Into brains of newborn mice, researchers implanted human “progenitor cells.”  These mature into a type of brain cell called astrocytes (see below).  They grew into human astrocytes, crowding out mouse astrocytes.  The mouse brains became chimeras of human and mouse, with the workhorse mouse brain cells – neurons – nurtured by billions of human astrocytes. 

Neuroscience is only beginning to discover what astrocytes do in brains.  One job that is known is that they help neurons build connections (synapses) with other neurons. (Firing neurotransmitter molecules across synapses is how neurons communicate.)  Human astrocytes are larger and more complex than those of other mammals.  Humans’ unique brain capabilities may depend on this complexity.

Human astrocyte at 23 weeks in brain culture: Wikipedia commons

Human astrocytes certainly inspired the mice.  Their neurons did indeed build stronger synapses.  (Perhaps this was because human astrocytes signal three times faster than mouse astrocytes do.)  Mouse learning sharpened, too.  On the first try, for instance, altered mice perceived the connection between a noise and an electric shock (a standard learning test in mouse research).  Normal mice need a few repetitions to get the idea.   Memories of the doctored mice were better too:  they remembered mazes, object locations, and the shock lessons longer.

The reciprocal pulsing of billions of human and mouse brain cells inside a mouse skull is a little creepy.  Imagine one of these hybrid mice exploring your living room.  Would you feel like a Stone Age tribesman observing a toy robot?  Does the thing think?

Astrocytes (red) among neurons (green) in cerebral cortex. Wikipedia commons

Neuroscience has no idea – none – of how a mind rises like a genie from the fleshy human brain.  It supposes, however, that the magic trick’s spoiler will turn out to reside in physics and chemistry of brain cells.  That is the discipline’s fundamental assumption.  Nowhere else can the mystery be hiding.

But we have no idea what’s happening as billions of human astrocytes animate rodent awareness inside the tiny skulls.  And “awareness” is one quality of “mind.”  Do billions of human cells have no effect on mouse awareness?  That seems unlikely.

S. H. Saey, Mice get brain boost from transplanted human tissue.  Science News, Vol. 183 #7, April 6, 2013

Xiaoning Han, et al., Forebrain Engraftment by Human Glial Progenitor Cells Enhances Synaptic Plasticity and Learning in Adult Mice, Cell Stem Cell, vol. 12, No.3, March 7, 2013.  http://download.cell.com/cell-stem-cell/pdf/PIIS1934590913000076.pdf?intermediate=true

This antibiotic is not new.  It is in fact natural, and probably a few thousand years old.  Nor is it rare:  it’s found in human sweat.  What is new is that researchers have revealed the structure of this undefeated weapon, and also how it kills a bacterium in one ten-thousandth of a second. 

“Dermcidin” is the researchers’ name for the protein molecule.  Its shape, like a stent in an artery, consists of six corkscrew-shaped protein sheets arranged as length-wise ribs of the tube.   It kills by puncturing the bacterium’s membrane skin and creating a pore.  In its image below, the bacterial membrane is the shadowy background for the colored corkscrews: Red spheres represent ions flowing through the pore.

Bacteria-puncturing membrane channel

Photo credit:  C. Song, et al., cited below.

The pore is like a hole punched through a submarine’s hull.  It abolishes the bacterium’s segregation of interior electrical charges from those outside.  Death is instant.

Dermcidin proteins seem to lie on a human skin, unassembled, and then spring into the killing stent-like shape when they encounter a microbe.

What’s unknown:  how the protein latches onto the bacterium’s shell, and how it is that bacteria haven’t evolved some Teflon-like variations to block it.

But they haven’t.

With the molecule’s structure now known, research can advance to copying it synthetically for medical use.

C. Song et al., Crystal structure and functional mechanism of a human antimicrobial membrane channel.  110 Proc. Natl. Acad. Sci. USA  (12) 4586-4591 March 19, 2013.  www.pnas.org/cgi/doe/10.1073/pnas.1214739110

A power source previously unknown.  It’s probably this that failed in Woody Guthrie’s and Lou Gehrig’s neurons.

But that physical development of a mammal’s body is altered by changes in gut microbes, this is astonishing.

Just discovered:  at puberty, gut microbe populations shift in male and female animals.  Before puberty, they’re similar.  Gut microbe shifts appear to drive male/female differences in post-puberty sex hormone production. 

Why did this matter?  Because a female-afflicting type of autoimmune diabetes could be treated by transplanting microbiome populations.  Today, these discoveries are mostly in lab animals.  But not all.

It is unexpected and astonishing that a mammal’s traits upon sexual maturity depend on gut microbes.

Not just sexuality, either.  Obesity, too:  lean mice become obese when transplanted with gut microbes from obese mice.

In humans, abnormal gut microbe populations induce a syndrome of acute malnourishment (kwashiorkor).  Even a nourishing diet does not cure the distended bellies and malnourishment of kwashiorkor children.  Mice develop kwashiorkor when transplanted with gut microbes of syndrome children.

Only in the last few years has knowledge of each human’s 100 trillion member microbiome become possible.  (Cheap, fast genetic sequencing made the difference.)  Now, decades of research can begin.  It will probe differences in bodies and health ensuing from nearly infinite permutations of microbes, each human’s genes, and diets.

J.Markle et al., Sex differences in the Gut Microbiome Drive Hormone-Dependent Regulation of Autoimmunity, 339 Science 1084-1088, 1 March 2013.  and M. Flak at al., Welcome to the Microgenderome, 339 Science 1044-1045, 1 March 2013.

But shake off sleepy familiarity and amazement re-awakes.  What, exactly, happens in a retina cell when it absorbs a photon of light?  How, from a fertilized egg, do 100 million retina cells acquire a structure that sends electrical flickers to the brain? 

This post doesn’t attempt to say all that’s known.  It reports a new discovery on how the vision machinery is built from an egg.

Mice were the research animals.  If a mouse pup is kept in darkness after birth, it becomes blind.  Tiny blood vessels in its eyes become overgrown and clog the path of light through the eye.  Too many retinal neurons grow, also.  The overgrowths cripple the intricate machinery.

Even before birth darkness cripples.  A mouse fetus’ eyes are ruined if the pregnant mother is kept in darkness in the last few days before birth.

Why the overgrowths in darkness?  It is the absence of a “brake” on certain genes whose protein products stimulate growth of retinal cells and blood vessels.  What is the brake?  It is another protein generated by a gene whose “on” switch is light.  Without light, the mouse eye lacks the “braking” protein.  Retinal neurons and blood vessels proliferate till vision is destroyed.

This amazing complexity is the first demonstration of eyes’ structure being sculpted by light-triggered protein cascades.  It is perhaps a clue (the researchers cautiously suggest) to processes by which some human infants born prematurely become blind from retinal defects.

S. Rao et al., A direct and melanopsin-dependent fetal light response regulates mouse eye development, 494 Nature 243 -246, 14 February 2013.

It turned out to be more complicated.

That only 1% of DNA turned out to be protein coding was the first surprise. The central dogma in that era was that proteins were what DNA coded for. DNA that didn’t code protein must be useless, if you believed that. The dogmatic verdict on the other 99%: “Junk.”

Heretical doubters showed otherwise by 2012, when worldwide research proved that the cell does use code in the erstwhile “junk”, and that producing RNA molecules (not proteins) is what it does with it. The compilation of this massive work is “ENCODE” (= Encyclopedia of Non-Coding DNA Elements.”)

RNA is similar to DNA, but usually a single strand, not double. Here’s a tidily simple diagram:

Tidy diagram of single stranded RNA

Picture credit: Wikipedia Creative Commons License

But RNAs’ actual structures aren’t so tidy. They may twist into countless tangled shapes that aren’t known for most RNAs (so new are these discoveries). The diagram below hints at the complexity: RNA (the linked lavender hexagons) entangled with proteins.

RNA diagram: linked hexagons tangled with proteins. Source: Wikimedia.

So the cell generates RNAs galore. But for what? What do they do? There’s an answer for only a few of them.  That answer:  they control when particular protein coding genes are turned “on,” and for how long their they keep churning out their proteins. But for most RNAs, no one knows yet what they do.

The complexity is awesome. What ENCODE found in humans was that multiple RNA-producing stretches of DNA overlap each protein coding gene. Some genes were overlapped by 10 RNA-coding sections. With this knowledge, even the question “what’s a gene?” is harder to answer. (Just the protein coding part? Or do RNA overlaps count too?) Some overlaps don’t even act on the gene they overlap. Instead, they regulate protein genes elsewhere on DNA.

And the overlapping sections aren’t all there is. ENCODE’s overlaps coded for so-called “long” RNA, meaning 100 or more base pairs. But cells make shorter RNAs, too: about 20 base pairs, for instance, in “microRNAs” (miRNA), the first of which was discovered only 20 years ago. (Hundreds are known today.) miRNAs regulate protein production too. Their dysfunctions are implicated in some cancers.

If mapping this complexity is even possible, the whole 21st century will not complete the project. And even more awesome is that cells replicate all this machinery when they divide. Epithelial cells in the gut do that two or more times each day.

J.T. Lee, Epigenetic Regulation by Long Noncoding RNAs. 338 Science 1435-1439, 14 December 2012.

Sydney Brenner recollection of Crick. 338 Science 1427-1428, 14 December, 2012.

A couple of them are a little clearer, today. 

DNA’s helix shape can be diagrammed as a twisted ladder, with 3 billion rungs (in humans).  Each rung is a pair of just four smaller molecules, denoted C, G, T and A (after the first letters of their chemical names).

In replication, the ladder “rails” separate as each rung splits at its midpoint.  The result:  two single strands. The helix “unzips” (to change the metaphor).

In replication, a new ½ ladder is built on each separate strand.  The result:  two identical DNA molecules, where there had been one.

Replication is possible because of “complementarity”.  Nature allows only C-G and T-A combinations (plus their flipped twins, G-C and A-T.)  C and G complement each other;  A and T do so too.  When ladder rungs are cleaved, each strand replicates by adding the correct complement to whatever C, G, T, or A is exposed on each now-cleaved rung.  Complementarity is the elegance that Crick and Watson saw immediately.

We say “that much is known,” about DNA replication.  What we really mean is, “that statement describes the overall result that we know happens.”

But exactly how do molecules achieve it?  How does DNA get unzipped, for instance, along billions of rungs?  What actually does the copying job and how?  Mysteries have balked decades of research.  The complexity that is known is a wonder of nature.  To understand all the details, someday — not generally, but exactly — is the obsession of great science.

Some amazing details are known.  A gigantic (by molecular standards) molecule splits the DNA helix, then wraps itself around one of the strands. It’s called DNA helicase (“-ase” denotes enzyme, which this thing is).  It’s roughly doughnut-shaped, and consists of six structures.  Here are a couple of artistic images:

Blue helicase unzipping DNA; photo: cs.stedwards.edu

Another artistic image of helicase; photo: fallingpixel.com

And here are images emphasizing the “six structures” (a/k/a “hexameter”):

Six blue "structures" & DNA strands threading; photo: biocomp.cng.csic.es

Head-on helicase; six colors denote hexameter's components; DNA strand threads through hole in center; photo: columbia.edu

(In the right-hand image, curlicue ribbons and bars portray structures made of numerous atoms;  colors distinguish the six components.

Rapidly, the helicase pulls one strand through its central channel;  the other slides along the doughnut elsewhere.  The helicase continues splitting the helix, reading the C’s, G’s, T’s, and A’s on newly-split rungs and swiftly attaching their complements to build the replication strand.  (It’s also believed that the helicase whirls around the strand as it moves.)

How fast does it move?  About 100 rungs per second in humans.  (About 1,000 in bacteria.)

Announced this month were two amazing feats of helicase, neither yet fully understood.

First, the helicase itself is like two stacked doughnuts.  The doughnuts separate, and speed in opposite directions along the single strand.  Nobody saw this discovery coming.

The second discovery:  how the helicase isn’t stalled by molecules that encrust DNA.  Liver cells, for instance, don’t make neurotransmitter molecules like brain cells do.  Why not?  Because, in liver cells, large proteins clamp onto its DNA atop the genes that would otherwise build neurotransmitter proteins. The clamps silence neurotransmitter genes by insulating them from liver cells’ protein-making machinery.  (See:  ”Why don’t liver cells make neurotransmitters” on this site.)

Bulky clamp proteins don’t even slow helicase down, however.  It goes over them, somehow.  No one knows how.  (Maybe it’s like a wrist-band that can stretches equally over fingertips and fists.)

And more than slipping over them, it (or some partner) somehow replicates those silencing proteins too, along with replicating the DNA.  If it didn’t, the new daughter liver cell’s DNA could start producing brain cell proteins.

What phenomenon in nature?

DNA replicates.

What was known before?

Many details of the molecular machinery of replication, but far from all of them.

What did this discovery show?

First:  DNA helicase (at least the one they studied) is a stacked double-doughnut that separates into single doughnuts that speed in opposite directions on the replicating strand.

Second:  DNA helicase passes over obstructions on the DNA strands without slowing down.

What remains unknown?

Much.  One unknown:  how exactly it surmounts those obstructions.  And another:  there are hundreds of varieties of helicases.  Do they act the same as the one studied here?

H. Yardimci, et al., Bypass of a protein barrier by a replicative DNA helicase, 492 Nature 205-209, 13 December 2012.

M.A. Trakselis, B.W. Graham, Molecular hurdles cleared with ease, 492 Nature 195-197, 13 December 2012

Here are five pigeon-holes for parceling out the news:

1. Genes: Everyone knows this breakthrough, from the 1950’s. The DNA molecule is like a long twisted ladder. About 3 billion rungs are on human DNA.

The rungs are pairs of molecules called nucleotides. The first letters of their chemical names denote them: C,G,T and A. Like a 4-letter alphabet, triplets of C, G, T and A make 3-letter words. Those words specify each of 20-member set of small molecules (called amino acids).

The cell’s machinery reads each triplet, grabs the amino acid it denotes, and hooks it onto a growing chain of amino acids.  The chain becomes a protein molecule. A “gene” is defined as the section of DNA whose triplets specify a particular protein. Some proteins contain thousands of amino acids.

Proteins are the stuff of living bodies: skin, muscle, brain. They are the molecules that run animal bodies, too: hormones, enzymes, and countless tiny machines inside cells. All proteins are combinations of those 20 types of amino acids. 20 is small enough that triplets of C, G, T and A can specify thousands of proteins. It seemed (this was the 1950’s) that once the protein-creating code was discovered, a chemical explanation of life was in sight.

But there was more.

2. DNA portions that aren’t “genes”. “Gene” = coding for proteins. (A simplification that’s fine for now.) But less than 5% of DNA does that. What about the rest? “Junk” was the answer for years. Billions of “letters” in the 4-letter alphabet are replicated in every cell division, but were all deemed “junk.”

But no. Worldwide research demonstrated that most of it regulates “genes”. That means governing when, where, and how much protein a gene produces. Humans have an estimated 25,000 protein-coding genes. That’s a large toolbox, but allows finite variation, if “on” or “off” were a gene’s only choices. But with gradations of “how much” or “how long” in DNA’s erstwhile “junk”, the permutations are nearly infinite.

3. Protein function. So genetics can identify what proteins DNA produces. Then what? What do the big molecules do? Our cells produce thousands of protein varieties. Some do their work in millionths of a second, and collaborate in Rube Goldberg “cascades” of reactions. How to track what they do?

A large protein (hexokinase) as ball-and-stick model. (Source: Wikipedia, public domain.)

The “proteome” project,” (aping “genome” project) aims to find out. It would catalogue all proteins, and their interactions. How long will this take? “The rest of the century” is an informed guess. And then there is the….

4. Protein folding project: Yes, DNA triplets specify which amino acids get hooked together, in what order, for each protein. But amino acids aren’t like beads, nor do proteins lie flat, like necklaces on a table. The long chains fold. They twist. They writhe into intricate tangles. The cell’s machinery requires exactly the right shape. Misfolded proteins are like wrenches in cellular machinery. Alzheimer’s and other neurodegenerative ailments result.

Protein folding before & after the chain is created. (Source: Wikipedia, public domain)

Proteins aren’t rigid and motionless, either. The cell’s machinery isn’t like clockwork, and proteins aren’t like gears. They wiggle and vibrate in millionths of the second. They would be invisible, like airplane propellers, even if they weren’t microscopic.

A few examples of folded proteins. (Source: Wikipedia, public domain.)

Worse, for explaining: some proteins seem to play multiple metabolic roles, not just one.

So figuring out how proteins fold into shapes necessary for the cellular machinery, is a sub-specialty of the proteome project. It has a long way to go, too: for 90% of the proteins whose amino acid sequence is known, the 3-dimensional (folded) shape can’t be predicted.

And while sleuthing tries to master the folded shapes, there’s this: about half of proteins in animals like us have large regions that seem to have no precisely ordered shape at all.  They’re just tangles.  Why?  And how do they function? Mostly unknown.

5. Microbiome. This means the assemblage that consists of our bodies’ cells (animal cells, of course) plus trillions of microorganisms — bacteria, fungi — that are not animal cells. Our human cells are symbiotic with these trillions of non-human creatures. Our immune system tolerates them. We do not digest food well without them. They even assist our immune system. To protect their own turf in our bodies, they kill off disease-causing microorganisms that would invade.

So biology goes from the gene to “junk” being genes’ governors. And then to blizzards of protein interactions. And then to protein folding. And finally, to non-animal creatures that outnumber our cells by trillions and cooperate peaceably to make our bodies run properly.

The dream of comprehending our bodies completely – or even doing that for a single cell — seems to recede like the horizon.

On protein folding: K. Dill and J. MacCallum, The Protein-Folding Problem, 50 Years On, 338 Science 1042-1046 23 November 2012.

A superior article on complexity is: E.C. Hayden, Life Is Complicated, 464 Nature 664-667, April, 1, 2010.

Darwin’s finches made gradual modifications a persuasive story.  Different species inhabited various Galapagos Islands.  (A tempest probably swept their common ancestor from Peru.)  On islands with hard-shelled seeds,Darwin found finches with heavy crushing beaks, for instance.  Finch beaks on other islands were more delicate.

And Australia and New Zealand:  vast lands split from Asia to drift for millions of years, carrying creatures whose descendants (platypus, kiwi, kangaroo) diverged bizarrely from anything in Asia.

But plenty of new species had no isolation.  New fish species arising in the same lake, for instance. Ancestors could swim anywhere to interbreed. A new trait might emerge randomly, of course, but wouldn’t interbreeding dilute it to nothingness in a generation or two?

But not necessarily.  East Africa’s famous example is a fish called a cichlid (pronounced “sick-lid”) that somehow spawned hundreds of species in the giant lakes (Victoria,Tanganyika and Malawi).  The proliferation happened rapidly, too (in evolutionary terms). So fast, in fact, that DNA in the species is almost identical, even though they differ in size, color and even habits.  (Some shelter their young in their mouths, for instance).

An African cichlid

Another cichlid

How could one ancestor’s offspring end up like this?  And why didn’t fish in America’s Great Lakes do it too?

Science begins to answer, now that DNA maps of five African species have been completed.

To understand what the comparisons showed, recall this background:

• DNA is a molecule made of smaller molecules, as links make a chain.
• Links come in only four types, but billions of links make up a DNA chain.
• A “gene” is a length of links (maybe thousands of them) in a specific pattern of the four types.  The pattern is a code.  The cell’s machinery reads it to produce proteins.
• Analogy:  a string of letters specifies a word in a sentence, a pattern of links on a DNA chain specifies a protein.

Proteins – hundreds of types of them — are the “stuff” that gives animals their appearance:  muscles, skin and organs…hormones and colors:

On the long DNA chain, some portions aren’t codes for making proteins.  Instead, their patterns instruct the cell’s machinery how long to keep producing a particular protein, or how much of it to produce, or when to start producing it.  They’re like on/off switches or the volume dials on a stereo. “Regulatory” DNA is what these sections are called.

Enough background:  DNA analysis of five cichlid species showed that the genes weren’t different.  That is, their protein coding genes were essentially identical.  What differed was the regulatory sections.

So what?  It shows, how, in DNA, gradual modifications arise in offspring.
Genes don’t change (at least not in these cichlids).  What changes is how the dials turn genes on or off, loud or soft.

Darwin lived a century before evolution’s machinery became known.  He would have loved to know this.

Still….while how DNA produces novel cichlids is interesting, why cichlids invent new species, and how they stay that way in a lake, is still a puzzle.  Scientists remain where they’ve been for decades:  observing countless details of cichlids and habitats, and deducing (or merely surmising) from those facts how fish might profit by diverging from ancestors.

One example:  different colors have evolved in males of a cichlid species.  Why?  Seemingly because (for reasons unknown) females became more eager to mate with differently colored males.  That females do mate more eagerly, humans observe.  As for why?  Who knows?  What pass for “thoughts” in female fish is unknowable.  But since human males strive to entice females’ mysterious preferences, we suppose that cichlids probably do too.

But America’s Great Lakes don’t have gaudy males.  Why?  We don’t know.

E. Santos and W. Salzburger, How Cichlids Diversify, 338 Science 619-621, 2 November 2012.  E. Wagner et al., Ecological opportunity and sexual selection together predict adaptive radiation, 487 Nature 366-369 19 July 2012.

No “ghost” in the brain aims the searchlight.  What else could?  Does your free will select one memory and thereby trigger chemical and electrical eruptions to make a neuron “fire”?  Does the immaterial mind, that is, fire up the physical brain?

Or is free will an illusion?  Does some internal clockwork fire up that neuron, clockwork you neither know of, nor control?

A volunteer silently remembered a clip of The Simpson’s.  The recollection triggered firing in the same neuron that had fired when he’d first seen the cartoon clip.  For this and more on the peculiar phenomenon of attention, see Truth from Error in Scientific American at:

http://blogs.scientificamerican.com/guest-blog/2012/10/10/how-the-brain-does-attention-is-still-unknown/