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Microbiology

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

Biomed Bites, Cancer, Genetics, Microbiology, Research, Videos

Packed and ready to go: The link between DNA folding and disease

Packed and ready to go: The link between DNA folding and disease

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

In cells, DNA doesn’t make a lovely, languid helix as popularly depicted. It’s scrunched up, bound with proteins that smoosh one meter of DNA into just one micrometer, a millionth of its size. DNA wound around proteins form a particle called a nucleosome.

Yahli Lorch, PhD, associate professor of structural biology, has studied nucleosomes since they were first discovered more than 20 years ago, as she mentions in the video above:

When I began working on the nucleosome, it was a largely neglected area since most people considered it just a packaging and nothing beyond that.

Since I discovered that it has a role and a very important role in the regulation of gene expression, the field has grown many fold and it’s one of the largest areas in biology now.

Many diseases have been linked to the packaging of DNA, including neurodegenerative diseases, autoimmune diseases and several types of cancer such as some pancreatic cancers. Enhancing the understanding of the basic biology of DNA folding is leading to new and improved treatments for these conditions, Lorch says.

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

Previously: DNA origami: How our genomes fold, DNA architecture fascinates Stanford researcher — and dictates biological outcomes and More than shiny: Stanford’s new sculpture by Alyson Shotz

Biomed Bites, Genetics, Medicine and Society, Microbiology, Research, Science, Videos

From yeast to coral reefs: Research that extends beyond the lab

From yeast to coral reefs: Research that extends beyond the lab

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

John Pringle, PhD, focused most of his career on yeast. Easy to culture in the lab, yeast offer scientists a malleable model to learn about all types of cells, including human cells.

As a professor of genetics, he still does a bit of that. But now, his heart is focused on saving the world’s coral reefs – no small task given that these living ecosystems are vulnerable to temperature changes, carbon dioxide concentrations and overfishing.

Pringle’s research concentrates on a small sea anemone known as Aiptasia pallida, as he explains in the video above:

We picked an experimental system that has huge advantages over the corals themselves and we try to learn basic things about their molecular and cellular biology that will help us with the more complex and less experimentally tractable system of the reefs.

Just as with his yeast work, the lessons learned from the anemones are directly applicable to human well-being. “Corals are important to hundreds of millions of people around the world for livelihood and for the beauty they bring and the food they provide,” he says. “We have the hopes that by doing basic research, we’ll contribute to an understanding of how coral reefs might be preserved.”

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

Previously: Bubble, bubble, toil and trouble — yeast dynasties give up their secrets, Yeast advance understanding of Parkinson’s disease, says Stanford study and My funny Valentine — or, how a tiny fish will change the world of aging research

Biomed Bites, Microbiology, Research, Videos

Long a mystery organelle, the primary cilium is giving up its secrets

Long a mystery organelle, the primary cilium is giving up its secrets

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

Picture a bacterium or a sperm cell — it has a flapping flagella, a hair-like structure that some species, and cells, use to move. There’s a different type of structure that protrudes out of the cells of many mammals called a primary cilium. Unlike flagella, this structure doesn’t move. Instead it receives mechanical and chemical signals from surrounding cells.

The primary cilium and its function is the focus of Max Nachury, PhD, an assistant professor of molecular and cellular physiology. His team is applying research on the cilium to learn more about a group of hereditary diseases characterized by a malfunctioning cilium such as Bardet-Biedl syndrome. Patients with BBS are often obese, have extra fingers or toes and have poor vision.

“These multi-symptomatic disorders caused by a defect in cilium function are really things we understand very poorly,” Nachury says in the video above. “We hope that our basic research can then feed back into the basic understanding of this disorder.”

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

Previously: Clues about kidney disease from an unexpected direction, Parent details practical ways to get care and support for your child’s rare disease and New search engine designed to help physicians and the public in diagnosing rare diseases

Autoimmune Disease, Cancer, Infectious Disease, Microbiology, Nutrition, Stanford News

Getting to the good gut: how to go about it

Getting to the good gut: how to go about it

In a blog post a few years ago I wrote, The Good Gutwith misplaced parenthetical self-assuredness:

Anybody who’s ever picked up an M&M off the sidewalk and popped it into his or her mouth (and, really, who among us hasn’t?) will be gratified to learn that the more germs you’re exposed to, the less likely you are to get asthma … hay fever and eczema.

I soon learned to my surprise, if not necessarily to my embarrassment, that virtually nobody – at least nobody over 6 – cops to having stooped-and-scooped as I routinely did as a kid on what I called my “lucky-sidewalk” days.

But those M&Ms may have been the best pills I ever took.

Stanford microbiologists Justin Sonnenburg, PhD, and Erica Sonnenburg, PhD, (they’re married) have written a new book, The Good Gut, about the importance of restocking our germ-depleted lower intestines.

Massive improvements in public sanitation and personal hygiene, the discovery of antibiotics and the advent of sedentary lifestyles have taken a toll on the number and diversity of microbes that wind up inhabiting our gut. According to The Good Gut, we need more, and more varieties, of them. And we need to treat them better. The dearth of friendly microorganisms in the contemporary colon is due not just to a lack of bug intake but to a lack of fiber in the modern Western diet. Indigestible to us, roughage is the food microbes feast on.

The Good Gut packages that message for non-scientists. “We wanted to convey the exciting findings in our field to the general public,” Justin Sonnenberg recently told me. “We’d noticed we were living our life differently due to our new understanding. We were eating differently and had modified both our own lifestyle and the way we were raising our children.”

In simple language, the Sonnenburgs explain how the pieces of our intestinal ecosystem fit together, what can go wrong (obesity, cancer, autoimmunity, allergy, depression and more), and how we may be able to improve our health by modifying our inner microbial profiles. Their book includes everything from theories to recipes, along with some frank discussion of digestive processes and a slew of anecdotes capturing their family’s knowledge-altered lifestyle.

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Evolution, Genetics, Microbiology, Pregnancy, Research, Science, Stanford News, Stem Cells

My baby, my… virus? Stanford researchers find viral proteins in human embryonic cells

My baby, my... virus? Stanford researchers find viral proteins in human embryonic cells

Wysocka - 560

One thing I really enjoy about my job is the opportunity to constantly be learning something new. For example, I hadn’t realized that about eight percent of human DNA is actually left-behind detritus from ancient viral infections. I knew they were there, but eight percent? That’s a lot of genetic baggage.

These sequences are often inactive in mature cells, but recent research has shown they can become activated in some tumor cells or in human embryonic stem cells. Now developmental biologist Joanna Wysocka, PhD, and graduate student Edward Grow, have shown that some of these viral bits and pieces spring back to life in early human embryos and may even affect their development.

Their research was published today in Nature. As I describe in our press release:

Retroviruses are a class of virus that insert their DNA into the genome of the host cell for later reactivation. In this stealth mode, the virus bides its time, taking advantage of cellular DNA replication to spread to each of an infected cell’s progeny every time the cell divides. HIV is one well-known example of a retrovirus that infects humans.

When a retrovirus infects a germ cell, which makes sperm and eggs, or infects a very early-stage embryo before the germ cells have arisen, the viral DNA is passed along to future generations. Over evolutionary time, however, these viral genomes often become mutated and inactivated. About 8 percent of the human genome is made up of viral sequences left behind during past infections. One retrovirus, HERVK, however, infected humans repeatedly relatively recently — within about 200,000 years. Much of HERVK’s genome is still snuggled, intact, in each of our cells.

Wysocka and Grow found that human embryonic cells begin making viral proteins from these HERVK sequences within just a few days after conception. What’s more, the non-human proteins have a noticeable effect on the cells, increasing the expression of a cell surface protein that makes them less susceptible to subsequent viral infection and also modulating human gene expression.

More from our release:

But it’s not clear whether this sequence of events is the result of thousands of years of co-existence, a kind of evolutionary symbiosis, or if it represents an ongoing battle between humans and viruses.

“Does the virus selfishly benefit by switching itself on in these early embryonic cells?” said Grow. “Or is the embryo instead commandeering the viral proteins to protect itself? Can they both benefit? That’s possible, but we don’t really know.”

Wysocka describes the findings as “fascinating, but a little creepy.” I agree. But I can’t wait to hear what they discover next.

Previously: Viruses can cause warts on your DNA, Stanford researcher wins Vilcek Prize for Creative Promise in Biomedical Science and Species-specific differences among placentas due to long-ago viral infection, say Stanford researchers
Photo of Joanna Wysocka by Steve Fisch

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