Structure of molecular machine that targets viral DNA for destruction determined

With a featured publication in the Aug. 7 issue of Science, Montana State University researchers have made a significant contribution to the understanding of a new field of DNA research, with the acronym CRISPR, that holds enormous promise for fighting infectious diseases and genetic disorders.

The MSU-led research provides the first detailed blueprint of a multi-subunit "molecular machinery" that bacteria use to detect and destroy invading viruses.

"We generally think of bacteria as making us sick, but rarely do we consider what happens when the bacteria themselves get sick. Viruses that infect bacteria are the most abundant biological agents on the planet, outnumbering their bacterial hosts 10 to 1," said Blake Wiedenheft, senior author of the paper and assistant professor in MSU's Department of Microbiology and Immunology.

"Bacteria have evolved sophisticated immune systems to fend off viruses. We now have a precise molecular blueprint of a surveillance machine that is critical for viral defense," Wiedenheft said.

These immune systems rely on a repetitive piece of DNA in the bacterial genome called a CRISPR. CRISPR is an acronym that stands for Clustered Regularly Interspaced Short Palindromic Repeats. These repetitive elements maintain a molecular memory of viral infection by inserting short segments of invading viral DNA into the DNA of the "defending" bacteria. This information is then used to guide the bacteria's immune system to destroy the invading viral DNA.

The molecular blueprint of the surveillance complex was determined by a team of scientists in Wiedenheft's lab at MSU using a technique called X-ray crystallography. Ryan Jackson, a postdoctoral fellow in the Wiedenheft lab, collected X-ray diffraction data from synchrotron radiation sources located in Chicago, Berkeley, and Stanford.

"Interpreting these X-ray diffraction patterns is a complex mathematical problem and Ryan is one of a few people in the world capable of interpreting this data," Wiedenheft said.

To help determine the structure, Wiedenheft sent Jackson to Duke University for a biannual meeting on X-ray crystallography. At the meeting, Jackson sat between "two of the greatest minds in the field of X-ray crystallography"- Randy Read from the University of Cambridge and Thomas Terwilliger from Los Alamos National Lab -- whose expertise facilitated the computational analysis of the data, which was critical for determining the structure.

"The structure of this biological machine is conceptually similar to an engineer's blueprint, and it explains how each of the parts in this complex assemble into a functional complex that efficiently identifies viral DNA when it enters the cell," Wiedenheft said. "This surveillance machine consists of 12 different parts and each part of the machine has a distinct job. If we're missing one part of the machine, it doesn't work."

Understanding how these machines work is leading to unanticipated new innovations in medicine and biotechnology and agriculture. These CRISPR-associated machines are programmable nucleases (molecular scissors) that are now being exploited for precisely altering the DNA sequence of almost any cell type of interest.

"In nature, these immune systems evolved to protect bacteria from viruses, but we are now repurposing these systems to cut viral DNA out of human cells infected with HIV. You can think of this as a form of DNA surgery. Therapies that were unimaginable may be possible in the future," Wiedenheft said.

"We know the genetic basis for many plant, animal, and human diseases, and these CRISRP-associated nucleases are now being used in research settings to surgically remove or repair defective genes," Wiedenheft said. "This technology is revolutionizing how molecular genetics is done and MSU has a large group of researchers that are at the cutting edge of this technological development."

Wiedenheft, a native of Fort Peck, was recently recruited by MSU from UC-Berkeley. Wiedenheft explained that the research environment, colleagues and support at MSU is second to none and the opportunity to move back to this great state was a "no-brainer."

In addition to Jackson, Read, Terwilliger and Wiedenheft, MSU co-authors on the Science paper are research associate Sarah Golden, graduate student Paul van Erp and undergraduate Joshua Carter. Additional collaborators included co-authors Edze Westra, Stan Brouns and John van der Oost from Wageningen University in the Netherlands.

Research in the Wiedenheft lab is supported by the National Institutes of Health, the National Science Foundation EPSCoR, the M.J. Murdock Charitable Trust, and the MSU Agricultural Experimental Station. Atomic coordinates for the Cascade structure have been deposited into the public repository (Protein Data Bank) under access code 4TVX.

Water 'microhabitats' in oil show potential for extraterrestrial life, oil cleanup: Extremophilic ecosystems writ small

An international team of researchers has found extremely small habitats that increase the potential for life on other planets while offering a way to clean up oil spills on our own.

Looking at samples from the world's largest natural asphalt lake, they found active microbes in droplets as small as a microliter, which is about 1/50th of a drop of water.

"We saw a huge diversity of bacteria and archaea," said Dirk Schulze-Makuch, a professor in Washington State University's School of the Environment and the only U.S. researcher on the team. "That's why we speak of an 'ecosystem,' because we have so much diversity in the water droplets."

Writing in the journal Science, the researchers report they also found the microbes were actively degrading oil in the asphalt, suggesting a similar phenomenon could be used to clean up oil spills.

"For me, the cool thing is I got into it from an astrobiology viewpoint, as an analog to Saturn's moon, Titan, where we have hydrocarbon lakes on the surface," said Schulze-Makuch. "But this shows astrobiology has also great environmental applications, because of the biodegradation of oil compounds."

Schulze-Makuch and his colleagues in 2011 found that the 100-acre Pitch Lake, on the Caribbean island of Trinidad, was teeming with microbial life, which is also thought to increase the likelihood of life on Titan.

The new paper adds a new, microscopic level of detail to how life can exist in such a harsh environment.

"We discovered that there are additional habitats where we have not looked at where life can occur and thrive," said Schulze-Makuch.

Analyzing the droplets' isotopic signatures and salt content, the researchers determined that they were not coming from rain or groundwater, but ancient sea water or a brine deep underground.

Story Source:

The above story is based on materials provided by Washington State University . Note: Materials may be edited for content and length.

Lyft’s Plan to Make On-Demand Carpools the Everyday Way to Commute

Lyft

Lyft is getting back to its roots. Before offering a smartphone app that let you summon other people’s private cars—each decked out with a pink mustache—Lyft was a startup called Zimride that matched up college students who wanted to take the same road trip. Now it’s offering much the same service to everyone going the same way.

Today, the company launched a new feature called Lyft Line that lets ride seekers anywhere in the city get matched up with other would-be passengers traveling a similar route, allowing everyone in the car to pay less. The option will be available as a new tab in the Lyft app, first only for passengers in Lyft’s home city of San Francisco.

Shared rides sound like a nice, cheaper, slightly greener way to get around, and the cooperative aspect fits Lyft’s image as a fist-bumping, sit-in-the-front alternative to regular taxis, limos, and its more luxe competitor, Uber. But Lyft wouldn’t be a San Francisco tech startup in 2014 if it didn’t have bigger ambitions. “Instead of public transit, we’re building what we call personal transit,” Lyft CEO Logan Green said at a private media event to unveil the service. Not to be outdone, Uber scooped Lyft Line’s launch last night by announcing a similar experiment in splitting rides called UberPool. As these two duke it out, we could be seeing the future of “ride-sharing” take shape—and this time, contrary to Uber’s motto of “your own private driver,” this future looks like actual shared rides.

Lyft

While still in college, Green served as a director on the board of the metro transit district in Santa Barbara, California, and he cited that experience when contending that public transit in the U.S. is limping along without a good fix in sight. Chronically underfunded agencies offer travel that takes longer than driving, which leads to meager use. Green said that 90 percent of the time, someone taking a Lyft is followed by someone else taking the same trip within five minutes. Instead of competing with just taxis, Lyft is now aspiring to vie with every mode of wheeled transportation, from buses to your own car, as the default way to get around. “Our hope is this is a product people can use twice a day,” Lyft co-founder John Zimmer said.

The Five-Dollar Ride

The way this becomes possible, Zimmer said, is through Lyft’s scale. The service now has about 60,000 drivers in 65 cities, and it’s now providing millions of trips a month, he said. Because of that density, Lyft believes finding multiple passengers for rides won’t be hard. “You have the type of frequency and demand that you can match it together efficiently,” he said.

One of the most interesting aspects of Lyft Line is that the discount compared to a regular Lyft ride varies depending on the algorithmically determined likelihood of finding a match. Unlike regular Lyft, Lyft Line requires putting a destination into the app when summoning the ride. The app will then quote a discount up to 60 percent off a regular fare (Lyft believes 30 to 40 percent off will be the average.) Even if you’re going somewhere that clearly no one else plans to go, Lyft will offer 10 percent off basically for trying.

The company also promises drivers will still get the same cut as they do from regular rides, and it claims shared rides may be even better for drivers because they tend to mean longer trips.

In its idealized version as presented by Lyft, shared rides become an increasingly tempting option for commuters and other frequent travelers the more the service is used. The greater the demand, the thinking goes, the more shared rides, which mean cheaper rides for everyone. Zimmer says the aspiration is a five-dollar ride wherever you need to go, with the added bonus of not needing to worry about parking.

Private Versus Public

Critics are likely to contend that, as with the much-lambasted private tech shuttles—i.e. the Google buses—a private version of public transit is just another form of tech solutionism, an abdication of the responsibility to seek the public good through public means. Lyft counters that it’s seeking to make its rides maximally affordable.

“Lyft’s mission is to continue to reduce the cost of transportation to make it as accessible as possible,” Green told WIRED.

Whether you agree with Lyft’s answer to public transit’s problems or not, it’s hard to disagree with at least one premise behind the creation of Lyft that Zimmer cites on a regular basis. When people drive in their own cars, most of what we’re all driving around is empty space. Driving alone in a car to work is a wasteful, traffic-creating mess. Better and more buses, trains, and streetcars are one remedy. Lyft’s shared rides another. Either way, commuting as it is now truly sucks—and in San Francisco in 2014, when suckiness calls, an app will surely follow.

Sprint Appoints New CEO And Drops Bid to Buy T-Mobile

Marcelo Claure speaking at the World Economic Forum World Economic Forum

Sprint has appointed Marcelo Claure as its new CEO, replacing longtime boss Dan Hesse, who has struggled recently in the face of the wireless provider’s dwindling subscriber base. Claure, who founded the wireless distributor BrightStar Corporation in 1997 and grew it into a $10.6 billion business, joined Sprint’s board of directors in January.

The announcement comes amid reports that Sprint has also dropped its bid to acquire fellow wireless company, T-Mobile, a move that would have made Sprint a sturdier opponent against the two dominant carriers, Verizon and AT&T. The merger also would have rankled regulators, who want to see greater competition in the telecom space. Though Sprint has not yet commented on that decision, Claure hinted at in a statement announcing his new role. “While consolidating makes sense in the long-term,” he said, “for now, we will focus on growing and repositioning Sprint.”

That ought to be a significant challenge for Sprint’s new leader. Sprint has been steadily losing subscribers to Verizon and AT&T, withsome 220,000 customers departing last quarter alone—and that was an improvement. This is partly to do with Sprint working to upgrade its wireless network, but it can also be attributed to its competitors radically cutting costs to attract new subscribers.

Merging with T-Mobile would have solidified Sprint’s ownership of the lower-end of the phone market, but it would also give consumers fewer options for wireless carriers. Now, as CEO, Claure will have to devise new ways to grow Sprint’s subscriber base on its own.

One method of achieving may be offering subscribers more creative pricing options. Last week, for instance, Sprint announced that it was launching a new low-cost wireless plan called Virgin Mobile Custom, a prepaid family plan that gives subscribers unlimited access to top apps like Facebook, Instagram, Twitter, or Pinterest for just $12. Subscribers can also tack on additional services like unlimited music streaming for $5, or unlimited talk and text for $35.

As Rajeev Chand, managing director of Rutberg & Co, a boutique investment bank, specializing in the wireless industry, told WIRED at the time, the Custom plan is as much a bid to lure subscribers with lower pricing as it is a marketing strategy. “T-Mobile, from a branding perspective, has become the un-carrier carrier,” Chand said. “Sprint could use a healthy dose of that kind of brand rejuvenation.” Perhaps a new entrepreneurial CEO will do the trick.

The Mathematics of Novelties and Innovations

Boegh/Flickr/CC

Our lives are filled with encounters with novelty. Whether it’s reading a new word or learning some new facts, these kinds of experiences are what makes life interesting. And often, these encounters lead us to find other new things; ever looked up one thing on Wikipedia and then discovered over an hour has passed as you have clicked from article to article, having fallen down the Wikipedia rabbit hole?

Well, are there mathematical regularities behind how we encounter novelties? And are these encounters similar to how we encounter innovations more generally?

Recently, a team of applied researchers (including Steven Strogatz, my graduate school advisor) set out to examine this. Their paper is very engaging and well-written so I really just recommend you go check out the whole thing, but here are some excerpts:

The notion that one new thing sometimes triggers another is, of course, commonsensical. But it has never been documented quantitatively, to the best of our knowledge. In the world before the Internet, our encounters with mundane novelties, and the possible correlations between them, rarely left a trace. Now, however, with the availability of extensive longitudinal records of human activity online, it has become possible to test whether everyday novelties crop up by chance alone, or whether one truly does pave the way for another.

The larger significance of these ideas has to do with their connection to Kauffman’s theoretical concept of the ‘‘adjacent possible’’, which he originally discussed in his investigations of molecular and biological evolution, and which has also been applied to the study of innovation and technological evolution. Loosely speaking, the adjacent possible consists of all those things (depending on the context, these could be ideas, molecules, genomes, technological products, etc.) that are one step away from what actually exists, and hence can arise from incremental modifications and recombinations of existing material. Whenever something new is created in this way, part of the formerly adjacent possible becomes actualized, and is therefore bounded in turn by a fresh adjacent possible. In this sense, every time a novelty occurs, the adjacent possible expands. This is Kauffman’s vision of how one new thing can ultimately lead to another. Unfortunately, it has not been clear how to extract testable predictions from it.

They conclude that the statistical features of the datasets that they look at are consistent with the idea of the continually expanding adjacent possible:

All four of our datasets displayed the same statistical patterns, both for the rates at which novel events occur and for the statistical signatures of triggering events. Two of the data sets involved innovations (the creation of brand new pages in Wikipedia and the introduction of brand new tags in del.icio.us), while the other two involved novelties that do not qualify as innovations (the first appearance of a word in a text, or the first time a user listens to an existing song). The fact that we observe the same statistical signatures for novelties and innovations strengthens the hypothesis that they could be two sides of the same coin, namely, manifestations of correlations generated by the expansion of the adjacent possible.

Read the rest to find out more about how they examined this.

Radical New Foursquare App Thinks You Want Even Less Privacy

WIRED

Growing concerns over online privacy have cost some internet companies lots of money, according to a new report, but that’s not stopping Foursquare. The five-year-old outfit hopes to boost its revenues by actively asking people to give up some of their online privacy.

A new version of Foursquare’s eponymous app, released today, is a radical departure for the company. Once a kind of online bragging system, the app is now more of a tracking machine. Gone is Foursquare’s best-known feature, a large “check in” button that users clicked to voluntarily share their location. Now, the app is keeping tabs on you at all times, sending your location back to Foursquare’s servers, which then push recommendations back to your smartphone, suggesting restaurants and stores to visit—and stuff to order and buy once you get there.

“To actually get an app to talk to you like a friend would talk to you. That’s what we’re going at here, and I think we’ve done a really good job of it,” says Foursquare CEO Dennis Crowley.

The shift to this kind of tracking is a big gamble for Foursquare, which is still unprofitable after five years. The startup is openly proposing a bold tradeoff: Users share intimate location data with the company and get (hopefully) useful and relevant suggestions about where to go in return, suggestions informed by Foursquare’s massive database of 6 billion-plus check-ins and of comments and ratings left by past users.

Fellow social network Facebook has proposed a similar tradeoff with its “nearby friends” feature, which lets people elect to be tracked by their friends, family, and, by extension, Facebook, and so many other online apps are gradually eroding our online privacy in various ways. The question is: how many of them will face serious consequences?

“To actually get an app to talk to you like a friend would talk to you. That’s what we’re going at here.”

The upside of the new Foursquare is that people who stopped checking in long ago might suddenly remember they have the app installed and start using it again as it begins pelting them with recommendations. The obvious downside is that people will fear how much data Foursquare is collecting about their physical movements and uninstall the thing.

Foursquare

Such concerns seem particularly warranted in light of recent revelations of extensive domestic spying by U.S. intelligence agencies. The data you share with Foursquare today could conceivably end up in the hands of the NSA, hackers, or private data brokers tomorrow. “These location data collection schemes create a honeypot for malicious actors,” says Adi Kamdar, a staff activist at the Electronic Frontier Foundation. “People tend to forget that these features are on, providing little benefit to the user while sending heaps of interesting—and personal—data over to companies.”

Crowley tells us that Foursquare doesn’t share private user actions “with anyone.” But it does approach to government snooping and private data brokers like “a lot of other companies”—small comfort given how pervasive information leakage and sharing has become in the tech industry. Users can at least opt out of the tracking system and then indicate their interests manually in the regular Foursquare app. And if they like the old check-in model, they can use a separate app called Swarm.

In my own experience with Foursquare’s tracking system—the service has been available on an opt-in basis since shortly after it was developed last year—it’s impossible to forget that I’m being tracked, because the app suggests places to visit several times a week. Therein lies another risk: That the new Foursquare will end up merely annoying its users.

Still, Foursquare is pouring a lot of technology into making the privacy tradeoff worthwhile. After completely reworking how it senses location and recognizes what venue users are at, Foursquare set about adding new tools that help people find places to go. Users can now tell the app about their tastes explicitly, by clicking on buttons, or implicitly, via their movements. You can tell Foursquare you like bourbon, for instance, or it can learn you like cupcake shops after you walk into a few of them. You can also leave “tips”—specific recommendations—about places that Foursquare senses you’ve visited.

The service then feeds all your movements, tips, reviews, and comments are into software that figures out whether you’re an expert in something—the SoHo neighborhood, say, or pizza, or cocktails, to cite three examples given by Foursquare. It may them use your tips to shape the recommendations others see on the app.

Yes, it’s a little disconcerting that there’s an internet database that knows precisely how much of a cocktail “expert” you are. You wouldn’t want that information to influence whether you get a job or how much you pay for health care. But Foursquare says the benefits far outweigh the costs. “We want to make super powers for local search, and this is our interpretation of that,” Crowley says.

Second Ebola Patient Arrives in the U.S., Shows Signs of Improvement

Nancy Writebol, an American aid worker from North Carolina who was infected with the Ebola virus while working in Liberia, arrives at Emory University Hospital in Atlanta, Tuesday, Aug. 5, 2014. The Journal & Constitution, John Spink via AP

ATLANTA, GA—A grey Gulfstream III carrying Nancy Writebol, an American aid worker diagnosed with Ebola, landed at Dobbins Air Force Base north of Atlanta Tuesday morning. An ambulance took her 14 miles to a special isolation facility at Emory University Hospital that was designed not just to treat the worst diseases, but to make sure those diseases don’t get any farther than its walls.

Writebol transited from ambulance to hospital on a gurney. She now joins Kent Brantly, a doctor who’d been volunteering in Liberia with with the Christian aid organizations Samaritan’s Purse and SIM USA when he, too, became infected with the deadly virus. Brantly and Writebol are the first people to be treated for Ebola on US soil—and despite some signs that an experimental drug has improved their condition, the virus still has no known cure. The only accepted treatments are rehydration and time.

Bruce Johnson, president of SIM USA, during a press conference following Writebol’s arrival at Emory. Carolyn Crist/WIRED

“Nancy is still very, very weak but shows signs of improvement, progress, and is moving in the right direction,” said Bruce Johnson, president of SIM USA, at a press conference following Writebol’s arrival. Samaritan’s Purse and SIM USA coordinated with the State Department, Atlanta-based private jet company Phoenix Air and the Centers for Disease Control and Prevention to set up the transport—at a price tag that has already topped $1 million for Samaritan’s Purse and SIM. Writebol, of North Carolina, and Brantly, of Texas, are just two of the 1,600 people who have contracted the virus in four West African nations, according to the World Health Organization. The virus brings on vomiting, hemorrhagic bleeding and organ failure, and more than 800 people have died over the course of this latest outbreak.

For all that researchers know about Ebola, they still have questions—like how Brantly and Writebol got it. Typically Ebola is transmitted via bodily fluids such as blood and urine, but Writebol didn’t have direct contact with patients. The aid groups that employed the patients have invited CDC officials to do a full review of protocols and determine what happened, and for now, the groups’ hospital in Liberia isn’t receiving new patients, just treating current ones. Last week, Samaritan’s Purse sent another doctor to the site, and a few days ago, a SIM USA doctor volunteered to go back to Liberia. “There’s always a possibility that another worker could be infected, but we’re trusting that won’t happen,” Johnson said. “I’m impressed the two doctors said ‘Put me back in,’ and their families supported it.”

Emory, CDC and SIM officials have offered few specifics about the patients’ conditions or treatment. In Monrovia, Writebol asked for potato soup and then yogurt before boarding the plane—doctors regard her increased appetite as a positive sign. Her sons Jeremy and Brian will visit the hospital Tuesday; her husband David is still in Liberia, working on transportation arrangements to the US. Brantly’s wife, Amber, has visited him at Emory—they spoke through a window on the isolation chamber.

It’s possible that Writebol and Brantly have improved because of an experimental drug. According to CNN, CDC officials shipped three vials of an experimental drug called ZMapp to Liberia before the two came to the US. Manufactured by San Diego biotech firm Mapp Biopharmaceutical, ZMapp hasn’t been approved by the FDA, but the two agreed to take it—it’s a monoclonal antibody created by exposing mice to the virus. Brantly initially offered Writebol the first thawed vial, but as his condition deteriorated, he asked to take it and improved within hours. Writebol took two doses in Liberia but was still in “serious” condition before she left Liberia. The difference between the two is likely due to age, Johnson said—Brantly is 33 and Writebol is 58.

When doctors first diagnosed the two workers, SIM officials didn’t consider evacuation. But then the charter flight came through, and Emory University doctors said they were willing to receive Ebola patients. With the CDC headquarters less than a mile from the hospital, Emory University, State Department and CDC officials saw it as an opportunity to closely monitor American citizens and possibly find a cure through research. “You’ve seen the reaction here. We needed to make sure the aircraft, hospital and facilities would have the infrastructure to handle what we’re dealing with here,” Johnson said. “Then we left the decision up to the patients, their doctors and families about who would come first.”

Emory’s purpose-built isolation unit was another reason to bring the two home. The hospital built it 12 years ago with CDC help—with an eye toward treating CDC officials, should the need arise. It’s one of only four facilities of its kind in the country. Negative-pressure airflow systems make sure that HEPA-filtered air flows only inward, from the hallway to the preparation room and then to the patient room, and not the other way. The unit has its own lab facilities to test samples, and the hospital cleans and incinerates the bedding after use.

With both patients now contained, a small team of doctors and nurses will provide care around the clock. Staff not directly involved with the cases aren’t allowed near the unit, said Emory University medical intern Deep Shah. After Brantly arrived Saturday, staff seemed tense but confident about how to treat the patients, he said. That’s because Ebola isn’t “some mystical pathogen with a bizarre mode of transportation,” said Bruce Ribner, the doctor who oversees the isolation unit. It is deadly but not highly contagious. It isn’t an airborne disease, can’t be transmitted by a sneeze and doesn’t survive long outside a host. “The stakes are higher, but it’s easily inactivated with typical hospital disinfectants,” said Tom Frieden, CDC director.

Nancy and David Writebol were making funeral arrangements for her last week in Liberia but now they’re holding off. Johnson talked to David Writebol by phone after Nancy’s departure from Liberia and said he’s not “anxious, fretful or fearful — just relieved.” Getting to the Emory facility has been a good move, too, Johnson said. “We still have a long way to go,” he said. “But we have reason for hope.”