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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.

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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.

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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

Bioengineering, Cancer, Imaging, Microbiology, Research, Science, Stanford News

Stanford team develops technique to magnetically levitate single cells

Stanford team develops technique to magnetically levitate single cells

Remember the levitating frog? That feat — the levitation of a live frog using a powerful magnet — was awarded the 2000 Ig Nobel Prize. Fascinating to watch, the demonstration also cemented a longstanding belief that levitating anything smaller than 20 microns was flat-out impossible. Much less something alive.

Not so, a team of Stanford-based researchers showed in a paper published today in the Proceedings of the National Academy of Sciences (PNAS). Using a 2-inch-long device made of two magnets affixed with plastic, the team showed it’s possible to levitate individual cells.

The video above demonstrates the technique in a population of breast cancer cells. Originally, the cells hover, suspended between the two magnets. But when exposed to an acid, they start to die and fall as their density increases.

“It has very broad implications in multiple diseases including cancer, especially for point-of-care applications where it can bring the central lab diagnostics to the comfort of patients’ homes or physicians’ office,” Utkan Demirci, PhD, a co-senior author and associate professor of radiology, told me.

The technique makes it possible to distinguish healthy cells from cancerous cells, monitor the real-time response of bacteria or yeast to drugs and distinguish other differences between cells that were thought to be homogenous, said Naside Gozde Durmus, PhD, a postdoctoral research fellow and first author of the paper.

Critically, the technique does not require treating the cells with antibodies or other markers, Durmus said. That ensures the cells are not altered by any treatments and makes the technique easy to use in a variety of settings, including potentially in physicians’ offices or in resource-poor settings.

The device works by balancing the gravitational mass of a cell against its inherent magnetic signature, which is negligible when compared with the cell’s density, Durmus said.

Interestingly, however, the cells — or bacteria treated with an antibiotic — do not die at the same rate, providing hints at their individual adaptations to environmental stressors, said co-senior author Lars Steinmetz, PhD, a professor of genetics.

To enhance the precision of the technique, the researchers can tweak the concentration of the solution that holds the cells, Durmus said. A highly concentrated solution allows for the differentiation of cells of similar densities, while a less concentrated solution can be used to examine a population of heterogeneous cells.

The team plans to investigate the applications of the device next, including its use in resource-poor settings where the cells can be observed using only a lens attached to an iPhone, Durmus said.

Previously: Harnessing magnetic levitation to analyze what we eat, Researchers develop device to sort blood cells with magnetic nanoparticles and Stanford-developed smart phone blood-testing device wins international award
Video courtesy of Naside Gozde Durmus

Genetics, Microbiology, Research, Science

Make it or break it — or both: New research reveals RNA’s dual role

Make it or break it — or both: New research reveals RNA's dual role

7314255232_8ee9474b2e_zBehind every big biomedical breakthrough lies boatloads of basic biology. In that vein, a new finding published today in Cell shakes up a fundamental view of RNA, the bridging material necessary to convert genes into proteins.

Previously, it was well known that RNA is degraded, broken down into its constituent parts so it could be used again. Otherwise, used RNA would accumulate in the cell, clogging it up. But everyone assumed that RNA was degraded only after it had transmitted its message to build a protein.

Now, a team of researchers led by Lars Steinmetz, PhD, professor of genetics, have discovered that RNA is broken down while it’s communicating the blueprint for protein assembly, a process known as translation. One end of the RNA is still making proteins while the other is being dismantled.

“In the bigger picture, decaying RNA was thought to be of little interest biologically,” Steinmetz said. “Our findings show that it contains hallmarks of the translation process.”

That finding could change the way researchers examine gene expression in live cells. Current methods use drugs that “freeze” the translation process, but that artificial interference alters the measurements of protein creation. A new method — which involves looking at the products of the RNA degradation — simplifies that process and produces more accurate results, said Wu Wei, PhD, a senior research scientist in biochemistry who worked on the research.

“People think that RNA is translated or degraded, but actually they can happen at the same time,” Wei said.

The researchers made the discovery almost accidently, when they spotted an unusual pattern in the byproducts of RNA that remained in the cell.

So far, their work has been in living yeast cells, but Wei said the team plans to move next to examining RNA degradation in human cells.

“Our approach provides a simple and straightforward way to measure ribosome dynamics in living cells. Both this study and research performed by our collaberators have proven that it is a powerful tool to investigate the regulation of translation, said Vicent Pelechano, PhD, who is based in Steinmetz’s laboratory at the European Molecular Biology Laboratory and designed the experimental aspects of the study.

Previously: The politics of destruction: Short-lived RNA helps stem cells turn on a dime, Step away from DNA? Circulating *RNA* in blood gives dynamic information about pregnancy, health and RNA Rosetta stone? Molecules’ second, structural language predicted from their first, linear one
Image by AJ Cann

Bioengineering, Microbiology, Research, Technology

Basic biochemical puzzles that help diagnose and treat disease

Basic biochemical puzzles that help diagnose and treat disease

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

Pehr Harbury, PhD, has made a career out of solving biochemical puzzles. An associate professor of biochemistry, Harbury and his team are juggling quite a few challenges, including an effort to assemble a library of small molecules. Here’s Harbury in the video above:

One central area has been to develop techniques to perform the directed evolution of small molecules in much the same way that nature has produced the vast collection of natural products that are central to medicine.

Team members then examine the molecules to search for ones that interact with natural compounds, potentially conferring beneficial properties.

Harbury is also working to understand the shapes that proteins make when they’re in solution – “a problem that remains largely unsolved.” He describes several other projects – some which he said could lead to an earlier diagnosis for pulmonary hypertension or cancer – in the video above.

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

Previously: Getting a glimpse of the shape molecules actually take in the cell, New painkiller could tackle pain, without risk of addiction and Another piece of the pulmonary-hypertension puzzle gets plugged into place

Big data, BigDataMed15, Events, Medicine and Society, Microbiology, Research, Technology

At Big Data in Biomedicine, Nobel laureate Michael Levitt and others talk computing and crowdsourcing

At Big Data in Biomedicine, Nobel laureate Michael Levitt and others talk computing and crowdsourcing

Levitt2Nobel laureate Michael Levitt, PhD, has been using big data since before data was big. A professor of structural biology at Stanford, Levitt’s simulations of protein structure and movement have tapped the most computing power he could access in his decades-long career.

Despite massive advances in technology, key challenges remain when using data to answer fundamental biological questions, Levitt told attendees of the second day of the Big Data in Biomedicine conference. It’s hard to translate gigabytes of data capturing a specific biological problem into a form that appeals to non-scientists. And even today’s supercomputers lack the ability to process information on the behavior of all atoms on Earth, Levitt pointed out.

Levitt’s address followed a panel discussion on computation and crowdsourcing, featuring computer-science specialists who are developing new ways to use computers to tackle biomedical challenges.

Kunle Olukotun, PhD, a Stanford professor of electrical engineering and computer science, had advice for biomedical scientists: Don’t waste your time on in-depth programming. Instead, harness the power of a domain specific language tailored to allow you to pursue your research goals efficiently.

Panelists Rhiju Das, PhD, assistant professor of biochemistry at Stanford, and Matthew Might, PhD, an associate professor of computer science at the University of Utah, have turned to the power of the crowd to solve problems. Das uses crowdsourcing to answer a universal problem (folding of RNA) and Might has used the crowd for a personal problem (his son’s rare genetic illness).

For Das, an online game called Eterna – and its players – have helped his team develop an algorithm that much more accurately predicts whether a sequence of RNA will fold correctly or not, a key step in developing treatments for diseases that use RNA such as HIV.

And for Might, crowdsourcing helped him discover other children who, like his son Bertrand, have an impaired NGLY1 gene. (His story is told in this New Yorker article.)

Panelist Eric Dishman, general manager of the Health and Life Sciences Group at Intel Corporation, offered conference attendees a reminder: Behind the technology lies a human. Heart rates, blood pressure and other biomarkers aren’t the only trends worth monitoring using technology, he said.

Behavioral traits also offer key insights into health, he explained. For example, his team has used location trackers to see which rooms elderly people spend time in. When there are too many breaks in the bathroom, or the person spends most of the day in the bedroom, health-care workers can see something is off, he said.

Action from the rest of the conference, which concludes today, is available via live-streaming and this app. You can also follow conversation on Twitter by using the hashtag #bigdatamed.

Previously: On the move: Big Data in Biomedicine goes mobile with discussion on mHealthGamers: The new face of scientific research?, Half-century climb in computer’s competence colloquially captured by Nobelist Michael Levitt and Decoding proteins using your very own super computer
Photo of Michael Levitt by Saul Bromberger

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