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Microbiology, Research, Science, Stanford News

Tiny balloon-like vesicles carry cellular chatter with remarkable specificity, say Stanford researchers

Tiny balloon-like vesicles carry cellular chatter with remarkable specificity, say Stanford researchers

6292985963_bbc06df590_z“BRUSH YOUR TEETH,” I bellowed up the stairs last night at my (seemingly deaf and clueless) children for what seemed like the one-millionth time since their birth. “Surely there has to be a better way,” I pondered, as I trudged up the stairs to deliver my threatening message in person.

The cells in our bodies don’t have the option to, however reluctantly, leave their metaphorical couch and wag their fingers under the noses of their intended recipients. And yet, without a fail-safe method of communication among distant participants, the orderly workings of our bodies would screech to a halt.

Now biologists Masamitsu Kanada, PhD, and Christopher Contag, PhD, have published in the Proceedings of the National Academy of Sciences an interesting and revealing glimpse into one tool cells can use to do the job: tiny balloon-like vesicles capable of delivering a payload of protein or genetic information from one cell to another. As Contag and Kanada explained to me in an email:

Extracellular vesicles are nanosized little containers of information that are produced by most, if not all, cells in the bodies of plants, animals and humans. From many studies it is apparent that adding vesicles from one cell type to another can affect the behavior of the recipient cells, both in a culture dish and in the living body, even across species from plants to animals and presumably humans.

We wanted to assess, under controlled sets of conditions, which biomolecules within vesicles transfer the most information most efficiently. We learned that the process is complex, and that a biomolecule in one type of vesicle is transferred in a way that affects other cells, but the same molecule in another type of vesicle may not affect cell function.

In other words, Contag, who co-directs Stanford’s Molecular Imaging Program, and his colleagues found that not all these vesicles are created equal. Some, whose outer layer was derived from the cell’s external plasma membrane (these are known as micro-vesicles), handily delivered both protein and DNA to recipient cells. Others, with outer layers derived from internal membranes in the cell (known as exosomes), were less capable and didn’t deliver any functional DNA. Interestingly, neither kind was able to deliver RNA, which was instead swiftly degraded.

The distinction between vesicle type and function is important as researchers increasingly rely on them to eavesdrop on cellular conversations or even to deliver particular biomolecules to be used for therapy or imaging. Understanding more about how they work will allow researchers to both better pick the right type for the job at hand and to learn more about how cells talk with one another. As Contag and Kanada said:

How cells communicate across distances is relevant to mobilization of immune cells to attack pathogens, depression of immune responses by tumor cells, signaling of cancer cells to metastasize, modulation of physiological processes in intestinal cells in response to plant-derived diets and to many other biological process. Understanding this form of cell-to-cell communication will bring us closer to controlling how cells talk to one another inside the body.

Now if only I could find the right kind of vesicle to communicate with my recalcitrant children. Perhaps a helium-filled balloon with a pointed message inside could float up the stairs and pop next to their ears? On second thought, that might not be the best choice.

Previously: Researchers develop imaging technologies to detect cancer earlier, faster
Photo by Matthew Faltz

Biomed Bites, Microbiology, Research, Science, Videos

By investigating cells, researchers can “stumble” on the next big thing in medicine

By investigating cells, researchers can "stumble" on the next big thing in medicine

Welcome to the latest edition of Biomed Bites, a weekly feature that introduces readers to some of Stanford’s most innovative researchers.

Tobias Meyer, PhD, was hooked on biology when he learned humans are made out of cells — 10 trillion distinct little entities, joining together to make a human. (“The way to remember this number is that it is approximately the same as the number of dollars in the American debt,” Meyer suggests in the video above.) He goes on to say:

What fascinated me is that each of these individual cells is really something like a small computer that senses the environment — for example hormones it senses but also pathogens like bacteria or even stress.

Then it processes that information, which makes it do things like secrete, divide, or move. So my lab is particularly interested in this question of how cells integrate all these important signals.

Now chair of the Department of Chemical and Systems Biology at Stanford, Meyer and his team try to decipher how the cells that make up the human body work together:

For example, we recently found a receptor that senses calcium in cells that has not been found before. We were able to show this is important in many different systems like immunology and now many drugs companies are using it to develop drugs they didn’t have before.

For Meyer, the takeaway from his experience in biomedical research is clear: “By doing fundamental research, we often stumble accidentally on a big thing that can have a big impact later in human health.”

Learn more about Stanford Medicine’s Biomedical Innovation Initiative and about other faculty leaders who are driving biomedical innovation here.

Cancer, Evolution, Genetics, Infectious Disease, Microbiology, Research, Stanford News

Bubble, bubble, toil and trouble – yeast dynasties give up their secrets

Bubble, bubble, toil and trouble - yeast dynasties give up their secrets

yeasty brew

Apologies to Shakespeare for the misquote (I’ve just learned to my surprise that it’s actually “Double, double, toil and trouble“), but it’s a too-perfect lead-in to geneticist Gavin Sherlock’s recent study on yeast population dynamics for me to be bothered by facts.

Sherlock, PhD, and his colleagues devised a way to label and track the fate of individual yeast cells and their progeny in a population using heritable DNA “barcodes” inserted into their genomes. In this way, they could track the rise and fall of dynasties as the yeast battled for ever more scarce resources (in this case, the sugar glucose), much like what happens in the gentle bubbling of a sourdough starter or a new batch of beer.

Their research was published today in Nature.

From our release:

Dividing yeast naturally accumulate mutations as they repeatedly copy their DNA. Some of these mutations may allow cells to gobble up the sugar in the broth more quickly than others, or perhaps give them an extra push to squeeze in just one more cell division than their competitors.

Sherlock and his colleagues found that about one percent of all randomly acquired mutations conferred a fitness benefit that allowed the progeny of one cell to increase in numbers more rapidly than their peers. They also learned that the growth of the population is driven at first by many mutations of modest benefit. Later generations see the rise of the big guns – a few mutations that give carriers a substantial advantage.

This type of clonal evolution mirrors how a bacterium or virus spreads through the human body, or how a cancer cell develops mutations that allow it to evade treatment. It is also somewhat similar to a problem that kept some snooty 19th century English scientists up at night, worried that aristocratic surnames would die out because rich and socially successful families were having fewer children than the working poor. As a result, these scientists developed what’s known as the “science of branching theory.” They described the research in a paper in 1875 called “On the probability of extinction of families,” and Sherlock and his colleagues used some of the mathematical principles described in the paper to conduct their analysis.

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Events, Immunology, Infectious Disease, Microbiology, Public Health

A look at our disappearing microbes

A look at our disappearing microbes

8146322408_5312e9deb2_zCould obesity, asthma, allergies, diabetes, and certain forms of cancer all share a common epidemiological origin? NYU microbiologist Martin Blaser, MD, thinks so – he calls these “modern plagues” and traces them to a diminished microbial presence in our bodies, caused by the overuse of antibiotics and the increased incidence of caesarian sections.

I attended a recent public lecture sponsored by UC Santa Cruz’s Microbiology and Environmental Toxicology department, during which the charismatic Blaser cited statistics about antibiotic use in childhood. Alarmingly, American children receive on average seventeen courses of antibiotics before they are twenty years old, taking a progressively bigger toll on their internal microbial ecosystems. We also have an unprecedented rate of c-sections – at nearly 33 percent. Babies delivered this way are deprived of contact with their mothers’ vaginal microbes, which in vaginal deliveries initiates the infant’s intestinal, respiratory, and skin flora. Breastfeeding has implications for beneficial bacterial transfer, too.

It’s not news that antibiotics are being overused – Stanford Medicine hosts an Antimicrobial Stewardship Program dedicated to this cause, and the CDC has been hosting a campaign for awareness about appropriate antibiotic use for several years, including their use in farm animals. (Seventy to eighty percent of antibiotic use takes place on farms to promote growth – that is, not for veterinary reasons.)

Overuse leads to antibiotic resistance, a serious problem. Meanwhile, research by Blaser and others – notably Stanford microbiologist David Relman, MD – has shown that abundant bacterial and viral life is essential to healthy bodies, and that imbalances in the microbial ecosystems that inhabit our gut play an important role in the chronic diseases of the modern age. Blaser said he is concerned that we’re going down a path where each generation has fewer and fewer species of microbes; part of his research is to compare human gut biodiversity in different parts of the globe, and people in remote areas of New Guinea have far more variety than those in Western nations.

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Applied Biotechnology, Bioengineering, Global Health, Microbiology, Stanford News

Foldscope beta testers share the wonders of the microcosmos

Foldscope beta testers share the wonders of the microcosmos

Foldscopes-TanzaniaChristmas came early for citizen-scientists who received the first batch of Foldscope build-your-own paper microscope kits from Stanford’s Prakash Lab over the last several months. These beta testers have begun sharing a variety of fascinating images, videos, tips and ideas on the Foldscope Explore website.

From this site, you can watch Foldscope videos of fluid pulsing through the brain of a live ant or the suction mechanism of a fly foot. One citizen scientist analyzes the structural differences between his brown and gray hair follicles. Another provides a tutorial on FBI bird-feather forensics. (Germophobes might want to skip the close-ups of a face mite or the fungus that grows in half-eaten yogurt cartons.)

Half the fun of receiving a Foldscope kit is the unboxing and building process, which has been captured in YouTube videos by Foldscope fans Christopher and Eric.


lens-mounterEach kit includes parts for building two microscopes, multiple lenses, magnets that attach a Foldscope to a smartphone camera lens, slide mounts, and a battery-powered light module. This allows users to view magnified images with the naked eye or projected on a wall. Photos or videos of Foldscope images can easily be captured and shared via smartphones.

For those of you who haven’t received your Foldscopes yet, rest assured that those who signed up on the beta test site will receive them soon. It’s taking longer than anticipated to build and ship 50,000 microscopes. (The gadget on the right was custom-designed to insert the tiny spherical ball lenses into the magnetic smartphone-mounting platform.)

For Foldscope updates, sharing and inspirations, bookmark Foldscope Explore.

Previously: Stanford bioengineer develops a 50-cent paper microscopeStanford microscope inventor invited to first White House Maker Faire, The pied piper of cool science tools and Free DIY microscope kits to citizen scientists with inspiring project ideas
Photo of Foldscope co-inventor Jim Cybulski and Tanzanian children building foldscopes by Manu Prakash; photo of lens mounting gadget by Kris Newby

Global Health, Infectious Disease, Microbiology, Public Health, Videos

'Tis the season for norovirus

'Tis the season for norovirus

The week before Thanksgiving, some kind of stomach bug, which I suspect was norovirus, spread like wildfire among my daughter’s daycare. Several of her classmates became sick and like dominos so did the parents, including us.

So I was more than sympathetic when I came across this video by John Green (of the vlogbrothers fame and author of “The Fault in Our Stars”) about his family’s Thanksgiving troubles with a norovirus infection that seems to have left no GI system untouched in their household.

Winter, from about November to April, is prime norovirus season. The treacherous illness, which as Green says “has amazing superpowers,” spreads when you come into contact with feces or vomit of an infected person. It can take less than a pinhead of virus particles to make this happen. Unlike other viruses, it can live on surfaces for surprising long periods, which is how a reusable grocery bag caused an outbreak among a girls soccer team in 2012. Plus, an infected person can continue to shed the virus for about three or four days after recovering. It’s possible to disinfect after an infection, but it’s a pretty intense job.

Given these characteristics it’s not surprising that this tiny virus (even by virus standards) causes about 20 million illnesses each year. Although for most people it’s a mild illness, for the very young,  old or those with compromised immune systems—it can be severe. About 56,000-71,000 people are hospitalized and 570-800 die from norovirus infections.

The situation is worse in developing countries, where, as Green points out, rehydration therapy is harder to come by for the most vulnerable. About 200,000 deaths are caused by norovirus infections in poor parts of the world.

In his typical funny and thoughtful style, Green talks about what lack of simple—and cheap—rehydration therapy means for many on our planet. It’s one more thing that it’s easy to take for granted, and one more thing to be thankful for.

Previously: Stanford pediatrician and others urge people to shun raw milk and products and Science weighs in on food safety and the three-second rule

Global Health, In the News, Infectious Disease, Microbiology, Public Health

Exploiting insect microbiomes to curb malaria and dengue

Original Title: Aa_FC2_23a.jpgEvery year, more than 200 million people are affected by malaria and 50 to 100 million new dengue infections occur. Now, a group of scientists from Johns Hopkins University may have found a novel way of curbing both diseases: by “vaccinating” mosquitos against the parasite that causes malaria and the virus that causes dengue. The researchers are using the bacteria Chromobacterium, which prevents the pathogens from effectively invading and colonizing mosquito guts.

As Science magazine reported last week:

Like humans and most other animals, mosquitoes are stuffed with microbes that live on and inside of them—their microbiome. When studying the microbes that make mosquitoes their home, researchers came across one called Chromobacterium sp. (Csp_P). They already knew that Csp_P’s close relatives were capable of producing powerful antibiotics, and they wondered if Csp_P might share the same talent.

In another experiment, done with mosquitoes that weren’t pretreated with antibiotics, Csp_P-fed mosquitoes were given blood containing the dengue virus and Plasmodium falciparum, a single-celled parasite that causes the most deadly type of malaria. Although a large number of the mosquitoes died within a few days of being infected by the Chromobacteriumthe malaria and dengue pathogens were far less successful at infecting the mosquitoes that did survive, the team reports today in PLOS Pathogens. That’s good news: If the mosquito isn’t infected by the disease-causing germs, it is less likely to be able to transmit the pathogens to humans.

The bacteria also inhibited growth of Plasmodium and dengue in lab cultures, indicating that Csp_P is producing compounds that are toxic to both pests. One possible application of these toxins is to develop treatment drugs for people already infected with malaria or dengue. Real-world applications of this research are many years in the future, but it hints at a whole new way of dealing with otherwise intractable diseases.

Previously: Close encounters: How we’re rubbing up against pathogen-packing pestsClosing the net on malaria and Fighting fire with fire? Using bacteria to inhibit the spread of dengue
Photo by Sanofi Pasteur

Immunology, Infectious Disease, Microbiology, Public Health, Research, Stanford News

Paradox: Antibiotics may increase contagion among Salmonella-infected animals

Paradox: Antibiotics may increase contagion among Salmonella-infected animals

cattleMake no mistake: Antibiotics have worked wonders, increasing human life expectancy as have few other public-health measures (let’s hear it for vaccines, folks). But about 80 percent of all antibiotics used in the United States are given to livestock – chiefly chickens, pigs, and cattle – at low doses, which boosts the animals’ growth rates. A long-raging debate in the public square concerns the possibility that this widespread practice fosters the emergence of antibiotic-resistant bugs.

But a new study led by Stanford bacteriologist Denise Monack, PhD, and just published in Proceedings of the National Academy of Sciences, adds a brand new wrinkle to concerns about the broad administration of antibiotics: the possibility that doing so may, at least  sometimes, actually encourage the spread of disease.

Take salmonella, for example. One strain of this bacterial pathogen, S. typhimurium, is responsible for an estimated 1 million cases of food poisoning, 19,000 hospitalizations and nearly 400 deaths annually in the United States. Upon invading the gut, S. typhimurium produces a potent inflammation-inducing endotoxin known as LPS.

Like its sister strain S. typhi (which  causes close to 200,00o typhoid-fever deaths worldwide per year), S. typhimurium doesn’t mete out its menace equally. While most get very sick, it is the symptom-free few who, by virtue of shedding much higher levels of disease-causing bacteria in their feces, account for the great majority of transmission. (One asymptomatic carrier was the infamous Typhoid Mary, a domestic cook who, early in the 20th century, cheerfully if unknowingly spread her typhoid infection to about 50 others before being forcibly, and tragically, quarantined for much of the rest of her life.)

You might think giving antibiotics to livestock, whence many of our S. typhi-induced food-poisoning outbreaks derive, would kill off the bad bug and stop its spread from farm animals to those of us (including me) who eat them. But maybe not.

From our release on the study:

When the scientists gave oral antibiotics to mice infected with Salmonella typhimurium, a bacterial cause of food poisoning, a small minority — so called “superspreaders” that had been shedding high numbers of salmonella in their feces for weeks — remained healthy; they were unaffected by either the disease or the antibiotic. The rest of the mice got sicker instead of better and, oddly, started shedding like superspreaders. The findings … pose ominous questions about the widespread, routine use of sub-therapeutic doses of antibiotics in livestock.

So, the superspreaders kept on spreading without missing a step, and the others became walking-dead pseudosuperspreaders. A lose-lose scenario all the way around.

“If this holds true for livestock as well – and I think it will – it would have obvious public health implications,” Monack told me. “We need to think about the possibility that we’re not only selecting for antibiotic-resistant microbes, but also impairing the health of our livestock and increasing the spread of contagious pathogens among them and us.”

Previously: Did microbes mess with Typhoid Mary’s macrophages?, Joyride: Brief post-antibiotic sugar spike gives pathogens a lift and What if gut-bacteria communities “remember” past antibiotic exposures?
Photo by Jean-Pierre

In the News, Microbiology, Public Health, Research

The end of antibiotics? Researchers warn of critical shortages

The end of antibiotics? Researchers warn of critical shortages

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Bacteria spark infection. Antibiotic kills most bacteria. Remaining bacteria evolve resistance. Second antibiotic wipes out all bacteria. Repeat. Repeat until, that is, there are no effective antibiotics, a scenario that looks increasingly likely, according to recent research from the Center for Molecular Discovery at Yale University led by Michael Kinch, PhD. Kinch now leads the Center for Research Innovation in Business at Washington University in St. Louis, which featured his work in a recent article:

The number of antibiotics available for clinical use, Kinch said, has declined to 96 from a peak of 113 in 2000. The rate of withdrawals is double the rate of new introductions, Kinch said. Antibiotics are being withdrawn because they don’t work anymore, because they’re too toxic, or because they’ve been replaced by new versions of the same drug. Introductions are declining because pharmaceutical companies are leaving the business of antibiotic use discovery and development.

Many of the major players like Pfizer, Eli Lilly, AstraZeneca and Bristol-Myers Squibb are no longer developing antibiotics, Kinch wrote in a recent article in Drug Discovery Today. In part, their disinterest is driven by a tight profit window. The drug approval process takes about 11 years, but a patent only provides 20 years of protection, leaving just nine years to recoup development costs, according to Kinch.

As outlined in the Washington University piece, at least two major initiatives are working to reverse this trend. The Infectious Diseases Society of America introduced the 10 x ’20 Initiative to spur efforts to create 10 new antibiotics by 2010. And Britain is sponsoring the Longitude Prize 2014, a £10 million award for a simple test that will quickly determine the type of bacteria causing an infection and therefore the most effective antibiotic.

Previously: Healthy gut bacteria help chicken producers avoid antibiotics, Free online course aims to education about “pressing public health threat” of antibiotic resistance and Side effects of long-term antibiotic use linked to oxidative stress
Photo by CDC Public Health Image Library

Immunology, Microbiology, Public Health, Research

Gut bacteria may influence effectiveness of flu vaccine

Gut bacteria may influence effectiveness of flu vaccine

flu_shotPast research has shown that the microbes living in your gut can dictate how body fat is stored, hormone response and glucose levels in the blood, which can ultimate set the stage for obesity and diabetes. Now new research suggests that the colonies of bacteria in our intestine play an important role in your body’s response to the flu vaccine.

In the study, Emory University immunologist Bali Pulendran, PhD, and colleagues followed up on a unexpected finding in a 2011 paper: the gene that codes for a protein called toll-like receptor 5 (TLR5) was associated with strong vaccine response. Science News reports that in the latest experiment:

[Researchers] gave the flu vaccine to three different groups: mice genetically engineered to lack the gene for TLR5, germ-free mice with no microorganisms in their bodies, and mice that had spent 4 weeks drinking water laced with antibiotics to obliterate most of their microbiome.

Seven days after vaccination, all three groups showed significantly reduced concentrations of vaccine-specific antibodies in their blood—up to an eightfold reduction compared with vaccinated control mice, the group reports online … in Immunity. The reduction was less marked by day 28, as blood antibody levels appeared to rebound. But when the researchers observed the mice lacking Tlr5 on the 85th day after vaccination, their antibodies seemed to have dipped again, suggesting that without this bacterial signaling, the effects of the flu vaccine wane more quickly.

Previously: The earlier the better: Study makes vaccination recommendations for next flu pandemic, Working to create a universal flu vaccine and Tiny hitchhikers, big health impact: Studying the microbiome to learn about disease
Photo by Queen’s University

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