Why is this important?  How intricate molecular machines evolve is largely unknown.  Today’s research shows novelties arising from simpler ancestors – but not byDarwin’s natural selection.  Now, no one knows how it happens.

Molecular “machines” work in all animal cells (including humans);  bacteria and plants have them too.  Gears, axles and crankshafts (their equivalents) are perfectly shaped molecules (thousands of atoms may constitute one molecule).   Motors made of molecules propel microscopic creatures.  Shuttles transport materials among cellular factories.  Pores screen molecules through cell walls.  Pumps expel poisons (e.g. chemotherapies from cancer cells!). 

The pump that is today’s subject is imaged at the end of this entry.  A few other machines are at:  www.ks.uiuc.edu/Highlights/?section=2004

How can we know how these things came to be, when their ancestors are extinct?

In fact, a few ancestors of modern machines are known.  This helps.  Chronological age and structural similarity show their evolution, sort of like knowing that tempus from Julius Caesar’s language is the ancestor of temps (French), tiempo (Spanish) and time.   But these proofs are few, and molecular clockworks are numerous.  To show how more of them came to be is a delight of science. 

Today’s research does that, and adds an enticing mystery, too. 

The research studied a pump that flushes electrically charged atoms out of cells.  All animals and plants have them.  One pump component is a ring (sort of like a ball-bearing housing for the pump’s spinning rotor).  Two varieties of protein hook together to make the ring.   The 2-protein ring works in all cell types, except one.  The exception is a fungus cell;  800 million years ago, it evolved a more complicated 3-protein ring for its pump.  The researchers asked:  How could this evolve and persist, when 2-protein-rings succeed in all other cells? 

At the molecular level, “gene duplication” was how the 3-protein ring arose.  Cells divide when, for instance, an embryo’s first cell is proliferating into a whole organ.  At each division, daughter cells may make an extra copy of a gene.  This is common.  At first, each duplicate gene produces the same protein.  But genes that were twins originally may mutate differently in later generations.  When descendants are no longer identical, they make different proteins. 

That’s what happened here.  A daughter cell duplicated one gene of the normal 2-protein ring.  The duplicate’s mutations eventually constructed a novel, third protein, but (surprisingly) that protein still worked in the pump’s ring.  For reasons unknown (see below), this 3-protein novelty became the norm for this fungus cell 800 million years ago. 

The researchers asked:  was it really true that ancient ancestors, 800 million years ago, had 2-protein rings?  Yes, which they ingeniously proved by genetically manipulating modern fungus cells to construct ancient versions with 2-protein ring pumps.  These ancestral “machines” worked;  they functioned as well as modern, 3-protein-rings do.  This shows that an ancestral 2-protein pump “worked,” and was the ancestor of today’s 3-protein version.

(How did they know the structure of the ancient proteins?  They deduced it from the structures of 139 similar proteins today.  (The analogy, again, is to Latin’s tempus, and today’s temps, tiempo and time. Evolution is deduced from gradual changes over time.))

The researchers’  last finding is the enticing mystery.   The 3-protein ring mutation wasn’t an improvement.  Cells with 3-protein rings didn’t live longer or reproduce more copiously than 2-protein ones.  The mutation was neutral.  So why did a more complicated gene duplication that brought no benefits become the norm in fungus cells for 800 million years? 

Evolutionary theory doesn’t know.  Darwinism posits that mutations (such as 3-proteins from 2-proteins) survive because of their advantages.  Mutants survive longer or reproduce more copiously:  that’s the theory.  But not here.  Here, there was no advantage.   

The researchers caution:  this is one example. Others aren’t yet known.  But it is a fascinating instance of evolution occurring, by means unknown, in one of nature’s most ubiquitous and complicated cellular machines. 

E. Finnigan et al., Evolution of increased complexity in a molecular machine, 481 Nature 360-364 (January 19, 2012);  W.F. Doolittle, A ratchet for protein complexity, ibid, 270-271.

Here are pictorial representations of the pump described in today’s entry.  Fig. 1 pictures protein components like carved machine parts.  The 3-protein “ring” consists of blue wedges labeled c, c’ and c”. 


Image link:  sackler.tufts.edu/…/Michael-Forgac

Proteins are not, obviously, blue wedges.  Nor are tan ellipses the real appearance of the proteins labeled A and B.  Figure 2’s diagrams, below, get closer to cells’ real complexity: 


Here, curlique tangles represent long protein molecules whose atoms bond in ribbon-like sheets.  The left-hand view looks downward into the channel between Fig. 1’s tan ellipses.  The right-hand view tilts the pump.  Fig. 2’s pale green and mauve ellipses represent the same pump components as Figure 1’s tan ellipses A and B.

Also amazing:  the proteins signified by Fig. 1’s tan ellipses whirl.  Fig. 1’s “D” and “d” are their protein axle, and the ring of c, c’ and c” is like the axle’s ball bearing housing.  (“Cytoplasm” is the interior of the cell.)

 Why is this important?   Sprawling proteins muffle all genes that a liver cell (for instance) has but doesn’t use.  This is how a body’s cells become specialized. 

 Every cell in an organism has the full complement of identical genes (its “genome”).  Despite having identical genes, cells of liver, lung, retina, brain (et cetera, et cetera) do different biochemical work: 

  • retinal cells translate light into electrical signals to the brain,
  • lung cells infuse oxygen into blood,
  • brain cells fire neurotransmitters and pulse with infinitesimal electrical ripples.

How does the same set of genes perform such different biochemistry?

Recall that the fertilized egg had the full complement of genes.  It divided, and each cell subsequently divided again and again as the embryo grew into a whole organism.  Each daughter cell replicated the full complement of genes that the fertilized egg had.  Eventually, cells became specialized for different biochemical work. 

So what stops a liver cell from generating neurotransmitters?  What stops lung cells from producing retinal proteins?  How do cells specialize for brain, retina, skin…or whatever they do?   

The answer is “gene silencing.”  In liver cells a swarm of proteins inactivates all genes not needed for liver biochemistry.   Lung cells silence all genes useless for oxygen absorption.  Brains, kidney, skin, muscle:  all permanently silence genes they don’t use. 

How, actually, do they do it?  That’s what this research showed. 

Start by recalling that genes are long DNA helix molecules.  The whole genome consists of genes attached together, like lengths of rope spliced into a very long rope of DNA molecules.  And finally the DNA “rope” wraps around a series of spool-like proteins.  Think big beads on a necklace:  here’s a diagram:


 Diagram cite:  https://youngbloodbiology.wikispaces.com/file/view/chromosome1.jpg/111553413/chromosome1.jpg

In silencing, multiple proteins encase DNA-wrapped spools of genes that a liver cell (for instance) won’t be using (such as neurotransmitter genes).  (Think of wrapping them in canvas.)  The liver cell’s protein-making machinery can’t reach them.

This is amazing, complex machinery by which a single genome is the blueprint for a complicated organism – such as a human being. 

Amazing, first, is how huge is the sprawl of silencing proteins.  A human’s entire genome, recall, is a long, long rope of DNA helix molecules.  A helix has a spiral staircase shape.  In a human’s genome, 120 million steps lie on the “staircase.”  A single gene may run for thousands  — thousands! — of helix “steps” and wrap around hundreds of “spools.”    Silencing molecules must encase all the gene’s steps and spools.    

That’s what this research showed:  the structure of (most) of one congregation of gene silencing proteins.  (Yes, it was a congregation, not one gigantic molecule.)  The proteins sprawl over the DNA (and spools too).  And how do they stay anchored?   By numerous electrical bonds, especially with the spools.  The researchers mapped many (but far from all) of the bonding locations.  . 

The second amazing feature:  cells replicate this silencing when they divide.  Daughter liver cells, for instance, remain liver cells.  Daughters replicate the whole genome, and also the proteins that silence all non-liver genes.   The liver cell has the genes for lung, brain, stomach, skin, kidney etc etc etc – and it silences them all.  It silences the bulk of its own genome. 

How that happens, is not yet known. 

K-J Armache et al., Structural Basis of Silencing:  Sir3 BAH Domain in Complex with a Nucleosome at 3.0 A Resolution, 334 Science 977-982, November 18, 2011.

A weakened immune system may allow dangerous cells to entrench themselves as tumors.

As a cell ages, damage accumulates in its DNA and the proteins DNA wraps around.  Diseases like cancer may follow.  Ageing’s various defects ensue too. 

Bodies have two protections.  One is a cell’s self-correction:  DNA damage triggers a chemical sequence that kills the cell. 

The other protection may not be quite what it seemed.  This is that defective cells stop dividing, but stay alive.  Healthy young cells (in your liver, say) regularly divide to replace old cells that die off).  It seemed beneficial that older, defective cells would just go dormant. 

Except that they’re not dormant, science now finds.  They don’t just stop functioning as they once did (liver cells ceasing to perform liver biochemistry, for instance).  They start secreting other chemicals that youthful cells don’t. 

This discovery is so recent that little is known of what the chemicals are, or of the harm (or benefit) they cause.  But the effects aren’t trivial.

First, ageing’s defects are somehow caused by whatever senile cells secrete.  Surprisingly, the biology of ageing’s ubiquitous degradations is largely unknown, but their causation by secretions from senile cells is proven by this:  when senile cells were exterminated in lab mice, ageing’s defects were slowed and even reversed.  (See “ageing cells” and “p16” on this site.)   Now medicine at least knows to focus on secretions of senile cells.

The second discovery seems momentous, too.  It links senile cells to cancer, and cancer prevention to the immune system.  Again, it’s lab mice.  What researchers did:

  • introduced a cancer-causing gene into mouse livers, which triggered….
  • chemical changes that made the liver cells senile, and then….
  • senile cells changed somehow, because….
  • mouse immune system cells found the senile cells and killed them, wholly clearing the mouse liver cancers. 

This mouse cancer prevention required pre-cancerous cells first to become senile.  (“Senescent” is biology’s term.)   Senescence requires certain biochemicals in cells.  Mice genetically engineered to lack them couldn’t induce senescence.  They got cancer.  It’s senescent pre-cancerous cells that immune cells find and kill. 

A healthy immune system was obviously necessary, too.  In mice lacking killer cells, senescent cells survived and cancers developed. 

The research inspires awe at scientists’ ingenuity and patience.  They alter mouse genes to cancel one gear after another, individually, in cells’ biochemical clockworks, and observe the result.  Methodically testing multitudes of permutations, they nail down exact proofs. 

Why is this important?   Cells are continuously ageing and deteriorating.  If defective cells go senescent (instead of self-destructing), a healthy immune system usually kills them off.   But a weak immune system may fail at that. 

Perhaps even temporary weakness of immunity – due to stress, or unrelated sickness – may allow a few damaged cells to survive and to entrench themselves as a stubborn cancer.   (Think cold sores, caused by herpes simplex viruses:  once you’re infected, the viruses inhabit you for a lifetime.  Normally, your immune system represses them.  But if it’s weakened, they erupt.  Maybe senescent cells are similar.) 

T. Kang, et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development, 479 Nature 547-551, November 24, 2011.  Also:  M. Serrano, Final act of senescence, 479 Nature 481-482, November 24, 2011.

Why is this important?  May be one reason that human intelligence excels. 

The brain thinks and acts through trillions of connections (synapses) among brain cells.  “Circuits” may link millions of synapses.  The brain learns by strengthening synapses in active circuits, pruning unused ones, and wiring entirely new circuits.  It does this “on its own,” sometimes.  Infants’ vision brain circuits are “wired” in the first year of life.  A stroke-damaged brain sometimes “re-wires” to restore function to a once-paralyzed hand. 

Neurons are the brain cells that handle most of this, we believe.  They differ in shapes, sizes, functions.  Some have 10,000 synapses with others.  Other brain cells that aren’t neurons probably outnumber neurons (no one is sure);  one type (called astrocytes) creates circuits with neurons (and with other astrocytes, too).     The human brain’s  complexity is such that experts  differ even on the number of neurons:   10 billion, 30 billion, 86 billion and even 100 billion are cited in books and leading journals.    Billions of brain cells and trillions of synapses make the brain work.

Synapses are molecular machines; they are made of protein molecules.  Genes in brain cells construct them.  Today’s discovery?  Genes in brain cells actually migrate on chromosomes.  They hop around.  This probably alters synaptic machinery in unpredictable ways.  This variability may be a molecular device for adaptable learning. 

Differences in genes drive differences in bodies, and bodies’ functions.   Mostly (simplification is mandatory) genes’ differences occur when a sperm cell and an egg cell shuffle their genes.   That’s fertilization.  Once a fertilized egg starts to grow, genes stay put on their chromosomes as the embryo’s cells divide and specialize (heart, bone, eyes, skin, brain, etc.).  So it was thought that neurons’ genes were stable, and would manage brain wiring in stable ways. 

But no.  It turns out that genes in neurons’ chromosomes hop around, even in adults.  Thousands – thousands! – of gene hoppings in neurons were detected in brain tissue from three donors from the Netherlands. 

Genes, recall, are long DNA helix molecules. Simplifying again, all 25,000 (or so) human genes link in awesomely long strings of DNA.  “Chromosomes” are those DNA strings wrapped around a million or so protein spools (like beads on a necklace;  here’s a link to a diagram:  www.ncbi.nlm.nih.gov/…/chromosome.html  ).

So how do genes “hop”?  By exiting their location in the DNA helix and re-inserting themselves into it elsewhere. They do this by hitchhiking on weird inserts in our DNA called “retrotransposons.”  Over 500,000 of these things infest human chromosomes.  They are DNA, but not genes.  They code for enzymes that snip the retrotransposon out of DNA and stitch it back elsewhere (after chemical steps too intricate to describe here [the “retro-“ prefix hints at them]).  Sometimes, the enzymes snip-and-grab adjacent genes along with the retrotransposon, hence the hitchhiking. 

Does it matter that genes hop around in the brain’s billions of neurons?  Nobody knows; the discovery’s fresh.  But probably it matters a lot, because the genes re-insert themselves into active protein coding genes (not, for instance, into DNA’s long stretches of inactive spacers.)  They can even reinsert themselves into another chromosome entirely (46 chromosomes lie in each human cell). 

How might it matter?  Maybe relocated genes alter neurons’ synapse-making chemical machinery.   Since the hoppings are random, and variable, maybe they accelerate “rewiring”  of synaptic circuits, as the brain adapts to novelties, i.e.  learns.  Retrotransposons are most common in humans and primates.   Maybe jumping genes accelerated brains’ abilities to manage the social complexities of primate bands. 

“Maybe….?”   “Probably… ?”   Today, no one knows.  It is remarkable that yet another level of human brain complexity is detected only now.   It’s another reason to be cautious about assertions that the immaterial mind can be illuminated by today’s neuroscience.  A vast new dimension of the human brain opens with the research reported here.

 J.K. Baillie et al., Somatic retrotransposition alters the genetic landscape of the human brain, 479 Nature 534-537, 24 November 2011.

 Biology knows that complex sequences of biochemicals construct animals from fertilized eggs.  But that’s not really knowledge.  We know Leonardo created Mona Lisa with paint, too.  “Biochemicals make animals.”  “Leonardo used paint.”  True, but useless.  We want to know how animals get built, just as artists long to know how that mysterious smile came to be.   

Animals’ complexity is so profound that today’s science must search minuscule parts of the whole.  Molecular explanations are impossible otherwise.  And narrowing rules out charismatic animals.  No dolphins, no people. 

Enough disclaimers:  here’s the minute detail actually proven.  It’s with fruit flies, the uncharismatic model animal studied for a century.  It’s the muscles that let flies fly.  It’s how those muscles develop in the pupa (the cocoon that fly larvae make).  It’s the biochemical clockwork that starts 8 hours after the pupa forms and in 16 hours has created wing muscles able to oscillate about 1,000 times a second. 

Or rather, it is one essential gear in that clockwork.

What did researchers find?  One gene – they name it “salm” – is expressed (meaning, the protein it codes for gets produced) inside the pupal cells that, joined together, become wing muscles.  salm is suppressed in cells that become leg and body muscles, and in all other cells too.  Salm turns muscle cells into the long fibres of wing muscles.  Leg and body muscles have tubular shapes instead.    

How to prove that salm created wing muscles?  By genetic manipulation researchers cancelled salm in some pupae.  Wing muscles didn’t develop;  these flies could only walk.  Leg and stomach muscle cells normally suppress salm but when injected with it, they developed into fibre muscles.  That proved salm’s causative power. 

That’s it.  That’s the discovery.   The salm gene’s protein is necessary for the biochemical clockwork that produces wing muscle cells. 

What’s still not known?  Plenty, including almost all of the rest of the clockwork that, in 16 hours, transforms maggot-white mush of larval cells into wing muscles, where salm is active – and elsewhere transforms mush into the rest of a fly.

A drill sergeant is necessary while army recruits transform into soldiers.  But he is not basic training itself.  salm is like that:  necessary for creating wing muscles, but not the clockwork itself, which – in its still-obscure intricacy – has been conserved for 280 million years in wasps, in other flies, and in flying beetles too.

Pause, finally, to appreciate the Zen-like patience of these researchers.  Dissecting minuscule muscle fibers of tiny flies under microscopes!  Genetically excising salm and peering at altered muscles!  Injecting salm’s protein – not just into tiny pupae, but into soon-to-be leg muscle cells of pupae! 

By these means they transcend the general idea (“it happens with chemicals”) and really know

C. Schonbauer et al., Spalt mediates an evolutionarily conserved switch to fibrillar muscle fate in insects, 479 Nature 406-409, November 17 2011.

Old age’s effects are too familiar:  cataracts, loss of fatty tissue, shrinking muscles, changes in skeleton, heart, arteries, and many, many more.  But the biology causing the pathologies is largely unknown. 

 To get a handhold, science finds differences between ageing cells and youthful ones.  Ageing cells stop dividing:  that’s a big difference.  They accumulate higher concentrations of some chemicals.  Maybe they secrete chemicals, too, which – as self-generated poisons — actually cause ageing’s defects. 

 The secretion theory is proven true by the research in this post.  What’s still to be learned is what secretions, and how they work.  That is, we have crossed a threshold, but still know almost nothing. 

The ingenious researchers identified one protein that builds up in ageing cells in mice.  “p16” (its simplified name for this post) became their marker for aging cells.  They genetically engineered mice so that a particular drug killed off p16-heavy cells.

What happened?  Ageing’s effects were slowed:  cataracts, hunchbacks, and muscle deterioration all came much later.  Better, exterminating p16 cells actually reversed ageing:  muscle mass improved, fitness on treadmills did too, and other ageing symptoms abated.   (The mice didn’t acquire eternal youth. Eventually, they aged and died.)

What did this prove?  That the p16 cells must secrete chemicals that harm other cells. 

Ageing defects arise in some tissues that don’t accumulate p16 (e.g. heart and arterial walls). These defects were unabated in mice whose p16 cells were exterminated.  Thus, p16 is not a universal marker of ageing cells. Other, non-p16 ageing cells must secrete poisons too. 

Why is this important?  Researchers can now strive to identify the self-poisoning chemicals.  Medicines might neutralize them some day.  Eternal youth?  No.  But a more robust old age, perhaps. 

 D.J. Baker et al., Clearance of p16Ink4a –positive senescent cells delays ageing-associated disorders, 479 Nature 232-236, 10 November 2011.

Engineering challenge:  build a mosquito-sized robot whose sensors find biteable humans by (a) carbon dioxide they exhale, (b) body heat and (c) various odors from their skin.

For over 20 years, scientists have tried to learn how mosquitoes’ sensors work, and why DEET (a powerful repellent) defeats them.

Now, they know – or at least they know a little. The answer is in molecular receptors on sensory nerve cells (which are on the insects’ antennae.)  (“Receptors,” recall, are long crinkled — so to speak – molecules.  Parts of them protrude from a cell.  Other molecules latch onto their intricate shapes, like keys into locks.  This signals the cell.)

Molecules of odors (sweat, for instance) or carbon dioxide lock onto those receptors on the antennae.  The receptor molecule then writhes to a different shape in thousandths of a second.  It is a long molecule;  one part dangles (so to speak) inside the nerve cell.  The writhing there triggers chemical machinery.  Its result:  electrical signals shoot from the antennae into nerve cells that pass for a “brain,” in the mosquito’s head.   The insect “knows” that a breathing human, or a sweating one, is near.

So how do DEET’s large molecules mess this up?  The answer is that over 60 different receptors respond to sweat or breathing or body heat or various odors.  (Mosquitoes bite any animal, and can find them all.)  Signals are copious, but the “brain” weaves them into “knowledge.”  DEET scrambles the signals to nonsense.  It inhibits some sensors, excites others, and does that to different degrees. 

It’s as if eyes see ”Warm human at 2 o’clock“, but a DEET-like chemical scrambles perception to “x#$g?& Q$#%^&.”  Mosquitoes are baffled too.  Bafflement was proven to be DEET’s effect.  Researchers also found mutant species whose receptor molecules can’t “lock” with DEET.  So DEET doesn’t work on them.

Why is this important?  “Importance” and “mosquitoes” may seem a preposterous combination:  grant that.  But….solving a 20 year old puzzle…well, it deserves notice. 

And isn’t it amazing that a mosquito “knows,” using this machinery of 60+ receptors?   Then think of trillions of them, emerging from fly-speck-sized eggs, via symphonies of bio-chemicals directed by DNA molecules.  An aquatic wriggling larva hatches in about a day.  It molts four times in a week or two, then forms a cocoon.  An airborne predator soon emerges, armed with these incredible sensory weapons.

M. Pellegrino et al., A natural polymorphism alters odour and DEET sensitivity in an insect odorant receptor, 478 Nature 511-514, 27 October 2011.

Why is this important?   Your trillions of cells use these molecular machines to respond to signals.   Medical uses, of course.  But outright amazement is “important” too:  infinitesimal, intricate, lightning-fast, and trillions of them are inside you.   

The intricate molecules are called “G protein coupled receptors” (GPCRs).  (The geeky name: don’t let it cancel their awesomeness.)  For forty years, researchers strove to see GPCRs’ structures.  They finally got the first one, completely.  It triggers chemical signals for “fight-or-flight” at dangers:  racing heartbeat and surging energy to muscles. 

It’s one of 800 different GPCRs.  Another (called rhodopsin) is in your retinal cells.  Light triggers it, loosing chemical signals that the brain translates into vision.

Other GPCRs clasp hormones and neurotransmitters.  GPCRs in your nose clasp molecules of fragrance;  in cells on your tongue, GPCRs grasp molecules that your brain translates into flavors. 

The first GPCR looks like this: 

1.  Seven corkscrew-shaped ribbons of atoms (connected to each other) weave through the cell’s membrane like laces on an American football.  Corkscrew-ends outside the cell splay out to catch molecules (called “agonists”) that trigger GPCR action.  An agonist is the mouse snapping the mousetrap.  (To see a picture, and the corkscrew ribbons, click this link to Nature.com:  http://www.nature.com/nrm/journal/v9/n1/fig_tab/nrm2299_F2.html )

2.  Three linked proteins await on the inner surface of the cell membrane.  These are the “G proteins”.  A unique three-protein “G” complements each GPCR.  Retinal cells’ “Gs” trigger chemistry of vision;  the “fight-or-flight” G’s do different work. 

3.   When the agonist binds to the corkscrew ends outside the cell, they twist, and their ends inside the cell twist too.  This gives the G-proteins a new place to bind on the corkscrew ribbon.

4.  Swiftly, they do, and the “G’s” first part swings open (like a hinge), and snaps back shut upon another molecule (call it the “key” here) that is floating (seemingly) nearby. 

5.  That sets loose the G’s other two parts to migrate inside the cell.  They latch onto other molecules.  This ignites fight-or-flight chemical signals to heart and muscles.

6.  The signaling ends when other chemicals extract that “key” from the G-protein, causing the G’s three parts to re-assemble and re-attach themselves to the cell membrane.  They are cocked (so to speak), for another agonist’s arrival. 

[See the other article in this site on GPCRs.]  

S. Rasmussen et al.  Crystal structure of the Beta-2 adrenergic receptor-Gs protein complex, 477 Nature 549-555, 29 September 2011.

 Why is this important?  “Arms race” is the standard notion of antibiotics and bacterial resistance.  Bacteria mutate to counter medicine’s weapons. 

But no:  30,000 year old bacteria  in Yukon permafrost had antibiotic genes. 

Perhaps evolution, too, sometimes creates novelties by mixing ancient genes, rather than by mutating to invent from scratch.

Permafrost lay beneath a layer of volcanic ash reliably dated to 30,000 years ago.  In the permafrost were chunks of ice.  Meticulously isolating the ice from modern contamination, researchers found entombed genetic material from ancient plants and extinct animals (e.g.mammoth, bison) but none from modern organisms.  This ice truly was ancient. 

It contained bacteria in abundance, too.  And the bacterial genes encoded resistance to major classes of antibiotics.  Examples: 

  • a gene whose protein weakens tetracycline’s chemical link to a bacterium
  • a penicillin-inactivating gene
  • an enzyme that blocks binding of several antibiotics.

The biggest surprise was resistance to vancomycin, which until the 1980’s was a wonder drug against bacteria resistant to other antibiotics.  Bacterial resistance to it requires three genes acting together.  The 30,000 year old permafrost contained all three of them, and they produced the enzymes that achieve resistance to modern vancomycin.

[See also the post on Hudson river cod’s PCB resistance, on this site.]

V. D’Costa et al., Antibiotic resistance is ancient, 477 Nature 457-461, September 22, 2011.

 Why is this important?  The “machines” handle signals among billions of cells, and very little is known about them.  A vast unknown in biology. 

Why else is it important?  Humans have over 800 “machines” of this type, but until now, none has been revealed while it’s actually working. 

Don’t be put off by the arcane name:  “G-protein-coupled receptors”  (GPCRs).   This first-imaged one weaves seven (yes, seven!) corkscrew-ribbons of atoms through a cell’s membrane, like laces of an American football.  Arms of some ribbons protrude outside the cell:  they are splayed out, to trap molecules out there.  (Hormones are one sort of signal that GPCRs trap.)  Other ribbon-ends dangle (so to speak) inside the cell. 

When a signal molecule (called an “agonist”) binds to the exterior splayed ribbons, it forces them to twist. The twist ripples through them, through the membrane, and alters the shape of corkscrew ribbon-ends dangling inside the cell.  The new shape opens a chemical binding site for particular “G-proteins.” (That  names a huge class of proteins inside cells.)  Suddenly bound on the newly twisted ribbon of atoms, those G-proteins trigger chemical machinery in the cell. 

All this happens swiftly:  the GPCR imaged here triggers your “fight or flight” reaction of quickened heartbeat, relaxing smooth muscles, and surges of energy-giving glucose into skeletal muscles that will either fight or flee.  Another GPCR is rhodopsin, which is in retinal cells.  Its “agonist” is not a molecule, but light waves.  When rhodopsin’s sheets of atoms twist, they trigger the biochemical machinery of vision.  It’s happening as you read this, in your retinas’ 200 million cells.  

Little is known of GPCRs’ structure, or how they work.  This research – a first — showed one GPCR’s corkscrew ribbons actually gripping an agonist, and revealed the description written in this post.    Why would you care about this?  Because (among other reasons) GPCR malfunctions cause disease. 

The difficulty of this research is amazing. Very hard to get crystals of GPCR molecules. Impossible (until the research reported here) to get crystals of a GPCR actually gripping an agonist.  And this isn’t even seeing a GPCR in action:  crystals are frozen, but GPCRs in cells jiggle in millionths of a second.  Here, the researchers programmed on computers a “very long molecular dynamics simulation” of a GPCR in action – “a record,” says the article.  Its duration?  30 millionths of a second!

A delight in biology is intricacies that Rube Goldberg would have scoffed at.  (An acquired sense of delight, I admit.)  One longs to know, “how did nature do it?”  With so little known today of how GPCRs work, knowing how nature produced them is a delight for the distant future.    

S. Sprang, Binding the receptor at both ends, 469 Nature 13 January 2011, 172-173.