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Aging, Immunology, Infectious Disease

Found: A molecule mediating memory meltdown in aging immune systems

Found: A molecule mediating memory meltdown in aging immune systems

persistence of memoryEven perfectly healthy older people don’t always remember names as quickly as they did when they were younger. So what. They also don’t walk as fast. Big deal.

A bigger deal: Older immune systems don’t respond as quickly or as well to invasions by pathogens. That’s in large part because they fail to remember previous encounters with pathogens (or their defanged doppelgängers, which we call vaccines). Why do they forget? Stanford immunologist Jorg Goronzy, MD, may have a handle on part of the reason.

In a study published in Cell Reports, Goronzy and his colleagues have shown that immune cells of a particular type are more likely to be marked, in older people, by a surface protein that sparks apoptosis, or cellular suicide. As a result, the immune system’s memory of pathogens or vaccinations of yore gets cloudy, leaving the door open to a repeat attack by intruders that a more adept immune system would have summarily squelched.

A healthy immune system bulks up vigorously in response to pathogens or vaccines. Different types of immune cells that are skilled at recognizing and/or warring with the foreign body start to multiply and morph. Many of these cells effectively become front-line warriors, throwing themselves into battle against the invading pathogen (or its harmless vaccine lookalike). Others are more like archers lobbing darts that can knock off the bad guys while sparing innocent bystanders (the body’s own tissues). Still others, known as CD4 cells, coordinate the whole counterattack, sending chemical signals to other cells, or rubbing up against them at close range to whisper secret instructions.

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Behavioral Science, Big data, Neuroscience, Research, Stanford News

What were you just looking at? Oh, wait, never mind – your brain’s signaling pattern just told me

What were you just looking at? Oh, wait, never mind - your brain's signaling pattern just told me

headI’ve blogged previously (here, here and here) about scientific developments that could be construed, to some degree, as advancing the art of mind-reading.

And now, brain scientists have devised an algorithm that spontaneously decodes human conscious thought at the speed of experience.

Well, let me qualify that a bit: In an experimental study published in PLOS Computational Biology, an algorithm assessing real-time streams of brain-activity data was able to tell with a very high rate of accuracy whether, less than half a second earlier, a person had been looking at an image of a house, an image of a face or neither.

Stanford neurosurgical resident Kai Miller, MD, PhD, along with colleagues at Stanford, the University of Washington and the Wadsworth Institute in Albany, NY, got these results by working with seven volunteer patients who had recurring epileptic seizures. These volunteers’ brain surfaces had already been temporarily (and, let us emphasize, painlessly) exposed, and electrode grids and strips had been placed over various areas of their brain surfaces. This was part of an exacting medical procedure performed so that their cerebral activity could be meticulously monitored in an effort to locate the seizures’ precise points of origin within each patient’s brain.

In the study, the volunteers were shown images (flashed on a monitor stationed near their bedside) of houses, faces or nothing at all. From all those electrodes emanated two separate streams of data – one recording synchronized brain-cell activity, and another recording statistically random brain-cell activity – which the algorithm, designed by the researchers, combined and parsed.

The result: The algorithm could predict whether the subject had been viewing a face, house, or neither at any given millisecond. Specifically, the researchers were able to ascertain whether a “house” or “face” image or no image at all had been presented to an experimental subject roughly 400 milliseconds earlier (that’s the time it takes the brain to process the image), plus or minus 20 milliseconds. The algorithm correctly nailed 96 percent of all images shown in the experiment. Moreover, it made very few lousy guesses: only one in 25 were rotten calls.

“Although this particular experiment involved only a limited set of image types, we hope the technique will someday contribute to the care of patents who’ve suffered neurological imagery,” Miller told me.

Admittedly, that kind of guesswork gets tougher as you add more viewing possibilities – for instance, “tool” or “animal” images. So this is still what scientists call an “early days” finding: We’re not exactly at the point where, come the day after tomorrow, you’re walking down the street, you randomly daydream about a fish for an eighth of a second, and suddenly a giant billboard in front of you starts flashing an ad for smoked salmon.

Not yet.

Previously: Mind-reading in real life: Study shows it can be done (but they’ll have to catch you first), A one-minute mind-reading machine? Brain-scan results distinguish mental states and From phrenology to neuroimaging: New finding bolsters theory about how brain operates
Photo by Kai Miller, Stanford University

Genetics, Immunology, Microbiology, Research, Stanford News

Special delivery: Discovery of viral receptor bodes better gene therapy

Special delivery: Discovery of viral receptor bodes better gene therapy

8565673108_28e017bf50_zGene therapy, whereby a patient’s disorder is treated by inserting a new gene, replacing a defective one, or disabling a harmful one, suffered a setback in 1999, when Jesse Gelsinger, an 18-year-old with a genetic liver disease, died from immense inflammatory complications four days after receiving gene therapy for his condition during a clinical trial. It was quite a while before clinical trials in gene therapy resumed.

But what Stanford virologist Jan Carette, PhD, describes as “intense interest” in the field is once again in full bloom. Gene therapies for several inherited genetic disorders have been approved in Europe, and a gene-therapy approach for countering congenital blindness is close to approval in the United States.

That a virologist would be paying such close attention to this topic isn’t odd, as the most well-worked-out method for introducing genetic material to human cells involves the use of a domesticated virus.

If there’s one thing viruses are really good at, it’s infecting cells. Another viral trick is transferring their genes into cellular DNA — it’s part of their modus operandi: hijacking cells’ replicative machinery and diverting it to production of numerous copies of themselves. Scientists have become increasingly adept at taming viruses, tweaking them so they retain their ability to infect cells and insert genes, but no longer contain factors that wreck tissues or taunt the infected victim’s immune system into a rage destructive to virus and victim alike.

Adenovirus-associated virus — ubiquitous in people and not associated with any disease – makes a great workhorse. Properly bioengineered, it can infect all kinds of cells without replicating itself inside of them or triggering much of an immune response, instead obediently depositing medically relevant genes into the infected cells to repair a patient’s defective metabolic, enzymatic, or synthetic pathways.

Figuring out how to tailor this viral servant so it will invade cells more efficiently, or invade some kinds of cells and tissues but not others, would broaden gene therapy’s utility and appeal. In a series of experiments described in a study in Nature, Carette’s group, with collaborators from Oregon Health & Science University and the Netherlands, used a sophisticated method pioneered by Carette to bring that capability a step closer.

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Autoimmune Disease, Immunology, Neuroscience, Research, Stanford News

New perspective: Potential multiple sclerosis drug is actually old (and safe and cheap)

New perspective: Potential multiple sclerosis drug is actually old (and safe and cheap)

new perspectiveAbout 400,000 people in the United States are affected by multiple sclerosis (often referred to by the acronym MS), an autoimmune disorder in which rogue immune cells attack the insulating layer surrounding many nerve cells in the central nervous system.  Some 200 new cases are diagnosed every week in the U.S.

I wrote a while back about a study by Paul Bollyky, MD, PhD, showing that blocking production of a naturally made substance in the body could potentially protect against type 1 diabetes, another autoimmune disorder in which the body’s immune system attacks the pancreas’s insulin-producing cells (the only place where insulin is made). It now appears possible that the same drug Bollyky’s team used to achieve that benefit may also be beneficial in MS.

The substance in question — hyaluronan, a hefty, complex carbohydrate substance — is usually present at trace concentrations in the extracellular matrix that pervades all tissues and, among other things, helps glue those tissues’ constituent cells together. Intriguingly, hyaluronan levels spike markedly at the site of an injury. If you twist your ankle or stub your toe, the swelling you see afterwards is mainly due to hyaluronan, which is prone to soaking up water. That causes fluid buildup, aka swelling,  in the injured region — a cardinal feature of inflammation, along with heat, redness and pain.

In a new study published in Proceedings of the National Academy of Sciences, Bollyky and his colleagues show that hyaluronan also abounds in sites of autoimmune attack in MS patients’ brains after they induced a mousie version of MS in laboratory mice. They confirmed that hyaluronan likewise accumulates near the mice’s MS lesions. And they showed that blocking new hyaluronan synthesis in the mice before symptoms developed prevented many of the mice from succumbing to MS and delayed disease onset and severity in those who did get it, while — importantly — blocking hyaluronan synthesis after symptoms developed alleviated those symptoms.

Perhaps most interesting of all: The drug they used to do that is already on the market for other indications.

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Health and Fitness, Microbiology, Nutrition, Public Health, Research, Stanford News

Can low-fiber diets’ damage to our gut-microbial ecosystems get passed down over generations?

Can low-fiber diets' damage to our gut-microbial ecosystems get passed down over generations?

fast food decisionsUh-oh.

A study conducted in mice raises suspicions that we humans may be halfway down the road to the permanent loss of friendly gut-dwelling bacteria who’ve been our constant companions for hundreds of millennia. That’s probably not good.

Virtually all health experts agree that low-fiber diets are sub-optimal. One big reason: Fiber, which can’t be digested by human enzymes, is the main food source for the friendly bacteria that colonize our colons. Thousands of distinct bacterial species thrive within every healthy mammal’s large intestine. Far from being victimized by these colonic cohabitants, we’d be hard put to live without them. They fend off pathogens, train our immune systems, help us digest food we’d otherwise be unable to use and even guide the development of our tissues.

From a news release I wrote about the new study, which was spearheaded by Stanford microbiology/nutrition explorers  (and husband/wife team) Justin Sonnenburg, PhD, and Erica Sonnenburg, PhD, and published in Nature:

[Previous] surveys of humans’ gut-dwelling microbes have shown that the diversity of bacterial species inhabiting the intestines of individual members of hunter-gatherer and rural agrarian populations greatly exceeds that of individuals living in modern industrialized societies. … In fact, these studies indicate the complete absence, throughout industrialized populations, of numerous bacterial species that are shared among many of the hunter-gatherer and rural agrarian populations surveyed, despite those groups’ being dispersed across vast geographic expanses ranging from Africa to South America to Papua New Guinea.

Another piece of information: The proliferation of nearly fiber-free, processed convenience foods since the mid-20th century has resulted in average-per-capita fiber consumption in industrialized societies of about 15 grams per day. That’s as little as one-tenth of the intake among the world’s dwindling hunter-gatherer and rural agrarian populations, whose living conditions and dietary intake presumably most closely resemble those of our common human ancestors.

Perhaps the most significant sources of our intestinal bacterial populations is our immediate family, especially our mothers during childbirth and infancy. So, if our low-fiber diets are depleting our intestinal ecosystems, could that depletion get passed down from one generation to the next?

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Mental Health, Neuroscience, Research, Stanford News

Hyperactivity in brain’s “self-control” center may stifle the pleasure-seeking urge

Hyperactivity in brain's "self-control" center may stifle the pleasure-seeking urge

no fun signDiagnosing depression in a rodent is no mean feat. If you ask a rat how it’s feeling, it won’t tell you. But with a little ingenuity you can test that rat’s willingness to expend some energy in the quest for a pleasurable outcome.

And with the right technology, you can manipulate the rat’s so-called reward circuitry – a network of brain areas collectively responsible for enjoyment – and see what happens. That provides strong clues about how the reward circuitry works in us people, because rats’ reward circuitry looks and functions very much like ours.

Practiced wisely, the pursuit of happiness ennobled by Thomas Jefferson in the Declaration of Independence is a successful species-survival strategy. It gets us to do more of exactly the kinds of things that keep us alive and result in our having more offspring: food-seeking and ingestion, hunting and hoarding, selecting a mate and, last but not least, actually mating.

The reward circuitry includes nerve bundles that run from deep inside the brain to numerous spots including, for example, the nucleus accumbens (associated with pleasure) and the more recently evolved prefrontal cortex, an executive-control center that guides our planning and decision-making, focuses our attention and generally keeps us organized. It’s also the case that nerve bundles convey signals in the opposite direction, from the prefrontal cortex to various components of the reward circuitry.

The medial prefrontal cortex, with its portfolio of high-level “executive function” activities, plays its own obvious role in survival. After all, what if all we did was seek momentary pleasures, ignoring our top-down control center’s “hey, cool it!” or “skip dessert!” or “get back to work!” commands? (When the reward circuitry escapes from this kind of control, the result can be addictive behavior.)

But Stanford neuroscientist and Howard Hughes Medical Institute investigator Karl Deisseroth, MD, PhD, in a study conducted with help from numerous other Stanford researchers and recently published in Science, has shown in rats that hyperactivity in the medial prefrontal cortex reduces signaling between key components of the reward circuitry and impairs rats’ reward-seeking behavior. In humans, this dulling of the drive to pursue pleasure, known as anhedonia, is seen in a number of psychiatric conditions including, notably, depression.

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Aging, Chronic Disease, Neuroscience, Patient Care, Research, Stanford News, Stroke

Stanford study: Commonly used sleeping pill may boost stroke recovery

Stanford study: Commonly used sleeping pill may boost stroke recovery

sleeping pillIf what works in mice works in people, a widely popular sleeping pill could someday start seeing action as an aid to stroke recovery, according to a study carried out by Stanford neuroscientists Gary Steinberg, MD, PhD, and Tonya Bliss, PhD, and published in Brain.

Count to 40. Chances are that sometime between when you start and when you finish, someone in the United States will experience a stroke. That’s how common they are: about 800,000 strokes every year in the U.S., and – far from being confined to rich countries – around 35 million worldwide.

But that’s just the number of new strokes annually. Unfortunately, a stroke isn’t something you just get and then get over. Few people fully recover, leaving some 5.4 million Americans currently saddled with stroke-caused disabilities.

The main way for anyone incurring a stroke to minimize its damage is to get to a treatment center right away. As I wrote in a news release summarizing the study’s findings:

A stroke’s initial damage, which arises when the blood supply to part of the brain is blocked, occurs within the first several hours. Drugs and mechanical devices for clearing the blockage are available, but to be effective they must be initiated within several hours of the stroke’s onset. As a result, fewer than 10 percent of stroke patients benefit from them.

I repeat: Get to a treatment center right away. Don’t wait “to see if it blows over.” But since even in the best-case scenario many stroke sufferers will sustain some brain damage, the next best thing is a treatment that could help undo that damage – if only there were one.

Sad to say, no effective treatments during the recovery phase exist other than physical therapy, which has been shown to be only marginally successful. So anything that could enhance patients’ recovery during the  three- to six-month post-stroke period when 90 percent of whatever recovery a patient’s going to experience occurs, as a rule, would be a home run.

In their study, Steinberg, Bliss and their colleagues swung for the fences. They induced strokes in animal models, then waited for a few days to make sure that what they planned to do next, if it helped, was working during the recovery phase rather than the rush-rush damage-control phase.

Then they gave some of the mice the FDA-approved insomnia drug zolpidem (better known by the trade name Ambien) and others a control solution that did not contain the drug. Over the next month, they compared the mice’s performance on various tests of sensory and motor-coordination ability. By several measures, the zolpidem-treated mice were back at their pre-stroke levels within a few days of treatment; the control mice took the entire month. (Unlike humans, mice do eventually recover from strokes even when untreated.)

Mice are mice, and humans are humans. But Zolpidem’s already-on-the-market status greatly improves the prospects for clinical trials of the drug. And wouldn’t it be ironic if faculties slumbering under a stroke’s spell could be awakened by a pill designed to put us asleep?

Previously: Targeted brain stimulation of specific brain cells aids stroke recovery in mice, Calling all pharmacologists: Stroke-recovery mechanism found, small molecule needed and Brain sponge: Stroke treatment may extend time to prevent brain damage
Photo by Guian Bolisay

Applied Biotechnology, Ethics, Medicine and Society, Public Safety, Science Policy, Stanford News

Stanford experts slam government’s myopic biosecurity oversight

Stanford experts slam government's myopic biosecurity oversight

blindfoldedJust because we can, does that mean we should?

In a hard-hitting editorial in Science, three Stanford thinkers – Stanford microbe wizard David Relman, MD; synthetic biologist Megan Palmer, PhD, of Stanford’s Center for International Security and Cooperation; and political theorist Francis Fukuyama, PhD, of the Freeman Spogli Institute for International Studies – have issued a scathing wake-up call to the scientific community and the federal government, sternly questioning the latter’s current plans for ensuring biosafety and biosecurity in the United States.

“Our strategies and institutions for managing biological risk in emerging technologies have not matured much in the last 40 years,” they write, adding:

With the advent of recombinant-DNA technology, scientific leaders resorted to halting research when confronted with uncertainty and public alarm about the risks of their work. To determine a framework for managing risk, they gathered at the now-fabled 1975 Asilomar meeting. Their conclusions led to the recombinant DNA guidelines still used today, and Asilomar is often invoked as a successful model for scientific self-governance.

But, the authors suggest, Asilomar’s legacy may not be all it’s cracked up to be:

Asilomar created risky expectations: that leading biological scientists are best suited for and wholly capable of designing their own systems of governance and that emerging issues can be treated as primarily technical matters.

“Unfortunately,” the editorial goes on to say, “today’s leadership on biological risk reflects Asilomar’s risky legacy: prioritizing scientific and technical expertise over expertise in governance, risk management, and organizational behavior.” Political leaders have largely ceded a strategic leadership role, leaving it up to the scientific community itself to judge the ethical and social implications of its own work.

“Leadership biased toward those that conduct the work in question can promote a culture dismissive of outside criticism and embolden a culture of invincibility” regarding emerging biotechnology risks,” the authors write.

The world of today is not the world of 1975. Since then, the scope and scale of biological science and technology have changed radically. To wit: The increased ease of reading and writing genetic information means that securing materials in a handful of established labs is not feasible, the editorial states. Like it or not, the tools for putting potentially dangerous knowledge into practice are increasingly portable.

For a scary scenario of what such new facility portends, please see this article I wrote a couple of years ago, which begins with the rhetorical question: “What if nuclear bombs could reproduce?”

With so much at stake, we may not want to restrict oversight of scientific advances to those who are making the advances. There’s knowledge, and there’s wisdom.

Previously: How-to manual for making bioweapons found on captured Islamic State computer, Microbial mushroom cloud: How real is the threat of bioterrorism? (Very) and Stanford bioterrorism expert comments on new review of anthrax case
Photo by Mirko Tobias Schafer

Bioengineering, Imaging, Neuroscience, Research, Stanford News

Brain radio: Switching nerve circuit’s firing frequency radically alters alertness levels in animal models

Brain radio: Switching nerve circuit's firing frequency radically alters alertness levels in animal models

brain radioIt’s a kick to consider that a part of the brain could act like a radio, with different stations operating at different frequencies, playing different kinds of music and variously attracting or repelling different “listening audiences.” A new study by Stanford neuroscientist Jin Hyung Lee, PhD, and her colleagues has isolated a brain circuit linking just such a “transmission station” in the midbrain to various “listener” regions in the forebrain.

The findings have clear therapeutic potential. In a news release about the research, I wrote:

In a case study published in 2007, [researchers] demonstrated that electrically stimulating the central portion of the thalamus — a deep-brain relay station routing inputs from the senses to myriad cognitive-processing centers throughout the cerebral cortex — could restore consciousness in a patient who’d been in a minimally conscious state for six years.

“But there was no way to know how it worked,” Lee told me.

Now, in a set of experiments published in eLife, she and her associates have used precisely targeted stimulation and recording techniques to show that forcing a set of nerve cells in the central thalamus to fire at 40 or 100 times a minute induces a state of arousal: Rats that were fast asleep wake up and start roving around and exploring their environments. Switch the same nerve cells to a firing frequency of 10 times a minute, and the same rats immediately go into a state of deep unconsciousness more akin to a coma or a petit mal seizure (a transient state of behavioral arrest) than to restful sleep.

In addition to these behavioral effects, forcing those central-thalamic nerve cells to fire at different rates causes distinct structures elsewhere in the brain to rev up or slack off. In a sense, firing at 100 times a minute was like blasting heavy-metal music – some forebrain regions leapt into the mosh pit, some ran for cover – while 10 times a minute (the easy-listenin’ channel?) variously appealed to or turned off different brain areas.

You can’t do that with a drug.

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Aging, Evolution, Genetics, Research, Science, Stem Cells

The war within: In our aging bodies, the “fittest” stem cells may not be the ones that ensure our survival

The war within: In our aging bodies, the "fittest" stem cells may not be the ones that ensure our survival

ageAnti-aging research has been in the news lately: for instance, here, here and (less recently and less frivolously) here.

Albert Einstein College of Medicine researcher Nir Barzilai, MD, who’s spearheading the groundbreaking anti-aging trials referred to in these articles, is far from frivolous. I remember really liking a talk he gave at Stanford a few years ago about his ongoing study of super-old Ashkenazis, at a symposium sponsored by Stanford’s Glenn Laboratories for the Biology of Aging.

Now, Tom Rando, MD, PhD, the director of Glenn Labs at Stanford, has co-authored a thought-provoking review in Science that advances a theory of why we age.

It’s not the only theory. Judy Campisi of the Buck Institute for Research on Aging, for example, has explored the detrimental activities of differentiated cells gone wrong within our tissues. The older the tissue, the wronger the cells in it go.

Rando and his co-author, Baylor College of Medicine regenerative-medicine expert Margaret Goodell, PhD, come at aging from the opposite end of the spectrum: stem cells, the least-differentiated cells in the body. In particular, Rando and Goodell target the aging-associated actions of so-called somatic stem cells, which reside in virtually all (and, probably, actually all) of our tissues and whose fates are restricted to spawning only cell types that belong in those tissues. While we’re growing up, those somatic stem cells are the reason why: They divide to generate the differentiated cells that bulk us up. Once we’ve matured, they mostly hang back, springing into action to replace tissue lost to injury or to wear and tear.

Radiation, noxious foreign substances, and plain old existence wreaks sporadic damage on somatic stem cells by triggering genetic mutations or by altering the cells’ epigenetic settings, the patterns of chemical stop-and-go signs that variously switch the 20,000-odd genes in each cell’s genome on or off. These insults pile up as life’s pages turn. Eventually, Rando and Goodell write, a curious, Darwin-like natural selection occurs among our tissue-resident stem cells.

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