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Global Health, Infectious Disease, Microbiology, Research, Stanford News

If you gum up a malaria parasite’s protein-chewing machine, it can’t do the things it used to do

If you gum up a malaria parasite's protein-chewing machine, it can't do the things it used to do

chewing gum“Life in the tropics” evokes images of rain forests, palm trees, tamarinds and toucans. It also has a downside. To wit: One-third of the Earth’s population – 2.3 billion people – is at risk for infection with the mosquito-borne parasite that causes malaria.

Thankfully, mortality rates are dropping because of large-scale global intervention efforts. But malaria remains stubbornly prevalent in sub-Saharan Africa and Southeast Asia, where hundreds of millions of people become infected each year and more than 400,000 of them – mostly children younger than 5 – still die from it.

The parasite has the knack of evolving rapidly to develop resistance to each new generation of drugs used to fend it off. Lately, resistance to the current front-line antimalarial drug, artemisinin, is spreading and has now been spotted in a half-dozen Southeast Asian countries.

So it’s encouraging to learn that Stanford drug-development pioneer Matt Bogyo, PhD, and his colleagues have designed a new compound that can effectively kill artemisinin-resistant malaria parasites. Better, exposure to low doses of this substances re-sensitizes them to artemisinin.

By exploiting tiny structural differences between the parasitic and human versions of an intercellular protein-recycling machine called the proteasome, the compound Bogyo’s team has created attacks the malaria parasite while sparing human cells.

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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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Biomed Bites, Microbiology, Research, Videos

Unwelcome guests: How viruses take over cells

Unwelcome guests: How viruses take over cells

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

Viruses are the ultimate uninvited guests. They barge in and make themselves perfectly at home — feeling free to use, say, your waffle maker to whip up a nice breakfast and to co-opt your favorite easy chair for their own purposes.

In cells, many mysteries remain about how viruses take over enzymes and other systems in cells to reproduce.

That’s exactly what Peter Sarnow, PhD, professor and chair of microbiology and immunology, and his team investigate. From the video above:

My lab is interested in studying virus-host interactions. In particular, we’re interested in learning how viruses subvert functions from the host cell such as using the ribosomes to synthesize their own proteins.

He explains a recent discovery his team has worked on that may lead to better treatments for hepatitis C infections. “I’m very optimistic this will be beneficial and is a good example of how basic science really translates into translational medicine,” Sarnow says.

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

Previously: Why are viruses so wily? One research thinks she knows — and is working to thwart them, Ending enablers: Stanford researcher examines genes to find virus helpers and To screen or not to screen for hepatitis C

Biomed Bites, Infectious Disease, Microbiology, Research, Videos

Improving infection recovery

Improving infection recovery

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

Think back on the last time you came down with something. First you were sick, acutely ill. But then, days or hours later, you were no longer ill, but also not well, stuck in the grey zone of recovery.

That’s the stage of illness that most interests David Schneider, PhD, an associate professor of microbiology and immunology, and those in his lab. As Schneider explains in the video above:

It looks like recovery is a different sort of process than getting sick. So we’re trying to take this apart first by working with fruit flies, then by working with mice and eventually by working with people.

Our goal is to be able to take someone suffering from an infection and really help them improve their recovery.

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

Previously: Immune cell linked to surgery recovery time, Stanford scientists find, Stanford team develops a method to prevent the viral infection that causes dengue fever and Shrugging off bugs: there’s more to beating infections than just fighting them

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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Genetics, Immunology, Microbiology, Research, Science, Stanford News

Stanley Falkow awarded National Medal of Science, White House announces today

Stanley Falkow awarded National Medal of Science, White House announces today

Falkow picExciting news today: Stanley Falkow, PhD, has been awarded the 2015 National Medal of Science. The honor was announced today by the White House. Falkow is being recognized for his pioneering work in studying how bacteria can cause human disease and how antibiotic resistance is transmitted.

Dean Lloyd Minor, MD, commented in our release:

Dr. Falkow is deeply deserving of this award. He has made invaluable contributions to the field of microbiology and the effect of bacteria on human health. We at Stanford Medicine are extremely proud and honored that he has been recognized by his peers in this way.

Falkow, 81, is an emeritus professor of microbiology and immunology and a member of the Stanford Cancer Institute. The award will be presented in a ceremony at the White House in January 2016.

Falkow is well known for his work on extrachromosomal elements called plasmids and their role in antibiotic resistance and pathogenicity in humans and animals. As a graduate student in the 1960s, he discovered that bacteria gained their resistance to antibiotics by sharing their genes much more promiscuously then had been thought possible. When Falkow arrived at Stanford in 1981, he set aside his study of plasmids to concentrate on how organisms as diverse as cholera, plague and whooping cough cause disease in humans. Along the way he’s mentored countless students and spoken out about the growing threat of antibiotic resistance due to the routine use of antibiotic in animal feed.

As Falkow, who learned of the award on Dec. 19 in an email from John Holdren, PhD, the president’s chief science advisor, said in our announcement:

It was a total surprise. I always say, ‘In science, it’s not ‘I,’ it’s ‘we.’ And it’s so true. There are hundreds of students and colleagues around the world with whom I’d like to share this honor.

I had the honor of writing about Falkow’s work in 2008, when he was awarded the Lasker-Koshland Award for Special Achievement in Medical Science. I thoroughly enjoyed my conversation with him and I’m so happy for today’s announcement.

Previously: National Medal of Science winner Lucy Shapiro: “It’s the most exciting thing in the world to be a scientist”Stanford’s Lucy Shapiro receives National Medal of Science and FDA changes regulation for antibiotic use in animals
Photo by Krista Conger

Genetics, Microbiology, Technology

The art of exploring the fecal-ome

The art of exploring the fecal-ome

Monet Cathédrale_de_Rouen.blue Monet La_Cathédrale_de_Rouen.yellowThe community of bacteria living inside our own guts is about as local an ecosystem as we’re likely to find. So you’d think navel-gazing biologists would already know all about it. But several barriers have made this ecosystem nearly as inaccessible as the forests of the Amazon River were for 18th century naturalists.

One problem has been that bacteria have traditionally been studied by growing them in glass or plastic dishes containing a “culture medium,” typically a sort of gelatin concoction containing mystery ingredients like calf serum. Lots of bacteria grow well on this stuff, but even more don’t. And most of what we know about bacteria comes from studies of the short of list bacteria that will grow in the lab.

Advances in genomics have revealed the presence of new species of bacteria everywhere biologists have looked. But, apparently, even that diversity is just the tip of the iceberg.

Computer scientists and geneticists at Stanford recently collaborated on a technique and uncovered an amazing amount of diversity in the gut contents of a human male, who volunteered a fecal sample. In the sample, the Stanford team found not just lots of species, but also lots of sub-strains — as many as five different strains of a single species. You can read more about the technique in the press release I wrote about the study, which appeared today in Nature Biotechnology.

The work’s similarity to an incredibly tough jigsaw puzzle captured my imagination.

Geneticist Michael Snyder, PhD, who is a senior author on the paper, explained to me that it’s now pretty easy to assemble the genome of a single person or bacterium from the short strands of DNA in a sample.

But when you have a mix of lots of different species, he said, it’s like assembling 100 jigsaw puzzles from a single pile of pieces from all those different jigsaw puzzles. Not only do you have to fit the pieces together, but you have to know which puzzle or species each piece came from.

If the jigsaw puzzles are as different as, say, a Van Gogh Sunflowers painting and Ansel Adams’ “Moonrise, Hernandez, New Mexico”, you wouldn’t have much trouble separating the pieces. But what if you’ve got several strains of the same bacterial species? That’s the equivalent of a mix of puzzles all depicting different versions of Monet’s paintings of Cathedral Rouen.

Previously: Microbiome explorations stoke researcher’s passionAt TEDMED 2015: How microbiome studies could improve the future of humanityInvestigating the human microbiome: “We’re only just beginning and there is so much more to explore
Monet image courtesy of KnightSerbia

Immunology, Microbiology, Research, Stanford News

Microbiome explorations stoke researcher’s passion

Microbiome explorations stoke researcher's passion

Dr. Ami Bhatt, MD., PhD, Department of Medicine and Department of Genetics at her lab at Stanford University , on Thursday, September 24, 2015.

Start talking with physician-scientist Ami Bhatt, MD, PhD, about the microbiome — the vast community of bacteria, fungi, and life that live on the body — and she’ll discuss the potential of these dynamic microscopic ecosystems with such contagious enthusiasm and clarity that you’ll find yourself nodding alongside her, agreeing with her every point.

Bhatt is intensely curious, a trait she’s had since childhood, and deeply committed to the idea of using science to help others. These dual instincts initially led her to medicine, where she found her calling as a physician-scientist.

I feel like I am one of those lucky few who get to do exactly what they want to do.

Today Bhatt runs her own laboratory at Stanford, where she studies how shifts in the microbiome affect human disease and patient outcomes.

“The fundamental thesis that drives our research,” Bhatt explained in a recently published piece on the Department of Medicine website, “is that patient outcomes are manipulated or modified by the alterations in their microbiota, and that we can discover these microbes using sequence-based technologies.”

Another of Bhatt’s initiatives aims to unravel a particularly interesting—and timely—question: What molecular changes occur during a fecal microbiota transfer? To answer this, Bhatt and her colleagues have developed a computational pipeline that will provide a time-based characterization of what actually happens during a transfer.

While her research goals are ambitious and varied, the source of Bhatt’s passion remains the same. “I’m still committed to the idea of being able to help people using science,” she said. “I feel like I am one of those lucky few who get to do exactly what they want to do.”

Previously: At TEDMED 2015: How microbiome studies could improve the future of humanity, Investigating the human microbiome: “We’re only just beginning and there is so much more to explore” and Tiny hitchhikers, big health impact: Studying the microbiome to learn about disease
Photo by Norbert von der Groeben

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

Excessive antibiotic use in flu season contributes to resistance

Excessive antibiotic use in flu season contributes to resistance

addiction-71573_1280The cold and flu season is upon us — and with that comes the potential overuse of antibiotics. All too often, physicians prescribe antibiotics for viral infections, which typically is ineffectual and can even be dangerous for elderly Medicare patients.

An estimated 2 million Americans are infected with drug-resistant organisms each year, resulting in 23,000 deaths and more than $20 billion in excess costs, according to the Centers for Disease Control and Prevention.

Excessive antibiotic use in cold and flu season is not only costly, but it also contributes to antibiotic resistance, writes Marcella Alsan, MD, PhD, and her co-authors in a study published in the December edition of Medical Care. The study’s objective was to develop an index of excessive antibiotic use in cold and flu season and determine its correlation with other indicators of clinically appropriate or inappropriate prescribing.

Alsan, a core faculty member at Stanford Health Policy, and senior author, Dartmouth economist Jonathan Skinner, PhD, concluded that flu-related antibiotic use was correlated with prescribing high-risk medications to the elderly.

“These findings suggest that excessive antibiotic use reflects low-quality prescribing,” the authors wrote. “They imply that practice and policy solutions should go beyond narrow, antibiotic specific, approaches to encourage evidence-based prescribing for the elderly Medicare population.”

To better understand patterns of antibiotic overuse and whether such patterns reflect prescribing quality, the authors developed a measure that isolates antibiotic prescribing in response to state-by-state influenza activity. They focused on the elderly, as national data on antibiotic use are readily available and because the interactions between multiple prescriptions are particularly important for this population.

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Chronic Disease, Infectious Disease, Microbiology, Research, Science, Stanford News

Bad actors: Viruses, pathogenic bacteria co-star in health-horrific biofilms

Bad actors: Viruses, pathogenic bacteria co-star in health-horrific biofilms

biofilmA group under the direction of Stanford infectious disease investigator Paul Bollyky, MD, PhD, has uncovered a criminal conspiracy between two microbial lowlifes that explains how some of medicine’s most recalcitrant bacterial infections resist being expunged.

In a study published today in Cell Host & Microbe, Bollyky and his associates reveal that bacterial pathogens responsible for a big chunk of chronic infections can team up with a type of virus that bacteria ordinarily consider their worst enemies to form biofilms, which, our news release on the study explains, are “slimy, antiobiotic-defying aggregates of bacteria and organic substances that stick to walls and inner linings of infected organs and to chronic wounds, making infections excruciatingly hard to eradicate.” More from that release:

Biofilms factor into 75 to 80 percent of hospital-acquired infections, such as those of the urinary tract, heart valves and knee-replacement prostheses, Bollyky said. “A familiar example of a biofilm is the plaque that forms on our teeth,” he said. “You can brush twice a day, but once that plaque’s in place you’re never going to get rid of it.”

The study first focused on Pseudamonas aeruginosa, which accounts for one in ten hospital-acquired infections, many chronic pneumonia cases and much of the air-passage obstruction afflicting cystic-fibrosis patients.

Cystic fibrosis is deadly mainly because of biofilms formed by P. aeruginosa, Bollyky told me. “These biofilms fill up all the air spaces, and antibiotics can’t seem to penetrate them,” he said.

But he and his colleagues found that P. aeruginosa forms biofilms only when it’s been infected itself.

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