Published by
Stanford Medicine



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.

Continue Reading »

Evolution, Infectious Disease, Microbiology, Pediatrics, Pregnancy, Research, Stanford News

Mastermind or freeloader? Viral proteins in early human embryos leave researchers puzzled

Mastermind or freeloader? Viral proteins in early human embryos leave researchers puzzled

and_virus_makes_four_fullI’m filing this finding firmly under the category of “Things I’m glad I didn’t know when I was pregnant.” (Other items include the abject terror of letting your teen get behind the steering wheel of a car for the first time, and the jaw-dropping number of zeros that can appear in a college financial aid package.) Recently, Stanford researchers found that the earliest stages of human development – those that occur within days of fertilization – may take place in a stew of viral proteins that lie in wait tucked inside the human genome. What do the viral proteins do? Who knows! Why are they popping up when we’re (arguably) at our most vulnerable? No idea!

Ugh. Like there’s not enough to worry about while growing another human inside your body.

I’m not being entirely fair here. Developmental biologist Joanna Wysocka, PhD, and graduate student Edward Grow, were some of the first researchers to show that ancient viral DNA sequences abandoned in our genome after long-ago infections can and do make viral proteins early in human development. I wrote about their finding on this blog earlier this year.

My article in the most recent issue of Stanford Medicine magazine expands on this story, describing how they made their finding and their future plans to learn more about our viral co-pilots. As I explain:

The finding raises questions as to who, or what, is really pulling the strings during human embryogenesis. Grow and Wysocka have found that these viral proteins are well-placed to manipulate some of the earliest steps in our development by affecting gene expression and even possibly protecting the embryo’s cells from further viral infection.

I’m often struck by how much parenting is like research. It’s a (seemingly) never-ending, but very rewarding, job. And for both, there’s clearly always lots to learn. As I write:

So, who’s in charge here? Us or the viruses? Or is there no longer any distinction? There’s certainly been plenty of evidence showing that humans are far from free operators when it comes to, well, pretty much anything. Our bodies are teeming masses of bacteria, viruses and even fungi that are collectively known as the microbiome. Many of these microorganisms, which are 10 times more numerous than our own cells, are essential to a healthy life, such as the gut bacteria that help us digest our food.

“What we’re learning now is that our ‘junk DNA,’ including some viral genes, is recycled for development in the first few days and weeks of life,” says [study co-author and former Stanford stem cell researcher Renee Reijo-Pera], who is now on the faculty of Montana State University. “The question is, what is it doing there?”

Previously: Stanford Medicine magazine tells why a healthy childhood mattersMy baby, my…virus? Stanford researchers find viral proteins in human embryonic cells and Species-specific differences among placentas due to long-ago viral infection, say Stanford researchers
Photo of Joanna Wysocka by Misha Gravenor

Dermatology, Genetics, Infectious Disease, Microbiology, Research, Stanford News

Inside job: Staphyloccus aureus gets critical assist from host-cell protein accomplice

Inside job: Staphyloccus aureus gets critical assist from host-cell protein accomplice

bank heistStaphylococcus aureus is a bacterium that colonizes the skin (and, often, the noses) of about one in three people, mostly just hanging out without causing symptoms. But when it breaches the skin barrier, it becomes a formidable pathogen.

S. aureus not only accounts for the majority of skin and soft-tissue infections in the U.S. and Europe, but can spread to deeper tissues leading to dangerous invasive infections in virtually every organ including the lungs, heart valves, and bones. These complications cause an estimated 11,000 deaths in the U.S. annually.

Making matters worse, antibiotic-resistant strains of S. aureus are becoming increasingly prevalent and even more difficult and costly to treat. All of which makes it crucial to understand the factors that control the bug’s virulence: What turns a common colonizer into a pathogen?

The answers that typically spring to mind involve molecules the pathogen produces that enable damage to cells of the host organism. Certainly S. aureus is no slouch in that arena. Prominent among the many virulence factors it produces, one called α-toxin aggregates on host cell surfaces to form pores that injure the cells’ outer membranes, often killing the cells.

But it turns out that forming pores appears not to be enough, by itself, for lethal host-cell injury. In a study published in Proceedings of the National Academy of Sciences, a team directed by Stanford microbe sleuths Manuel Amieva, MD, PhD, and Jan Carette, PhD, identified several hitherto-unsuspected molecules produced within host cells themselves that determine whether the cells live or die after α-toxin-induced pore formation.

Continue Reading »

Imaging, In the News, Microbiology, Stanford News

Stanford image takes big honors at 2015 Nikon Small World Photomicrography Competition

Stanford image takes big honors at 2015 Nikon Small World Photomicrography Competition


Small things seldom get big press, but once a year the microscopic world takes front and center stage at Nikon’s annual Small World Photomicrography Competition. This year, a Stanford Medicine team took second place in the competition, edging out more than 2,000 entries from 83 countries around the world.

Their award-winning photo is a cacophony of color that uses immunofluorescence to illuminate a mouse colon colonized with human microbiota.

Four Stanford researchers were responsible for this mosaic of microbes: photographer Kristen Earle, PhD; second-year graduate student Gabriel Billings; KC Huang, PhD, a bioengineer and microbiologist; and Justin Sonnenburg, PhD, a microbiologist and co-author of The Good Gut.

Earle told me she took this image while working on a study with Sonnenburg that explores how images, like this one, can help researchers count microbes and see how they’re organized in a cross-section of gut.

Previously: Why C. difficile-defanging mouse cure may work in people, tooDrugs for bugs: Industry seeks small molecules to target, tweak and tune up our gut microbes and Civilization and its dietary (dis)contents: Do modern diets starve our gut-microbial community?
Image courtesy of Kristen Earle, Gabriel Billings, KC Huang and Justin Sonnenburg

Infectious Disease, Microbiology, Research, Stanford News

Why C. difficile-defanging mouse cure may work in people, too

Why C. difficile-defanging mouse cure may work in people, too

CdiffI wrote a news release last week about a study just published in Science Translational Medicine. The study, despite it having been conducted in mice, not humans, received a fair amount of coverage – by The Washington Post, Yahoo!, Fox News, NBC, CBS and Reuters, among other places – and deserved the attention it got. It demonstrated the efficacy of a small-molecule drug that can disable the nasty intestinal pathogen C. difficile without killing it – and, importantly, without decimating the “good” bacteria that populate our gut by the trillions.

That’s a big deal. If you want to see a lot of ugly weeds pop up, there’s no better way to go about it than letting your lawn go to hell.

C. difficile – responsible for more than 250,000 hospitalizations and 15,000 deaths per year in the United States and a $4 billion annual health-care tab in the U.S. alone – is typically treated by antibiotics, which have the unfortunate side effect of wiping out much of our intestinal microbe population. That loss of carpeting, ironically, lays the groundwork for a dangerous and all-too-common comeback of C. difficile infection.

A question worth asking about this study, conducted by what-makes-pathogens-tick expert Matt Bogyo, PhD, and a team of Stanford associates: Why should we think that what works in mice is going to work in people?

The only sure answer isn’t a torrent of language but a clinical trial of the drug, ebselen, in real, live people with C. difficile infections or at risk for them. (Bogyo has already started accumulating funding to initiate a trial along those lines.)

But there’s also reassurance to be drawn from the fact that ebselen isn’t an entirely exotic newcomer to the world of medical research. As I noted in my release:

Bogyo and his associates focused on … ebselen because, in addition to having a strong inhibitory effect, ebselen also has been tested in clinical trials for chemotherapy-related hearing loss and for stroke. Preclinical testing provided evidence that ebselen is safe and tolerable, and it has shown no significant adverse effects in ensuing clinical trials.

Continue Reading »

Genetics, Microbiology, Neuroscience, Research, Science, Stanford News

Quest for molecular cause of ALS points fingers at protein transport, say Stanford researchers

Quest for molecular cause of ALS points fingers at protein transport, say Stanford researchers

Amyotrophic lateral sclerosis, or ALS, is a progressive, fatal neurodegenerative disease made famous by Lou Gehrig, who was diagnosed with the disorder in 1939. Although it can be inherited among families, ALS more often occurs sporadically. Researchers have tried for years to identify genetic mutations associated with the disease, as well as the molecular underpinnings of the loss of functioning neurons that gradually leaves sufferers unable to move, speak or even breathe.

We hope that our research may one day lead to new potential therapies for these devastating, progressive conditions

Now Stanford geneticist Aaron Gitler, PhD, and postdoctoral scholar Ana Jovicic, PhD, have investigated how a recently identified mutation in a gene called C9orf72  may cause neurons to degenerate. In particular, a repeated sequence of six nucleotides in C9orf72 is associated with the development of ALS and another, similar disorder called frontotemporal dementia. They published their results today in Nature Neuroscience.

As Gitler explained in our release:

Healthy people have two to five repeats of this six-nucleotide pattern. But in some people, this region is expanded into hundreds or thousands of copies. This mutation is found in about 40 to 60 percent of ALS inherited within families and in about 10 percent of all ALS cases. This is by far the most common cause of ALS, so everyone has been trying to figure out how this expansion of the repeat contributes to the disease.

Gitler and Jovicic turned to a slightly unusual, but uncommonly useful, model organism to study the effect of this expanded repeat:

Previous research has shown that proteins made from the expanded section of nucleotides are toxic to fruit fly and mammalian cells and trigger neurodegeneration in animal models. However, it’s not been clear why. Gitler and Jovicic used a yeast-based system to understand what happens in these cells. Although yeast are a single-celled organism without nerves, Gitler has shown that, because they share many molecular pathways with more-complex organisms, they can be used to model some aspects of neuronal disease.

Using a variety of yeast-biology techniques, Jovicic was able to identify several genes that modulated the toxicity of the proteins. Many of those are known to be involved in some way in shepherding proteins in and out of a cell’s nucleus. They then created neurons from skin samples from people with and without the expanded repeat. Those with the expanded repeat, they found, often had a protein normally found in the nucleus hanging out instead in the cell’s cytoplasm.

Jovicic and Gitler’s findings are reinforced by those of two other research groups, who will publish their results in Nature tomorrow. Those groups used different model organisms, but came to the same conclusions, suggesting that the researchers may be close to cracking the molecular code for this devastating disease.

As Jovicic told me, “Neurodegenerative diseases are very complicated. They likely occur as a result of a defect or defects in basic biology, which is conserved among many distantly related species. We hope that our research may one day lead to new potential therapies for these devastating, progressive conditions.”

Previously: Stanford researchers provide insights into how human neurons control muscle movement, Researchers pinpoint genetic suspects in ALS and In Stanford/Gladstone study, yeast genetics further ALS research

Medical Education, Microbiology, NIH, Public Health, Research, Videos

Investigating the human microbiome: “We’re only just beginning and there is so much more to explore”

Investigating the human microbiome: "We’re only just beginning and there is so much more to explore"

The more scientists learn about the body’s community of bacteria, the more they believe that the human microbiome plays an important role in our overall health. For example, research published earlier this week suggests that a specific pattern of high bacterial diversity in the vagina during pregnancy increases a woman’s risk of giving birth prematurely.

Despite these and other insightful findings, researchers have a long way to go to understand the composition of our internal microbial ecosystems. As Keisha Findley, a postdoctoral fellow at the National Human Genome Research Institute says in the above video, “We’re only just beginning and there is so much more to explore.”

Findley and colleagues are working to survey all of the fungi and bacteria living on healthy human skin and develop a baseline to determine how these microbial communities may influence skin conditions such as acne, athlete’s foot, skin ulcers and eczema. Watch the LabTV video above to learn more about her work.

Previously: Drugs for bugs: Industry seeks small molecules to target, tweak and tune up our gut microbes, A look at our disappearing microbes, Exploring the microbes that inhabit our bodies and Diverse microbes discovered in healthy lungs shed new light on cystic fibrosis
Via NIH Director’s Blog

Microbiology, Pregnancy, Research, Stanford News

Stanford microbiome research offers new clues to the mystery of preterm birth

Stanford microbiome research offers new clues to the mystery of preterm birth

preemie-holdinghandsPremature birth affects 450,000 U.S. babies each year and is the leading cause of newborn deaths. But in about half of cases, doctors never figure out what triggered premature labor in the pregnant mom.

Now, there’s a new clue: A Stanford study, published today, gives important details of how the microbiome – the body’s community of bacteria – behaves in women whose pregnancies go to the full 40-week term, and what’s different in women whose babies come three weeks, or more, early. A specific pattern of vaginal bacteria was linked to greater risk of preterm delivery, and the longer the pattern persisted, the greater the risk, the study found.

The work is one piece of a larger effort by the March of Dimes Prematurity Research Center at Stanford to bring experts from many branches of science together to work on preterm birth. The researchers collected weekly bacterial samples throughout pregnancy from four body sites for 49 pregnant women, of whom 15 delivered prematurely. Patterns of vaginal bacteria that were dominated by lactobacillus bacteria were linked to low prematurity risk. Such patterns had already been shown to be linked to health in non-pregnant women.

A pattern of high bacterial diversity, low lactobacillus and high levels of gardnerella and ureaplasma bacteria was linked to higher prematurity risk, the study also showed. This was especially true if the high-diversity pattern persisted for several weeks. From our press release about the new research:

“I think our data suggest that if the microbiome plays a role in premature birth, it may be something that is long in the making,” said the study’s lead author, Daniel DiGiulio, MD, a research associate and clinical instructor in medicine. “It may be that an event in the first trimester or early second trimester, or even prior to pregnancy, starts the clock ticking.”

The researchers also followed the women’s bacterial communities for up to a year after their deliveries and found that all new mothers shifted to the high-risk pattern, regardless of if their babies were born early or on time or if they had a c-section or vaginal delivery. This finding may help explain why women with closely-spaced pregnancies are more likely to have a preterm baby the second time around, however more work is needed to better understand this discovery, concluded researchers.

Ultimately, the research team hopes to use their findings to develop interventions that could prevent preterm birth. That would definitely be good news for moms and babies.

Previously: Counseling parents of the earliest-born preemies: A mom and two physicians talk about the challenges, Stanford/VA study finds link between PTSD and premature birth and Maternal obesity linked to earliest premature births, says Stanford study
Photo by bradleyolin

Imaging, Microbiology, Stanford News

When bacteria swarm: H. pylori home in on our stomach cells

Imagine you’re thrown into wild ocean waters, battered by waves until you can’t tell which way is up. Your only chance of survival is to somehow sense the location of a rock outcropping and cling to it. Now factor in that the churning water is highly acidic and lethal – that’s the predicament facing Helicobacter pylori, a bacterium that makes its home in one out of every two human stomachs and, for an unfortunate 20 percent of its hosts, causes ulcers.

H. pyloris safe haven is our stomach’s lining with its protective mucus and nutrient-rich cells. New research from the lab of Stanford microbiologist Manuel Amieva, MD, PhD, published today in Cell Host & Microbe demonstrates that the bacteria are able to detect and home in on metabolic molecules released by human stomach cells. The behavior, captured in the video above, shows H. pylori swarming to a microscopic needle releasing either a solution collected from stomach cells or the molecule urea.

The corkscrew-shaped bacterium moves with the help of its tail-like flagella. The bundle of flagella spin in one direction to propel the bacteria forward. When they reverse the spin, said Amieva, the flagella become like helicopter blades, pulling H. pylori backwards.

Previous experiments have shown the bacteria swim away from acid and H. pylori is known to have four chemical sensing receptors. “But this is the first time we’ve observed in real time the bacteria swimming towards something,” said graduate student and lead author, Julie Huang, referring to the technique that allowed the lab to watch H. pylori’s swimming behavior directly.

Continue Reading »

Imaging, Microbiology, Research, Science, Stanford News, Technology

3-D structure of key signaling protein and receptor revealed

3-D structure of key signaling protein and receptor revealed

Using ultra-bright X-rays at SLAC National Accelerator Laboratory, a team of international researchers has captured the 3-D structure of a key signaling protein and its receptor for the first time.

The discovery provides new insight into the functioning of a common cell receptor called a G protein-coupled receptor or GPCR. Researchers estimate this protein, and its relatives, are the targets of about 40 percent of pharmaceuticals. From a SLAC release:

“This work has tremendous therapeutic implications,” said Jeffrey Benovic, PhD, a biochemist who was not involved with the study. “The study is a critical first step and provides key insight into the structural interactions in these protein complexes.”

Specifically, the researchers were able to illuminate the structure of the GPCR bonded with a signaling protein called arrestin. Arrestins and G proteins both dock with the GPCRs, however, researchers had previously only examined a bonded G protein. G proteins are generally the “on” switch, while arrestins usually signal the GPCR to turn off:

Many of the available drugs that activate or deactivate GPCRs block both G proteins and arrestins from docking.

“The new paradigm in drug discovery is that you want to find this selective pathway – how to activate either the arrestin pathway or the G-protein pathway but not both — for a better effect,” said Eric Xu, PhD, a scientist at the Van Andel Research Institute in Michigan who led the experiment. The study notes that a wide range of drugs would likely be more effective and have fewer side effects with this selective activation.

Previously: Why Stanford Nobel Prize winner Brian Kobilka is a “tour de force of science”, Funding basic science leads to clinical discoveries, eventually and Video of Brian Kobilka’s Nobel lecture
Video by SLAC National Accelerator Laboratory

Stanford Medicine Resources: