The National Academy of Sciences recently celebrated its 150th birthday by, among other things, conferring membership on Ben Barres, MD, PhD. Additional NAS admittees from Stanford were sleep scientist Emmanuel Mignot, MD, PhD, and bioengineer Steve Quake, PhD.

A distinguished scientist by anybody’s yardstick, as well as the chair of Stanford’s ironically named neurobiology department, Barres is a leading light in the study of glial cells (collectively known as glia), the 90 percent of all the cells in the brain that aren’t nerve cells.

The term”glia” is derived from the Greek word for glue. Like Rodney Dangerfield, glial cells once got no respect. They were thought of, in fact, as not much more than “brain glue”: mere structural scaffolds for the organ’s much more revered nerve cells.

Barres’ research has proved that hypothesis incorrect, to say the least. (For details, click here.) Discoveries coming out of his lab include, to name one example, glial cells’ crucial role in determining exactly when and where nerve-cell connections in the brain are made, tweaked to strengthen or weaken them, or destroyed.

You don’t get much more respectable than that: Those connections pretty much define the thoughts we have, the emotions and sensations we experience and the actions we take.

The man who, as much as anyone, has brought a set of unsung cells a newly elevated status would like to see another group get more respect: the estimated 0.3 percent of Americans who are transgender.

“I’m the first transgender scientist to make into the National Academy of Science,” says Barres, who began life under another first name: Barbara.

“We don’t know if other members past or present are or were transgender,” demurs an NAS representative. And after all, how would they? What kind of statistics could be compiled by an organization that doesn’t ask or track the sexual orientations, much less the gender identities, of its membership? Who would have even considered asking such a question 20 or 30 years ago, much less running sex-chromosome tests on cheek swabs from prospective, current or posthumous members?

But it’s a pretty safe bet that if any previously admitted NAS member were openly transgender, we’d have heard about it. (Transgendered computer scientist Lynn Conway was admitted to the National Academy of Engineering in 1989.)

One is tempted to compare Barres to Jackie Robinson, who broke the Major League Baseball’s color barrier in 1947 - except that the latter had to put up with a whole lot more grief from his fellow major-league ballplayers than Barres is likely to encounter from his peers.

“We heartily congratulate Prof. Barres on his election,” says NAS spokesperson Bill Skane.

In science, if anywhere, diverse perspectives drive innovation. ”Don’t ever let anyone make you feel bad about being different,” Barres tells young scientists. “Your difference is your greatest advantage.”

Previously: Malfunctioning glia - brains cells that aren’t nerve cells - may contribute big time to ALS and other neurological disorders, Neuroinflammation, microglia, and brain health in the balance and Unsung brain-cell population implicated in variety of autism

So-called Lewy bodies - gumball-like clumps rich in a mystery molecule called alpha-synuclein - abound in Parkinson patients’ brains and are considered the hallmark of the disease. Up to now, researchers have had few solid clues as to what this “black hat” protein is doing in the brain in the first place.

But a team led by Stanford neuroscientists Tom Sudhof, MD, and Axel Brunger, PhD, has revealed a likely critical role played by alpha-synuclein in healthy brains. Their discovery is described in an article just published in the open-access online journal eLife.

Each of the human brain’s roughly 200 billion nerve cells communicates directly with, on average, 10,000 others by squirting signaling chemicals called neurotransmitters at them. It is all this squirting that underpins our thoughts, feelings and movements.

Of course, the brain’s activity is no mob squirt-gun shootout. Consider: The 2 quadrillion separate nerve-cell connections in your brain or mine roughly equal the number of stars in 7,000 Milky Way galaxies. For our most exalted organ to do its job, the signals that nerve cells send must be marked by profound precision, both in their intensity and in their timing.

As I wrote in my release accompanying the eLife article:

Nerve cells don’t simply squirt out neurotransmitters willy-nilly. Within the complex networks that constitute our brains, every individual nerve cell has a lengthy, snaking, tubular extension cord, or axon, that hooks up with thousands of other nerve cells. Neurotransmitters are housed within tiny bubble-like packets in the cell. These packets congregate in myriad small, bulbous nozzles dotting the axon, with each bulb abutting a downstream nerve cell. When an electrical impulse travels down the axon on which those bulbs reside, it triggers the fusion of the neurotransmitter-packed packets with the nerve cell’s outer membrane. The packets’ contents then spill into the narrow space separating the bulbs from the nerve cells they abut.

The Sudhof-and-Brunger team was able to show that alpha-synuclein helps regulate the orderly clustering of the neurotransmitter-loaded packets near their release sites. Alpha-synuclein has to be present in the right amounts, though; too much or too little has untoward consequences - which could explain why previous research has yielded conflicting results.

It’s nice to know, before messing around with it in living people, that in the healthy brain alpha-synuclein is a lot more than just a raw material in a gumball factory. Drug companies may have perhaps been led down some blind alleys as a result of locking in, too early, on the notion that yet another clump-generating protein, A-beta, was the Bad Guy in Alzheimer’s disease and that, it followed, getting rid of it would be a good idea. Maybe not so fast…

Previously: Nervous breakdown: Preventing demolition of faulty proteins counters neurodegeneration in lab mice, Stanford scientist sets sail on new publishing model with launch of open-access, embargo-free journal and Stanford study identifies molecular mechanism that triggers Parkinson’s
Photo by akeg

A luminescent lab mouse, genetically engineered to produce the same protein that makes fireflies’ tails light up, may accelerate progress in coming up with treatments for muscular dystrophy. This bioengineered mouse also has a genetic defect that, like its counterpart gene defect in people, causes the disease.

The luminescence happens only in damaged muscle tissue, and its intensity is in direct proportion to the amount of damage sustained in that tissue. So each glowing mouse muscle gives researchers an accurate real-time readout of just how much the disease has progressed and where.

It adds up to vastly expedited drug research. Tom Rando, MD, PhD, director of Stanford’s Glenn Laboratories for the Biology of Aging and founding director of Stanford’s Muscular Dystrophy Association Clinic, told me. As I wrote in my release about his new report in the Journal of Clinical Investigation about the Rando lab’s invention:

No truly effective treatments for muscular dystrophy exist. “Drug therapies now available for muscular dystrophy can reduce symptoms a bit, but do nothing to prevent or slow disease progression,” said Rando. Testing a drug’s ability to slow or arrest muscular dystrophy in one of the existing mouse models means sacrificing a few of them every couple of weeks and conducting labor-intensive, time-consuming microscopic and biochemical examinations of muscle-tissue samples taken from them, he said.

With an eye to vastly speeding up drug testing while simultaneously dropping its cost, Rando and his colleagues developed the new experimental strain whose glow (you see it through the skin) gives investigators an instantaneous, accurate reflection of what’s going on inside a mouse’s muscles, well before the degenerative changes could have been observed using standard detection techniques - without any need to kill the mouse in order to get the results.

Trivia point: The word “muscle” comes from the Latin musculus, meaning “little mouse.” More than mere coincidence?

Okay, probably not. But I thought it was worth mentioning.

Previously: Aging research comes of age, Can we reset the aging clock, one cell at a time? and Mouse model of muscular dystrophy points finger at stem cells
Photo by Goldring

Your brain and my brain are shaped slightly differently. But, it’s a good bet, in almost the identical spot within each of them sits a clump of perhaps 1 to 2 million nerve cells that gets much more excited at the sight of numerals (“5,” for example) than when we see their spelled-out equivalents (“five”), lookalike letters (“5″ versus “S”) or scrambled symbols composed of rearranged components of the numerals themselves.

Josef Parvizi, MD, PhD, director of Stanford’s Human Intracranial Cognitive Electrophysiology Program, and his colleagues identified this numeral-recognition module by recording electrical activity directly from the brain surfaces of epileptic volunteers. Their study describing these experiments was just published in The Journal of Neuroscience.

As I explained in my release about the work:

[A]s a first step toward possible surgery to relieve unremitting seizures that weren’t responding to therapeutic drugs, [the patients had] had a small section of their skulls removed and electrodes applied directly to the brain’s surface. The procedure, which doesn’t destroy any brain tissue or disrupt the brain’s function, had been undertaken so that the patients could be monitored for several days to help attending neurologists find the exact location of their seizures’ origination points. While these patients are bedridden in the hospital for as much as a week of such monitoring, they are fully conscious, in no pain and, frankly, a bit bored.

Seven patients, in whom electrodes happened to be positioned near the area Parvizi’s team wanted to explore, gave the researchers permission to perform about an hour’s worth of tests. In the first, they watched a laptop screen on which appeared a rapid-fire random series of letters or numerals, scrambled versions of them, or foreign number symbols with which the experimental subjects were unfamiliar. In a second test, the experimental subjects viewed, again in thoroughly mixed-up sequence, numerals along with words for them as well as words that sounded the same (1″, “one”, “won”, “2″, “two”, “too”, etc.).

A region within a part of the brain called the inferior temporal gyrus showed activity in response to all kinds of squiggly lines, angles and curves. But within that area a small spot measuring about one-fifth of an inch across lit up preferentially in response to numerals compared with all the other stimuli.

The fact that this spot is embedded in a larger brain area generally responsive to lines, angles, and curves testifies to the human brain’s “plasticity:” its ability to tailor its form and function according to the dictates of experience.

“Humans aren’t born with the ability to recognize numbers,” says Parvizi. He thinks evolution may have generated, in the brains of our tree-dwelling primate ancestors, a brain region particularly adept at computing lines, angles and curves, facilitating snap decisions required for swinging quickly from one branch to the next.

Apparently, one particular spot within that larger tree-branch-interesection recognition area is easily diverted to the numeral-recognition activity constantly rewarded by parents and teachers during the numeracy boot camp called childhood.

Nobody can say those little monkeys don’t learn anything in kindergarten.

Previously: Metamorphosis: At the push of a button, a familiar face becomes a strange one and Why memory and math don’t mix: They require opposing states of the same brain circuitry
Photo by qthomasbower

Ever wonder - say, while sitting quietly in a concert hall or screaming your lungs out in a crowded ampitheater - whether the musical experience you’re having is anything like that of the person three seats up or three sheets to the wind on your right?

A partial answer is in: Our brains process music in pretty much the same way, providing it’s got the requisite combination of components (rhythm, melody, harmony, etc.), according to Stanford neuroscientist Vinod Menon, PhD. In a just-published study, Menon’s group monitored several healthy peoples’ brains while these subjects listened to the same piece of music. As the music played on, activity in a broadly distributed network of neuroanatomically connected brain areas waxed and waned very similarly for each listener. This synchrony among individual responses was absent when participants listened to “pseudomusic” stripped of either rhythmic or tonal characteristics.

The inter-subject synchronization extended to the brain’s movement-planning zone. Evolution, it seems, has designed us this way. As I wrote in my release about the study:

[O]ur brains respond naturally to musical stimulation by foreshadowing movements that typically accompany music listening: clapping, dancing, marching, singing or head-bobbing. The apparently similar activation patterns among normal individuals make it more likely our movements will be socially coordinated.

It’s easy to imagine the survival value of coordinated movement in response to auditory cues. Hunting, gathering, warmaking - all benefit from choreography. That would objectively explain how people who run, shout and pump their fists in synch might win the evolutionary race.

But about the subjective aspect of this synchronization, I’m not so sure.

Look. It’s important that our brains respond similarly to identical stimuli. But what about our minds? In the house of mirrors that is our consciousness, how can we know whether music sounds the same, or color looks the same, to different people?

This takes me back to long ago when, as a philosophy major at the University of Wisconsin, I flunked a course in epistemology. That’s the philosophy of what we know and how we know it, and what we think we know that, actually, we don’t. Turns out I didn’t know much.

One day, the professor - a tweedy, pipe-puffing Princeton man who paced the room in an elbow-patch-bedecked jacket - shouted to the motley assortment of assembled esistentialist ectomorphs: “I PROPOSE. THAT. WHEN I SAY: ‘BLUE!’ ALL OF YOU. SEE. EXACTLY. THE SAME. COLOR!!!”

He paused. “Refute. That. Hypothesis,” he snarled, taking a toke from his pugnacious pipe.

I didn’t raise my hand. It raised itself. He called on me. “I see the same color slightly differently with each eye,” I said, illustrating my claim with alternating winks of my left and right eye. Seemed like a slam-dunk to this Milwaukee boy. (It also happened to be true.)

He glared at me, cross-examined me fiendishly for five long minutes and, striding to the blackboard (I did tell you this was long ago), multiplied the number of minutes we had dueled by the dwindled number of my classmates and thundered: “You’ve wasted 45 student-minutes of class time!”

It was right about then that I started thinking maybe I should switch to science.

So, what is “music,” really? Well, we don’t really know. But whatever it is, it makes us wanna shout, kick our heels up and shout, throw our hands up and shout, throw our heads back and shout.

Previously: New research tracks “math anxiety” in the brain, Why memory and math don’t mix: They require opposing states of the same circuitry and Can playing familiar music boost cognitive response among patients with brain damage?
Photo by gilmorec

Earlier today I wrote about a breakthrough method called CLARITY, pioneered by Stanford psychiatrist/bioengineer Karl Deisseroth, MD, PhD, for rendering intact tissue samples transparent. Above is a video clip showing off the new method’s capabilities. First you’ll witness a “fly-through” of a complete mouse brain using fluorescent imaging. The immediately following clip - it’s spectacular! - provides a three-dimensional view of a mouse hippocampus (the brain’s brain’s memory hub), with projecting neurons depicted in green, connecting interneurons in red, and layers of support cells, or glia, in blue.

Note that in both cases, there was no need to slice the tissue into ultra-thin sections, analyze them chemically and/or optically and then laboriously “sew” them back together via computer algorithms in order to reconstruct a 3-D virtual image of the biological sample. All that was required, after performing the necessary hocus-pocus, was to ”send in the stain” (i.e., use histochemical means to paint different cell types different colors) and move the sample or camera lens or shift the latter’s focal length. Nice trick. With big implications for biomedical research.

Previously: Lightning strikes twice: Optogenetics pioneer Karl Deisseroth’s newest technique renders tissues transparent, yet structurally intact, Visualizing the brain as a Universe of synapses and A federal push to further brain research

Stanford psychiatrist and bioengineer Karl Deisseroth, MD, PhD, spent much of this century’s first decade developing a revolutionary method for studying the brain: optogenetics. In 2010, Nature Methods heralded optogenetics as its “method of the year.”

It looks as though lightning has struck the Deisseroth lab again.

Suppose, just for a moment, that you’re conducting espionage on a heavily guarded multi-story building strongly suspected to be an advanced nuclear-weapons facility. The building quickly proves utterly inaccesible. Fortunately, you manage (through methods too covert to be revealed here) to procure a floor plan. Nice going. Now, you know a lot about the floors themselves and a bit of cross-sectional detail on the bases of whatever’s sitting on them. Better than nothing.

Now, imagine - in fantasyland, anything goes - that you can don goggles enabling you to peer right through the building’s outer walls and directly observe its three-dimensional structure, including its concealed laboratories and the instruments and manufacturing machinery inside of them. Payday!

An analogous technique developed by Deisseroth promises to revolutionize cell biology. Exploring connections among, and contents within, the billions of cells in a chunk of tissue often involves slicing the chunk into ultra-thin sections, exposing each slice’s top and bottom surfaces for microscopy or histochemical and electrical manipulation. Sophisticated computation can stitch the slices back together (virtually), roughly reconstructing the sample’s three-dimensional structure. (That’s the floor plan I mentioned earlier.)

Unfortunately, all this sawing disrupts key connections within the tissue and distorts its constitutent cells’ geography. Plus, while those sections are thin, they’re not infinitely thin. Light and chemicals can penetrate only so far. Volumes of valuable information about their innards remains concealed.

Deisseroth’s paradigm-shifting method, called CLARITY, renders tissue transparent while leaving it structurally intact, yet accessible to large “detective” molecules scientist use to gain information about cells’ surface features and genetic contents. In a study just published in Nature, a group led by Deisseroth (who discusses his work in the video above) converted an entire adult mouse brain into an optically transparent, histochemically permeable replica of itself. The position and structure of proteins embedded in the membranes of cells and their intracellular organelles remained intact.

Okay, step back with me for a minute. Essentially, all cells are liquid-filled bubbles of oil. (Nerve cells are better visualized as long, branching, liquid-filled tubes whose walls are made of fat.) These oil/fat (in science-speak, “lipid“) bubbles and walls (“membranes”) both house and compartmentalize their contents, so operations inside them can be carried out in relative isolation. Dotting membranes’ surfaces are all kinds of proteins performing innumerable activities key to the health of the cells they enclose and the tissues those cells compose.

Evolution designed lipid membranes to be mostly impermeable to large molecules, and they happen to be opaque (or else we’d all be transparent). In a feat of chemical engineering, Deisseroth’s team replaced the lipids with, for all purposes, clear plastic. With their work, you could literally read a newspaper through the mouse’s brain. Formerly membrane-bound proteins remained anchored in the membranes’ doppelgangers, retaining their structures (a big deal, as a protein’s structure determines its function). The tissue was also nanoporous: It permitted bulky “reporter”molecules such as stain-carrying antibodies and strips of DNA to flow deep into the transformed tissue sample and out again.

Obviously you wouldn’t want to try this on yourself, although Plastic Man certainly seems to have worked out the kinks.

Previously: Researchers induce social deficits associated with autism, schizophrenia in mice, Anti-anxiety circuit found in unlikely brain region and Nature Methods names optogenetics its “Method of the Year
Photo in featured entry box by kainet

Stem-cell therapy for damaged hearts is a brilliant idea whose time has not yet come. To date, human and animal trials - there have been quite a few - in which stem cells were injected into cardiac tissue to treat severe heart attacks or substantial heart failure have mostly produced poor results.

Stanford’s Sam Gambhir, PhD, MD, who heads the medical school’s Department of Radiology, thinks he knows part of the reason why, and he may have found a way around it.

At present, there’s no way to ensure against faulty initial placement, he told me in an interview about his study describing the proposed solution, just published in Science Translational Medicine. “You can use ultrasound to visualize the needle through which you deliver stem cells to the heart. But once those cells leave the needle, you’ve lost track of them.”

In my release about the work, I wrote:

As a result, key questions go unanswered: Did the cells actually get to the heart wall? If they did, did they stay there, or did they diffuse away from the heart? If they got there and remained there, for how long did they stay alive? Did they replicate and develop into heart tissue?

Gammbhir’s lab has figured out a way to “mark” stem cells before infusing them into the heart, rendering them visible to standard ultrasound as they’re squeezed out of the needle. The key was to invent an innovative imaging agent, in the form of nanoparticles whose diameters clustered just below one-third of a micron — less than one-three-thousandth the width of a human hair. The nanoparticles’ main ingredient, silica, shows up on ultrasound. The particles were also doped with the rare-earth element gadolinium, so they can also be observed using MRI.

It turns out that mesenchymal stem cells — a class of cells often used in heart-regeneration research because they can differentiate into beating heart cells and because they can sometimes be harvested directly from the patients themselves, avoiding possible immune-compatibility problems — were happy to gobble up the nanoparticles in a lab dish without losing any of their ability to survive, thrive, and replicate themselves.

When Gambhir and his associates infused these nanoparticle-loaded stem cells into the hearts of healthy mice, they were indeed able to monitor the cells via ultrasound after they left the needle tip, guide them to the targeted area of the heart wall, and still get a strong MRI signal from the cells two weeks later.

Stem-cell therapy for damaged hearts isn’t going to be cheap anytime soon. (A wild guess of, say, $50,000 per procedure is probably not too far off the mark.) But a one-time delivery, if it worked, could replace a lifetime of constant drug administration. Adding what Gambhir estimates might be another $2,500 a pop for the added imaging capability is likely to be hugely cost-effective, because it could greatly improve the odds of the procedure’s success.

Previously: Nanoparticles home in on human tumors growing in mice’s brains, increase accuracy of surgical removal, Nanomedicine moves ones step closer to reality and Developing a new molecular imaging system and technique for early disease detection
Photo by miguelb

You’ve heard of Sputnik, that little tiny antenna-clad chunk of metal heaved into low orbit on October 4, 1957, effectively kicking off the Space Age?

Well, make way for Gutnik. A news release issued by NASA’s Ames Research Center foretells the launch into space of a satellite inhabited by a bunch of nano-mariners who, left to their own devices, would no doubt rather curl up inside a bowel.

Sometime in the next one to three years, according to the release, a so-called “nanosatellite” weighing about 30 pounds and peopled by the intestinal bug E. coli will streak into the sky, with the mission of amassing data on whether the zero-gravity environment that cloaks our planet might increase microbes’ resistance to antibiotics. That’s important, because, as the release states:

Bacterial antibiotic resistance may pose a danger to astronauts in microgravity, where the immune response is weakened. Scientist believe that the results of this experiment could help design effective countermeasures to protect astronauts’ health during long-duration human space missions.

E. coli is probably the most-studied micro-organism in all of science. While most strains are harmless and actually quite friendly (producing vitamin K for us, just to name one of the nice things they do), some of them can cause food poisoning, urinary-tract infections and more.

Gutnik (whose real name is EcAMSat) is the brainchild of Stanford microbiologist A.C. Matin, PhD, the principal investigator for the joint NASA/Stanford University School of Medicine project. Matin’s previous inventions include microbes capable of gobbling up environmental toxins like uranium and chromium, as well as magnetic-field-seeking bacteria that can increase the contrast of magnetic-resonance imaging. So this new satellite caper is just one more in a series of wild but potentially very useful feats of imagination.

The thing that really knocks me out, though, is how all these scientists and engineers will manage to get those billions of little tiny bugs to sit still while the chin straps on their little tiny space helmets are being fastened.

Previously: Space: A new frontier for doctors and patients and Outer-space ultrasound technologies land on Earth
Photo by Per Olof Forsberg

Sparks flew at a symposium hosted by the Stanford Center for Health Research on Women & Sex Differences in Medicine, which I attended yesterday. One invited speaker -Louann Brizendine, MD, of the University of California at San Francisco - is the author of a couple of books titled The Male Brain and The Female Brain. Another invited speaker - neuroscientist Daphna Joel, PhD, who’d flown in from the University of Tel Aviv, in Israel - emphatically maintained that there is no such thing as a “male” brain or a “female” brain. “What we know,” she said bluntly, “is that males have brains and females have brains.”

Whatever the semantics of that debate, two things are pretty clear any way you slice it. First, male and female brains are mostly alike. Second, there are measurable and meaningful differences in what goes on inside male versus female brains. As another neuroscientist, UCLA’s Art Arnold, PhD, put it: “Every cell in a female’s brain expresses a set of genes that the cells in a male’s brain express at much lower levels, if at all.”

Adding heft to Arnold’s comment was a presentation by Nirao Shah, MD, PhD, of UCSF. The neuroanatomist showcased research in his lab that had pinpointed specific genes whose activity levels differed significantly in the brains of male and female mice. Many of these genes, he noted, have human analogs that have been implicated in alcoholism, autism, breast and prostate cancers, and more. By conducting rigorous experiments with mice in which one or another of such genes had been put out of commission, Shah and his colleagues were able to tease out the behavioral consequences of specific genes’ inactivation. For example, knocking out a particular gene in female mouse moms results in a massive dimunition in their willingness to defend their nests from intruders - a maternal mandate that normal female mice observe rigorously - yet has no other observable effect on their maternal or sexual behavior. Torpedoing a different gene radically reduces Minnie Mouse’s mating mood; but the Mickeys in which this gene has been trashed “are completely normal, as far as we can tell,” Shah said.

The upshot: Yes, there are significant differences in behavior (and therefore in brain action) and in gene activity in the brain cells of males and females. Those of male and female mice, that is. What about humans’?

Well, nobody was talking about knocking any genes out of people to see if the men indulge in fewer barroom brawls and the women start laughing off their babies’ cries of distress. But there are certainly some strong hints of medically significant differences: The ratio of men to women with autism run somewhere in the neighborhood of 8:1 or even 16:1. Depression is twice as common among women as among men - but only between menarche and menopause. Alzheimer’s disease abounds more in women, even after taking into consideration women’s greater longevity (itself a medically important difference), as does autoimmunity. On the other hand, Parkinson’s and schizophrenia preferentially affect men. There seems to be more at work here than the simple “absorption of gender stereotypes,” and it’s good to see hardcore biologists attacking the problem with all the scientific rigor at their disposal.

Let’s not call the whole thing off.

Previously: A call to advance research on women’s health issues
Photo by namuit