Neuroscience: Thought experiment

Japanese hospitals are using near-infrared imaging to help diagnose psychiatric disorders. But critics are not sure the technique is ready for the clinic.

David Cyranoski

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In a room full of psychiatrists in downtown Tokyo, I prepare to have my mental health assessed. No probing questions are asked. Instead, I don an odd type of swimming cap, criss-crossed with cables and studded with red and blue knobs. At the flick of a switch, the 17 red knobs send infrared light 2 to 3 centimetres into my brain, where it is absorbed or scattered by neurons. Photoreceptors in the 16 blue knobs retrieve whatever light bounces back to the surface. Buried in the signals, say the researchers operating the system, are clues that can distinguish depression, bipolar disorder, schizophrenia and a normal state of mind.
More than 1,000 people have already been subjects of the technique, called near-infrared spectroscopy (NIRS) and developed by Masato Fukuda, a psychiatrist and neuroscientist at Gunma University Hospital in Maebashi, and the Hitachi Medical Corporation in Tokyo. Most of those were research subjects. But since April 2009, when NIRS was approved by the health ministry as an "advanced medical technology" to assist psychiatric diagnoses, more than 300 people have paid ¥13,000 (US$160) out of their own pocket to access the technique. The University of Tokyo Hospital, one of eight leading Japanese research hospitals now offering NIRS diagnostic neuroimaging, found demand for it to be so high that the hospital stopped taking appointments twice. Gunma University Hospital is fully booked to the end of March. "We've been overwhelmed by requests," says Fukuda.

The appeal of NIRS is its promise of fast, clear-cut diagnoses of psychiatric conditions which, with their messily overlapping symptoms, are frequently diagnosed wrongly or not diagnosed at all. US studies, for example, found that some 70% of bipolar patients were initially misdiagnosed^1,2. As for patients, says Fukuda, "They want some kind of hard evidence," especially when they have to explain absences from work.

“Demand was so high that the hospital stopped taking appointments twice.”

NIRS could offer an objective measure of mental health reliable and convenient enough for routine use in the clinic. Fukuda says that it can help point to a diagnosis much like a chest X-ray might be used to help diagnose pneumonia or an electrocardiogram to define a heart problem. Aside from Fukuda and a group of doctors in Japan, however, few scientists are persuaded. Critics charge that the studies so far have been too few, too small and too weakly designed to warrant the technique's clinical use. "It's attractive as a research topic, but the data are not convincing enough," says Masahiko Haruno, a neuroscientist at Tamagawa University in Tokyo. John Sweeney, a neuroscientist at the University of Illinois, Chicago, who has spent two decades looking for connections between various brain-monitoring techniques and diseases such as schizophrenia, says that "none has ever been validated to anyone's satisfaction". And NIRS is the least developed of them all, he says, calling it "the thinnest of ice to be treading upon. We are nowhere near ready to tell patients and families that they should have these kinds of tests."

New kid on the block

Sporting the knobbled cap, I stare at a screen showing Japanese phonetic characters and say aloud words beginning with each sound. The words don't come readily, particularly in front of an audience of psychiatrists and neuroscientists. Coming from all over Japan, they meet every month to discuss NIRS results and strategies.

Having entered the research scene some 15 years ago, NIRS is relatively new compared with functional magnetic resonance imaging (fMRI) or electroencephalography (EEG), but in Japan it has raced ahead to the clinic. (The two biggest suppliers of NIRS analytic devices — Hitachi and Kyoto-based Shimadzu — are both based in Japan and the country accounts for two-thirds of publications using NIRS analysis.) The technique takes advantage of the fact that compared with constituents of other tissues, haemoglobin in blood absorbs more light in the near-infrared spectrum. Blood flow to a particular brain region increases when neurons there are active. So monitoring the changes in haemoglobin concentration gives a site-specific read on blood flow and thus on neuronal activity³. Fukuda's NIRS device focuses on the prefrontal cortex and temporal cortex, regions that are implicated in many of the symptoms seen in psychiatric disorders; the signature pattern of blood flow associated with each disorder is used to help diagnose it. NIRS lacks the precision and depth of fMRI, which can pinpoint changes in blood flow throughout the brain and with much greater spatial resolution. But NIRS is relatively cheap and mobile, and subjects can sit upright without having to endure a spell in the large, loud and sometimes nerve-wracking tube of an fMRI machine. This means that NIRS is easier to use on fidgety subjects such as children, and people with psychotic conditions or anxiety. The advantages have made infrared imaging increasingly popular with brain researchers worldwide. Devices from the largest maker in the United States, NIRx Medical Technologies of Glen Head, New York, are being used to study areas ranging from autism to brain–computer interfaces. Hitachi now offers a stripped-down version that allows the brains of four people interacting in a room to be analysed wirelessly.

Fukuda, though, has focused on applying the technology to diagnoses. Lean and grey-haired, he speaks thoughtfully and is confident in the technique and its potential to help people. He started using a basic NIRS device in 1997, when he was an associate professor at the University of Tokyo already working with EEG. Since then, he has been measuring the brain activity of people with a variety of disorders and has reported that those with depression, bipolar disorder or schizophrenia have, when averaged across groups of 10–20, a characteristic pattern of brain activation^4,5. Fukuda boils the data down to graphs describing activity in the prefrontal and temporal cortices for the first 60 seconds or so of each task (see 'Traces of troubled minds'). He says that the NIRS test on its own classifies patients correctly 80% of the time.

Click for larger image

These studies have not convinced other neuroscientists. Haruno says the patient numbers in the published studies are "far too small" to distinguish patterns, and that even if such patterns are found when signals are averaged across groups, this does not mean that one person's pattern can be used to assign them to a group. "What does that mean for an individual patient? It's very misleading," Haruno says.
Even Fukuda's collaborator, Andreas Fallgatter of the University of Tübingen in Germany, who has used NIRS for 14 years on about 1,000 patients and is now repeating Fukuda's language test in German, says "NIRS is still a research method." Still, he says, "Obviously, Dr Fukuda could successfully convince the Japanese authorities."
That approval came via a fast-track process instituted by the national health ministry's Advanced Medical Technology programme in 2005 in an attempt to spur the development of biomedical technologies. Teruhiko Higuchi, a clinician and researcher specializing in depression and president of the National Center of Neurology and Psychiatry, led the evaluation of NIRS. He concluded that the technology was safe, effective and fast, and could help to make critical distinctions between different mental states (major depression, bipolar disorder or schizophrenia) at an early stage, when used with other diagnostic techniques. "It is, in the end, only to assist diagnosis," he told the members of the evaluation committee, according to meeting minutes posted online. Higuchi's centre now offers the technique. Other committee members raised concerns about the small numbers of patients in the studies, and the fact that some were receiving drugs, but they did not object to its approval.
Fukuda says that a larger study involving more than 500 patients will be submitted for publication soon and will answer many of his critics. He says that doubling the number of knobs and other methodological modifications reveal a much sharper distinction between the conditions, and that controlling for medicated versus non-medicated patients showed that drugs do not obscure a patient's NIRS profile. He acknowledges the validity of criticism about using group averages to diagnose individuals: "Strictly speaking, this criticism is right." But he says the same is true for many other measurements, such as electrocardiograms and EEG, which vary from one individual to the next and thus require interpretation, but can still be clinically useful. "Clinical diagnosis and NIRS examination are complementary to each other," he says. "We stress this complementary nature to all the patients."
But in at least some cases, NIRS seems to take the lead in diagnosis. For example, when Fukuda calculates his success rates, NIRS results that match the clinical diagnosis are considered a success. If the results don't match, Fukuda says he will ask the patient and patient's family "repeatedly" whether they might have missed something — for example, whether a depressed patient whose NIRS examination suggests schizophrenia might have forgotten to mention that he was experiencing hallucinations. Andreas Meyer-Lindenberg, an expert in neuroimaging and mental health at the University of Heidelberg, Germany, says that studies of patients without an existing diagnosis or psychiatric medication would be more persuasive. "You would need a sample of unclear cases, as you would get in the clinic, classify them and then ascertain their diagnosis by following them up."
Fukuda and his colleagues are already moving on to NIRS studies that might aid diagnoses of a range of disorders, including those centring on panic, attention deficit and post-traumatic stress.

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My own NIRS results, however, are short on clarity. Within 15 minutes, including the tests and a quick computer analysis, Fukuda is able to look at my traces and deliver a diagnosis: normal. When I later compared them to the patterns published in the literature, however, my trace seems to describe a brain somewhere between normal and bipolar.
Later, Fukuda says that my pattern is not a normal 'norm

source : http://www.nature.com/news/2011/110112/full/469148a.html

Transgenic chickens curb bird flu transmission

Genetic modification quells virus, but questions linger about use in developing countries.

Virginia Hughes

GM chickens could pave way for H5N1-resistant flocks if tall political, technical and economic hurdles can be overcome.Image by Norrie Russell, courtesy of Valerie White and The Roslin Institute

Researchers have made genetically modified chickens that can't infect other birds with bird flu. The H5N1 strain of influenza — which raged through southeast Asia a decade ago and has killed hundreds of people to date — remains a problem in some developing countries, where it is endemic.

The birds carry a genetic tweak that diverts an enzyme crucial for transmitting the H5N1 strain. Although they die of the disease within days, the molecular decoy somehow impedes the virus from infecting others. The findings are published today in Science¹.

The researchers say that although large-scale distribution of the genetically modified (GM) birds will one day be feasible, their study is meant only to show proof-of-concept of the technique.
"We have more ambitious objectives in terms of getting full flu resistance before we would propose to put these chickens into true production," says Laurence Tiley, a molecular virologist at the University of Cambridge, UK, and lead investigator for the study. His team is now working on further genetic tweaks that would inhibit the virus in different ways. "It would be a bit like combination drug therapy for HIV," he says.
Other experts point out that even if the GM chickens carried full resistance to influenza, there are political and economic hurdles to their widespread commercial use — not least the public's aversion to GM food.
"It's the beginning of something which will require a certain number of years to see whether it is accepted by the public," says Ilaria Capua, head of virology at the Experimental Animal Health Care Institute of Venice in Legnaro, Italy.

Path of destruction

H5N1 is endemic in at least five countries, and is particularly threatening in Egypt and Indonesia, says Capua. So far, the virus has not been able to spread from human to human, but some public health experts worry that eventually it will adapt to do so.
In developed countries, H5N1 outbreaks are controlled by swiftly culling the animals. In poor countries, however, there are lots of small farms, few health regulations and long-held cultural practices involving birds. "In the developing world, we cannot follow the slaughter strategy used in the developed world," says Arnold Monto, an epidemiologist at the University of Michigan School of Public Health in Ann Arbor. "Politically they can't do it, and practically they can't do it."
Instead, developing countries try to control H5N1 by vaccinating birds. This doesn't prevent them from silently acquiring mild forms of the disease and, if not monitored well, transmitting it to healthy birds. What's more, flu viruses mutate quickly and are famous for evading vaccines.
If made commercially available, the GM birds wouldn't have these issues. They carry a genetic 'cassette' dubbed a short-hairpin RNA, which includes genetic sequences that match up with an enzyme that influenza viruses use for replication and packaging. These sequences can bind with the enzyme, somehow stopping it from working with the virus.
The enzyme could mutate to evade this decoy, but if it did so it would no longer be able to match up with its binding sites on the virus. So for the virus to escape, it would need to simultaneously change its own genome and that of the enzyme in eight different spots — a highly unlikely event.
The chickens were modified by a team led by Helen Sang, a geneticist at the Roslin Institute of the University of Edinburgh, UK. The researchers modified the chickens by injecting a lentivirus carrying the cassette into clusters of cells on top of egg yolks. In some of the resulting chicks, the cassette integrates into germ cells. These animals can be cross-bred to produce chickens that carry the cassette in every cell.
The researchers infected decoy-carrying birds with H5N1 and housed them with uninfected birds, some with the transgene and some without. Most of the birds that received the primary infection died, but didn't pass on the flu to any of their uninfected cagemates.
The researchers found that the amount of virus present in the infected GM birds was not significantly different from that in non-transgenic controls.
"It must be something above and beyond the effect on replication that's having this effect," says Tiley. It could be, for example, that the hairpin disrupts the packaging of the virus, preventing it from being taken up normally in the next animal.

Don't count your chickens

Sang says that using their methods, it costs approximately £50,000 (US$79,000) to produce "a small number of stable transgenic birds you can characterize and breed from". She and Tiley argue that getting similar transgenic birds into global production would be possible because there are only a handful of companies providing purebred chicken lines.
But this approach would not be feasible in poorer countries. "This will only become affordable for the people who are well off," says Marc Van Ranst, a virologist at the Dutch-speaking Catholic University of Leuven in Belgium.

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The technique may become most useful not for preventing the spread of H5N1, but for using similar cassettes to create resistance to other common poultry diseases.
Tiley's study was partially funded by Cobb-Vantress, a major international chicken-breeding company. Cobb-Vantress told Nature they have no plans to continue funding this work.
"All the companies are fairly sensitive to public perceptions," says Karel Schat, a virologist and immunologist at Cornell University in Ithaca, New York. Schat is a paid consultant for another company that is also funding research on using transgenes for disease resistance. "Scientists are excited. But it may well be that people at the higher level of the companies are trying to be a little bit more careful." 

source : http://www.nature.com/news/2011/110113/full/news.2011.16.html

Future of food could be bright

French agencies' study punctures assumptions about the state of global agriculture.

Barbara Casassus

Feeding the nine billion people predicted for 2050 will be possible, a new report suggests.Ingram Publishing

The world will be able to feed the predicted 2050 population of nine billion people, according to two French agricultural research organizations. In a joint report published today, they lay out findings gleaned from 2006 to 2008 that could overturn some current assumptions about the state of global farming.

The report, titled Agrimonde¹, is published by the French National Institute for Agricultural Research (INRA) and the Centre for International Cooperation in Agronomic Research for Development (CIRAD), both headquartered in Paris. It contains some surprise findings on Africa and other regions — the latest results from an ongoing study by the two research agencies.

Agricultural productivity in Africa doubled between 1961 and 2003 — a finding that overturns most assumptions "and is one of the most surprising results of our work", Patrick Caron, CIRAD's director-general for research and strategy, told reporters last night.
African productivity remains the lowest in the world, however, averaging 10,000 kilocalories per hectare (kcal ha^–1) compared with 20,000 kcal ha^–1 globally and 25,000 kcal ha^–1 in Asia. Productivity elsewhere doubled or tripled over the same period.

Asian aggregate

Asia scored higher on productivity than in other studies, because the agencies looked at aggregate rather than independent annual yields of wheat, rice and other crops, explains Bruno Dorin, an economist at CIRAD and one of the report's authors. "In Asia, the wheat yield may be lower, but if you take account of rice and other crops grown in the same year, the total yield is higher," he says.
Another finding to emerge is that major reserves of potential farmland exist across the globe, especially in Africa and Latin America, Dorin says. "The 1.5 billion hectares of land now cultivated could be increased to 4 billion, but this would of course be at the expense of pastures and forests, which are a reservoir of biodiversity and carbon," he adds.
More a confirmation than a surprise was that in the past 15 years, yields of wheat have stagnated in Europe and other major producing regions such as northern India, says François Houllier, INRA's deputy director-general in charge of scientific organization, resources and evaluation. This was caused partly by a reduction in inputs such as fertilizer and changes in farming practices. For example, farmers stopped alternating wheat with pulses, which fix nitrogen in the soil, he says.

Food figures

The study encompasses research and foresight studies carried out by the two agencies, drawing on 30 billion statistics from the United Nations Food and Agriculture Organization.
The conclusion that the world will be able to feed its predicted population of nine billion in 2050 came from consideration of two scenarios. One stresses economic growth but gives low priority to the environment, whereas the other emphasizes feeding the world while preserving ecosystems. The second scenario, based on a food intake of 3,000 kcal per person per day in all regions of the world, including 500 kcal per day of animal origin, would require an increase of 30% in farm output — compared with 80% for the first scenario — and would mean a substantial cut in food consumption in some countries and a big increase in others.

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The figure of 3,000 kcal per day is the current world average for individual food intake, with consumption ranging from 4,000 kcal per day in the industrialized countries within the Organisation for Economic Cooperation and Development (OECD) to less than 2,500 kcal per day in sub-Saharan Africa.
The report leaves out details on issues such as land use, biofuel and climate change, as these will be addressed in future studies by the agencies' joint interdisciplinary Agrimonde platform, which brings together a steering committee, project team and expert panel. Neither does the report make any policy recommendations. "That is not our job," officials say. The aim is now to identify key agricultural questions to be taken up by the international research community.
Changes in food needs, living standards, climate and other factors call for new avenues of research, according to the report. The two agencies have already started work on several programmes in response to questions raised by their study. These include the Dualine project on food sustainability; European projects looking at the longevity of animal production; food-market regulation; and the use of international consortiums to develop new production strategies for rice, wheat and other cereals. Another priority is land usage modelling.
The study recognizes the scale of the task, concluding that in "a world of rare resources, the rarest of all may be time".
source : http://www.nature.com/news/2011/110112/full/news.2011.14.html

Chemistry: It's not easy being green

In the past two decades, the green-chemistry movement has helped industry become much cleaner. But mindsets change slowly, and the revolution still has a long way to go.

Katharine Sanderson

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By the latter half of the 1980s, the worldwide chemical industry knew that it had to clean up its act: its environmental reputation was dismal. Still fresh in the public mind was the 1984 disaster at Bhopal, India, where at least 3,000 people died and hundreds of thousands were injured by a toxic gas leak at a Union Carbide pesticide plant. Also fresh were memories of the 1978 Love Canal incident in Niagara Falls, New York, where the discovery of buried toxic waste forced the abandonment of an entire neighbourhood, and the discovery of dioxin contamination a few years later that forced the evacuation of an entire town — Times Beach, Missouri.

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Even when companies did try to deal responsibly with their waste, which typically included volatile organic solvents and other hard-to-clean-up agents, the volumes were daunting. Global statistics were, and still are, fragmentary. But in the United States, according to the earliest systematic data gathered by the Environmental Protection Agency (EPA), some 278 million tonnes of hazardous waste were generated in 1991 at more than 24,000 sites. Not all of it came from chemical companies, but much of it did. More than 10% of the total, some 30 million tonnes, came from one firm alone: the Dow Chemical Company, headquartered in Midland, Michigan. And other firms, such as petrochemical giant Amoco, headquartered in Chicago, Illinois, and DuPont, of Wilmington, Delaware, were not far behind.

The result, as chemical companies struggled to deal with increasingly stringent environmental regulations, was an industry-wide move towards what is often called 'green chemistry' — a term introduced in 1991 by Paul Anastas, then a 28-year-old staff chemist with the EPA.

The goal of green chemistry was never just clean-up, explains Anastas, who is currently on leave from Yale University to head the EPA's research division. In his conception, green chemistry is about redesigning chemical processes from the ground up. It's about making industrial chemistry safer, cleaner and more energy-efficient throughout the product's life cycle, from synthesis to clean-up to disposal. It's about using renewable feedstocks wherever possible, carrying out reactions at ambient temperature and pressure — and above all, minimizing or eliminating toxic waste from the outset, instead of constantly paying to clean up messes after the fact. "It's more effective, it's more efficient, it's more elegant, it's simply better chemistry," says Anastas.
If the green-chemistry ideal is simple to state, however, achieving it has been anything but simple. Yes, says Eric Beckman, a chemical engineer at the University of Pittsburgh in Pennsylvania, "Companies these days are being very attentive to rendering their current processes greener." In 2009, for example, the total US output of hazardous waste was down by an order of magnitude over 1991, to 35 million tonnes. The largest generator in that year, DSM Chemicals in Augusta, Georgia, produced just 3.4 million tonnes.
But the greening of any given process is always a trade-off among benefits, feasibility and cost, says Beckman — and green is not always the winner. Furthermore, he says, industry's adoption of green chemistry has so far been focused mainly on incremental improvements in existing processes.
"It's embryonic at best," says Beckman, who speaks for many observers when he says that the real 'green revolution', in the form of processes redesigned from scratch and plants rebuilt from the ground up, is only just beginning.

“It's more effective, it's more efficient, It's more elegant, It's simply better chemistry.”

The progress of green chemistry so far has been partly a matter of technical feasibility, as researchers have developed less toxic alternatives to conventional methods. A prime example is supercritical carbon dioxide: ordinary, non-toxic carbon dioxide that has been heated and pressurized above its 'critical point' of 31.1 °C and 7.39 megapascals, beyond which it behaves like both a gas and a liquid, and readily serves as a solvent for a wide range of organic and inorganic reactions. Other non-toxic replacements for solvents have been found among the ionic liquids: exotic cousins to ordinary table salt that happen to be liquid at or near room temperature.

The E-factor

Green chemistry's progress has also benefited from an awareness campaign by Anastas and his allies. A key first step was the 1991 coining of the name itself, says John Warner, president of the Warner-Babcock Institute for Green Chemistry in Wilmington, Massachusetts, who at the time was director of exploratory research at the Polaroid Corporation in Minnetonka, Minnesota. "Identifying green chemistry as a field of science differentiated it from a political and social movement," he says.

Another key step was the drawing up by Anastas and Warner of a set of principles intended to help scientists define and practise green chemistry (see 'The twelve principles of green chemistry'). And yet another came in 1995, when Anastas helped to persuade US President Bill Clinton to launch the Presidential Green Chemistry Challenge, which still awards five citations each year to companies and academics who have done an outstanding job of implementing the principles.

Mostly, however, green chemistry's progress has been a matter of corporate buy-in, as epitomized by its promotion by the chemical industry's own voluntary initiative, Responsible Care (http://www.responsiblecare.org/), which works with national industry associations to improve the industry's health, safety and environmental performance. Founded in Canada in 1985, membership has grown from 6 national associations to 53.

The pharmaceutical sector has embraced green chemistry most enthusiastically, perhaps because it has the most to gain. Pharmaceutical plants typically generate 25 to 100 kilograms of waste per kilogram of product, a ratio known as the environmental factor, or 'E-factor'. So there is plenty of room to increase efficiency — and cut costs.
At drug-maker Pfizer, for example, the first laboratory synthesis of its anti-impotence drug sildenafil citrate (Viagra) had an E-factor of 105. But long before Viagra went on the market in 1998, a team at Pfizer's plant in Sandwich, UK, was rigorously re-examining every step of the synthesis. The researchers replaced all the chlorinated solvents with less toxic alternatives, and then introduced measures to recover and reuse these solvents. They eliminated the need to use hydrogen peroxide, which can cause burns. They also eliminated any requirement for oxalyl chloride, a reagent that produces carbon monoxide in reactions and is therefore a safety concern. Eventually, Pfizer's researchers cut Viagra's E-factor to 8.
After that success, Peter Dunn, the leader of the Viagra synthesis team, became head of the more systematic green-chemistry drive started by Pfizer in 2001. Dunn says he is not free to talk about specific cash savings, but can point to sweeping changes made across the company. Pfizer has reduced the E-factor of the anticonvulsant pregabalin (Lyrica) from 86 to 9, he says, and has made similar improvements for the antidepressant sertraline and the non-steroidal anti-inflammatory celecoxib. "These three products alone have eliminated more than half a million metric tons of chemical waste," says Dunn.

Creative chemistry

Nor is Pfizer alone; the pharmaceutical sector is so competitive that no company can afford to ignore green chemistry's potential savings. The Pharmaceutical Roundtable, first convened in 2005 by the American Chemical Society's Green Chemistry Institute, now has 14 member companies that jointly fund academic research in the field and share pre-competitive information.
In 2002, the chemicals giant BASF, based in Ludwigshafen, Germany, introduced an industrial-scale process that uses ambient-temperature ionic liquids to remove acid by-products from reaction mixtures — a common chemical manufacturing step that had previously been much more cumbersome. But BASF's embrace of green chemistry (which the company prefers to call 'sustainable chemistry') goes much further, notes Pete Licence, a green chemist at the University of Nottingham, UK. "You're getting sensible and joined-up thinking about the way that chemical plants are created," he says. "They have this integrated reaction system where the products and the by-products of reactions are actually the starting materials for the plant that is next door." The plants are also designed to maximize energy efficiency, Licence says: "Waste heat from one process is the warm-up for the feedstock for the next."
But the comprehensive restructuring required illustrates why the shift to green chemistry has been comparatively slow among bulk-chemicals manufacturers. These firms deal with products that are made in much larger volumes than pharmaceuticals, and their industrial processes are already highly optimized, with E-factors typically in the range of 1 to 5. Although it is possible to go much lower — E-factors for petrochemicals are on the 0.1 scale — doing so is not always economic. "Once you have a plant, it will run for 30 or 40 years because you have made a huge investment," says Walter Leitner at the Institute for Technical and Macromolecular Chemistry at the University of Aachen, Germany.
Nor does it always pay to be green in the speciality chemicals sector — as Thomas Swan and Company in Consett, UK, learned the hard way. In 2001, building on the work of chemist Martyn Poliakoff at Nottingham University, it opened the world's first continuous-flow reactor using supercritical carbon dioxide as a solvent. "It looked as if it could have been game-changing within the industry," says managing director Harry Swan. But when no government subsidies were forthcoming, the plant could not provide chemicals more cheaply than those made by the standard non-green methods, he says. So the facility was mothballed, and may soon be decommissioned and dismantled.

“Green chemistry should just be second nature, the default value.”

Other roadblocks to the adoption of green chemistry are technical. For example, even after decades of research, green solvents are not always more efficient than the widely used chlorinated solvents. Nor have chemists completely eliminated the need for catalysts containing precious or toxic metals — although Dunn, for one, is optimistic that this may eventually be possible through advances in enzyme technology. And how to make bulk chemicals from biomass and other renewable feedstocks, rather than from crude oil, is still an open challenge. "It's a different way of looking at a chemical synthesis," says Leitner, who points out that the conventional problem gets turned on its head. Instead of starting out with a relatively simple hydrocarbon extracted from oil, and then adding side groups to the molecule to give it the desired properties, chemists have to start with the incredibly complex mixture of biomolecules typical of most renewable feedstocks, and get to what they want by snipping off pieces in a controlled manner.
But many advocates say that the most fundamental barrier to the wider adoption of green chemistry is mindset — which largely reflects the way chemists are taught. "In the United States, chemists get trained rigorously in chemistry, but don't see any engineering, product design, or life-cycle analysis," says Beckman. Or, as Anastas puts it, "you usually get the safety course that says, 'Wear your goggles and your coat, and don't blow things up — and by the way, here's the number to call if you do.' But I don't think that's the same as treating the consequences of what we do as an intrinsic part of our work".
This curricular conservatism may well reflect the often negative reactions of academic chemists to green chemistry. Especially in its early years, the field was seen as fuzzy and non-rigorous, recalls Neil Winterton of the University of Liverpool, UK, a former critic who has since become more accepting of the movement. The word 'green' conveyed the impression that certain techniques were being promoted for reasons of political correctness, he says. "It needed a little bit more fundamental underpinning to establish whether what was being proposed was or wasn't a major contribution to improving the efficiency of chemical processes."
Sceptics also questioned whether green chemistry was anything more than a trendy new buzzword used to get money for projects of dubious environmental value. "It's something that can dupe the public, it can dupe other scientists working in the area, and much, much more importantly, it can dupe decision-makers", concedes Licence.
Scepticism hasn't gone away entirely; a mention of green chemistry in a gathering of chemists can still provoke sighs and eye-rolling, says Warner. But scepticism has lessened as research has improved. The EPA, for example, has made notable progress in lifting one barrier to effective green chemistry, which is that researchers trying to create a new, non-toxic manufacturing process often don't know if a given compound is 'green' or not. No one has had the time or money to gather the toxicity data, which typically requires expensive animal testing.
The EPA's answer is a high-throughput screening project called ToxCast, which has been running at its Research Triangle Park facility in North Carolina since 2007. The ToxCast team has applied a battery of standard high-throughput biochemical assays, which measure such things as binding to cellular receptors, to 1,000 chemicals that already have animal toxicology data. These data have then been used to build statistical and computational models that attempt to predict any compound's toxicity from the assays alone.
A ToxCast prediction costs US$20,000 per chemical, compared with the $6 million to $12 million typical of animal toxicology tests, says Robert Kavlock, who oversees the project as head of the EPA's National Center for Computational Toxicology at Research Triangle Park. So if these models can be made reliable enough, he says, "then we've got a way to address the chemicals that we can't afford to test in animals" — and in the process, help companies to choose compounds that will make their chemistry truly green.

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Now that Anastas is the EPA's research chief, he has been trying to spread the green-chemistry approach through staff meetings at the agency's labs across the country. He wants to move the EPA away from a culture of regulating and banning to one where products are designed to be synthesized in a way that reduces or eliminates the use of hazardous substances in the first place. As EPA chief Lisa Jackson puts it: "It's the difference between treating disease and pursuing wellness."
If that change in attitude happens, says Anastas, it will represent a "seismic shift" at the agency — "the culmination of the work of my career". But in a sense, he adds, it will also be just the beginning: "I believe that the ultimate goal for green chemistry is for the term to go away, because it is simply the way chemistry is always done. Green chemistry should just be second nature, the default value
from :  http://www.nature.com/news/2011/110105/full/469018a.html

Chemistry: The trials of new carbon

source : http://www.nature.com/nature/journal/v469/n7328/full/469005a.html 

Researchers have spent 25 years exploring the remarkable properties of fullerenes, carbon nanotubes and graphene. But commercializing them is neither quick nor easy.

Richard Van Noorden

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In fairy tales, third place is often the best: it's usually the third casket that contains the treasure, and the third child who finds fame and fortune. And so it may be for graphene, the third and most recently discovered form of 'new carbon'. The football-shaped fullerenes¹, discovered in 1985, and the hollow cylindrical carbon nanotubes², first characterized in 1991, have so far had a limited impact on industry. But now graphene, a one-atom-thick flat sheet of carbon, seems to be surrounded by favourable omens — not the least of which is the speed with which groundbreaking experiments on its properties were rewarded with the 2010 Nobel Prize in Physics.

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It has been just six years since Nobel laureates Andre Geim and Kostya Novoselov at the University of Manchester, UK, first reported using sticky tape to peel atomically thin layers of graphene from lumps of graphite³. But the material — essentially just an unrolled nanotube — has turned out to have properties just shy of miraculous: a single layer of graphene is simultaneously the world's thinnest, strongest and stiffest material, as well as being an excellent conductor of both heat and electricity.

Graphene has been showered with media attention as companies vie to bring those attributes to market. Last year, graphene was the subject of around 3,000 research papers and more than 400 patent applications. South Korea is planning a US$300-million investment to commercialize the material, and companies ranging from IBM to Samsung are testing graphene electronics — ultra-small, ultra-fast devices that might one day replace the silicon chip. The hype over graphene has reached such a pitch that a casual follower might wonder why it hasn't conquered the technological world already.
The reality is not such a fairy tale. Graphene's carbon forebears were once hyped in much the same way. Yet fullerenes have found hardly any practical applications. And although nanotubes have done better, they are costly to produce and difficult to control. Their subdued industrial impact is a lesson in just how hard commercialization of a new material can be.
Yet the story of nanotubes has some encouraging features. High-tech electronics applications are still years in the future, but a more low-tech application — nanotube-based conducting films for energy storage or touch screens — is much closer to commercialization. Another, comparatively straightforward use — nanotube-reinforced composite materials for aeroplanes and automobiles — is now reaching the market. Anticipating growing demand, nano-tube manufacturers have scaled up production to many hundreds of tonnes a year.

For that very reason, the graphene manufacturers following in their wake may have hit on the right moment to start mass-producing the sheets. Graphene is being considered for the same types of application as nanotubes, but it has some key advantages in ease of production and handling, and should benefit from two decades of research with nanotubes. That hindsight also means that graphene manufacturers have a better idea of which applications are worth chasing, and of how to avoid the false starts that nanotubes made in their first decade.

New carbon in the lab

A carbon playground

The remarkable properties shared by nanotubes and graphene arise from their common structure: an atomically thin mesh of carbon atoms arranged in a honeycomb pattern. Immensely strong carbon–carbon bonds produce an exceptionally high strength-to-weight ratio. Such is the strength of graphene, for example, that according to the Nobel prize committee, a hypothetical 1-metre-square hammock of perfect graphene could support a 4-kilogram cat. The hammock would weigh 0.77 milligrams — less than the weight of a cat's whisker — and would be virtually invisible.
The symmetry with which carbon atoms are arranged on the hexagonal lattice also allows both forms of nano-carbon to conduct electricity far more easily than the silicon used in computer chips. This means that they have much lower electrical resistance and generate much less heat — an increasingly useful property as chip manufacturers try to pack features ever more densely onto circuits.
Furthermore, even small variations in carbon structure can create a multitude of new properties. In graphene, for example, electronic behaviour depends on the size of a given sheet, the presence or absence of defects in the sheet's lattice and whether it is lying on a conductive surface. In nanotubes, likewise, a given structure can be made semiconducting or metallic just by changing its diameter, length or 'twist' (the angle between the lines of hexagons and the direction of the tube). And there are differences between single tubes and those in which several cylinders are nested inside each other — called multi-walled nanotubes.

These properties have long sparked hopes of game-changing electronics applications. And researchers have made great progress — in the laboratory. In 1998, for example, physicists demonstrated a transistor made from a single, semiconducting nanotube⁴. And in 2007, researchers reported the synthesis of a carbon-nanotube-based transistor radio⁵.

But for industrial-scale mass production of such circuits, the great variability of nanotubes is a curse. They are most commonly produced in a reactor, in which catalysts guide formation of the tubes from a carbon-rich vapour. This typically leaves a jumble of multi-walled, single-walled, semiconducting and metallic tubes of various lengths and diameters, all with different electronic properties. "Diversity is great until you have too diverse a population: then it becomes a real headache," says John Rogers, a physical chemist at the University of Illinois in Urbana-Champaign.

“A lot of companies are bringing new capacity online at the same time right now.”

Only in the past five years have researchers worked out how to sort nanotubes into semiconducting and metallic types⁶. But there are further difficulties in assembling selected nanotubes in predetermined places on a chip and connecting these separate tubes together without compromising performance, so most physicists have come to believe that it is impractical for carbon nanotubes to replace silicon. "An integrated circuit would have to involve billions of identical carbon-nanotube transistors, all switching at exactly the same voltage," says Phaedon Avouris, who works on nanoscale electronics at IBM's Thomas J. Watson Research Center in Yorktown Heights, New York. This is not feasible with current technology.

Graphene offers a bit more cause for optimism. The highest-quality sheets are currently made by heating a wafer of silicon carbide in a vacuum, leaving a layer of pure graphene on the top surface. This method has fewer problems with uncontrollable variety from batch to batch than does nanotube synthesis, and the flat sheets that result are bigger and easier to handle than nanotubes.
But graphene has problems too. A single graphene sheet conducts charge so well that it is hard to make the current stop, something that must be solved if the material is ever going to be used in digital devices such as transistors, which control the flow of current like on–off switches. To change the material's electronic properties in the appropriate way — creating a 'band gap', or break in electron energy levels, which essentially turns it into a semiconductor — the sheet must be sliced up into thin ribbons. This is probably easier than trying to place billions of nanotubes on a chip, says Avouris — but it is still not currently possible with commercial technologies.
These processing difficulties suggest that graphene won't soon displace silicon chips. "There have been millions of person-years and trillions of dollars put into the development of silicon electronics," notes James Tour, an organic chemist who specializes in nanotechnology at Rice University in Houston, Texas. "Asking graphene to compete with silicon now is like asking a 10-year-old to be a concert pianist because we've been giving him piano lessons for the last six years."
In the meantime, nano-carbon structures may be more competitive in less demanding electronics, such as conductive flat films for transparent electrodes in touch-screen displays or in solar cells. Bundles of dissimilar carbon nanotubes might very well provide enough conductivity for such electrodes, as might cheaper, lower-quality graphene sheets made by methods other than the silicon carbide process.

Lowering the sights

In June 2010, for example, a team led by Byung Hee Hong at Sungkyunkwan University in Suwon, South Korea, reported using carbon-rich vapour to deposit graphene films measuring 75 centimetres diagonally on copper plates, which are then etched away and recycled⁷. South Korean electronics giant Samsung is already testing this technique for use in commercial touch screens, which Hong estimates could be just two to three years away.

The question is whether the graphene films can compete with existing touch-screen materials such as indium tin oxide (ITO). Hong is optimistic; the cost of ITO has been increasing rapidly, because indium is scarce. But again, carbon nanotubes offer a cautionary tale. Early on, it was hoped that the tubes would form the television screens of the future, thanks to their ability to emit electrons from their tips to excite phosphors on the screen. In practice, competing plasma and liquid-crystal displays got better faster — and these are the screens most commonly used today.

New carbon in the market

One sweet spot for nano-carbon may be in the still-emerging market for flexible electronics. These are displays and sensors that could be worn on clothes, stuck to walls or printed on rollable sheets. Here, the only competition is from organic conducting polymers, because other materials cannot be printed on plastic. The performance of these polymers is quite low, says Rogers, so nanotubes and graphene circuits — which can be transferred to flexible substrates — could compete effectively.
But even these specialist electronics are still in the future. For now, the hundreds of tonnes of commercial nano-carbon being turned out every year are mostly going into composites for sporting goods, lithium-ion batteries and cars.
The aim is to disperse nano-carbon sheets or tubes within resins or polymers, so that they not only make the material tougher by blocking cracks that would otherwise spread, but also help to dissipate heat and electrical charge. For example, the Audi A4 car now has plastic fuel filters containing carbon nano-tubes, which protect against static electricity. And nanotube additives in lithium-ion battery electrodes were one of the first nanotube applications marketed by Showa Denko, a Tokyo-based chemical-engineering company.

Cutting costs

Basic processing problems with nanotubes initially hampered progress. They tended to clump together like tangled string as they came out of the reactor, making it hard to disperse the nanotubes evenly through plastic or resin. Despite improvements, this limits nanotube content to 1–2% by weight in the final product, compared with the 20–30% typical of conventional carbon fibre. The other problem was, and still is, cost. Materials such as steel, aluminium and plastics, and fillers such as carbon black, sell for just dollars or cents a kilogram, says David Hwang at Lux Research, a technology-evaluation company in New York. Meanwhile, multi-walled nanotubes retail for $100 a kilogram. The price is coming down as production scales up, but will drop only to about $50 a kilogram by 2020, according to Lux forecasts.

Composite-quality graphene has the potential to be a lot cheaper, although costs are currently similar. As Geim and Novoselov showed in 2004, graphene platelets of varying sizes can easily be peeled away from graphite³, a raw material that costs a few dollars a kilogram. Graphene is also easier to disperse in a resin than are nanotubes.

But promising as this is, says Steve Hahn, a senior scientist with Dow Chemical's Ventures and Business Development Group in Midland, Michigan, the reality is that these applications are still niche. "I've been trying to find outlets for graphene for a couple of years," he says. But there is usually something quite a lot cheaper that does the same job, says Hahn.

“Graphene will have its place, but it will just take longer than people think.”

Michael Knox, president of XG Sciences, a start-up graphene-manufacturing company in East Lansing, Michigan, agrees. Adding graphene platelets to composites is not a transformational application, "it's an incremental improvement", he says. Yet that is not to be sniffed at. "If I could demonstrate a 10–20% improvement in a polypropylene composite at a reasonable price, I could probably sell a million tonnes of it a year — and car manufacturers would be pretty excited by that," says Knox.
The trick for young graphene-manufacturing companies is to find specific applications and then work out how to scale up production capacity without overstretching themselves. Vorbeck Materials in Jessup, Maryland, for example, has decided to focus on making graphene-based conducting inks. John Lettow, co-founder and president of Vorbeck, says that the inks will be in smart cards and radio-frequency identification tags in retail stores in the first quarter of 2011.
One near-term application may be supercapacitors, which use crumpled-up sheets of graphene to pack a massive surface area into a small space — to store more electric charge per gram than any other material. Other researchers are looking at using nano-carbon to make catalyst electrodes in fuel cells, or even to make water-purification membranes — but, as usual, finding clear advantages over existing materials such as activated carbon will be the problem.
Carbon nanotubes do have one property that graphene sheets don't: they can be very long. The nanotubes currently mixed into resins and plastics are typically short stubs, but Nanocomp Technologies in Concord, New Hampshire, says that it can spin long nanotube fibres into lightweight, electrically conducting yarns or sheets that could replace copper wiring in some applications. "There are about 60 miles of copper wire in an aeroplane," says Nanocomp chief executive Peter Antoinette — so replacing this with the much lighter nanotube wire could save substantially on weight and fuel use.
Such activity is very encouraging for carbon nanotubes, says Hwang. "There was a huge amount of research that had to be done before nanotubes got to be commercially viable. Now if you look at the next five years, the commercial trajectory will be very different."

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But have carbon nanotubes really taken a disproportionate time to get going? It takes 20 years or more for any new material to make an impact in industry, point out many nanotube makers. "Research on carbon fibre started in the 1950s; it took 15 years or so before aerospace and military used it — and we didn't hear about that until much later — and it wasn't until the mid-1970s that you started seeing commercial aircraft with small quantities of structures made out of carbon-fibre composites," says Brian Wardle, who directs the nano-engineered aerospace structures consortium at the Massachusetts Institute of Technology in Cambridge. Nanotubes may simply be on the usual trajectory from discovery to industry — and graphene may find that it follows the same path. "Graphene will have its place, but it will just take longer than people think," says Antoinette.
And what will happen in the meantime? "A lot of companies are bringing new capacity online at the same time right now," notes Hahn. "They will either go out of business or find a market somewhere. Whatever happens, it'll be a great lesson to all of us in how new materials are commercialized."