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Autoimmune Disease, Immunology, Public Health, Research, Sleep, Stanford News

Cause of 2009 swine-flu-vaccine association with narcolepsy revealed?

Cause of 2009 swine-flu-vaccine association with narcolepsy revealed?

syringesBack in 2001, in the wacko cinematic tour de farce “Rat Race,” British actor Rowan Atkinson – a.k.a. the iconic “Mr. Bean” – put a humorous face on narcolepsy, a rare, chronic, incurable and lifelong sleep disorder that can strike at any time, even in the heat of a foot race.

In 2009, narcolepsy suddenly became, for a time, not quite so rare.

The swine flu pandemic sweeping the world that year was no joke. In the United States alone, the H1N1 strain of influenza virus responsible for that pandemic resulted in 274,304 hospitalizations and 12,469 deaths, as mentioned in our news release on a just-published study in Science Translational Medicine.

There probably would have been far more hospitalizations and deaths had not several vaccines tailored to that particular influenza strain been rushed to the market. Two vaccines in particular — Focetria, manufactured by Novartis, and Pandemrix, made by GlaxoSmithKline — are credited with saving a lot of lives in Europe. But there was a dark side. As our news release notes:

Populations that had been immunized with GlaxoSmithKline’s Pandemrix vaccine showed an increase in narcolepsy, but those immunized with Novartis’ Focetria did not.

That’s not news; it’s been known for some time. But the findings in the new study, whose senior author is Stanford neuroimmunologist Larry Steinman, MD, may explain why.

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Aging, Cancer, Dermatology, Genetics, Research, Stanford News

Genetic secrets of youthful skin

Genetic secrets of youthful skin

new hatEvery year, upwards of $140 billion a year gets spent on cosmetics. In the United States alone, says an authoritative report, a recent year saw upwards of 5.6 million Botox procedures, 1.1 million chemical peels, almost a half-million laser skin procedures, 196,286 eyelid surgeries and a whole bunch of face lifts.

If you’ve got the courage to compare your present-tense face with the one you were wearing 20 or even 10 years ago, you’ll see why. As I wrote in a just-published Stanford Medicine article, “Wither youth?”:

The terrain of aging skin grows all too familiar with the passing years: bags under the eyes, crow’s feet, jowls, tiny tangles of blood vessels, ever more pronounced pores and pits and pigmentation irregularities. Then there are wrinkles — long, deep “frown lines” radiating upward from the inside edges of the eyebrows and “laugh lines” that trace a furrow from our nostrils to the edges of our lips in our 40s, and finer lines that start crisscrossing our faces in our 50s. Sagging skin gets more prominent in our later years as we lose bone and fat.

“And,” I added wistfully, “it’s all right there on the very outside of us, where everyone else can see it.”

Stanford dermatologist Anne Chang, MD, who sees a whole lot of skin, got to wondering: Why does skin grow old? Armed with a sophisticated understanding of genetics, she went beyond lamenting lost youth and resolved to address the question scientifically, asking: “Can you turn back time? Can aging effects be reversed? Can you rejuvenate skin, make it young again?”

The answers she’s come up with so far – from hereditary factors to a possible underlying genetic basis for how some treatments now in common commercial cosmetic use (such as broadband light therapy) could potentially slow or even reverse the aging of skin – are described in my magazine article.

Previously: This summer’s Stanford Medicine magazine shows some skinResearchers identify genetic basis for rosacea, New study: Genes may affect skin youthfulness and Aging research comes of age
Photo by thepeachpeddler

Cancer, Imaging, Research, Stanford News, Surgery

Better tumor-imaging contrast agent: the surgical equivalent of “cut along dotted line”?

cut horseIt would be tough for most people to take a snubbed-nose scissors to an 8-1/2″ x 11″ sheet of blank paper and carve out a perfect silhouette of, say, a horse from scratch. But any kid can be an artist if it means merely cutting along a boundary separating two zones of different colors.

Tumor-excision surgery requires an artist’s touch. It can be tough to distinguish cancerous from healthy tissues, yet the surgeon needs to approach perfection in precisely removing every possible trace of the tumor while leaving as much healthy tissue intact as possible. To help surgeons out, technologists have been designing contrast agents that target only tumor cells, thus providing at least a dotted line for scalpel wielders.

Stanford pathologist and molecular-probe designer Matthew Bogyo, PhD, in a study published in ACS Chemical Biology, has now demonstrated, using mouse models of breast, lung and colon cancer, the effectiveness of a fluorescence-emitting optical contrast agent that selectively accumulates in tumors and can be used to guide surgery. In effect, the probe lights up the tumor, providing a convenient, high-resolution dotted line for its excision.

Perhaps more striking, the new study showed that this probe, designed by Bogyo’s group, is compatible with a robotic remote minimally invasive surgery system that is already enjoying widespread commercial use. Intuitive Surgical, Inc., the company that sells this system, collaborated on the study.

Previously: Stanford researchers explore new ways of identifying colon cancer, Cat guts, car crashes, and warp-speed Toxoplasma infections and Compound clogs Plasmodium’s in-house garbage disposal, hitting malaria parasite where it hurts
Photo by Merryl Zorza

Genetics, Imaging, Neuroscience, Research, Stanford News

From phrenology to neuroimaging: New finding bolsters theory about how brain operates

From phrenology to neuroimaging: New finding bolsters theory about how brain operates

phrenologyNeuroscience has come a long way since the days of phrenology, when lumps on the outside of the skull were believed to denote enhanced size and strength of the particular brain region responsible for particular individual functions. Today’s far more advanced neuroimaging technologies allow scientists to peer deep into the living brain, revealing not only its anatomical structures and the tracts connecting them but, in recent years, physiological descriptions of the brain at work.

Visualized this way, the brain appears to contain numerous “functional networks:” clusters of remote brain regions that are connected directly via white-matter tracts or indirectly through connections with mediating regions. These networks’ tightly coupled brain regions not only are wired together, but fire together. Their pulses, purrs and pauses, so to speak, are closely coordinated in phase and frequency.

Well over a dozen functional networks, responsible for brain operations such as memory, language processing, vision and emotion, have been identified via a technique called resting-state functional magnetic resonance imaging. In a resting-state fMRI scan, the individual is asked to simply lie still, eyes closed, for several minutes and relax. These scans indicate that even at rest, the brain’s functional networks continue to hum along — albeit at lower volumes — at distinguishable frequencies and phases, like so many different radio stations playing simultaneously on the same radio.

But whether the images obtained via resting-state fMRI truly reflect neuronal activity or are some kind of artifact has been controversial. Now, a new study led by neuroscientist Michael Greicius, MD, and just published in Science, has found genetic evidence that convincingly bolsters neuroimaging-based depictions of these brain-activity patterns.

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Big data, Cardiovascular Medicine, Patient Care, Public Health, Research, Stanford News

Widely prescribed heartburn drugs may heighten heart-attack risk

Widely prescribed heartburn drugs may heighten heart-attack risk

PrilosecHeartburn – that burning sensation in the chest that occurs when stomach acid rises up into your esophagus – has absolutely nothing whatsoever to do with the heart. People with heartburn (that’s a lot of us) are at no increased risk of developing heart disease. At least, not unless they’re taking the most commonly used class of drugs for treating heartburn.

That drug class would be proton-pump inhibitors, or PPIs, and it includes omeprazole (Prilosec), lansoprazole (Prevacid), esomeprazole (Nexium) and a few more. All three are available over the counter. Although the labels direct users not to take these drugs for longer than a couple of weeks without consulting their physicians, people often pop them on a daily basis for months or years on end.

But a new PLOS ONE study, led by Stanford biomedical-informatics expert Nigam Shah, PhD, MBBS, and cardiovascular surgeon Nick Leeper, MD, shows a clear association between prior use of PPIs for heartburn and elevated risk of serious cardiovascular events including heart attacks. In a news release covering that “big data” study, which combed through nearly 3 million electronic health records to ferret out the PPI/cardiovascular-risk connection, I wrote:

… PPIs are among the world’s most widely prescribed drugs, with $14 billion in annual sales… In any given year, more than 20 million Americans – about one in every 14 – use PPIs… More than 100 million prescriptions are filled every year in the United States for PPIs, a class of drugs long considered benign except for people concurrently taking the blood thinner clopidogrel (Plavix). However, the new study upends this view: It indicates that PPI use was associated with a roughly 20 percent increase in the rate of subsequent heart-attack risk among all adult PPI users, even when excluding those also taking clopidogrel.

That increased risk was seen among younger adults (under age 45), too.

The study, in other words, found that everybody’s cardiovascular risk goes up if they use PPIs. Now, a 20 percent increase in risk may not amount to much if your baseline risk is very low to begin with (say, that of a 20-year-old woman in top physical condition with no genetic predisposition to high blood pressure or elevated cholesterol). But for many of us, especially if we’re middle-aged, a little pudgy, or struggling with hypertension or hypercholesterolemia, that 20 percent looms larger.

Importantly, people who take the second-most-widely prescribed class of drugs prescribed for heartburn, so-called H2 blockers, appear to suffer no ill effects from them in the cardiovascular-risk department, according to the study’s findings. H2 blockers, which have been around longer than PPIs, are reasonably effective.

So, why do PPIs, but not H2 blockers, cause trouble? As I noted in my release:

The study’s findings lend support to an explanation for an untoward effect of PPIs on heart-disease risk proposed by Stanford scientists a few years ago. Research done then showed that PPIs impede the production of an important substance, nitric oxide, in the endothelial cells that line all of the nearly 100,000 miles of blood vessels in an averag adult’s body.

Nitric oxide relaxes blood vessels. So it figures that chronic use of a drug that shuts down that chemical’s generation could cause chronic blood-vessel constriction and follow-on cardiovascular problems.

Read those labels, people.

Previously: How efforts to mine electronic health records are beginnning to influence critical care, New research scrutinizes off-label drug use and Damage to dead-cell disposal system may increase heart disease
Photo by John

 

Evolution, Genetics, HIV/AIDS, Immunology, Infectious Disease, Research, Stanford News

Study: Chimps teach people a thing or two about HIV resistance

Study: Chimps teach people a thing or two about HIV resistance

I, personally, have never had trouble distinguishing a human being from a chimp. I look, and I know.

But I’m not a molecular biologist. Today’s sophisticated DNA-sequencing technologies show that the genetic materials of the two species, which diverged only 5 million or so years ago (an eye-blink in evolutionary time), are about 98 percent identical. Think about that next time you eat a banana.

One major exception to that parallelism: a set of three genes collectively called the major histocompatibility complex, or MHC. These genes code for proteins that sit on the surfaces of each cell in your body, where they serve as jewel cases that display bits of proteins that were once inside that cell but have since been chopped into pieces by molecular garbage disposals, transported to the cell surface and encased in one or another of the MHC proteins. That makes the protein bits highly visible to roving immune cells patrolling our tissues to see if any of the cells within are harboring any funny-looking proteins. If those roving sentry cells spot a foreign-looking protein bit, they flag the cell on whose surface it’s displayed as possibly having been infected by a virus or begun to become cancerous.

Viruses replicate frequently and furiously, so they evolve super-rapidly. If they can evade immune detection, that’s groovy from their perspective. So our MHC has to evolve rapidly, too, and as a result, different species’ MHC genes  diverge relatively quickly.  To the extent they don’t, there’s probably a good reason.

Stanford immunologist and evolutionary theorist Peter Parham, PhD, pays a lot of attention to the MHC genes. In a new study in PLOS Biology, he and his colleagues have made a discovery that may prove relevant to AIDS research, by analyzing genetic material found in chimp feces. Not zoo chimps. Wild Tanzanian chimps. As I noted in a news release about the study:

The wild chimps inhabit Gombe Stream National Park, a 13.5-square-mile preserve where they have been continuously observed from afar since famed primatologist Jane Goodall, PhD, began monitoring them more than 50 years ago.

One thing that sets the Gombe chimps apart from captive chimps, unfortunately, is a high rate of infection by the simian equivalent of HIV, the virus responsible for AIDS.

The study’s lead author, postdoc Emily Wroblewski, PhD, set up shop in a corner of Parham’s lab and extracted DNA from fecal samples legally obtained by other researchers (close contact with the animals is prohibited). Each sample could be tied to a particular Gombe-resident chimp. RNA extracted from the same sample indicated that chimp’s infection status.

Parham, Wroblewski and their colleagues found that one particular MHC gene came in 11 different varieties – astounding diversity for such a small collection of chimps (fewer than 125 of them in the entire Gombe). Surprisingly, one small part of one of those 11 gene variants was nearly identical to a piece of a protective version of its human counterpart gene, a version that seems to protect HIV- infected people slowing HIV progression to full-blown AIDS.

Why is that important? Because any piece of an MHC gene that has maintained its sequence in the face of 5 million years of intense evolutionary pressure must be worth something.

Sure enough, fecal samples from chimps with that MHC gene variant, so strikingly analogous to the protective human variant, had lower counts of virus that those from infected chimps carrying other versions of the gene.

You can believe that scientists will be closely examining the DNA sequence contained in both the human and chimp gene variant, as well as the part of the MHC protein that DNA sequence codes for. Because it must be doing something right.

Previously: Revealed: Epic evolutionary struggle between reproduction and immunity to infectious disease, Our species’ twisted family tree and Humans share history – and a fair amount of genetic material – with Neanderthals
Photo by Emily Wroblewski

Behavioral Science, Imaging, Neuroscience, Research, Stanford News

Stanford researchers tie unexpected brain structures to creativity – and to stifling it

Stanford researchers tie unexpected brain structures to creativity - and to stifling it

EinsteinHow often does the accountant turn out to be the life of the party? How often do the Nike sneakers, rather than the Armani suits, call the shots? Yet that may be the case when it comes to – of all things! – creativity.

As I wrote in this news release about an imaging study just published in Scientific Reports:

[Stanford scientists] have found a surprising link between creative problem-solving and heightened activity in the cerebellum, a structure located in the back of the brain and more typically thought of as the body’s movement-coordination center… The cerebellum, traditionally viewed as the brain’s practice-makes-perfect, movement-control center, hasn’t been previously recognized as critical to creativity.

That’s putting it mildly. And that’s not the only bizarre outcome of the study, whose findings also suggest that shifting the brain’s higher-level, executive-control centers into higher gear impairs, rather than enhances, creativity.

When I interviewed neuroscientist Allan Reiss, MD, the study’s senior author, about the research, he told me:

We found that activation of the brain’s executive-control centers – the parts of the brain that enable you to plan, organize and manage your activities – is negatively associated with creative task performance.

Creativity is one of the most valuable human attributes, as well as one of the hardest to measure. Tying it to activity in particular brain structures in a living, thinking human brain is a brainteaser in itself.

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Autoimmune Disease, Bioengineering, Immunology, Research, Stanford News

Adult humans harbor lots of risky autoreactive immune cells, study finds

Adult humans harbor lots of risky autoreactive immune cells, study finds

dangerIf a new study published in Immunity is on the mark, the question immunologists may start asking themselves will be not “Why do some people get autoimmune disease?” but “Why doesn’t everybody get it?”

The study, by pioneering Stanford immunologist Mark Davis, PhD, and colleagues, found that vast numbers of self-reactive immune cells remain in circulation well into adulthood, upending a long-established consensus among immunologist that these self-reactive immune cells are weeded out early in life in an organ called the thymus.

A particular type of immune cell, called “killer T cells,” is particularly adept at attacking cells showing signs of harboring viruses or of becoming cancerous. As I wrote in my news release about Davis’s study:

[The human immune system generates] a formidable repertoire of such cells, collectively capable of recognizing and distinguishing between a vast array of different antigens – the biochemical bits that mark pathogens or cancerous cells (as well as healthy cells) for immune detection. For this reason, pathogenic invaders and cancerous cells seldom get away with their nefarious plans.

Trouble is, I wrote:

[This repertoire includes] not only immune cells that can become appropriately aroused by any of the billions of different antigens characteristic of pathogens or tumors, but also immune cells whose activation could be triggered by myriad antigens in the body’s healthy tissues. This does happen on occasion, giving rise to autoimmune disease. But it happens among few enough people and, mostly, late enough in life that it seems obvious that something is keeping it from happening to the rest of us from day one.

It’s been previously thought that the human body solves this problem by eliminating all the self-reactive T cells during our early years via a mysterious select-and-delete operation performed in a mysterious gland called the thymus that’s nestled between your heart and your breastbone. Sometime in or near your early teens, the thymus mysteriously begins to shrink, eventually withering and largely turning to useless fat. (Is that mysterious enough for you? It sure creeps me out.)

But Davis and his team used some sophisticated technology – some of it originally invented by Davis, some of it by Stanford bioengineering professor and fellow study co-author Stephen Quake, PhD – to show that, contrary to prevailing dogma, tons of self-reactive killer T-cells remain in circulation well into adulthood. Then the scientists proceeded to explore possible reasons why the immune system keeps these risky cells around (it boils down to: just in case a pathogen from Mars comes along and we need to throw the kitchen sink at it) and why (at least most of the time) they leave our healthy tissues alone: A still-to-be-fully-elucidated set of molecular mechanisms keeps these self-reactive cells locked in the biochemical equivalent of parking gear, shifting out of which requires unambiguous signs of an actual pathogen’s presence: bits of debris from a bacterial cell wall, or stretches of characteristically viral DNA.

That’s our immune system, folks. Complicated, mysterious, and yet somehow incredibly efficient. You really don’t want to leave home – or even the womb – without it.

Previously: In human defenses against disease, environment beats heredity, study of twins shows, Knight in lab: In days of yore, postdoc armed with quaint research tools found immunology’s Holy Grail, In men, a high testosterone count can mean a low immune response and Deja vu: Adults’ immune systems “remember” microscopic monsters they’ve never seen before
Photo by Frederic Bisson

Big data, Emergency Medicine, Genetics, Infectious Disease, Research, Stanford News

Study means an early, accurate, life-saving sepsis diagnosis could be coming soon

Study means an early, accurate, life-saving sepsis diagnosis could be coming soon

image.img.320.highA blood test for quickly and accurately detecting sepsis, a deadly immune-system panic attack set off when our body wildly overreacts to the presence of infectious pathogens, may soon be at hand.

Sepsis is the leading cause of hospital deaths in the United States and is tied to the early deaths of at least 750,000 Americans each year. Usually caused by bacterial rather than viral infections, this intense, dangerous and rapidly progressing whole-body inflammatory syndrome is best treated with antibiotics.

The trouble is, sepsis is exceedingly difficult to distinguish from its non-infectious doppelganger: an outwardly similar but pathogen-free systemic syndrome called sterile inflammation, which can arise in response to traumatic injuries, surgery, blood clots or other noninfectious causes.

In a recent news release, I wrote:

[H]ospital clinicians are pressured to treat anybody showing signs of systemic inflammation with antibiotics. That can encourage bacterial drug resistance and, by killing off harmless bacteria in the gut, lead to colonization by pathogenic bacteria, such as Clostridium difficile.

Not ideal. When a patient has a sterile inflammation, antibiotics not only don’t help but are counterproductive. However, the occasion for my news release was the identification, by Stanford biomedical informatics wizard Purvesh Khatri, PhD, and his colleagues, of a tiny set of genes that act differently under the onslaught of sepsis from they way they behave when a patient is undergoing sterile inflammation instead.

In a study published in Science Translational Medicine, Khatri’s team pulled a needle out of a haystack – activity levels of more than 80 percent of all of a person’s genes change markedly, and in a chaotically fluctuating manner over time, in response to both sepsis and sterile inflammation. To cut through the chaos, the investigators applied some clever analytical logic to a “big data” search of gene-activity results on more than 2,900 blood samples from nearly 1,600 patients in 27 different data sets containing medical information on diverse patient groups: men and women, young and old, some suffering from sterile inflammation and other experiencing sepsis,  and (as a control) healthy people.

The needle that emerged from that 20,000-gene-strong haystack of haywire fluctuations in gene activity consisted of an 11-gene “signature” that, Khatri thinks, could serve up a speedy, sensitive, and specific diagnosis of sepsis in the form of a simple blood test.

The 11-gene blood test still has to be validated by independent researchers, licensed to manufacturers, and approved by the FDA. Let’s hope for smooth sailing. Every hour saved in figuring out a possible sepsis sufferer’s actual condition represents, potentially, thousands of lives saved annually in the United States alone, not to mention billions of dollars in savings to the U.S. health-care system.

Previously: Extracting signal from noise to combat organ rejection and Can battling sepsis in a game improve the odds for material world wins?
Photo by Lightspring/Shutterstock

Big data, Ethics, Genetics, Science Policy, Stanford News

Stanford panel: Big issues will loom when everyone has their genomic sequence on a thumb drive

Stanford panel: Big issues will loom when everyone has their genomic sequence on a thumb drive

When I was a biology grad student in the early 1980s, we used to joke about people who were getting their PhDs by spending six long years sequencing a single gene. They worked around the clock seven days a week – and seven nights, too, sleeping on their lab benches when they slept at all.

A few years later the Human Genome Project came along and sped things up quite a bit. But it still took 13 years and a billion dollars to fully sequence a single human genome.

It’s a different story now. With a one-day, $1,000 genome sequence in sight, a 20-minute, $100 sequence can’t be far off. It appears that within 15 years or so, the average individual’s genomic sequence will be just another lengthy, standard supplemental addition to that person’s electronic medical record.

That raises a lot of questions. Last Saturday, I had the great privilege of asking a few of them to a panel of three tier-one Stanford experts: Mildred Cho, PhD, associate director of the Stanford Center for Biomedical Ethics; Hank Greely, JD, director of the Center for Law and the Biosciences, and Mike Snyder, MD, PhD, chair of Stanford’s genetics department and director of the Center for Genomics and Personalized Medicine. (I was the moderator.)

The panel, titled “Genetic Privacy: The Right (Not) to Know,” was a lively one, part of a day-long Alumni Day event sponsored by the Stanford Medical Center Alumni Association. (Here’s a link to the video above). Cho, Greely and Snyder have their own well-developed perspectives and policy preferences on the utility of mass genomic-sequence availability, and they articulated those views with passion and aplomb.

The 300 people in the audience, most of them doctors, had plenty of questions of their own. Several were ones I’d hoped to ask but hadn’t had time.

By the time I walked away from this consciousness-raising clash of perspectives, newly aware of just how fast the future is coming at us, I had another question: Once everyone has the equivalent of a thumb drive with their complete genome on it, can you imagine a kind of online matchmaking service in which you upload your genome to a server, which then picks out a date or a mate for you? The selection is guided by what you say you’re looking for: short-term mutual attraction, an enduring monogamous relationship, robust offspring … Is that now thinkable?

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