Heatwaves blamed on global warming.

Unusually high frequency points to human influence.

NASA climatologist James Hansen made headlines during the US heatwave of 1988, declaring in testimony to Congress and during interviews on prime-time television that a build-up of greenhouse gases was increasing the probability of weather extremes. Now, as much of the United States sizzles through another torrid summer and the Midwest endures a historic drought, Hansen, director of NASA’s Goddard Institute for Space Studies in New York, claims that the future he predicted has arrived.

“The climate dice are now loaded to a degree that a perceptive person old enough to remember the climate of 1951–1980 should recognize the existence of climate change, especially in summer,” he and his colleagues write in a paper entitled ‘Perceptions of Climate Change1 published on 6 August. Just days earlier, on 1 August, Republican senators had challenged mainstream climate scientists over the existence of anthropogenic global warming at a hearing in Washington DC, underscoring the stubborn political divide over climate policy. Just as he did 24 years ago, Hansen has plunged into the debate, pre-empting the publication of his study with an opinion article in The Washington Post2.

Hansen’s team used seasonal temperature records for 1951–80, a period of relatively stable climate, as a baseline, then analysed the frequency and scale of subsequent temperature anomalies. On average, the team concludes, the globe has warmed by only about 0.5–0.6 °C since that time, but the shift has had a significant impact on many parts of the world (see ‘What a scorcher’).

Extremely hot summers — classified as about 3.5 °C warmer than average — have affected about 10% of the world’s land since 2006, an order of magnitude higher than during the period from 1951 to 1980.

The study is not the first to show a link between global warming and extreme weather3, but it goes well beyond its predecessors, concluding that greenhouse gases alone are responsible for the hot summers and heatwaves. “The likelihood that these events would have occurred without global warming is minuscule,” Hansen says.

A poll by researchers at Yale University in New Haven, Connecticut, and George Mason University in Fairfax, Virginia, suggests that most people in the United States accept the link between hot weather and global warming4. But Hansen’s assertion is running into some heavy weather among scientists.

Martin Hoerling, a meteorologist at the National Oceanic and Atmospheric Administration in Boulder, Colorado, calls Hansen’s paper an “extended Op-Ed piece”, arguing that the broader climate record does not support the link to individual heatwaves. Last year, Hoerling co-authored a paper5 suggesting that the 2010 drought in Russia was so far outside the realm of normal weather that the small rise in global temperatures could not account for it. He says that natural variability can explain most extremes, and that global warming merely enhances them.

Hansen notes that his study is purely statistical and does not try to explain how climate change could cause extremely hot summers. Kevin Trenberth, a climatologist at the US National Center for Atmospheric Research (NCAR) in Boulder, says that Hansen’s statistics are illustrative of a trend that should help people to understand global warming and the profound effect humans have had on the climate system. “It is never due to humans alone, nor is it ever, these days, just natural variability.”

In a paper to be published in the Journal of Geophysical Research6, Trenberth and a team of researchers investigate the physical mechanisms that drove some extreme weather events in 2010. Using a climate model developed at the NCAR, the team investigated links between a pair of El Niño and La Niña events (in which warm or cold surface waters, respectively, built up in the eastern Pacific Ocean) and weather events such as stronger monsoons in Asia and droughts in Russia and the Amazon. Although he thinks that global warming could have a role in such extreme events, Trenberth says that climate models have not yet been able to tease out the details.

“Models have a hard time doing extremes well,” Trenberth says. But because of limited data sets for extreme weather and inadequate climate models, he worries that some people could draw the wrong conclusion: “that there is no human influence”.

Source: Nature.


Cancer research: Open ambition.

Jay Bradner believes that cancer can be defeated through control of epigenetics — and he is not shy about spreading the word.

Jay Bradner has a knack for getting the word out online. You can follow him on Twitter; you can become one of more than 400,000 online viewers of the TEDx talk he gave in Boston, Massachusetts, last year; you can see the three-dimensional structure of a cancer-drug prototype created in his laboratory and you can e-mail him to request a sample of the compound.

Bradner, a physician and chemical biologist at the Dana-Farber Cancer Institute in Boston, makes defeating cancer sound easy — one just has to play tricks on its memory. “With all the things cancer is trying to do to kill our patient, how does it remember it is cancer?” he asked his rapt TEDx audience. Bradner says that the answer lies in epigenetics, the programmes that manage the genome.

DNA serves as the basic blueprint for all cellular activity, and DNA mutations have long been known to have a role in cancer. But much of a cell’s identity is determined by modifications to chromatin, which comprises DNA and the proteins that bind and package it. Epigenetic instructions, in the form of chemical marks that cling to chromatin, tell cells how to interpret the underlying genetic sequence, defining a cell’s identity as, say, blood or muscle.

Findings over the past ten years have strongly implicated dysregulation of epigenetic instructions in cancer, where growth-driving genes express like crazy and genes that keep cell division in check are silenced. Bradner’s aim is to create a drug that can rewrite those instructions so that cancer cells forget what they are and cease their deadly proliferation.

Bradner thinks that this epigenetic approach could strike down one of cancer’s most treacherous drivers, the DNA-binding protein Myc. Myc is involved in up to 70% of cancers but is generally considered ‘undruggable’, because the active parts of its structure are not accessible to the kinds of small-molecule drugs that chemists generally create. “Myc is one of those things that people dream of targeting,” says Dash Dhanak, head of cancer epigenetics at GlaxoSmithKline (GSK) in Collegeville, Pennsylvania.

Just as audacious is Bradner’s commitment to making his reagents available and his ideas accessible to scientists and laypeople alike, a rare attitude in the highly competitive world of drug discovery. Researchers in Bradner’s lab have developed a compound that interferes with Myc by manipulating epigenetic instructions, and he has sent it out to hundreds of collaborators worldwide. “That’s not common in practice,” says Bradner, “but from first principles, it’s the right thing to do.”

Detractors may scoff at Bradner’s flashy approach, but those who have followed his career say that there is substance to go with the style. “Jay has figured out translational science,” says Stuart Schreiber, director of chemical biology at the Broad Institute in Cambridge, Massachusetts, and Bradner’s former postdoctoral adviser. “He’s really just good at making important discoveries while staying connected to their clinical potential.”

In 1992, while Bradner was an undergraduate at Harvard University, also in Cambridge, he took a chemistry class taught by Schreiber on small-molecule discovery. By the time he graduated, Bradner knew that he wanted to apply the methods he had learned to cancer-drug development. He headed west to Illinois, to study the disease at the Pritzker School of Medicine at the University of Chicago.

Marked for death

In 1999, Bradner returned to Massachusetts for a clinical residency at Brigham and Women’s Hospital in Boston, and in 2004 he joined Schreiber’s lab as a postdoctoral researcher. Schreiber’s team was researching chemical compounds that override normal epigenetic control of gene expression by modulating chromatin. Such control systems generally involve three types of protein: ‘writers’, ‘readers’ and ‘erasers’ (see ‘Rewriting memory’). Writers attach chemical marks, such as methyl groups (to DNA) or acetyl groups (to the histone proteins that DNA wraps around); readers bind to these marks and influence gene expression; erasers remove the marks. The marks serve as instructions that are passed down as cells divide, providing a sort of cellular memory to ensure that skin cells, for example, beget other skin cells. Epigenetics has become one of the hottest areas of biological research.

Schreiber and his group had long been looking at histone deacetylases (HDACs), eraser proteins that remove acetyl groups from histones. Some chromatin regions in cancer cells contain fewer acetyl groups than those in normal cells, and drugs called HDAC inhibitors increase acetylation. Since 2006, two such drugs — vorinostat and romidepsin — have been approved by the US Food and Drug Administration to treat cutaneous T-cell lymphoma, a rare immune-cell cancer that affects the skin. The drugs generated excitement among cancer researchers, but because they block many types of HDAC — in both healthy and cancerous cells — they can be toxic. Several trials for other cancers turned up disappointing results.

Bradner experienced the let-down of the HDAC inhibitors first-hand in 2008, soon after starting his own lab. Chris French, a pathologist at Brigham and Women’s Hospital, consulted with Bradner about a ten-year-old boy he was treating for a rare and aggressive cancer called NUT midline carcinoma (NMC), which typically kills patients within a year of diagnosis. French, an expert on NMC, diagnosed the disease after cardiac surgeons had opened the boy’s chest and found a tumour the size of a baseball in his heart. Chemotherapy was not an option, as it would have hampered his recovery from surgery. Bradner and French discussed other treatments.

French had shown in 2003 that NMC is caused by a fusion of two genes1: BRD4, which encodes a reader protein, and a previously unknown gene called NUT. This fusion encodes a mutant protein, NUT–BRD4, which seems to act as a reader, spurring errant gene expression and forcing cells to lose their identity and become cancerous. No inhibitors of reader proteins were available then, but French and Bradner knew that vorinostat increased histone acetylation. Perhaps, they thought, if acetylation were increased, NUT–BRD4 would be so busy ‘reading’ elsewhere that it would overlook the region that was causing cells to become cancerous. Bradner calls the concept “the chemical equivalent of a smokescreen”.

It was thin reasoning, but Bradner and French agreed that the emergency at hand warranted an experiment. They tried the drug on cancer cells extracted from the boy, and the cells seemed to forget their cancerous marching orders, reverting from round, proliferating cells into flat, skin-like cells. This gave them the confidence to try treating the boy. The tumour seemed to respond after five weeks, but the toxicity proved too high. “It was taking him four hours to swallow three pills because he kept vomiting them back up,” French says. The boy stopped the treatment and died not long afterwards.

Bradner dwelled on the case, especially on BRD4, a little-studied protein that now seemed to be capable of causing cancer. Disparate lines of study suggested that BRD4 might be linked to the expression of Myc, a target most drug developers had abandoned. If Bradner could defuse BRD4, perhaps he could bring down one of cancer’s most notorious dragons.

In 2009, Bradner happened upon a patent from Mitsubishi Tanabe Pharma in Osaka, Japan, for a diazepine-based compound that inhibited BRD4 by blocking its bromodomain, the region that recognizes acetyl groups on histones. Diazepines on the market, such as the anxiety medication alprazolam (Xanax), have only weak interactions with the bromodomain. “You’d be in a coma by the time you inhibited BRD4,” Bradner says. So he began searching for molecules that were similar in structure but more potent. Jun Qi, a researcher in Bradner’s lab, synthesized more than 400 diazepines in search of a candidate.

By the end of 2009, they had one. Named JQ1 after Qi, the compound slips into a groove of BRD4, preventing it from binding to acetylated histones and activating genes. With JQ1, the researchers hoped to tease apart which genes BRD4 switches on — and whether any of them cause cancer.

Research promise

In March 2010, French introduced Bradner to another patient with NMC, a 29-year-old firefighter from Connecticut. Chemotherapy and romidepsin treatment had failed. Bradner asked the man if he could use his cells for research, pledging that the work would help to find cures. The man agreed. He died that July, but his cells made it possible to test JQ1. The compound stopped the cancer cells from dividing and transformed them into non-cancerous cells, both in culture and in mice2.

It takes years for promising molecules to lead to clinically useful drugs. Had drug-company researchers discovered JQ1, a single team would have forged ahead, probably in secret, to develop the compound. But Bradner decided that the quickest path to the clinic was to do the research openly, with as many collaborators as possible. Since January 2011, Bradner’s team has shipped JQ1 to more than 250 labs worldwide. Work on the molecule has produced at least ten publications in top journals.

“People like jay have been tremendous in pushing forward the frontiers.”

One of these publications3, a collaboration between Bradner and Constantine Mitsiades, a cancer biologist at Dana-Farber, bolstered BRD4’s connection to Myc. Mitsiades had found that multiple-myeloma cells express high levels of Myc and BRD4, but without a compound to target either of them, it was difficult to learn much more. With Bradner, he found that JQ1 reduced expression of Myc and its target genes and stopped myeloma cells from dividing in mice3.

Chris Vakoc, a cancer biologist at Cold Spring Harbor Laboratory in New York, was studying the role of BRD4 in leukaemia when he first learned of JQ1. He phoned Bradner immediately. “The next day he sent us a huge amount of the compound,” Vakoc says. In Vakoc’s hands, JQ1 stopped cancer-cell proliferation in mice with leukaemia and significantly extended their lifespans4. JQ1 has also been used to study infectious diseases such as those caused by Epstein-Barr virus5 and HIV6.

“In 20 years, my lab could not accomplish all of the research that has unfolded on JQ1 in one year through this open approach,” says Bradner. With US$15 million in venture capital from HealthCare Ventures of Cambridge, Massachusetts, Bradner has launched Tensha Therapeutics, a biotechnology company focused on bromodomain inhibition. The Cambridge-based biotech is now screening JQ1 derivatives to learn which are likely to have the fewest side effects — an essential early step in drug development.

Bradner is impatient, however, and is always on the lookout for drugs already in development that would be safe to use in NMC. In 2010, scientists at GSK published a study on an inhibitor of BRD4 and related molecules for treating sepsis7. Bradner asked the GSK researchers to try one of their compounds in patients with NMC at Dana-Farber. (Dhanak says that the company had been quietly working on BRD4 inhibitors since French’s NUT–BRD4 paper in 2003.) GSK agreed.

The first attempt was in March this year, when oncologists at Dana-Farber used the company’s BRD4 inhibitor GSK525762 to treat a 23-year-old engineering graduate student with NMC. The patient died about three weeks into the treatment. French says he suspects that the dose was too low and that combining the drug with HDAC inhibitors or other epigenetic drugs could yield better results. Dhanak says that GSK might test combinations in the near future.

Any clinical trial for NMC is bound to move slowly — the disease is aggressive, and only 90 cases have been diagnosed in the past decade. To raise awareness of NMC and make it easier for patients to enrol in trials, in 2011 Bradner and his colleagues created an international NMC registry (http://www.nmcregistry.org). It seems to be working. “We were concerned we’d have a problem finding patients, and now, through social media, the patients are finding us,” Bradner says.

Making good

Not all scientists share Bradner’s optimism. “Epigenetics is the new horizon, but when you get down to it, the fact is that people are just mucking around with it and finding interesting effects,” says Gerard Evans, a cancer biologist who studies epigenetic signalling at the University of Cambridge, UK. Epigenetics affects many cellular functions, and researchers are only beginning to learn how it influences cell memory.

Whatever the outcome, some see hopeful signs in Bradner’s open approach. Dhanak says that he welcomes it. “People like Jay have been tremendous in pushing forward the frontiers,” he says.

What Bradner wants most is to fulfil his pledge to the firefighter who died from NMC. “His gift of that rare tumour, given at a time when he was beyond all conceivable treatment, was a powerful experience,” Bradner says. If bromodomain inhibition fails, Bradner will apply the same open-source strategy to another target. “More and more, I feel it is so important to impact patients’ suffering from cancer, and it doesn’t matter whether that’s with our molecules or someone else’s,” he says.

Source: Nature.

Extreme mechanics: Buckling down.

Mechanical instability is usually a problem that engineers try to avoid. But now some are using it to fold, stretch and crumple materials in remarkable ways.

Katia Bertoldi is talking fast. She has only 12 minutes to present her work in the burgeoning field of ‘extreme mechanics’. But first, the Harvard University engineer smiles at the physicists gathered in Boston at the March 2012 meeting of the American Physical Society. She has to show them what she found in a toy shop.

Projected onto the screen, the Hoberman Twist-O looks like a hollow football made of garishly coloured plastic links. Twist it just so, however, and hinges between the links allow it to collapse into a ball a fraction of its original size. Twist it the other way, and it springs back open. Bertoldi explains that the Twist-O inspired her group to create a spherical device that collapses and re-expands, not with hinges but through mechanical instabilities: carefully designed weak spots that behave in a predictable way. Applications might include lightweight, self-assembling portable shelters or nanometre-scale drug-delivery capsules that would expand and release their cargo only after they had passed through the bloodstream and reached their target.

The challenge, Bertoldi says, is to figure out the exact instabilities a structure needs to achieve its desired behaviour. She quickly describes the necessary geometry and runs down a list of constraints. There are just 25 shapes that satisfy all the requirements, she explains, glossing over the months of computation it took to solve the problem. Then she starts a video to show the assembled throng the design that her team has come up with.

An image of a rubbery chartreuse ball with 24 carefully spaced round dimples (pictured) materializes on the screen. The test begins and the ball slowly collapses, each dimple squeezing shut as the structure twists into a smaller version of itself. There is a moment of silence, then everyone in the room begins to clap.

Student engineers have always been taught that mechanical instabilities are a problem to avoid. Such instabilities can quickly lead to structural failures — the collapse of a weight-bearing pillar, the crumpling of a flat steel plate or the buckling of a metal shell. From failures come disasters, such as the Second World War Liberty Ships that broke up while at sea. And the devilishly complex mathematical analysis of buckling structures ground to a halt in the late nineteenth century, because it was unworkable with the methods then available.

The collapsing buckliball

Carefully designed areas of instability (the dimples) allow this buckliball to smoothly collapse in on itself.

During the past half-decade or so, however, a new generation of physicists and engineers has begun to embrace instability. These researchers have been inspired, in part, by advances in geometry and nonlinear mathematics that have allowed them to progress where their forebears could not. They have already, for example, devised a theory for why cabbage leaves and torn plastic rubbish bags ripple1; calculated the patterns of wrinkles in fabric and crumples in paper2; and accounted for the way coils and loops develop in the guts of vertebrate embryos3.

On the practical side, one source of inspiration has been the widespread availability of flexible polymers and silicone materials, as epitomized by the vast selection of soft yet tough covers for smart phones. Such materials make it possible to imagine electronics, robots, tools and vehicles whose structures can radically deform yet still recover their original shapes.

The resulting extreme-mechanics movement has grown rapidly. The first three conference sessions to bear the name, totalling fewer than 40 presentations, were held during the March 2010 meeting of the American Physical Society (APS). Just two years later, Bertoldi’s talk on collapsible spheres was one of 111 presentations on extreme mechanics spread across 8 sessions. Hundreds of researchers are now active in the field worldwide. In spring 2011, the US National Science Foundation announced an opportunity for substantial funding in the field: it would allot up to US$2 million over four years to projects in Origami Design for Integration of Self-assembling Systems for Engineering Innovation (ODISSEI). The foundation expects to announce the awards this month.

Fold everything

“It was as if they wrote the solicitation just for us,” says Christian Santangelo, a physicist at the University of Massachusetts Amherst and a co-principal investigator on an ODISSEI proposal. Along with two origami artists and an expert in origami mathematics, Santangelo and his colleague Ryan Hayward, a chemical engineer at Amherst who specializes in polymers, are proposing a new kind of three-dimensional (3D) printer. Instead of slowly building an object with layers and layers of polymer, as current 3D printers do, they would print a flat polymer sheet with a two-dimensional (2D) origami-like pattern, then force it to fold into a close approximation of the desired 3D object.

One part of the project will involve refining a computer program developed by one of the origami artists, physicist Robert Lang of Alamo, California. Given a desired shape, the program will generate a diagram of the required fold pattern. At present, the program states only whether a particular fold on a sheet should be convex (in origami terms, a mountain fold) or concave (a valley fold). The user still has to devise a sequence of manipulations that can achieve those folds and create the figure. But the kinds of folding required by the project could quickly reach such levels of complexity that a human solution would be impossible. What the researchers foresee instead is a completely automated process in which a 2D sheet is inscribed with a computer-generated pattern of instabilities, and then folds correctly in one smooth, coordinated motion.

Unfortunately, in Hayward’s experiments so far, the folds just buckle into mountains or valleys at random. A potential solution may lie in the wavy-leaf-edge phenomenon, says Santangelo. If cells along the edge of a growing plant leaf multiply faster than those in the interior, he explains, they run out of room to lie smoothly in a plane, and the leaf edge is forced to ripple to accommodate them. If he and Hayward can work out how to make the polymer sheet swell in a way that varies from point to point, they could produce a complex pattern of rippling and curling that would help to control the sheet’s folding.

Just as natural phenomena can inform extreme mechanics, the discipline’s researchers can also use their knowledge to explain peculiarities in natural structures. “This field is filled with small secrets,” says Pedro Reis, an engineer at the Massachusetts Institute of Technology in Cambridge and one of the leaders of the movement.

Take the mechanisms at work in a grain of pollen, for example. Reis pulls out a small torpedo-like shape made of a light green, rubbery material. He stretches it, then crushes it in his fist. A pollen grain undergoes torture, he says: it gets wet, swells, dries out and is crushed, so plants have evolved strategies such as built-in soft spots to help their pollen to avoid damage. Reis pokes a dimple in the torpedo. Scientists can learn from this that a shell with a soft spot is more resistant to failure than one that is completely rigid, he says. “We are trying to learn from nature. How it evolved to deal with these problems for which we have no intuition is very inspiring.”

“How nature evolved to deal with problems for which we have no intuition is very inspiring.”

Reis sets the torpedo aside and, twisting an imaginary string between his fingers, moves on to the subject of the sea-floor cables that carry Internet traffic around the globe. Mechanical instabilities can cause complex behaviour in these structures, too, he says. Lay too much cable, and it will curl and kink, resulting in poor signal quality. Lay too little, and the line will be tense and vulnerable to snapping. When a ship dragging its anchor sliced through one such cable in February, six countries in East Africa lost Internet connectivity. Although a better understanding of long, thin objects’ instabilities wouldn’t have prevented the accident, Reis says, it might have made for a cable more resilient to breakage. An improved theory of cables could also be of great use to fields ranging from the oil industry to the mechanics of DNA.

In an effort to turn such insights into engineered structures, Reis’s lab is competing for one of the ODISSEI grants in partnership with Bertoldi and several others. One of their goals is to compile a lexicon of shapes: polyhedra that will buckle, bend, stretch, collapse and expand in predictable ways in response to specific stimuli. The shapes are based on spherical shells with holes cut in them. But surrounding the holes are ligaments designed to contain weak spots that buckle when stressed. In principle, these buckling polyhedra could be made in a range of sizes, whether it’s a nanometre-scale sphere designed for drug delivery or a retractable roof for an athletics stadium. The team calls the resulting structures ‘buckliballs’ — the subject of Bertoldi’s presentation at this year’s APS meeting.

Buckliballs, with their geometric design and near-magical behaviour, encapsulate the cleverness and beauty for which extreme-mechanics researchers yearn. Looking ahead, the more theoretically minded foresee a new set of general rules that could describe the behaviour of any flexible solid as it crumples. Meanwhile, those with an engineering bent imagine robots with appendages that can transform into tools or squeeze, octopus-like, through tiny spaces; backpacks that expand into tents; and mobile phones that users can roll up and stick behind their ears like a pencil. They see a whole realm of devices that transmute failure into function. That could all be years in the making — but Bertoldi and her rapt audience already see far more in this field than engineers’ toys.

Source: Nature.



Mars rover sizes up the field.

After a picture-perfect landing, Curiosity’s science team ponders its first moves at Gale Crater.

The mountain rises in the late-afternoon sun: a daunting challenge to the vehicle before it. In a photograph taken minutes after Curiosity landed on the surface of Mars, the rover’s shadow already seems to be reaching for the distant slope that it was built to climb.

On 6 August, Curiosity — the rover for NASA’s Mars Science Laboratory mission — arrived at its destination at the bottom of Gale Crater, a basin with the area of Lake Ontario. Its goal is to explore the ancient rocks of Mars for organic molecules and the remains of watery environments that could have provided a habitat for life. It will do that by climbing a mountain that rises from the centre of the crater: Aeolis Mons — informally dubbed Mount Sharp by mission scientists — which contains 5.5 kilometres of layered rocks representing hundreds of millions of years of Martian history. As the 900-kilogram rover climbs those slopes, on a journey that could take a decade or more, it will carry not only the most extensive suite of instruments ever sent to Mars, but also the hopes and dreams of engineers and explorers who see the mission as a prelude to an eventual human presence on the planet.

“The wheels of Curiosity have begun to blaze a trail for human footprints on the surface of Mars,” said NASA administrator Charles Bolden at an emotional briefing at the Jet Propulsion Laboratory (JPL) in Pasadena, California, shortly after the landing. For now, the 400-strong rover science team must work to ensure that their US$2.5-billion mission exceeds the achievements of all previous excursions to the red planet.

Complicated technology was needed to drop the rover precisely between Mount Sharp and the walls of Gale Crater. Over 7 minutes, a combination of a heat shield, a parachute, retro­rockets and a ‘sky crane’ decelerated the rover from 5,900 metres per second to less than 1 metre per second and set it down gently on the surface (see Nature 488, 16–17; 2012).

“Touchdown confirmed,” said Allen Chen, the JPL’soperations lead for entry, descent and landing, whose voice remained calm and steady throughout the tense sequence. His words triggered hugs, high-fives and tears of relief. Moments later, the first pictures from the rover’s front and rear hazard-avoidance cameras were relayed to Earth by Mars Odyssey, an 11-year-old orbiter that was passing over the crater.

Doug McCuistion, director of the Mars exploration programme at NASA headquarters in Washington DC, doesn’t want this new landing capability, developed over the course of a decade, to go to waste. A rover like Curiosity could be built more cheaply and quickly now, he says, because he directed the JPL to “treat this like we’re going to build them again and again and again”. If the mission were to be repeated, the rover might cost 500 million dollars less. But that is still beyond the budget of NASA’s planetary science programme, which has no further Mars landings on the books for now. However, the programme does have an opportunity for a Mars mission in 2018, costing between $700 million and $800 million; later this month, NASA science chief John Grunsfeld is scheduled to reveal the results of a study exploring the best use of this window.

While the descent team basked in the post-landing limelight, mission engineers set about testing the car-sized rover. During the vehicle’s first hours on Mars, data arrived in a relative trickle. The following day, engineers commanded the rover to deploy a communications antenna that will increase the data rate. The unstowing of the rover’s mast, which contains several cameras, is planned for the day after that, and should unleash a cascade of colour photos of the landing site later this week. It will be a further several days before a drive is attempted.

The rover is starting its exploration essentially where mission planners had hoped. The day after the landing, Mike Malin, president of Malin Space Science Systems in San Diego, California, and principal investigator for a camera on the belly of the rover, unveiled a dramatic video showing the final 150 seconds of the rover’s descent. By cross-checking those images with high-resolution photos from the Mars Reconnaissance Orbiter — which caught the spacecraft in the act of descending beneath its parachute — Malin was able to pinpoint the rover on a barren plain just 6.5 kilometres from Mount Sharp .

Now, project scientist John Grotzinger, a geologist at the California Institute of Technology in Pasadena, needs to decide on the direction of the rover’s first foray. Should he turn Curiosity away from Mount Sharp and drive it towards an intriguing fan of material at the crater’s rim? The feature, called an alluvial fan, is thought to have been formed by water that swept sediments over the lip of the basin. An instrument on Odyssey has detected that materials in the fan retain heat longer than the surrounding soil in the cold Martian night. Grotzinger says that this could indicate that the materials in the fan are firmer and more consolidated than the rest. “That implicates water as one way to cement them together,” he says.

Alternatively, Curiosity could travel in the opposite direction: towards the base of Mount Sharp, where rock beds contain water-altered clays and sulphates. Whichever direction he chooses, Grotzinger wants to explore the rocks near the landing site to learn how layers of sediment from the base of Mount Sharp interweave with layers from the alluvial fan, and find out which was laid down first. Answers might lie in small craters or other features that cut through the rock layers near the rover, so the mission team will create a route based on those objects. “We’re going to try to string together as many pearls as we think we can identify from orbit, and then explore them as we drive along,” says Grotzinger.

Curiosity is more powerful than NASA’s previous Mars rovers, Spirit and Opportunity, and more efficient at exploring a three-dimensional area. And the strata of the crater and mountain offer an abundant view of the fourth dimension — time. Grotzinger notes that although Spirit and Opportunity have travelled more than 42 kilo­metres between them since they landed in 2004, they have crossed only tens of metres of strata. At Mount Sharp, Curiosity has 5,500 metres of strata to traverse.

Curiosity itself has time on its side. Its nuclear-powered energy source could sustain it for many years beyond its nominal two-year lifetime. So as tempting as it is to turn Curiosity into a mountain climber immediately, Grotzinger is happy to be patient. “If it takes a year to get there,” he says, “that’s okay.”

Source: Nature.

Stem-cell pioneer banks on future therapies.

Japanese researcher plans cache of induced stem cells to supply clinical trials.

Progress toward stem-cell therapies has been frustratingly slow, delayed by research challenges, ethical and legal barriers and corporate jitters. Now, stem-cell pioneer Shinya Yamanaka of Kyoto University in Japan plans to jump-start the field by building up a bank of stem cells for therapeutic use. The bank would store dozens of lines of induced pluripotent stem (iPS) cells, putting Japan in an unfamiliar position: at the forefront of efforts to introduce a pioneering biomedical technology.

A long-held dream of Yamanaka’s, the iPS Cell Stock project received a boost last month, when a Japanese health-ministry committee decided to allow the creation of cell lines from the thousands of samples of fetal umbilical-cord blood held around the country. Yamanaka’s plan to store the cells for use in medicine is “a bold move”, says George Daley, a stem-cell biologist at Harvard Medical School in Boston, Massachusetts. But some researchers question whether iPS cells are ready for the clinic.

Yamanaka was the first researcher to show, in 2006, that mature mouse skin cells could be prodded into reverting to stem cells1 capable of forming all bodily tissues. The experiment, which he repeated2 with human cells in 2007, could bypass ethical issues associated with stem cells derived from embryos, and the cells could be tailor-made to match each patient, thereby avoiding rejection by the immune system.

Japan is pumping tens of millions of dollars every year into eight long-term projects to translate iPS cell therapies to the clinic, including a US$2.5-million-per-year effort to relieve Parkinson’s disease at Kyoto University’s Center for iPS Cell Research and Application (CiRA), which Yamanaka directs. That programme is at least three years away from clinical trials. The first human clinical trials using iPS cells, an effort to repair diseased retinas, are planned for next year at the RIKEN Center for Developmental Biology in Kobe.

Those trials will not use cells from Yamanaka’s Stock. But if they or any other iPS cell trials succeed, demand for the cells will explode, creating a supply challenge. Deriving and testing iPS cells tailored to individual patients could take six months for each cell line and cost tens of thousands of dollars.

Yamanaka’s plan is to create, by 2020, a standard array of 75 iPS cell lines that are a good enough match to be tolerated by 80% of the population. To do that, Yamanaka needs to find donors who have two identical copies of each of three key genes that code for immune-related cell-surface proteins called human leukocyte antigens (HLAs). He calculates that he will have to sift through samples from some 64,000 people to find 75 suitable donors.

Using blood from Japan’s eight cord-blood banks will make that easier. The banks hold some 29,000 samples, all HLA-characterized, and Yamanaka is negotiating to gain access to those that prove unusable for other medical procedures. One issue remains unresolved: whether the banks need to seek further informed consent from donors, most of whom gave the blood under the understanding that it would be used for treating or studying leukaemia. Each bank will determine for itself whether further consent is needed.

Yamanaka has already built a cell-processing facility on the second floor of CiRA and is now applying for ethics approval from Kyoto University to create the stock. Takafumi Kimura, a CiRA biologist and head of the project’s HLA analysis unit, says that the team hopes to derive the first line, carrying a set of HLA proteins that matches that of 8% of Japan’s population, by next March.

Yamanaka’s project has an advantage in that genetic diversity in Japan is relatively low; elsewhere, therapeutic banks would have to be larger and costlier. Most iPS banks outside Japan specialize in cells from people with diseases, for use in research rather than treatment. The California Institute for Regenerative Medicine (CIRM) in San Francisco, for example, plans to bank some 3,000 cell lines for distribution to researchers.

Alan Trounson, president of CIRM, says that unresolved research questions about iPS cells make it “premature” to begin therapeutic trials. “We don’t have complete pictures of how good they would be,” he says, noting that such cells accumulate mutations and other defects as they are produced from differentiated cells. Irving Weissman, a stem-cell biologist at Stanford University in California, warns that iPS cells derived from blood cells have been shown to form tumours3.

Kimura says that the answer is to carefully avoid the white blood cells that cause tumours when deriving the cell lines, and he stresses that all safety concerns will be addressed. “We’re building a national resource. It has to be safe and have the confidence of the people.”

Daley, who last month toured CiRA’s facility, calls it “nothing short of spectacular, pristine, perfect”. He agrees that proving the safety of the cells will be tough, but he is enthusiastic about the effort. “It’s clear they’re readying themselves for a big project,” he says.

Source: Nature.


Britain’s big bet on graphene.

Manchester institute will focus on commercial applications of atom-thick carbon sheets.

Kostya Novoselov has the tour down pat. After a friendly introduction, visitors are whisked to a clean room so that they can repeat the experiment that helped to win him a share of the Nobel Prize in Physics in 2010. The important bit can be done in seconds: press some sticky tape onto a chunk of graphite, then press it again onto an ultraclean silicon wafer. Peel it off, and some of the silver flakes dotting the wafer’s surface are atom-thick sheets of honeycombed carbon known as graphene.

The material has had a meteoric rise since Novoselov, his fellow Nobel laureate Andre Geim and their team at the University of Manchester, UK, reported this deceptively simple way of making graphene1. Hundreds of groups around the world have investigated its remarkable range of properties. It is highly conductive, and exhibits a variety of quantum-mechanical behaviours that had previously been seen only in more complex materials. It is thin and flexible, and its electrical and mechanical properties change in response to its surroundings. These characteristics and others suggest various electronics applications, including touch screens, sensors and frequency generators.

Now, the UK government is hoping that Novoselov and Geim can make money from graphene. In February, the UK Engineering and Physical Sciences Research Council (EPSRC) announced £38 million (US$59 million) in funding for a National Graphene Institute at the university. Scheduled to open in 2015, the centre will be a hub for translating basic research into industrial applications. Researchers at Manchester will mingle with industrial scientists loaned by domestic and overseas technology firms. Spin-off companies will flourish in off-campus research parks, sparking a technology revolution in a city that was once at the centre of the Industrial Revolution. That’s the vision, at least.

The initiative has its share of critics. Some academics in the United Kingdom say that the government wants to turn campuses into money-making enterprises. Elsewhere, it is not difficult to find researchers who say that graphene’s commercial value may be overhyped. Many doubt that a single material, however promising, can revive Britain’s atrophied electronics industry.

Novoselov acknowledges these arguments, but thinks that the investment will pay off. “These millions will come back quite soon,” he says. It will certainly mean an expansion of his own research enterprise, which is currently looking at how to combine graphene with other two-dimensional materials. It will also allow companies large and small to come to the university and conduct research that might further their own industrial ambitions.

The University of Manchester is a microcosm of a global boom in graphene research (see ‘Graphene goes global’). More than 20 academics from its chemistry, biology, materials science and engineering departments participate in weekly meetings about the material. The discussions are not only about electronics: some colleagues are studying graphene for use in biosensors, and others want to incorporate it into advanced materials.

Demand for graphene from other departments has been so high that the group cannot keep up, so Branson Belle, one of Novoselov’s postdocs, launched a start-up firm in May to supply the rest of the university. Novoselov and Geim’s core group is growing too, and lab space is getting tight.

Novoselov and Geim were already asking the university for more room last year, and administrators were thinking about how to capitalize on the graphene explosion, says Nancy Rothwell, president and vice-chancellor of the University of Manchester. The pair, together with the university and the city council, submitted a proposal to the EPSRC, which awarded the university £26 million to build the graphene institute, along with £12 million for equipment.

The funding comes at a time of austerity for UK scientists, and it has raised eyebrows in other parts of the physical-sciences community. “The institute looks great and will certainly produce outstanding science,” says Pascal André, who works on nanomaterials at the University of St Andrews, UK. But he questions the wisdom of plunging £38 million into a single subject and location when the EPSRC is slashing research budgets elsewhere. “Will the whole UK innovation of the next 5–10 years be solely based around graphene?” André asks.

Novoselov says that he agreed to the institute only after he was assured that the money would not come at the expense of research grants.

Whether the government’s gambit will help the United Kingdom to compete in the global electronics market is uncertain. Britain lags behind the rest of the world in graphene patents, according to Quentin Tannock, the chairman of Cambridge IP, an independent patent consulting firm in Cambridge, UK. The country is competing with others such as South Korea, a major producer of consumer electronics, which already has a US$20-million, five-year programme to develop graphene-based display panels and other devices, according to Byung Hee Hong, a graphene researcher at Seoul National University. Hong’s group has been perfecting methods for producing sheets of graphene on an industrial scale. “I’m now working with seven different companies,” he says. But Hong adds that the strong commercial interest in Seoul may actually bode well for the new Manchester centre. “Korean companies are not working only in Korea,” he says.

“Will the whole UK innovation of the next 5–10 years be solely based around graphene?”

Even if companies are curious, graphene may still flounder as a commercial product, cautions Phaedon Avouris, a materials scientist at the IBM T. J. Watson Research Center in Yorktown Heights, New York. “There has been this circulating myth that graphene will replace silicon,” Avouris says. In fact, the material is not a semiconductor and lacks the necessary bandgap that would allow it to serve as a transistor — the basic element of all electronics — on its own. Avouris thinks that the material could find a use in niche markets such as high-frequency electronic devices, but he questions whether it will ever hit the big time.

Novoselov does not disagree. But, he adds, there have been enough suggested uses for graphene in different areas to make him want to look at other applications. “What I know for sure is that if we are not going to work on this, it will definitely not happen,” he says.

Novoselov has thrown himself into the project to build the graphene institute, meeting with architects and possible industrial partners on a weekly basis. Geim, who declined to be interviewed, is heavily involved too. Their group, however, is still at the cutting edge of graphene research, and is investigating the properties of layered graphene as well as other two-dimensional crystals such as boron nitride, molybdenum disulphide and niobium diselenide. Like graphene alone, the layered systems display exotic quantum behaviours and could have various applications. For example, in February, the group reported building a transistor by sandwiching boron nitride between two graphene sheets. When a voltage was applied, electrons tunnelled from one graphene sheet to the other, through the boron nitride barrier2.

“We’ve been doing good science for some time and we will do it for the years to come,” says Novoselov. But he is quick to add that now is the right time to make that science pay. “Our government is right: if we have this chance, we should take it.”

Source: Nature.




A new atmospherically relevant oxidant of sulphur dioxide.

Atmospheric oxidation is a key phenomenon that connects atmospheric chemistry with globally challenging environmental issues, such as climate change1, stratospheric ozone loss2, acidification of soils and water3, and health effects of air quality4. Ozone, the hydroxyl radical and the nitrate radical are generally considered to be the dominant oxidants that initiate the removal of trace gases, including pollutants, from the atmosphere. Here we present atmospheric observations from a boreal forest region in Finland, supported by laboratory experiments and theoretical considerations, that allow us to identify another compound, probably a stabilized Criegee intermediate (a carbonyl oxide with two free-radical sites) or its derivative, which has a significant capacity to oxidize sulphur dioxide and potentially other trace gases. This compound probably enhances the reactivity of the atmosphere, particularly with regard to the production of sulphuric acid, and consequently atmospheric aerosol formation. Our findings suggest that this new atmospherically relevant oxidation route is important relative to oxidation by the hydroxyl radical, at least at moderate concentrations of that radical. We also find that the oxidation chemistry of this compound seems to be tightly linked to the presence of alkenes of biogenic origin.

Source: Nature.

Water balance of global aquifers revealed by groundwater footprint.

Groundwater is a life-sustaining resource that supplies water to billions of people, plays a central part in irrigated agriculture and influences the health of many ecosystems1, 2. Most assessments of global water resources have focused on surface water3, 4, 5, 6, but unsustainable depletion of groundwater has recently been documented on both regional7, 8 and global scales9, 10, 11. It remains unclear how the rate of global groundwater depletion compares to the rate of natural renewal and the supply needed to support ecosystems. Here we define the groundwater footprint (the area required to sustain groundwater use and groundwater-dependent ecosystem services) and show that humans are overexploiting groundwater in many large aquifers that are critical to agriculture, especially in Asia and North America. We estimate that the size of the global groundwater footprint is currently about 3.5 times the actual area of aquifers and that about 1.7 billion people live in areas where groundwater resources and/or groundwater-dependent ecosystems are under threat. That said, 80 per cent of aquifers have a groundwater footprint that is less than their area, meaning that the net global value is driven by a few heavily overexploited aquifers. The groundwater footprint is the first tool suitable for consistently evaluating the use, renewal and ecosystem requirements of groundwater at an aquifer scale. It can be combined with the water footprint and virtual water calculations12, 13, 14, and be used to assess the potential for increasing agricultural yields with renewable groundwaterref15. The method could be modified to evaluate other resources with renewal rates that are slow and spatially heterogeneous, such as fisheries, forestry or soil.

Source: Nature.

Unplug! Too Much Light at Night May Lead to Depression.

When you climb into bed for the night, is your bedroom “littered” with dim light from streetlights, passing traffic, a computer, night-light or television set?

Even if the light is so dim that you can easily sleep through it, light pollution can prompt biological changes that have a very significant, and potentially serious, impact on your physical and mental health.

Obvious examples would be the glow that can be seen from miles outside of a big city, or the absence of stars in the night sky if you live in an urban environment.

More subtle examples of light pollution are the strips of light that come in around your curtains at night, or even the glow from your clock radio.

All of these light sources disrupt the natural rhythms of nature, as like most other creatures, humans need darkness. When this natural rule is violated, the consequences can be steep …

Dim Light at Night May Lead to Depression

A study done with hamsters at Ohio State University Medical Center has found that chronic exposure to dim light at night can cause signs of depression after just a few weeks.1 The study also showed changes in the hamsters’ hippocampus similar to brain changes seen in depressed people.  They pointed out that rates of depression have risen along with exposure to artificial light at night:

“Exposure to artificial light at night (LAN) has surged in prevalence during the past 50 years, coinciding with rising rates of depression.”

The link could be due to the production of the hormone melatonin, which is interrupted when you’re exposed to light at night. There are many studies that suggest melatonin levels (and by proxy light exposures) control mood-related symptoms, such as those associated with depression — especially winter depression (aka, seasonal affective disorder, or SAD).

In a study published by researchers at the Oregon Health and Science University (OHSU), it was found that melatonin relieved SAD.2 The study found insomniacs have a circadian misalignment in which they are “out of phase” with natural sleeping times.

This misalignment can be corrected either by exposure to bright lights (during daylight hours), or by taking a melatonin supplement at a certain time of day. While your body will begin to produce melatonin only after it’s dark outside, the level of melatonin produced is related to the amount of exposure you have had to bright sunshine the previous day; the less bright light exposure the lower your melatonin levels.

Yet another study about melatonin and circadian phase misalignment found a correlation between circadian misalignment and severity of depression symptoms.3

Studies have also linked low melatonin levels to depression in a variety of populations, including multiple sclerosis patients4 and post-menopausal women.5 Clearly, anything that negatively effects melatonin production is likely to have a detrimental effect on your mood. Melatonin’s immediate precursor is the neurotransmitter serotonin, which is a major player in uplifting your mood.

Too Much Light at Night May Also Contribute to Cancer

Normally, your brain starts secreting melatonin around 9 or 10 pm, which makes you sleepy. These regularly occurring secretions thus help regulate your sleep cycle.

The good news is the condition appears to be reversible by simply going back to regular light-dark cycles and minimalizing exposure to artificial light at night. But when light receptors in your eyes are triggered, such as by the glow from your television set, they signal your brain to ‘stay awake.’ To do that, your brain stops secreting melatonin, which is not only a hormone but also a potent antioxidant against cancer.

Melatonin is secreted primarily in your brain and at night it triggers a host of biochemical activities, including a nocturnal reduction in your body’s estrogen levels. It’s thought that chronically decreasing your melatonin production at night — as occurs when you’re exposed to nighttime light – thereby allows your body to be exposed to higher estrogen levels, which increases your risk of developing estrogen-sensitive cancers, such as breast cancer.6

In addition to dampening your mood and increasing your cancer risk, a confused body clock from too much light exposure at night can result in increased appetite and unwanted weight gain.

Light at Night Might Even Make You Fat

Exposure to light during the night can seriously impact your body’s internal clock, even leading to metabolic changes and weight gain. In fact, mice that were exposed to dim light during the night gained 50 percent more weight over an eight-week period than mice kept in complete darkness at night.7 They also had increased levels of glucose intolerance, a marker for pre-diabetes.

The weight gain occurred even though the mice were fed the same amount of food and had similar activity levels, and the researchers believe the findings may hold true for humans as well.

When mice were exposed to nighttime light, they ended up eating more of their food when they would normally be sleeping and this lead to significant weight gain. However, in a second experiment when researchers restricted meals to times of day when the mice would normally eat, they did not gain weight, even when exposed to light at night.

This suggests that the timing of your meals, for instance eating late at night when you’d normally be sleeping, may throw off your body’s internal clock and lead to weight gain. In this case, the artificial light, such as a glow from your TV or computer, can serve as a stimulus for keeping you awake and, possibly, eating, when you should really be asleep.

In other words, while it’s typically thought that your biological clock is what tells you when it’s time to wake up or go to sleep, light and dark signals actually control your biological clock. In turn, your biological clock regulates your metabolism. So when your light and dark signals become disrupted it not only changes the times you may normally eat, it also throws your metabolism off kilter, likely leading to weight gain.

More Consequences of Nighttime Light Exposure

Your circadian rhythm has evolved over many centuries to align your physiology with your environment. However, it is operating under the assumption that you’re still behaving as your ancestors have for countless generations: sleeping at night and being awake during the day.

If you push these limits by staying up late at night, depriving yourself of sleep, or even being exposed to the glow from your computer when you should be sleeping, your body doesn’t know whether it should be producing chemicals to tell you to go to sleep, or gear up for the beginning of your day.

But maintaining this natural circadian rhythm affects far more than just your sleep pattern. Your body actually has many internal clocks — in your brain, lungs, liver, heart and even your skeletal muscles — and they all work to keep your body running smoothly by controlling temperature and the release of hormones.

Disrupting your natural rhythm can also make you more vulnerable to disease, including not only cancer, as mentioned above, but also many others. A report from the American Medical Association highlighted the health risks that changes in circadian rhythms pose: 8

  • Carcinogenic effects related to melatonin suppression, especially breast cancer
  • Obesity
  • Diabetes
  • Depression and mood disorders
  • Reproductive problems

Researchers concluded:

“The natural 24-hour cycle of light and dark helps maintain precise alignment of circadian biological rhythms, the general activation of the central nervous system and various biological and cellular processes, and entrainment of melatonin release from the pineal gland. Pervasive use of nighttime lighting disrupts these endogenous processes and creates potentially harmful health effects and/or hazardous situations with varying degrees of harm.”

The Damage is Reversible!

Even though too much light at nighttime causes undeniable health damage, it appears you can undo some of the harm by turning out the lights … in the featured study, the hamsters depressive symptoms went away when they were allowed eight hours of darkness each day.

For you, this may mean turning off your laptop and television earlier than normal, or conducting a light check of your bedroom to wipe out any light pollution creeping in. Even very low levels of light can be enough to suppress melatonin production, so it’s important to keep your sleeping environment as pitch-black as possible. If your bedroom is currently affected by light pollution, you will notice a major improvement when you eliminate it.  To get your room as dark as possible, consider taking the following actions:

  • Install blackout drapes
  • Close your bedroom door if light comes through it; if light seeps in underneath your door, put a towel along the base
  • Wear an effective face mask that blocks out light — a very inexpensive solution and very easy to implement when you are travelling. Many hotels I stay at during my travels do not have blackout drapes so I use this to get darkness at night. Also useful for sleeping on planes at night.
  • Get rid of your electric clock radio (or at least cover it up at night)
  • Avoid night lights of any kind
  • Keep all light off at night (even if you get up to go to the bathroom) — and this includes your computer and TV (computer screens and most light bulbs emit blue light, to which your eyes are particularly sensitive simply because it’s the type of light most common outdoors during daytime hours. As a result, they can disrupt your melatonin production)
  • If possible, avoid working any night shifts.
  • Please note that red light has a wavelength that has minimal impact on your melatonin production. I actually use a red LED alarm clock in my normally very dark room so I know what time it is, as the alarm will cause adrenal stress.

Source: By Dr. Mercola

Bacterial infections in end-stage liver disease: current challenges and future directions.


Bacterial infections continue to be a leading cause of mortality andacute-on-chronic liver failure in end-stage liver disease (ESLD). The consequences of infection include prolonged hospitalisation, acute kidney injury (AKI), death, de-listing from liver transplant and susceptibility to further infections. The diagnosis of infections in cirrhosis is fraught due to the background of a partial systemic inflammatory response syndrome (SIRS) state and negative cultures in 30-50% of patients. Furthermore, the lack of multi-center studies limits the generalisability of currently available results. The modulation of infections by the underlying immune state, gut barrier function and super-imposed medications such as beta-blockers, proton pump inhibitors and antibiotics is required. A rational approach to the diagnosis and prevention of AKI associated with infection, withjudicious use of crystalloids and albumin, is also needed. Changes in bacteriology including emergence of multi-resistant organisms and Clostridium difficile have also recently changed the approach for prophylaxis and therapy of infections. Effective strategies for the prevention, diagnosis, and management of infections in ESLD form a large unmet need. A systematic approach to study the epidemiology, bacteriology, resistance patterns, and procedure and medication utilisation specific to ESLD is needed to improve outcomes.

Bacterial infections in patients with end-stage liver disease affect candidacy for liver transplantation. Up to one-third of all hospitalised patients with cirrhosis are infected.1–5 With sepsis, mortality increases to more than 50% and is associated with significant costs.6 A recent systematic review demonstrated a fourfold increased risk of death in infected cirrhotic patients compared with their non-infected counterparts.7 More importantly, intensive care unit (ICU) mortality of patients with cirrhosis has remained unchanged over 50 years, unlike disease states such as cardiac failure where mortality has decreased.8 Therefore the prevention, diagnosis and management of infections in patients with end-stage liver disease form a large unmet need. This commentary briefly reviews infections in patients with cirrhosis, and outlines specific areas that need to be addressed in such patients hospitalised with infections.

Scope of the problem

The magnitude of the problem of infections in cirrhosis is not quantifiable for many reasons. Infections are often difficult to recognise in patients with cirrhosis because 30–50% of infections, such as spontaneous bacterial peritonitis (SBP), can remain culture negative.9 Conventional risk-scoring strategies, such as the systemic inflammatory response syndrome (SIRS) criteria, cannot reliably differentiate sepsis (SIRS plus infection) from non-infectious SIRS.10 This is important because a partial SIRS-like state is present in most patients with decompensated end-stage liver disease and therefore in itself cannot be used to differentiate between infected and uninfected patients. There are also difficulties diagnosing the presence of infections, especially in hospitalised cirrhotic patients.5 Strategies such as measuring C-reactive protein and procalcitonin may be helpful in selected patients, but a specific differentiator is still needed.11 ,12 Time-appropriate strategies are needed to suspect infections and send cultures early so as to initiate appropriate antimicrobial therapy. Also a heightened suspicion of potentially resistant organisms is required in order to change therapy as needed.2 In addition, most current studies are single centre, and there are limited data on the emergence of multiresistant strains and healthcare-associated (which develop <48 h after admission in patients with previous exposure to healthcare services in the preceding 90 or 180 days) and nosocomial (which develop >48 h after admission) infections.

Some idea of the magnitude of the problem may be obtained from the US nationwide inpatient sample (NIS), which analyses data from 20% of acute care hospitals and includes 8 million discharge records from 38 states. The NIS identified 65 072 patients in 2006 with a discharge diagnosis of cirrhosis. The total costs incurred were approximately US$14 billion per year. Of the hospitalised patients, 26 300 had presumed infection and required ICU support, as identified by mechanical ventilation and invasive cardiovascular monitoring. The in-house mortality of the hospitalised cirrhotic patients was 53%, or 13 800 deaths a year nationwide. The mean length of hospitalisation was 13.8 days. The total costs associated with ICU admissions in cirrhotic patients with presumed infection were US$3 billion, with mean costs of US$116 200 per admission and average daily costs of US$16 589 in non-survivors.

Another study from the NIS showed that Clostridium difficile infection in patients with cirrhosis was associated with a significantly higher mortality, length of stay and total costs compared with patients admitted with cirrhosis without C difficile and patients with C difficile without cirrhosis. This is striking because the mean age of the patients with C difficile without cirrhosis was significantly higher than that of patients with C difficile and cirrhosis.13 In the Korean National database, patients with cirrhosis and bacteraemia were significantly more likely to die than those without cirrhosis.14 Bacteraemia in cirrhotic patients was more likely to be due to intra-abdominal infections and Klebsiella pneumoniae, and less likely to be due to coagulase-negative Staphylococcus. Multivariate analysis confirmed cirrhosis as an independent risk factor for mortality (HR 2.11, 95% CI 1.43 to 3.13).14

The North American Consortium for the Study of End-Stage Liver Disease (NACSELD) currently includes 12 centres throughout North America focused on determining outcomes after infections in patients with cirrhosis.15 Preliminary data from the NACSELD study noted that, in 176 patients from nine sites, the majority of infections were SBP and urinary tract infection (UTI), followed by spontaneous bacteraemia, skin, respiratory and C difficile infections. Gram-positive (36%) organisms were the most common, followed by Gram-negative (30%) organisms. The remainder were either fungal (4%) in origin or infections without an isolated organism. The death rate was highest for respiratory (44%), bacteraemia (38%) and C difficile (41%) infections, and lowest for urinary (21%) and skin (29%) infections or SBP (17%). The index infections were healthcare-associated (56%) or nosocomial (20%), and, importantly, 28% of patients developed a second infection during hospitalisation. The overall mortality was 25%, and patients who died had a higher Model for End-Stage Liver Disease (MELD) score at admission (25±8 vs 19±7, p<0.001) and were more likely to have hepatic encephalopathy (HE), hepatorenal syndrome (HRS), mechanical ventilation and ICU stay during hospitalisation (all p<0.0001). There was a higher incidence of second infections during hospitalisation in patients who died than in patients who survived (53% vs 20%, p=0.0001). Patients who developed a second infection were more likely to have a Gram-negative first infection, an ICU stay, lower albumin, greater length of hospitalisation and higher MELD score. Multivariate analysis showed that only second infection (p=0.0009) and MELD score (p<0.0001) were associated with death. Therefore there is a need to develop early diagnostic and prognostic markers, including biomarkers, for a better understanding of infections so as to improve outcomes.

Contribution of drugs such as antibiotics, proton pump inhibitors (PPIs) and ß blockers to infections and underlying immune status

Changes in gut bacteria in cirrhosis can lead to bacterial overgrowth with subsequent enhanced bacterial translocation from the gut to the systemic circulation and ascites, identified by bacterial DNA or by isolating bacteria in systemic biofluids. Bacterial translocation is the major pathogenetic factor for infections.5 ,16–18 Bacterial translocation can be silent or can result in florid infections.19 Even in the absence of infection, bacterial translocation can increase mortality.20 ,21 It is also a process that is facilitated by acid suppression22 ,23 and increased intestinal permeability in cirrhosis, specifically with advanced disease. Sepsis as a result of bacterial translocation and small-bowel bacterial overgrowth is a key component of the natural history of infections.20 However, one of the key modulators of outcomes of infections is the underlying immune status, which is negatively affected at multiple levels in cirrhosis. Specifically, the neutrophil burst, phagocytosis and opsonisation are impaired.21 Recent evidence has also indicated that antimicrobial peptides and NOD2 genetic variants are altered in patients with cirrhosis.24 ,25 A deeper understanding of the bacterial–immune interface either at the intestinal wall or within the ascitic fluid or mesenteric lymph nodes is important for developing biomarkers that would predict development of infection with an overall view to prevention.26

Single-centre studies have associated the use of PPIs with SBP and C difficile.13 ,27 This is an important observation, as PPIs are some of the most overprescribed drugs for cirrhosis.28 An appropriate indication for PPI use exists in fewer than half of the patients.29 PPIs predispose to bacterial overgrowth and adversely affect immune function.30 Another seemingly contradictory association is the effect of non-selective ß blockers (NSBBs) on the negative outcomes in cirrhosis. While a meta-analysis showed a reduced development of SBP in previous studies, a recent non-randomised study demonstrated a worse survival in the subset with refractory ascites.31 ,32 The effect of NSBBs on cirrhosis outcomes has led to the formulation of a ‘window hypothesis’, which suggests that NSBBs only improve outcomes in a narrow window of the cirrhosis natural history between those who have medium to large varices before the development of end-stage liver disease.33 Therefore the clinical role of NSBBs in cirrhosis needs to be elucidated further.

The role of non-absorbable antibiotics, such as rifaximin, in the modulation of infections in cirrhosis is also emerging. Whereas the pivotal HE trial did not show a significant difference in the rate of infections between groups, subsequent small studies reported a protective role of rifaximin against endotoxaemia and SBP.34–36 Outpatient prophylaxis using fluoroquinolones or sulfamethoxazole/trimethoprim in patients with previous SBP has been clearly shown to reduce subsequent episodes of SBP, but not survival.37 It is not completely clear whether these agents can improve outcomes in subgroups of patients with ascites fluid albumin <1.0 g/dl. SBP prophylaxis has been associated with the development of C difficile in a single-centre study.13 The study of SBP prophylaxis becomes more nuanced, especially when the emergence of multiresistant strains is considered.2 Further studies into the use of antibiotics are required to determine their role in reducing infections and mortality.

Thus several lines of evidence suggest the influence of outpatient medication on infection risk. Considering the small sample size and retrospective nature of most of these studies, further evaluation of drugs such as PPIs, non-absorbable antibiotics (such as rifaximin) and NSBBs is needed to determine their role in infections.

Prognosis and management in the ICU

Several precipitating factors are associated with deterioration in cirrhosis leading to multiple organ failure. These include infection, gastrointestinal bleeding, alcoholic hepatitis, superimposed viral hepatitis, drug-induced hepatotoxicity, and surgery. The response to infection in patients with cirrhosis is often exaggerated, leading to ICU admission because of sepsis, severe sepsis and septic shock.38 MELD score has been validated as a predictor of mortality in cirrhotic patients in the ICU and may have better prognostic capacity than the Child–Turcotte–Pugh score and the Simplified Acute Physiology Score II. The Acute Physiology and Chronic Health Evaluation III score is another predictor of early ICU mortality. The Sequential Organ Failure Assessment score correlates with mortality: failure of two organ systems is associated with a mortality of 55%, and failure of three or more organs with almost 100% mortality.39 Even when supportive measures are introduced, the underlying immune dysfunction state (immune paralysis following the first infection which contributes to secondary infections), poor nutrition, ongoing portal hypertension-related systemic haemodynamic changes, HE and gastrointestinal bleeding prevent recovery in these patients. Liver transplantation is ultimately an effective form of therapy for these patients, and worsening liver and renal function increase the MELD score, but ongoing infection and multiorgan system dysfunction make them generally poor candidates.

The ‘sepsis bundle’ has been accepted as the standard of care in patients with severe sepsis in the ICU.40 It is not clear whether these recommendations apply to patients with cirrhosis and severe sepsis. For example, arterial lines and central venous catheters are recommended for monitoring of mean arterial pressure and central venous pressure in severe sepsis. However, in critically ill cirrhotic patients, such vascular access may be associated with a significantly increased risk of bleeding. Red blood cell transfusions are recommended to increase central venous oxygen saturation. However, red blood cell transfusions in cirrhotic patients may be associated with an increased risk of variceal bleeding. Thus the role of the sepsis bundle in cirrhosis needs validation.

The key areas of need in the management of cirrhotic patients in the ICU is the prevention of nosocomial and second infections, reduction of unnecessary instrumentation, judicious use of antibiotic and antifungal agents, and validation of prognostic scores that take into account the underlying liver disease severity. Additional areas that need to be addressed are whether albumin is the preferred volume expander, how coagulopathy should be corrected, the optimal vasopressor support, the methodology for determining adrenal insufficiency, and the situations in which steroids should be given and the doses that should be used.6 Finally, the role of artificial and bioartificial liver support devices needs to be determined in this population.41

Prevention and treatment of acute kidney injury (AKI) in infected patients with cirrhosis

A critical need is to prevent and adequately treat renal dysfunction in infected cirrhotic patients. This is because renal dysfunction with AKI has emerged as a major determinant of mortality in patients with cirrhosis.42 ,43 AKI, including HRS, is associated with a markedly shorter survival. In patients with decompensated cirrhosis admitted to hospital, increased creatinine concentration within 24 h of admission is associated with poorer survival. Even more profound is the requirement of renal replacement therapy, which is associated with 94% in-hospital mortality.44 While most cases of functional renal impairment respond to volume challenge, with return of renal function to baseline levels, approximately one-third of patients are not volume responsive; these include patients with HRS or acute tubular necrosis.45 Therefore the first line of management of AKI in hospitalised cirrhotic patients is volume expansion, the response to which can determine the prognosis and subsequent management—for example, the use of vasoconstrictors would be indicated for volume-unresponsive cases of AKI such as HRS. Acute or type 1 HRS is defined as renal failure, which is characterised by a doubling of the initial serum creatinine to a level of >2.5 mg/dl in <2 weeks, which has been reported in about 10% of cirrhotic inpatients. Chronic or type 2 HRS is characterised by moderate renal failure, with serum creatinine between 1.5 and 2.5 mg/dl.45 Whereas type 2 HRS is usually associated with refractory ascites and follows a steady declining course, type 1 HRS is usually precipitated by an acute event and is often part of multiorgan system failure.46 The most common precipitating factor of type 1 HRS is bacterial infection,47 ,48 and this may occur despite clearance of the bacterial infection. The inflammatory response to bacterial infections increases systemic arterial vasodilatation, with further reduction of the effective arterial blood volume and further renal vasoconstriction, leading to renal failure.

SBP was the first bacterial infection recognised to be associated with a high incidence of renal failure in cirrhosis. This occurs in approximately one-third of patients despite resolution of the infection,48 ,49 and is associated with an in-hospital mortality of 42–67%.49 ,50 However, it was soon recognised that any bacterial infection could precipitate renal failure in cirrhosis.51 Patients who develop renal failure with bacterial infection have a higher MELD score and lower mean arterial pressure.47 Biliary or gastrointestinal tract infections are more likely to be associated with the development of renal failure, followed by SBP and UTI, although other infections such as pneumonia or even skin infections are associated with the development of renal failure. Once renal failure develops, it can be transient, resolving with the clearance of the infection, or it can persist, or even progress despite the clearance of infection.51 Biliary or gastrointestinal infection-induced renal failure is most likely to progress, followed by SBP- and UTI-related renal failure.47 Once renal failure sets in, the probability of survival at 3 months is only 31%, and decreases with higher MELD scores.52

Prevention of renal failure in the setting of infections remains a challenge. With SBP, patients given albumin have a lower incidence of renal failure, associated with improved survival.53 Underlying liver and renal function determine the risk of developing renal dysfunction associated with SBP. In one study, using the definition of high risk as plasma urea ≥60 mg/dl and serum bilirubin ≥4 mg/dl, almost 30% of patients who presented with SBP could be regarded as low risk for the development of renal failure and therefore were not given albumin. Renal failure only developed in 4.7% of the low-risk group, which had a 3.1% mortality. In contrast, 40% of the patients with SBP in the high-risk group (70% of the entire cohort) already had renal failure at the time of SBP diagnosis, while an additional 26% developed renal failure before SBP resolution.54 Those in the high-risk group treated with albumin had a significantly improved 90-day survival (p=0.01). The number of patients needed to treat in the high-risk group to avoid one death was 5.5. Similar findings were also reported by Sigal et al55 and Terg et al. 56 Thus the need for universal administration of albumin for the treatment of SBP needs to be re-evaluated. The need for albumin to prevent the development of renal failure in other bacterial infections also needs to be examined.

A small study assessed the effects of 2 mg/day terlipressin (a systemic vasoconstrictor) in addition to ceftriaxone (1 g every 12 h) on systemic haemodynamics and clinical outcome in patients with SBP.57 This regimen improved the hyperdynamic circulation compared with ceftriaxone alone. There was a significant increase in SBP reversal and a reduction in mortality with terlipressin at 48 h. Therefore the use of a vasoconstrictor should be investigated as a potential alternative, or additive, to albumin in the prevention of renal impairment in SBP.

Renal dysfunction, especially HRS type 1, is treated with vasoconstrictors and albumin infusion. The choice of vasoconstrictor depends on local availability: midodrine in North America in combination with octreotide, and terlipressin for most other parts of the world.45 Given the poor survival of patients with cirrhosis, bacterial infections and established renal failure,47 there is now a trend towards treating renal impairment at an earlier stage than defined type 1 HRS. One challenge has been to define an early stage of renal dysfunction, as serum creatinine is an inaccurate measure of renal function.58 ,59

A new definition of AKI in cirrhosis has been proposed,60 which is an increase in serum creatinine of 0.3 mg/dl in <48 h (table 1).61 The exact prevalence of AKI according to this new definition is unknown, but is an important question because it appears that such small increases in serum creatinine in patients with cirrhosis may negatively affect survival.

View this table:

Table 1

Proposed definition of kidney disease in cirrhosis60

Several newer concepts are helping to shape treatment strategies. These include the understanding that both the acute deterioration in renal function and the background chronic renal dysfunction can be functional or structural in nature, and the recent recognition that the inflammatory response to bacterial infection may be partly responsible for the development of renal failure.

Measures for prevention, surveillance and identification of healthcare-associated and nosocomial infections and multiresistant bacteria and C difficile

The emergence of multiresistant species and the looming spectre of nosocomial and healthcare-associated infections are concerning. Nosocomial infections in the general population are estimated to affect 1.7 million persons a year, cost at least US$5 billion annually, and are the sixth leading cause of death in the USA.62–65 Although healthcare-associated and nosocomial infections are different, they both increase length of stay, cost and mortality, and occur more commonly in ‘sicker’ patients following procedures such as surgery or in those who need mechanical ventilation or vascular or urinary catheters.66 The organisms responsible are often resistant to the ‘first line’ antibiotics often given for similar community-acquired infections, making empiric antibiotic treatment decisions more challenging and expensive.2 ,67–69

Nosocomial infections in non-cirrhotic patients are usually broken down into four categories62 ,66–68 as shown in table 2. However, there has been little published on nosocomial infections in patients with cirrhosis. Fernandez et al studied multiresistant organisms and nosocomial infections occurring in a single centre over three time periods: 1998–2002 (n=572), 2005–2007 (n=507) and 2010–2011 (n=162).2 ,3 Infection was present in one-third of hospital admissions: 25–32% healthcare associated and 36–45% nosocomial. Community-acquired infections were most commonly SBP (35%) and cellulitis (19%), healthcare-associated infections were most commonly SBP (28%) and UTIs (24%), and nosocomial infections were dominated by UTIs (31%).2 C difficile was not studied. Overall, multidrug-resistant (MDR) organisms caused 4% of community-acquired, 14% of healthcare-associated and 35% of nosocomial infections (p<0.001).2 This high risk of MDR organisms decreased the efficacy of their ‘standard of care’ antibiotic regimens to 40% in nosocomial infections, and doubled mortality in patients infected with MDR organisms. In another European single-centre study, Merli and colleagues found that one-third of 150 hospitalised patients with cirrhosis experienced at least one infection; 78% were healthcare-associated or nosocomial infections.4 UTIs were most common, and 64% were caused by MDR organisms. MDR organisms were predominantly Gram-negative isolates in SBP, such as Escherichia coli and K pneumoniae with extended spectrum β lactamase activity. The change in bacteriology also reflects an emergence of Gram-positive pathogens. A disturbing trend is the increased isolation of methicillin-resistant Staphylococcus aureus.70 Enterococcus faecalis and Enterococcus faecium have been isolated in 10–24% of infections in the setting of cirrhosis and are associated with a mortality of 25%. Focusing on specific infections, it has been found that SBP is an important cause of both community-acquired and nosocomial infections in patients with cirrhosis.71 ,72 Whereas community-acquired SBP is more commonly caused by Gram-negative rods, nosocomial SBP has an increased prevalence of Gram-positive cocci. In addition, nosocomial acquisition increases the risk of resistance to cephalosporin and fluoroquinolone and significantly increases mortality. Although previous reports on nosocomial infections did not include C difficile infection, it was a common nosocomial infection found in the NACSELD study and had the highest risk of mortality (28%).15 This is similar to the previous C difficile National Database study in cirrhosis in which length of stay doubled, mortality markedly increased, and cost increased by US$43 665/infected admission.13

View this table:

Table 2

Categories of nosocomial infections in the non-cirrhotic population66

We propose, on the basis of our and other previous work in this area, that healthcare-associated and nosocomial infections in cirrhosis be broken down into six categories: spontaneous bloodstream infections unrelated to interventions or infections at other sites, UTIs, pulmonary infections, SBP, C difficile and intervention-related infections (table 3). Although up to one-third of all nosocomial infections should be preventable,73 ‘success in curbing their emergence remains elusive.’74 It should be emphasised that the data available on healthcare-associated and nosocomial infections in cirrhosis are largely limited to single centres, although smaller multicentre studies exist.1–4 ,13 ,71 ,72 ,75–80

View this table:

Table 3

Proposed categories of nosocomial infections in cirrhosis


Because of the high morbidity and mortality in patients with cirrhosis who become infected (many of whom may be denied liver transplantation because of multiple organ failure) and the paucity of data in this field, we propose the studies outlined in table 4. Only through systematic study of epidemiology, bacteriology, resistance patterns, and procedure and medication utilisation specific to patients with cirrhosis will we discover how to routinely accomplish this in the most cost-effective way.

View this table:

Table 4

Challenges and future directions of bacterial infection management in cirrhosis


  • Funding This was partly funded by the NIH grant NIDDK RO1DK087913 and partly from an educational grant from Grifols Pharmaceuticals.
  • Competing interests None.
  • Provenance and peer review Not commissioned; externally peer reviewed.


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