thousand LSD trips, wanted to volunteer to be a psychonaut but he had a history of violence, both on and off the drug.  “Ever since I was small,” confessed Harold, “I go ape when I’m bothered.”

.. [a grim description of Harold murdering two hikers outside Santa Barbara in 1984 follows.  Yes, Harold had “drank some beer, smoked a little marijuana, and swallowed a few amphetamine tablets along with a full dose of LSD.”  But he’d also “been bothered by financial problems.  He was passing bad checks and had failed to make child-support payments to his ex-wife.”  So I’m not sure the drugs were at the root of his malaise.]

Cases like Harold’s tend to confuse the issue of intoxication and violence.  Violent people are often intoxicated but the violence is usually rooted in the personality, not the drug.  . . . What seems difficult for us to understand is that despite overt behaviors, the subjective experience can still be fun.  In other words, one’s inner feelings and sensations can be under the influence but such influence may not extend to outside acts in the real world that remain chillingly sober.  This is most difficult to accept if users are obviously intoxicated when they commit criminal acts.  The subjective intoxication can remain an enjoyable experience, despite our desire to blame the fires inside for the destruction outside.

Used incorrectly, psychedelic drugs are awful.  They disrupt habits, seeming to dissolve the mental filters that allow humans to function despite constant bombardment by thoughts and memories and myriad sensations from the world.  This newfound wonderment & reset can help, of course, but for someone in a bad place, it can be horrible.

mdma1Then again, for someone with post-traumatic stress disorder, the world might be horrible already – even if the chance that psychedelics could help were low, they’d be worth investigating.  Thankfully, the FDA finally granted permission for a trial to be run on the use of methylene dioxy methamphetamine (ecstasy – when I was a TA for undergraduate organic chemistry at Stanford, I wrote most of the quizes.  After they learned about acetal protection of ketones, all 200 or so pre-meds wrote out a partial synthesis for MDMA.  The reactants and products were unnamed, so I don’t think the students or the other TAs noticed) to treat PTSD .

In other experiments, LSD and psilocin seem to help terminal cancer patients overcome depression.  Ayahuasca is also being tested as a treatment for depression and those seeking to quit substance abuse (peyote has long been used for the latter), although these studies are far from the FDA clinical ideal.

Many people, as they live, drift into routine and no longer consider the implications of their actions.  I’m well aware that drugs can wreck lives, but sometimes we need a jolt.  I wish people weren’t shunted to jail for drug addiction – and obviously the dudes in there wish they were almost anywhere else – but a surprising number are grateful that something interrupted their habits.  Junkies don’t want to look back on a wasted life, either.

pills-750x400I’m not super keen on the rich & entitled using psychedelics for fun & games, and psychedelics certainly should not be used often.  But these molecules, treated respectfully, can heal damaged lives.

Even in the ostensibly healthy, psychedelics can do good.  Does the way you choose to spend your time benefit the world?