By the year 2030, one-quarter of all people alive will be at least 60 years old. You’ve heard that 60 is the new 40, and in some respects that’s certainly true. But when it comes to fighting off infectious disease, “60 is the new 59″ might be more like it.

“Aided by improved sanitation and antibiotics, vaccines have vastly reduced the toll of infectious diseases, enabling kids to grow up – and, eventually, to grow old,” I wrote in a 2009 Stanford Medicine article about this subject.

The trouble is, the older we get the weaker our immune systems tend to become. Infectious diseases we could have fought off with ease in our youth become life-threatening in old age. Adding insult to injury, vaccines that work fine in younger people don’t always get the job done among seniors.

In a review article just published in Science Translational Medicine, a set of thought-leaders including Stanford immunologist Jorg Goronzy, MD, write:

The preventive strategies (vaccines) that are currently… effective in controlling many infectious diseases may not be suited for treating the elderly population because the aged immune system does not react with the same rules as that of a younger adult.

Scientists have been leaning in to learn how those rules work. The review article summarizes factors underlying waning immune responsiveness with advancing age, strategies for restoring that responsiveness, and specific diseases for which upping vaccine potency and usage rates among older people make sense.

Our immune response declines slowly but surely starting at around age 40, Goronzy told me in an interview last year. “While 90 percent of young adults respond to most vaccines, after age 60 that response rate is down to around 40-45 percent. With some vaccines, it’s as low as 20 percent.” But he and his colleagues have shown that blocking the action of a single protein found in a particular class of white blood cells may halt typical age-related declines in immune responsiveness.

It’s going to be a while before exciting findings such as this translate into radical enhancements of aging people’s ability to combat infection. What to do in the meantime?

First, keep moving. As the review article’s authors write, “Physical exercise is strongly recommended. It has been demonstrated that moderate physical exercise greatly improves the immune reactions of elderly people.”

Second, eat right – but don’t starve yourself. We’re told by public-health authorities that the ideal ratio of weight to height (calculated via a formula called body-mass index, or BMI) is between 20 and 25. But that’s open to some question, as some studies (including this recent one conducted by the Centers for Disease Control and Prevention) suggest that the ideal ratio, from a health standpoint if not from a fashion perspective, might be a little higher. As for seniors and infection, the STM review article sides with the latter position: “The risk of death from infectious disease in people over 70 years of age has been calculated to be minimal with a BMI of 25 to 30.”

Previously: Age-related drop in immune responsiveness may be reversible, Aging stem cells have clinical implications, say Stanford researchers and Exercise may protect aging brain from memory loss following infection, injury
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Rotavirus, the most common cause of severe diarrhea among infants and young children, causes somewhere approaching a half million deaths annually, 100,000 of them in India and half of those among children less than a year old.

So the positive results announced today for a Phase III clinical trial of a rotavirus vaccine developed and manufactured in India are great news. The new vaccine cut cases of severe rotavirus-induced diarrhea by more than half – 56 percent – during the first year of life, with protection continuing into the second year of life. That compares favorably with the efficacy of the currently licensed rotavirus vaccines in low-income parts of the globe.

An Indian company, Bharat Biotech, sponsored the randomized, double-blind, placebo-controlled study and will soon file for registration of the vaccine in India.

The trial was conducted at three sites in India. About 6,800 infants who were between six and eight weeks old when they were enrolled received either the vaccine or a placebo in three doses spread over about two months, simultaneously with their routine immunizations for polio.

Stanford virologist Harry Greenberg, MD, a professor of medicine and of microbiology and immunology and the medical school’s senior associate dean for research, is a member of the senior scientific advisory group involved in all aspects of the vaccine’s development. Greenberg’s own past research was instrumental in producing the first-ever rotavirus vaccine, licensed in 1998. That vaccine was pulled off the market upon the discovery of a rare but life-threatening side effect called intussusception. But a study published in the New England Journal of Medicine in 2011 showed that intussusception risk is not only vastly outweighed by the benefits of vaccination, but may actually be at least as strongly associated with rotavirus infection itself as with the vaccine.

Two companies’ competing rotavirus vaccines are already licensed. But with one costing about $37 per two-dose course and the other going for about $50 per three-dose course, they’re prohibitively expensive for the vast majority of Indians. Bharat, the Indian biotech, has stated that it will sell this vaccine (its brand name is ROTAVAC) for a dollar a dose. At that price, assuming the product’s approval, it will save many, many thousands of lives every year.

Previously: Trials, and tribulations, of a rotavirus vaccine
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Man bites dog. As reported on the Wonkblog and elsewhere yesterday, a new analysis indicates that the rate of gun-induced homicide has plummeted by half over the past two decades.

Asked in a March Pew Research Center survey whether crimes involving guns have increased, held steady or been in remission since twenty years ago, more than half of all respondents said such crimes were on the rise.

Wrong. In 1993 – a year remembered by many of us through a Vaseline-coated lens of nostalgia – the gun-homicide rate in the United States was twice what it is today. The 49 percent drop since then is consistent with a general and steady, if unheralded, drop-off in rates of all violent crimes, as the federal Department of Justice’s Bureau of Justice Statistics confirms.

Actually, the rate of firearm-related homicides began a rapid ascent in the 1960s, peaked in the early 1990s, and has now returned to that of the early 1960s. (Gun-related suicides have also declined, but not as dramatically.)

These statistics do not bring back to life a single innocent person who has been killed, by guns or otherwise, in the past two decades. But they do provide some perspective in what has been an emotion-charged and too-often fact-challenged debate. As I’ve previously written, I fear that the debate leading to the Affordable Care Act – now proving famously tough to implement -a few years ago involved some misconceptions concerning the state of health care in the United States. People on both sides of the current debate on gun-control legislation would be well advised to get the facts straight.

Previously: U.S. health system’s sketchy WHO rating is bogus, says horse’s mouth and Rush to judgment regarding the state of U.S. health care?
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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 it 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. (Transgender 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
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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
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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?
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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
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