To protect and save. A new chapter opens on biodiversity conservation

A more complete catalogue of the Earth''s fauna and flora and a more holistic view of man-made environmental problems could help to slow the rate of biodiversity loss.In the wake of the admission from the United Nations (UN) that, to date, efforts have failed to even slow down the rate of extinction across almost all plant and animal taxa (CBD, 2010), the fight to reverse the human-induced loss of biodiversity is entering a new chapter. The failure to achieve the targets set in 2002 for reducing decline has led to a revised strategy from the Campaign for Biodiversity (CBD). This new approach recognizes that species conservation cannot be treated in isolation from other issues facing humans, including climate change, water scarcity, poverty, agricultural development and global conflict. It also acknowledges that declining biodiversity cannot be tackled properly without a more accurate inventory of the species in existence today. Thus, a large part of the strategy to combat species decline focuses on building an exhaustive catalogue of life.The Global Strategy for Plant Conservation includes such a plan. The intention is to compile an online flora of known plants by 2020, which should enable comprehensive conservation efforts to gather steam. Peter Wyse Jackson, president of the Missouri Botanical Garden in the USA, said that around 25% of the estimated 400,000 plant species in the world, are thought to be threatened. He said that around 850 botanical gardens have, between them, collected around 100,000 species, but only a quarter of these are from the threatened group. “World Flora online will then be an essential baseline to determine the status of individual plant species and threats to them,” Jackson explained. “By 2020 it is proposed that at least 75% of known threatened plants should be conserved both in the wild and in existing collections.”…an online flora of known plants […] should enable comprehensive conservation efforts to gather steamMissouri Botanical Gardens will have an important role in the project and Jackson commented that the first step of the plan has already been achieved: the establishment of an online checklist of flora that is needed to build a comprehensive database of the plant species in the world.Yet, some other plans to halt species decline have drawn criticism. “In my opinion, whilst such international targets are useful to motivate individuals, states and wider society to do conservation, they are not necessarily realistic because they are often ‘pulled out of the hat'' with very little science behind them,” commented Shonil Bhagwat, senior research fellow at the School of Geography and the Environment at Oxford University.The revised CBD plan specifies measures for reversing the decline in biodiversity. One target is to enlarge protected areas for wildlife, within which activities such as logging are prohibited. Ecological corridors could then connect these areas to allow migration and create a network of ‘safe'' places for wildlife.Such a corridor is being created between two parts of the Brazilian Atlantic rainforest—the Pau Brasil National Park and the Monte Pascoal National Park—both of which are already protected. “Well-managed protected areas keep away biodiversity threats, such as deforestation, invasive species, hunting and poaching,” explained Arnd Alexander Rose, marketing manager for Brazil at The Nature Conservancy, a conservation organization that operates on all continents. “We think that the connectivity between the national parks is essential for the long-term permanence of local species, especially fauna,” Rose said.Worldwide, only around 6% of coastlines are within protected areas, but around 12% of the total land area is protected—a figure that is perhaps higher than many would expect, reflecting the large size of many national parks and other designated wildlife zones. Nevertheless, the coverage of different habitats varies greatly: “Only 5% of the world''s temperate needle-leaf forests and woodlands, 4.4% of temperate grasslands and 2.2% of lake systems are protected” (CBD, 2010). The aim of the CBD is to increase the total area of protected land to 17% by 2020, and also to expand the protected coastal zones, as well as extending the area of protected oceans to 10%.Things at sea, however, are different; both in terms of biodiversity and protection. The biggest threat to many marine species is not direct human activity—poaching or habitat encroachment, for example—but the impact of increased ocean acidity due to rising atmospheric carbon dioxide levels. Halting or reversing this increase will therefore contribute to the marine conservation effort and biodiversity in the long term.However, the first task is to establish the extent of marine biodiversity, particularly in terms of invertebrate animals, which are not well catalogued. Ian Poiner is CEO of the Australian Institute of Marine Science and chair of the steering committee for the first Census of Marine Life (Census of Marine Life, 2010), which has revealed the enormity of our remaining uncertainty. “So far 250,000 species [of invertebrates] have been formally described, but at least another 750,000 remain to be discovered, and I think it could be as many as 10 million,” Poiner said. As evidence for this uncertainty he points to the continuing high rate of discovery of new species around coral reefs, where each organism also tends to come with a new parasite. The situation is compounded by the problem of how to define diversity among prokaryotes.“…250,000 species [of invertebrates] have been formally described, but at least another 750,000 remain to be discovered…”Even if the number of non-vertebrate marine species remaining to be discovered turns out to be at the low end of estimates, Poiner points out that the abundance and diversity of life in the oceans will still be far greater than was expected before the census. For fish—a group that has been more extensively analysed than invertebrates—Poiner notes that there are several thousand species yet to be discovered, in addition to the 25,000 or more known species.The levels of diversity are perhaps most surprising for microorganisms. It was expected that these organisms would be present in astronomically large numbers—they are thought to account for 50–90% of the biomass in the oceans, as measured by total amount of carbon—but the high degree of genetic divergence found within even relatively small areas was unexpected. “We found there are about 38,000 kinds of bacteria in a litre of sea water,” Poiner said. “We also found that rarity is common, especially for microbes. If you take two separate litre samples of sea water just 10 or 20 kilometres apart, only a small percentage of the 38,000 bacteria types in each one are of the same kind. The challenge now is to find out why most are so rare.”This mystery is confounded by another result of the census: there is a much greater degree of connectedness than had been expected. Many fish, and even smaller invertebrate species, travel huge distances and navigate with great accuracy, rather like migratory birds. “Pacific white sharks will travel long distances and come back to within 50 metres from where they started,” Poiner said, by way of example.The behaviour of the sharks was discovered by using new tags, measuring just a few centimetres across, that can be attached to the heads of any large creatures to track their location and measure temperature, conductivity—and thereby salinity—and depth. For smaller creatures, such as baby salmon, a different technology is used that involves the attachment of passive acoustic sensors to their bodies. These trigger a signal when the fish swim through arrays of acoustic receivers that are installed in shallower waters at locations throughout the oceans.Although tagging and acoustic monitoring are providing new information about the movements and interactions of many species throughout the oceans, the huge task remains of identifying and cataloguing those species. For this, the quickly maturing technique of DNA barcoding has been useful and provides a relatively inexpensive and convenient way of assessing whether a specimen belongs to a new species or not. The method uses a short DNA sequence in the mitochondrial gene for cytochrome c oxidase subunit 1 (CO1)—around 600 base pairs in most species—which differs little within species but significantly between them (Kress & Erickson, 2008).The Marine Census programme involves several barcoding centres that have determined barcodes for more than 2,000 of the 7,000 known species of holozooplankton, for example (Census of Marine Zooplankton: http://www.cmarz.org). Holozooplankton are small, completely planktonic invertebrates—which spend their lives floating or swimming in open water—and are a particularly sensitive marker of environmental changes such as ocean warming or acidification.DNA barcoding can also be applied to prokaryotes, although it requires alternative sequences owing to the lack of mitochondria. In addition, horizontal gene transfer and uncertainty about how to define prokaryotic species complicate the task of cataloguing them. Nevertheless, by targeting a suitable core subset of a few genes, bacteria and archaea can be identified quite accurately, and barcoding can increase our knowledge and understanding of their behaviour and evolution.Such techniques could be applied to the identification of marine prokaryotic species, but Poiner argues that they need further refinement and will probably need to be combined with analytical methods that help estimate the total diversity, given that it is impossible to identify every single species at present. Indeed, the task of assessing the diversity of even land-based microorganisms is difficult, but such cataloguing is a prerequisite for accurate assessment of their response to environmental change.“There is a general rule that the smaller things are the less we know about them,” commented Stephen Blackmore, Regius Keeper of the Royal Botanical Gardens in Edinburgh, UK, a leading centre for conservation research. “I think it is very difficult or too early to say how biodiversity at the microscopic level is being impacted. Some of the newer approaches using DNA diversity to see, for example, what microorganisms are present in soil, will be important.”In the immediate future, advanced DNA analysis techniques have a more urgent application: the identification of genetic diversity within eukaryotic species. This is important because it determines the ability of populations to cope with rapid change: a species with greater genetic diversity is more likely to have individuals with phenotypes capable of surviving changes in habitat, temperature or nutrient availability. Genetic evidence will help to determine the secret of success for many invasive species of plants and animals, as they have already adapted to human influence.“A major emerging theme is to look at the genetic diversity present in wild plant populations and to try to correlate this with identifying the populations that are best suited for coping with climate change,” Blackmore said. “But it''s a very new field and so far not much is being funded. Meanwhile, the immediate prospect is that plants will continue slipping away more or less un-noticed. Even where the landscape appears green there is generally a steady erosion of plant biodiversity going, on driven by the shrinking of natural habitats, the encroachment of invasive species, climate change and land management practices.”Yet Blackmore is optimistic that knowledge of how to preserve biodiversity is increasing, even for less adaptable species. “We know how to, for example, grow food crops in ways that are more beneficial to biodiversity, but the desire for the cheapest food means that uptake is too limited. We know how to do most of the things needed to protect biodiversity. Unfortunately they are not being done.”There is hope, though, that increased understanding of biodiversity as a single, interconnected problem—rather than a series of unrelated hot spots and particular species—will lead to more coherent strategies for arresting global decline. The fate of flowering plants, for example, is intimately tied to their pollinators and seed dispersers. Most land animals in turn depend directly or indirectly on plants. “Since plants are the base of the food chain in all terrestrial environments, the threats to animals are increasing even more rapidly than those to the plants they depend upon,” Blackmore noted. “It is still the case, however, that most conservation action is framed in terms of charismatic animals—such as tigers, whales, polar bears and pandas—rather than on the continuation of the kinds of place they require to live in.”Due to human nature, this ‘cute'' framing of the problem is perhaps inevitable. However, if it creates a groundswell of public concern leading to voluntary involvement and donation towards biodiversity conservation, then all species might benefit in the end. After all, animals and plants do not respect arbitrary human boundaries, so an ecological corridor and protected habitat created for tigers will also benefit other, less ‘cuddly'' species.     

Adolescent idiopathic scoliosis: natural history and long term treatment effects

ABSTRACT : Adolescent idiopathic scoliosis is a lifetime, probably systemic condition of unknown cause, resulting in a spinal curve or curves of ten degrees or more in about 2.5% of most populations. However, in only about 0.25% does the curve progress to the point that treatment is warranted.Untreated, adolescent idiopathic scoliosis does not increase mortality rate, even though on rare occasions it can progress to the >100 degrees range and cause premature death. The rate of shortness of breath is not increased, although patients with 50 degrees curves at maturity or 80 degrees curves during adulthood are at increased risk of developing shortness of breath. Compared to non-scoliotic controls, most patients with untreated adolescent idiopathic scoliosis function at or near normal levels. They do have increased pain prevalence and may or may not have increased pain severity. Self-image is often decreased. Mental health is usually not affected. Social function, including marriage and childbearing may be affected, but only at the threshold of relatively larger curves.Non-operative treatment consists of bracing for curves of 25 degrees to 35 degrees or 40 degrees in patients with one to two years or more of growth remaining. Curve progression of >/= 6 degrees is 20 to 40% more likely with observation than with bracing. Operative treatment consists of instrumentation and arthrodesis to realign and stabilize the most affected portion of the spine. Lasting curve improvement of approximately 40% is usually achieved.In the most completely studied series to date, at 20 to 28 years follow-up both braced and operated patients had similar, significant, and clinically meaningful reduced function and increased pain compared to non-scoliotic controls. However, their function and pain scores were much closer to normal than patient groups with other, more serious conditions.Risks associated with treatment include temporary decrease in self-image in braced patients. Operated patients face the usual risks of major surgery, a 6 to 29% chance of requiring re-operation, and the remote possibility of developing a pain management problem.Knowledge of adolescent idiopathic scoliosis natural history and long-term treatment effects is and will always remain somewhat incomplete. However, enough is know to provide patients and parents the information needed to make informed decisions about management options.     

Pelvis morphology, trunk posture and standing imbalance and their relations to the Cobb angle in moderate and severe untreated AIS

Adolescent idiopathic scoliosis (AIS) is the most common form of scoliosis and usually affects young girls. Studies mostly describe the differences between scoliotic and non-scoliotic girls and focus primarily on a single set of parameters derived from spinal and pelvis morphology, posture or standing imbalance. No study addressed all these three biomechanical aspects simultaneously in pre-braced AIS girls of different scoliosis severity but with similar curve type and their interaction with scoliosis progression. The first objective of this study was to test if there are differences in these parameters between pre-braced AIS girls with a right thoracic scoliosis of moderate (less than 27°) and severe (more than 27°) deformity. The second objective was to identify which of these parameters are related to the Cobb angle progression either individually or in combination of thereof. Forty-five scoliotic girls, randomly selected by an orthopedic surgeon from the hospital scoliosis clinic, participated in this study. Parameters related to pelvis morphology, pelvis orientation, trunk posture and quiet standing balance were measured. Generally moderate pre-brace idiopathic scoliosis patients displayed lower values than the severe group characterized by a Cobb angle greater than 27°. Only pelvis morphology and trunk posture were statistically different between the groups while pelvis orientation and standing imbalance were similar in both groups. Statistically significant Pearson coefficients of correlation between individual parameters and Cobb angle ranged between 0.32 and 0.53. Collectively trunk posture, pelvis morphology and standing balance parameters are correlated with Cobb angle at 0.82. The results suggest that spinal deformity progression is not only a question of trunk morphology distortion by itself but is also related to pelvis asymmetrical bone growth and standing neuromuscular imbalance.     

A cost-effectiveness analysis of "test" versus "treat" patients hospitalized with suspected influenza in Hong Kong

Background

Seasonal and 2009 H1N1 influenza viruses may cause severe diseases and result in excess hospitalization and mortality in the older and younger adults, respectively. Early antiviral treatment may improve clinical outcomes. We examined potential outcomes and costs of test-guided versus empirical treatment in patients hospitalized for suspected influenza in Hong Kong.

Methods

We designed a decision tree to simulate potential outcomes of four management strategies in adults hospitalized for severe respiratory infection suspected of influenza: “immunofluorescence-assay” (IFA) or “polymerase-chain-reaction” (PCR)-guided oseltamivir treatment, “empirical treatment plus PCR” and “empirical treatment alone”. Model inputs were derived from literature. The average prevalence (11%) of influenza in 2010–2011 (58% being 2009 H1N1) among cases of respiratory infections was used in the base-case analysis. Primary outcome simulated was cost per quality-adjusted life-year (QALY) expected (ICER) from the Hong Kong healthcare providers'' perspective.

Results

In base-case analysis, “empirical treatment alone” was shown to be the most cost-effective strategy and dominated the other three options. Sensitivity analyses showed that “PCR-guided treatment” would dominate “empirical treatment alone” when the daily cost of oseltamivir exceeded USD18, or when influenza prevalence was <2.5% and the predominant circulating viruses were not 2009 H1N1. Using USD50,000 as the threshold of willingness-to-pay, “empirical treatment alone” and “PCR-guided treatment” were cost-effective 97% and 3% of time, respectively, in 10,000 Monte-Carlo simulations.

Conclusions

During influenza epidemics, empirical antiviral treatment appears to be a cost-effective strategy in managing patients hospitalized with severe respiratory infection suspected of influenza, from the perspective of healthcare providers in Hong Kong.     

The psycho gene

While the idea of a ‘criminal gene'' is nonsense, there is growing evidence that some psychopathic behaviour might indeed be grounded in genesThe notion that genes play an important role in many diseases has been widely accepted, but many find it much harder to acknowledge a similar link with particular behaviour or even predisposition to crime. Partly for this reason, the study of behavioural genetics remains a controversial topic, with disagreement not just over the science itself, but even more so about the therapeutic, societal and legal implications.Too much might have been made too soon of early findings that made correlations between alleles of certain genes and tendencies to antisocial or criminal behaviour. Indeed, most researchers in the field were appalled by the decision of an Italian appeal court in 2009 to cut the sentence of a convicted murderer by one year on the grounds that he had a version of the MAOA gene, which has been linked to aggression and violence (Feresin, 2009). There is equal dismay over some US courts that went the other way and accepted genetic factors as evidence for the prosecution, leading to higher sentences on the basis that people with particular alleles cannot be cured and will remain a risk to society for longer.“Taking genetic factors into account when sentencing is plain stupid, unless we are talking about something like Down''s syndrome or some other syndrome that drastically reduces intelligence and executive functioning,” insisted Anthony Walsh from the Criminal Justice Department at Boise State University in Idaho, USA. “This is the kind of “genetic determinism” that liberals have worried themselves silly over. They just have to take one or two neuroscience and genetic classes to dispense with their ‘my genes/neurons'' made me do it. Nothing relieves one of the obligation to behave civilized.”Nonetheless, the case against specific alleles has been accumulating, notably for the low-expression variant of MAOA, known as MAOA-L, which has been linked in various studies with increased risk of violent and aggressive behaviour. The gene MAOA encodes monoamine oxidase A, an enzyme that degrades amine neurotransmitters, such as dopamine, noradrenalin and serotonin. A rare genetic disorder caused by an MAOA mutation leads to MAOA deficiency and in turn an excess of monoamine transmitters, causing excessive impulsive behaviour including hypersexuality, sleep disorder and extreme mood swings as well as a tendency to violence, which is known as Brunner syndrome.…the study of behavioural genetics remains a controversial topic, with disagreement not just over the science itself, but even more so about the therapeutic, societal and legal implicationsBut while Brunner''s syndrome is rare, having only been identified in five males of one extended family, the MAOA-L variant is extremely common and occurs in about 40% of the population. Clearly, most of these people are peaceable and have never committed a crime, and yet a study involving researchers from Austria, Italy and the USA—headed by Andreas Meyer-Lindenberg, Director of the Central Institute of Mental Health in Mannheim, Germany—has discovered that at least males with this variant had neurobiological structural factors that would predispose them to violence (Meyer et al, 2006).Using structural MRI scanning, the study identified that people with MAOA-L were more likely to have a smaller limbic system—the hippocampus, amygdala, anterior thalamic nuclei and limbic cortex—which participates in emotion, behaviour and long-term memory. The team then applied functional MRI, which measures changes in blood flow, and discovered that the MAOA-L group also showed hyperresponsiveness of the amygdala during tasks such as copying facial expressions. The amygdala is associated with emotional processing and the MAOA-L group was less able to inhibit strong emotional impulses.But some trigger is still needed to tip MAOA-L people towards violence. An earlier study suggested that this trigger could be persistent maltreatment during childhood (Caspi et al, 2002). At first sight, this suggests that nearly half the human population are predisposed to violence given these triggers, but the situation is not quite that bad—it is merely nearly half of men. Women are protected in two ways: the MAOA gene is linked to the X chromosome so that women with the MAOA-L variety on one chromosome usually have a normal allele on the other; and there is circumstantial evidence that women are also protected by other genes from being disposed to violence.In any case, caution is needed to interpret the findings of Mayer-Lindenberg''s group about the MAOA-L allele, according to Ahmad Hariri, Investigator at the Institute for Genome Sciences & Policy at Duke University (Durham, NC, USA). “This is a significant basic science finding linking genes to brain to behaviour,” he said. “But it is not a significant clinical finding in and of itself. Only in as much as this very, very, very subtle bias in the brain tips the balance toward an aggressive response to provocation is this finding even remotely clinically relevant.” In fact, as Meyer-Lindenberg himself has commented, the MAOA-L allele is just one of several genes—most of which are still not identified—that increase risk of violent or antisocial behaviour.But the whole story takes a rather different turn in the case of psychopathy, which is now widely regarded as a congenital state characterized by lack of empathy or moral compass and defined at least partly by genes, in contrast to other forms of sociopathy or antisocial personality disorder (APD), in which environmental factors make a major contribution (Fontaine & Viding, 2008).“Taking genetic factors into account when sentencing is plain stupid…”“…it is useful to think of psychopathy as mainly the product of genes and sociopathy as more subject to environmental influences”“Psychopathy does seem to be heritable, and appears to have its basis at least in part in “biological” factors linked to basic emotional systems, so that the mature psychopath never develops a complete set of pro-social emotions like empathy, guilt, and the ability to truly care about and for others,” said Richard Wiebe, who specializes in the link between psychology and criminology at Fitchburg State College in Fitchburg, MA, USA. Wiebe added though that the heritability of underlying genetic factors had yet to be conclusively established. “In other words, we know that the dependent variable, that is psychopathy, is heritable, but not enough about its causes to say that they are heritable. Nevertheless it is useful to think of psychopathy as mainly the product of genes and sociopathy as more subject to environmental influences.”Environmental factors do play a part in the behaviour of psychopaths, but in a different way than in other people who develop antisocial tendencies. The condition is more common than was once thought and affects about 0.6% of the population, according to a recent study conducted in the UK (Coid et al, 2009). Obviously, psychopathy does not always lead to crime or extreme violent behaviour; indeed its occurrence in the population used to be significantly underestimated because it was diagnosed only in people who had already shown extreme behaviour when many psychopaths do not.As there is no genetic or clinical test as yet, psychopathy is still diagnosed in terms of behaviour, but taking account of various factors in combination. Robert Hare, who led the UK study and is now at the Department of Psychology of the University of British Columbia in Vancouver, Canada, has designed a test known as the ‘Psychopathy Checklist—Revised'' of about 20 symptoms that he uses to diagnose psychopathy. These include pathological lying, superficial charm, lack of empathy and guilt, proneness to boredom and sexual promiscuity.Although it is not part of the Hare checklist, psychopaths can also be detected by their lack of a “startle reflex”, which means failure of their nervous system to respond to images or events that frighten or shock other people, such as pictures of a decapitated corpse. These tests work just as well for psychopaths who have never indulged in violence and apparently lead normal lives. They can also be used to identify psychopathy in children, who exhibit the same symptoms, in particular pathological lying, lack of empathy, tendency to violence, and lack of startle reflex—in fact, several studies have found evidence of inherited psychopathy in quite young children (Viding et al, 2005).It also appears that psychopathy is more common in men than women. This supports the theory that psychopathy might be an adaptive personality trait that gives men a reproductive advantage through greater tendency and ability to form numerous relationships and so have more children. This is unproven, but it is certainly true that male psychopaths tend to form large numbers of short-term relationships and can have an almost seductive charm.However, the trait would lose its advantage if it became too common in the population. A particular trait tends only to be advantageous in certain environmental conditions as was pointed out in the context of psychopathy by Essi Viding, Co-Director of the Developmental Risk and Resilience Unit at the Department of Psychology at University College London, UK. “I think that the simple game of evolution is to ensure survival of the species under different environmental conditions,” she said. “In some conditions it may be adaptive to be anxious and cooperative, in other conditions it may be good to exploit and be antisocial. This of course is effectively contrasting alleles that have very different effects. Hence, the same allele may serve an individual very well (and in a socially acceptable manner) in one situation, but not in another.”…psychopathy might be an adaptive personality trait that gives men a reproductive advantage through greater tendency and ability to form numerous relationships and so have more childrenThis leads back to the observation that psychopathy seems to be more common in men than women, which could have two possible explanations. First, it might be true at the genetic and neurological level, in particular if some of the relevant genes are linked to the X chromosome. Yet, this is speculative as few genes have been identified that contribute specifically to psychopathy, with most of the evidence for its heritability being statistical. There is the case of the X-linked MAOA gene, but that has only been associated with general antisocial tendencies.…irrespective of where future research leads, genes should not influence sentencing decisions one way or the other because they can never be deemed responsible for behaviourThere is in any case an alternative explanation for the apparent gender difference in psychopathic prevalence. Alice Jones, specialist in childhood and adolescent psychopathy and antisocial behaviour at Goldsmiths College, University of London, UK, suggests that the condition could be much more common among women than studies suggest. It might be that women will, in many cases, fail to register on the Hare Psychopathy Checklist—Revised because the more extreme traits are cushioned by other female factors. “There is some evidence to support this idea,” said Jones, citing work by Randy Salekin at the University of Alabama, in the USA (Salekin et al, 1997) who found that just as many women as men pass the Hare test in terms of their lack of empathy, but not on the more violent and impulsive criteria. “So, while the interpersonal aspects of psychopathy seem to be present and similar in males and females, the behavioural aspects of psychopathy are very much male-heavy,” said Jones.This comes back to the question of treatment and sentencing. Viding argues that irrespective of where future research leads, genes should not influence sentencing decisions one way or the other because they can never be deemed responsible for behaviour. “Any gene alone will be neither necessary, nor sufficient to predispose someone to high levels of psychopathic traits and as such, the responsibility for choosing to offend still resides with an individual,” she said. “Most ‘risk genes'' are common in the population and yet do not cause the majority of the individuals carrying them to offend.”But the situation is different when it comes to treatment—the appropriate therapy will depend on underlying personality tendencies. Psychopaths tend not to respond well to punishment because they cannot associate it with acts they do not consider in any way morally wrong, according to Jones. But they are more likely to respond to reward. “One example of this is currently underway at a school in Buckinghamshire (UK) for primary aged children with Emotional and Behavioural Difficulties,” said Jones. “There have been very encouraging reports from teachers so far. The intervention is largely reward based, and the pupils gain rewards by working toward reaching their behavioural targets each week. Pupils can ‘cash-in'' their rewards daily, or they can save them up for a more substantial reward later in the week.”Whether this will help these children to lead constructive adult lives remains to be seen. It does provide further evidence though that while it might not be possible to cure psychopaths, it may be possible to direct their selfish tendencies away from crime and violence towards more positive and creative activities.     

Natural healing: How does Nature repair itself after an oil spill?

Few environmental disasters are as indicting of humanity as major oil spills. Yet Nature has sometimes shown a remarkable ability to clean up the oil on its own.In late April 2010, the BP-owned semi-submersible oilrig known as Deepwater Horizon exploded just off the coast of Louisiana. Over the following 84 days, the well from which it had been pumping spewed 4.4 million barrels of crude oil into the Gulf of Mexico, according to the latest independent report (Crone & Tolstoy, 2010). In August, the US Government released an even grimmer estimate: according to the federal Flow Rate Technical Group, up to 4.9 million barrels were excreted during the course of the disaster. Whatever the actual figure, images from NASA show that around 184.8 million gallons of oil have darkened the waters just 80 km from the Louisiana coast, where the Mississippi Delta harbours marshlands and an abundance of biodiversity (NASA Jet Propulsion Laboratory, 2010; Fig 1).…the Deepwater incident is not the first time that a massive oil spill has devastated marine and terrestrial ecosystems, nor is it likely to be the lastOpen in a separate windowFigure 1Images of the Deepwater Horizon oil slick in the Gulf of Mexico. These images were recorded by NASA''s Terra spacecraft in May 2010. The image dimensions are 346 × 258 kilometres and North is toward the top. In the upper panel, the oil appears bright turquoise owing to the combination of images that were used from the Multi-angle Imaging SpectroRadiometer (MISR) aboard the craft. The Mississippi Delta, which harbors marshlands and an abundance of biodiversity, is visible in the top left of the image. The white arrow points to a plume of smoke and the red cross-hairs indicate the former location of the drilling rig. The lower two panels are enlargements of the smoke plume, which is probably the result of controlled burning of collected oil on the surface.© NASA/GSFC/LaRC/JPL, MISR TeamThe resulting environmental and economic situation in the Gulf is undoubtedly dreadful—the shrimp-fishing industry has been badly hit, for example. Yet the Deepwater incident is not the first time that a massive oil spill has devastated marine and terrestrial ecosystems, nor is it likely to be the last. In fact, the US National Oceanic and Atmospheric Association (NOAA) deals with approximately 300 oil spills per year and the Deepwater catastrophe—despite its extent and the enormous amount of oil released—might not be as terrible for the environment as was originally feared. Jacqueline Michel, a geochemist who has worked on almost every major oil spill since the 1970s and who is a member of NOAA''s scientific support team for the Gulf spill, commented that “the marshes and grass are showing some of the highest progresses of [oil] degradation because of the wetness.” This rapid degradation is partly due to an increased number of oil-consuming microbes in the water, whose population growth in response to the spill is cleaning things up at a relatively fast pace (Hazen et al, 2010).It therefore seems that, however bad the damage, Nature''s capacity to repair itself might prevent the unmitigated disaster that many feared on first sight of the Deepwater spill. As the late social satirist George Carlin (1937–2008) once put it: “The planet will shake us off like a bad case of fleas, a surface nuisance[.] The planet will be here for a long, long—LONG—time after we''re gone, and it will heal itself, it will cleanse itself, because that''s what it does, it''s a self-correcting system.”Michel believes that there are times when it is best to leave nature alone. In such cases the oil will degrade naturally by processes as simple as exposure to sunlight—which can break it down—or exposure to the air—which evaporates many of its components. “There have been spills where there was no response because we knew we were going to cause more harm,” Michel said. “Although we''re going to remove heavier layers of surface oil [in this case], the decision has been made to leave oil on the beach because we believe it will degrade in a timescale of months […] through natural processing.”To predict the rate of general environmental recovery, Michel said one should examine the area''s fauna, the progress of which can be very variable. Species have different recovery rates and although it takes only weeks or months for tiny organisms such as plankton to bounce back to their normal population density, it can take years for larger species such as the endangered sea turtle to recover.…however bad the damage, Nature''s capacity to repair itself might prevent the unmitigated disaster that many feared on first sight…Kimberly Gray, professor of environmental chemistry and toxicology at Northwestern University (Evanston, IL, USA), is most concerned about the oil damaging the bottom of the food chain. “Small hits at the bottom are amplified as you move up,” she explained. “The most chronic effects will be at the base of the food chain […] we may see lingering effects with the shrimp population, which in time may crash. With Deepwater, it''s sort of like the straw that broke the shrimp''s back.”Wetlands in particular are a crucial component of the natural recovery of ecosystems, as they provide flora that are crucial to the diets of many organisms. They also provide nesting grounds and protective areas where fish and other animals find refuge from predation. “Wetlands and marsh systems are Nature''s kidneys and they''ve been damaged,” Gray said. The problem is exacerbated because the Louisiana wetlands are already stressed in the aftermath of Hurricane Katrina, which devastated the Gulf coast in August 2005, and because of constant human activity and environmental damage. As Gray commented, “Nature has a very powerful capacity to repair itself, but what''s happening in the modern day is assault after assault.”Ron Thom, a marine ecologist at Pacific Northwest National Laboratory—a US government-funded research facility (Richland, WA, USA)—has done important research on coastal ecosystems. He believes that such habitats are able to decontaminate themselves to a limited degree because of evolution. “[Coastal-related ecosystems are] pretty resilient because they''ve been around a long time and know how to survive,” he said.As a result, wetlands can decontaminate themselves of pollutants such as oil, nitrate and phosphate. However, encountering large amounts of pollutants in a short period of time can overwhelm the healing process, or even stop it altogether. “We did some experiments here in the early 90s looking at the ability for salt marshes to break down oil,” Thom said. “When we put too much oil on the surface of the marsh it killed everything.” He explained that the oil also destroyed the sediment–soil column, where plant roots are located. Eventually, the roots disintegrated and the entire soil core fell apart. According to Thom, the Louisiana marshes were weakened by sediment and nutrient starvation, which suggests that the Deepwater spill destroyed below-ground material in some locations. “You can alter a place through a disturbance so drastic that it never recovers to what it used to be because things have changed so much,” he said.“Nature has a very powerful capacity to repair itself, but what''s happening in the modern day is assault after assault”Michael Blum, a coastal marsh ecologist at Tulane University in New Orleans, said that it is hard to determine the long-term effects of the oil because little is known about the relevant ecotoxicology—the effect of toxic agents on ecosystems. He has conducted extensive research on how coastal marsh plants respond to stress: some marshes might be highly susceptible to oil whereas others could have evolved to deal with natural oil seepage to metabolize hydrocarbons. In the former, marshes might perish after drastic exposure to oil leading to major shifts in plant communities. In the latter case, the process of coping with oil could involve the uptake of pollutants in the oil—known as polycyclic aromatic hydrocarbons (PAHs)—and their reintroduction into the environment. “If plants are growing in the polluted sediments and tapping into those contaminated sources, they can pull that material out of the soil and put it back into the water column or back into the leaf tissue that is a food source for other organisms,” Blum explained.In addition to understanding the responses of various flora, scientists also need to know how the presence of oil in an ecosystem affects the fauna. One model that is used to predict the effects of oil on vertebrates is the killifish; a group of minnows that thrive in the waters of Virginia''s Elizabeth River, where they are continuously exposed to PAHs deposited in the water by a creosote factory (Meyer & Di Giulio, 2003). “The killifish have evolved tolerance to the exposure of PAHs over chronic, long-term conditions,” Blum said. “This suggests that something similar may occur elsewhere, including in Gulf Coast marshes exposed to oil.”Although Michel is optimistic about the potential for environmental recovery, she pointed out that no two spills are the same. “There are lot of things we don''t know, we never had a spill that had surface release for so long at this water depth,” she said. Nevertheless, to better predict the long-term effects, scientists have turned to data from similar incidents.In 1989, the petroleum tanker Exxon Valdez struck Bligh Reef off the coast of Prince William Sound in Alaska and poured a minimum of 11 million gallons of oil into the water—enough to fill 125 Olympic-sized swimming pools. Senior scientist at NOAA, Stanley Rice of Juno, Alaska, studies the long-term effects of the spill and the resulting oil-related issues in Prince William Sound. Rice has worked with the spill since day 3 and, 20 years later, he is seeing major progress. “I never want to give the impression that we had this devastating oil spill in 1989 and it''s still devastating,” he said. “We have pockets of a few species where lingering oil hurts their survival, but in terms of looking at the Sound in its entirety […] it''s done a lot of recovery in 20 years.”…little is known about the relevant ecotoxicology—the effect of toxic agents on ecosystemsDespite the progress, Rice is still concerned about one group of otters. The cold temperature of the water in the Sound—rarely above 5 °C—slows the disintegration of the oil and, every so often, the otters come in contact with a lingering pocket. When they are searching for food, for example, the otters often dig into pits containing oil and become contaminated, which damages their ability to maintain body temperature. As a result, they cannot catch as much food and starve because they need to consume the equivalent of 25% of their body weight every day (Rice, 2009).“Common colds or worse, pneumonia, are extremely debilitating to an animal that has to work literally 365 days a year, almost 8 to 12 hours a day,” Rice explained. “If they don''t eat enough to sustain themselves, they die of hyperthermia.” Nevertheless, in just the last two years, Rice has finally seen the otter population rebound.Unlike the otters, one pod of orca whales has not been so lucky. Since it no longer has any reproductive females, the pod will eventually become extinct. However, as it dies out, orca prey such as seals and otters will have a better chance of reproducing. “There are always some winners and losers in these types of events,” Rice said. “Nature is never static.”The only ‘loser'' that Rice is concerned about at the moment is the herring, as many of their populations have remained damaged for the past 20 years. “Herring are critical to the ecosystem,” he said. “[They are] a base diet for many species […] Prince William Sound isn''t fully recovered until the herring recover.”North America is not alone in dealing with oil-spill disasters—Europe has had plenty of experience too. One of the worst spills occurred when the oil tanker Prestige leaked around 20 million gallons of oil into the waters of the Galacian coast in Northern Spain in 2002. This also affected the coastline of France and is considered Spain''s worst ecological disaster.“The impacts of the Prestige were indeed severe in comparison with other spills around the world,” said attorney Xabier Ezeizabarrena, who represented the Fishermen Guilds of Gipuzkoa in a lawsuit relating to the spill. “Some incidents aren''t even reported, but in the European Union the ratio is at least one oil spill every six months.”For disasters involving oil, oceanographic data to monitor and predict the movement of the spill is essentialIn Ezeizabarrena''s estimation, Spanish officials did not respond appropriately to the leak. The government was denounced for towing the shipwreck further out into the Atlantic Ocean—where it eventually sank—rather than to a port. “There was a huge lack of measures and tools from the Spanish government in particular,” Ezeizabarrena said. “[However], there was a huge response from civil society […] to work together [on restoration efforts].”Ionan Marigómez, professor of cellular biology at the University of the Basque Country, Spain, was the principal investigator on a federal coastal-surveillance programme named Orbankosta. He recorded the effects of the oil on the Basque coast and was a member of the Basque government''s technical advisory commission for the response to the Prestige spill. He was also chair of the government''s scientific committee. “Unfortunately, most of us scientists were not prepared to answer questions related to the biological impact of restoration strategies,” Marigómez said. “We lacked data to support our advice since continued monitoring is not conducted in the area […] and most of us had developed our scientific activity with too much focus on each one''s particular area when the problem needed a holistic view.”…the world consumes approximately 31 billion barrels of oil per year; more than 700 times the amount that leaked during the Deepwater spillFor disasters involving oil, oceanographic data to monitor and predict the movement of the spill is essential. Clean-up efforts were initially encouraged in Spain, but data provided by coastal-inspection programmes such as Orbankosta informed the decision to not clean up the Basque shoreline, allowing the remaining oil debris to disintegrate naturally. In fact, the cleaning activity that took place in Galicia only extended the oil pollution to the supralittoral zone—the area of the beach splashed by the high tide, rather than submerged by it—as well as to local soil deposits. On the Basque coast, restoration efforts were limited to regions where people were at risk, such as rocky areas near beaches and marinas.Eight years later, Galicia still suffers from the after-effects of the Prestige disaster. Thick subsurface layers of grey sand are found on beaches, sometimes under sand that seems to be uncontaminated. In Corme-Laxe Bay and Cies Island in Galicia, PAH levels have decreased. Studies have confirmed, however, that organisms exposed to the area''s sediments had accumulated PAHs in their bodies. Marigómez, for example, studied the long-term effects of the spill on mussels. Depending on their location, PAH levels decreased in the sampled mussel tissue between one and two years after the spill. However, later research showed that certain sites suffered later increases in the level of PAHs, due to the remobilization of oil residues (Cajaraville et al, 2006). Indeed, many populations of macroinvertebrate species—which are the keystones of coastal ecosystems—became extinct at the most-affected locations, although neighbouring populations recolonized these areas. The evidence suggests that only time will tell what will happen to the Galicia ecosystem. The same goes for oil-polluted environments around the world.The concern whether nature can recover from oil spills might seem extreme, considering that oil is a natural product derived from the earth. But too much of anything can be harmful and oil would remain locked underground without human efforts to extract it. “As from Paracelsus'' aphorism, the dose makes the poison,” Marigómez said.According to the US Energy Information Administration, the world consumes approximately 31 billion barrels of oil per year; more than 700 times the amount that leaked during the Deepwater spill. Humanity continues, in the words of some US politicians, to “drill, baby, drill!” On 12 October 2010, less than a year after the Gulf Coast disaster, US President Barack Obama declared that he was lifting the ban on deepwater drilling. It appears that George Carlin got it right again when he satirized a famous American anthem: “America, America, man sheds his waste on thee, and hides the pines with billboard signs from sea to oily sea!”     

Genomes, race and health. Racial profiling in medicine might just be a stepping stone towards personalized health care

Considering a patient''s ethnic background can make some diagnoses easier. Yet, ‘racial profiling'' is a highly controversial concept and might soon be replaced by the advent of individualized medicine.In 2005, the US Food and Drug Administration (FDA; Bethesda, MD, USA) approved BiDil—a combination of vasodilators to treat heart failure—and hailed it as the first drug to specifically treat an ethnic group. “Approval of a drug to treat severe heart failure in self-identified black population is a striking example of how a treatment can benefit some patients even if it does not help all patients,” announced Robert Temple, the FDA''s Director of Medical Policy. “The information presented to the FDA clearly showed that blacks suffering from heart failure will now have an additional safe and effective option for treating their condition” (Temple & Stockbridge, 2007). Even the National Medical Association—the African-American version of the American Medical Association—advocated the drug, which was developed by NitroMed, Inc. (Lexington, MA, USA). A new era in medicine based on racial profiling seemed to be in the offing.By January 2008, however, the ‘breakthrough'' had gone bust. NitroMed shut down its promotional campaign for BiDil—a combination of the vasodilators isosorbide dinitrate, which affects arteries and veins, and hydralazine hydrochloride, which predominantly affects arteries. In 2009, it sold its BiDil interests and was itself acquired by another pharmaceutical company.In the meantime, critics had largely discredited the efforts of NitroMed, thereby striking a blow against the drug if not the concept of racial profiling or race-based medicine. Jonathan Kahn, a historian and law professor at Hamline University (St Paul, MN, USA), described the BiDil strategy as “a leap to genetics.” He demonstrated that NitroMed, motivated to extend its US patent scheduled to expire in 2007, purported to discover an advantage for a subpopulation of self-identified black people (Kahn, 2009). He noted that NitroMed conducted a race-specific trial to gain FDA approval, but, as there were no comparisons with other populations, it never had conclusive data to show that BiDil worked in black people differently from anyone else.“If you want to understand heart failure, you look at heart failure, and if you want to understand racial disparities in conditions such as heart failure or hypertension, there is much to look at that has nothing to do with genetics,” Kahn said, adding “that jumping to race as a genetic construct is premature at best and reckless generally in practice.” The USA, he explained, has a century-old tradition of marketing to racial and ethnic groups. “BiDil brought to the fore the notion that you can have ethnic markets not only in things like cigarettes and food, but also in pharmaceuticals,” Kahn commented.“BiDil brought to the fore the notion that you can have ethnic markets not only in things like cigarettes and food, but also in pharmaceuticals”However, despite BiDil''s failure, the search for race-based therapies and diagnostics is not over. “What I have found is an increasing, almost exponential, rise in the use of racial and ethnic categories in biotechnology-related patents,” Kahn said. “A lot of these products are still in the pipeline. They''re still patent applications, they''re not out on the market yet so it''s hard to know how they''ll play out.”The growing knowledge of the human genome is also providing new opportunities to market medical products aimed at specific ethnic groups. The first bumpy steps were taken with screening for genetic risk factors for breast cancers. Myriad Genetics (Salt Lake City, UT, USA) holds broad patents in the USA for breast-cancer screening tests that are based on mutations of the BRCA1 and BRCA2 genes, but it faced challenges in Europe, where critics raised concerns about the high costs of screening.The growing knowledge of the human genome is also providing new opportunities to market medical products aimed at specific ethnic groupsThe European Patent Office initially granted Myriad patents for the BRCA1 and BRCA2-based tests in 2001, after years of debate. But it revoked the patent on BRCA1 in 2005, which was again reversed in 2009. In 2005 Myriad decided to narrow the scope of BRCA2 testing on the basis of ethnicity. The company won a patent to predict breast-cancer risk in Ashkenazi Jewish women on the basis of BRCA2 mutations, which occur in one in 100 of these women. Physicians offering the test are supposed to ask their patients whether they are in this ethnic group, and then pay a fee to Myriad.Kahn said Myriad took this approach to package the test differently in order to protect its financial interests. However, he commented, the idea of ethnic profiling by asking women whether they identify themselves as Ashkenazi Jewish and then paying extra for an ‘ethnic'' medical test did not work in Europe. “It''s ridiculous,” Kahn commented.After the preliminary sequence of the human genome was published a decade ago, experts noted that humans were almost the same genetically, implying that race was irrelevant. In fact, the validity of race as a concept in science—let alone the use of the word—has been hotly debated. “Race, inasmuch as the concept ought to be used at all, is a social concept, not a biological one. And using it as though it were a biological one is as a much an ethical problem as a scientific problem,” commented Samia Hurst, a physician and bioethicist at Geneva University Medical School in Switzerland.​Switzerland.Open in a separate window© Monalyn Gracia/CorbisCiting a popular slogan: “There is no gene for race,” she noted, “there doesn''t seem to be a single cluster of genes that fits with identification within an ethnic group, let alone with disease risks as well. We''re also in an increasingly mixed world where many people—and I count myself among them—just don''t know what to check on the box. If you start counting up your grandparents and end up with four different ethnic groups, what are you going to do? So there are an increasing number of people who just don''t fit into those categories at all.”Still, some dismiss criticism of racial profiling as political correctness that could potentially prevent patients from receiving proper care. Sally Satel, a psychiatrist in Washington, DC, USA, does not shy away from describing herself as a racially profiling physician and argues that it is good medicine. A commentator and resident scholar at the nonpartisan conservative think tank, the American Enterprise Institute (Washington, DC, USA), Satel wrote the book PC, M.D.: How Political Correctness is Corrupting Medicine. “In practicing medicine, I am not color blind. I take note of my patient''s race. So do many of my colleagues,” she wrote in a New York Times article entitled “I am a racially profiling doctor” (Satel, 2002).…some dismiss criticism of racial profiling as political correctness that could potentially prevent patients from receiving proper careSatel noted in an interview that it is an undeniable fact that black people tend to have more renal disease, Native Americans have more diabetes and white people have more cystic fibrosis. She said these differences can help doctors to decide which drugs to prescribe at which dose and could potentially lead researchers to discover new therapies on the basis of race.Satel added that the mention of race and medicine makes many people nervous. “You can dispel that worry by taking pains to specify biological lineage. Simply put, members of a group have more genes in common than members of the population at large. Some day geneticists hope to be able to conduct genomic profiles of each individual, making group identity irrelevant, but until then, race-based therapeutics has its virtues,” she said. “Denying the relationship between race and medicine flies in the face of clinical reality, and pretending that we are all at equal risk for health problems carries its own dangers.”However, Hurst contended that this approach may be good epidemiology, rather than racial profiling. Physicians therefore need to be cautious about using skin colour, genomic data and epidemiological data in decision making. “If African Americans are at a higher risk for hypertension, are you not going to check for hypertension in white people? You need to check in everyone in any case,” she commented.Hurst said European physicians, similarly to their American colleagues, deal with race and racial profiling, albeit in a different way. “The way in which we struggle with it is strongly determined by the history behind what could be called the biases that we have. If you have been a colonial power, if the past is slavery or if the past or present is immigration, it does change some things,” she said. “On the other hand, you always have the difficulty of doing fair and good medicine in a social situation that has a kind of ‘them and us'' structure. Because you''re not supposed to do medicine in a ‘them and us'' structure, you''re supposed to treat everyone according to their medical needs and not according to whether they''re part of ‘your tribe'' or ‘another tribe''.”Indeed, social factors largely determine one''s health, rather than ethnic or genetic factors. August A. White III, an African-American orthopaedic surgeon at Harvard Medical School (Boston, MA, USA) and author of the book Seeing Patients: Unconscious Bias In Health Care, noted that race is linked to disparities in health care in the USA. A similar point can be made in Europe where, for example, Romani people face discrimination in several countries.White said that although genetic research shows that race is not a scientific concept, the way people are labelled in society and how they are treated needs to be taken into account. “It''d be wonderful at some point if we can pop one''s key genetic information into a computer and get a printout of which medications are best of them and which doses are best for them,” he commented. “In the meantime though, I advocate careful operational attempts to treat everyone as human beings and to value everyone''s life, not devalue old people, or devalue women, or devalue different religious faiths, etc.”Notwithstanding the scientific denunciation, a major obstacle for the concept of racial profiling has been the fact that the word ‘race'' itself is politically loaded, as a result of, among other things, the baggage of eugenics and Nazi racism and the legacies of slavery and colonialism. Richard Tutton, a sociologist at Lancaster University in the UK, said that British scientists he interviewed for a Wellcome Trust project a few years ago prefer the term ethnicity to race. “Race is used in a legal sense in relation to inequality, but certainly otherwise, ethnicity is the preferred term, which obviously is different to the US” he said. “I remember having conversations with German academics and obviously in Germany you couldn''t use the R-word.”Jan Helge Solbakk, a physician, theologian and medical ethicist at the University of Oslo in Norway, said the use of the term race in Europe is a non-starter because it makes it impossible for the public and policy-makers to communicate. “I think in Europe it would be politically impossible to launch a project targeting racial differences on the genetic level. The challenge is to find not just a more politically correct concept, but a genetically more accurate concept and to pursue such research questions,” he said. According to Kahn, researchers therefore tend to refer to ethnicity rather than race: “They''re talking about European, Asian and African, but they''re referring to it as ethnicity instead of race because they think somehow that''s more palatable.”Regardless, race-based medicine might just be a stepping stone towards more refined and accurate methods, with the advent of personalized medicine based on genomics, according to Leroy Hood, whose work has helped to develop tools to analyse the human genome. The focus of his company—the Institute for Systems Biology (Seattle, WA, USA)—is to identify genetic variants that can inform and help patients to pioneer individualized health care.“Race as a concept is disappearing with interbreeding,” Hood said. “Race distinction is going to slowly fade away. We can use it now because we have signposts for race, which are colour, fairness, kinkiness of hair, but compared to a conglomeration of things that define a race, those are very few features. The race-defining features are going to be segregating away from one another more and more as the population becomes racially heterogeneous, so I think it''s going to become a moot point.”Hood instead advocates “4P” health care—“Predictive, Personalized, Preventive and Participatory.” “My overall feeling about the race-based correlations is that it is far more important to think about the individual and their individual unique spectra of health and wellness,” he explained. “I think we are not going to deal in the future with racial or ethnic populations, rather medicine of the future is going to be focused entirely on the individual.”Yet, Arthur Caplan, Director of the Center for Bioethics at the University of Pennsylvania (Philadelphia, PA, USA), is skeptical about the prospects for both race-based and personalized medicine. “Race-based medicine will play a minor role over the next few years in health care because race is a minor factor in health,” he said. “It''s not like we have a group of people who keel over dead at 40 who are in the same ethnic group.”Caplan also argued that establishing personalized genomic medicine in a decade is a pipe dream. “The reason I say that is it''s not just the science,” he explained. “You have to redo the whole health-care system to make that possible. You have to find manufacturers who can figure out how to profit from personalized medicine who are both in Europe and the United States. You have to have doctors that know how to prescribe them. It''s a big, big revamping. That''s not going to happen in 10 years.”Hood, however, is more optimistic and plans to advance the concept with pilot projects; he believes that Europe might be the better testing ground. “I think the European systems are much more efficient for pioneering personalized medicine than the United States because the US health-care system is utterly chaotic. We have every combination of every kind of health care and health delivery. We have no common shared vision,” he said. “In the end we may well go to Europe to persuade a country to really undertake this. The possibility of facilitating a revolution in health care is greater in Europe than in the United States.”     

Let's make Golgi

Does the Golgi self-organize or does it form around an instructive template? Evidence on both sides is piling up, but a definitive conclusion is proving elusive.In the battle to define the Golgi, discussions easily spiral into what can appear like nitpicking. In a contentious poster session, an entire worldview rests on whether you think a particular mutant is arrested with vesicles that are close to but distinct from the ER or almost budded from but still attached to the ER.Sometimes obscured by these details are the larger issues. This debate “gets to the fundamental issue of how you think of the Golgi,” says Ben Glick of the University of Chicago (Chicago, IL). “The dogma has been that you need a template to build an organelle. But in the secretory system it''s possible in principle that you could get de novo organization of structure. That''s the issue that stirs people emotionally and intellectually.”Then there are the collateral issues. There is an ongoing controversy about the nature of forward transport through the Golgi—it may occur via forward movement of small vesicles, or by gradual maturation of one cisterna to form the next. The cisternal maturation model “argues for a Golgi that can be made and consumed,” says Graham Warren (Yale University, New Haven, CT)—a situation that is more difficult to reconcile with Warren''s template-determined universe.Even more confusing is the situation in mitosis. Accounts vary wildly on how much of the Golgi disappears into the ER during mitosis. The answer would determine to what extent the cell has to rebuild the Golgi after mitosis, and what method it might use to do so.Several laboratories have made major contributions to address these issues. But none define them so clearly as those of Warren and Jennifer Lippincott-Schwartz (National Institutes of Health, Bethesda, MD). At almost every turn, on almost every issue, it seems that Warren and Lippincott-Schwartz reach opposite conclusions, sometimes based on similar or identical data.And yet, at least in public, there is a remarkable lack of rancor. “These are not easy experiments for us to do,” says Warren. “It''s all cutting-edge research and we are pushing the technology to the limit. Part of that is that you push your own interpretation.” For her part, Lippincott-Schwartz approaches a lengthy poster-session debate with Warren with something approaching glee. This is not triumphal glee, however. Rather, Lippincott-Schwartz seems to relish the opportunity to exchange ideas, and on this point Warren agrees. “Complacency is the worst thing to have in a field,” he says. The debate “has made all of us think a lot harder.”     

Rupture of a Duodenal Ulcer During Cortical Extract Therapy for Serum Sickness

Newer techniques of exercise which rely on a static or isometric muscle contraction of six seconds'' duration once daily offer great possibilities in the treatment of patients incapacitated by low cardiac reserve, joints that are painful on movement or debility too severe to permit a conventional exercise program for general conditioning. Increments of strength of up to two per cent per day can be thus achieved in normal muscles. Muscles deconditioned by immobilization respond at a faster rate. However, no significant muscle hypertrophy can be achieved by this technique.This form of exercise can also be used by persons who are “too busy to exercise” but who may be willing to give two minutes a day to an exercise program designed to increase and maintain muscle tone and strength.A considerable number of medical conditions could be treated more effectively and with less resultant disability if therapeutic exercises—passive, active and progressive—were accurately prescribed and supervised by a physician as part of the treatment program. Among the many conditions to be considered are poliomyelitis, peripheral nerve injuries, the neuritides, postural defects and cardiac diseases.     

Trunk rotational strength asymmetry in adolescents with idiopathic scoliosis: an observational study

Background

Body image and HRQL are significant issues for patients with scoliosis due to cosmetic deformity, physical and psychological symptoms, and treatment factors. A selective review of scoliosis literature revealed that self report measures of body image and HRQL share unreliable correlations with radiographic measures and clinician recommendations for surgery. However, current body image and HRQL measures do not indicate which aspects of scoliosis deformity are the most distressing for patients. The WRVAS is an instrument designed to evaluate patient self assessment of deformity, and may show some promise in identifying aspects of deformity most troubling to patients. Previous research on adolescents with scoliosis supports the use of the WRVAS as a clinical tool, as the instrument shares strong correlations with radiographic measures and quality of life instruments. There has been limited use of this instrument on adult populations.

Methods

The WRVAS and the SF-36v2, a HRQL measure, were administered to 71 adults with scoliosis, along with a form to report age and gender. Preliminary validation analyses were performed on the WRVAS (floor and ceiling effects, internal consistency and collinearity, correlations with the SF-36v2, and multiple regression with the WRVAS total score as the predictor, and SF-36v2 scores as outcomes).

Results

The psychometric properties of the WRVAS were acceptable. Older participants perceived their deformities as more severe than younger participants. More severe deformities were associated with lower scores on the Physical Component Summary Score of the SF-36v2. Total WRVAS score also predicted Physical Component Summary scores.

Conclusion

The results of the current study indicate that the WRVAS is a reliable tool to use with adult patients, and that patient self assessment of deformity shared a relationship with physical rather than psychological aspects of HRQL. The current and previous studies concur that revision of the WRVAS is necessary to more accurately represent the diversity of scoliosis deformities. Ability to identify disturbing aspects of deformity could potentially be improved by evaluating each WRVAS items against indicators of pain, physical/psychosocial function, and self image from previous measures such as the SRS, SF-36 or BSSQ-deformity.     

Crop shortages

A lack of breeders to apply the knowledge from plant science is jeopardizing public breeding programmes and the training of future plant scientistsIn the midst of an economic downturn, many college and university students in the USA face an uncertain future. There is one crop of graduates, though, who need not worry about unemployment: plant breeders. “Our students start with six-digit salaries once they leave and they have three or four offers. We have people coming to molecular biology and they can''t find jobs. People coming to plant breeding, they have as many jobs as they want,” said Edward Buckler, a geneticist with the US Department of Agriculture''s Agricultural Research Service Institute for Genomic Diversity at Cornell University (Ithaca, NY, USA).The lure of Big Ag depletes universities and research institutes of plant breeders […] and jeopardizes the training of future generations of plant scientists and breedersThe secret behind the success of qualified breeders on the job market is that they can join ‘Big Ag''—big agriculture—that is, major seed companies. Roger Boerma, coordinator of academic research for the Center for Applied Genetic Technologies at the University of Georgia (Athens, GA, USA), said that most of his graduate and postdoctoral students find jobs at companies such as Pioneer, Monsanto and Syngenta, rather than working in the orchards and fields of academic research. According to Todd Wehner, a professor and cucurbit breeder at the Department of Horticultural Science, North Carolina State University (Raleigh, NC, USA), the best-paying jobs—US$100,000 plus good benefits and research conditions—are at seed companies that deal with the main crops (Guner & Wehner, 2003). By contrast, university positions typically start at US$75,000 and tenure track.As a result, Wehner said, public crop breeding in the USA has begun to disappear. “To be clear, there is no shortage of plant breeders,” he said. “There is a shortage of plant breeders in the public sector.” The lure of Big Ag depletes universities and research institutes of plant breeders—who, after all, are the ones who create new plant varieties for agriculture—and jeopardizes the training of future generations of plant scientists and breeders. Moreover, there is an increasing demand for breeders to address the challenge of creating environmentally sustainable ways to grow more food for an increasing human population on Earth.At the same time, basic plant research is making rapid progress. The genomes of most of the main crop plants and many vegetables have been sequenced, which has enabled researchers to better understand the molecular details of how plants fend off pests and pathogens, or withstand drought and flooding. This research has also generated molecular markers—short regions of DNA that are linked to, for example, better resistance to fungi or other pathogens. So-called marker-assisted breeding based on this information is now able to create new plant varieties more effectively than would be possible with the classical strategy of crossing, selection and backcrossing.However, applying the genomic knowledge requires both breeders and plant scientists with a better understanding of each other''s expertise. As David Baulcombe, professor of botany at the University of Cambridge, UK, commented, “I think the important gap is actually in making sure that the fundamental scientists working on genomics understand breeding, and equally that those people doing breeding understand the potential of genomics. This is part of the translational gap. There''s incomplete understanding on both sides.”…applying the genomic knowledge requires both breeders and plant scientists with a better understanding of each other''s expertiseIn the genomic age, plant breeding has an image problem: like other hands-on agricultural work, it is dirty and unglamorous. “A research project in agriculture in the twenty-first century resembles agriculture for farmers in the eighteenth century,” Wehner said. “Harvesting in the fields in the summer might be considered one of the worst jobs, but not to me. I''m harvesting cucumbers just like everybody else. I don''t mind working at 105 degrees, with 95% humidity and insects biting my ankles. I actually like that. I like that better than office work.”For most students, however, genomics is the more appealing option as a cutting-edge and glamorous research field. “The exciting photographs that you always see are people holding up glass test tubes and working in front of big computer screens,” Wehner explained.In addition, Wehner said that federal and state governments have given greater priority and funding to molecular genetics than to plant breeding. “The reason we''ve gone away from plant breeding of course is that faculty can get competitive grants for large amounts of money to do things that are more in the area of molecular genetics,” he explained. “Plant breeders have switched over to molecular genetics because they can get money there and they can''t get money in plant breeding.”“The frontiers of science shifted from agriculture to genetics, especially the genetics of corn, wheat and rice,” agreed Richard Flavell, former Director of the John Innes Centre (Norwich, UK) and now Chief Scientific Officer of Ceres (Thousand Oaks, CA, USA). “As university departments have chased their money, chased the bright students, they have [focused on] programmes that pull in research dollars on the frontiers, and plant breeding has been left behind as something of a Cinderella subject.”In the genomic age, plant breeding has an image problem: like other hands-on agricultural work, it is dirty and unglamorousIn a sense, public plant breeding has become a victim of its own success. Wehner explained that over the past century, the protection of intellectual property has created a profitable market for private corporations to the detriment of public programmes. “It started out where they could protect seed-propagated crops,” he said. “The companies began to hire plant breeders and develop their own varieties. And that started the whole agricultural business, which is now huge.”As a result, Wehner said, the private sector can now outmanoeuvre public breeders at will. “[Seed companies] have huge teams that can go much faster than I can go. They have winter nurseries and big greenhouses and lots of pathologists and molecular geneticists and they have large databases and seed technologists and sales reps and catalogue artists and all those things. They can do much faster cucumber breeding than I can. They can beat me in any area that they choose to focus on.”He said that seed corporations turn only to public breeders when they are looking for rare seeds obtained on expeditions around the world or special knowledge. These crops and the breeders and other scientists who work on them receive far less financial support from government than do the more profitable crops, such as corn and soybean. In effect, these crops are in an analogous position to orphan drugs that receive little attention because the patients who need them represent a small economic market.The dwindling support for public breeding programmes is also a result of larger political developments. Since the 1980s, when British Prime Minister Margaret Thatcher and US President Ronald Regan championed the private sector in all things, government has consistently withdrawn support for public research programmes wherever the private sector can profit. “Plant breeding programmes are expensive. My programme costs about US$500,000 a year to run for my crops, watermelon and cucumber. Universities don''t want to spend that money if they don''t have to, especially if it''s already being done by the private sector,” Wehner said.“Over the last 30 years or so, food supplies and food security have fallen off the agenda of policymakers”…“Over the last 30 years or so, food supplies and food security have fallen off the agenda of policymakers,” Baulcombe explained. “Applied research in academic institutions is disappearing, and so the opportunities for linking the achievements of basic research with applications, at least in the public sector, are disappearing. You''ve got these two areas of the work going in opposite directions.”There''s another problem for plant breeding in the publish-or-perish world of academia. According to Ian Graham, Director of the Centre for Novel Agricultural Products at York University in the UK, potential academics in the plant sciences are turned off by plant breeding as a discipline because it is difficult to publish the research in high-impact journals.Graham, who is funded by the Bill & Melinda Gates Foundation to breed new varieties of Artemisia—the plant that produces the anti-malarial compound artemisinin—said this could change. “Now with the new [genomic] technologies, the whole subject of plant breeding has come back into the limelight. We can start thinking seriously about not just the conventional crops […] but all the marginal crops as well that we can really start employing these technologies on and doing exciting science and linking phenotypes to genes and phenotypes to the underlying biology,” he said. “It takes us back again closer to the science. That will bring more people into plant breeding.”…potential academics in the plant sciences are turned off by plant breeding as a discipline because it is difficult to publish the research in high-impact journalsBuckler, who specializes in functional genomic approaches to dissect complex traits in maize, wheat and Arabidopsis, said that public breeding still moves at a slower pace. “The seed companies are trying to figure out how to move genomics from gene discovery all the way to the breeding side. And it''s moving forward,” he said. “There have been some real intellectual questions that people are trying to overcome as to how fast to integrate genomics. I think it''s starting to occur also with a lot of the public breeders. A lot of it has been that the cost of genotyping, especially for specialty crops, was too high to develop marker systems that would really accelerate breeding.”Things might be about to change on the cost side as well. Buckler said that decreasing costs for sequencing and genotyping will give public breeding a boost. Using today''s genomic tools, researchers and plant breeders could match the achievements of the last century in maize breeding within three years. He said that comparable gains could be made in specialty crops, the forte of public breeding. “Right now, most of the simulations suggest that we can accelerate it about threefold,” Buckler said. “Maybe as our knowledge increases, maybe we can approach a 15-fold rate increase.”Indeed, the increasing knowledge from basic research could well contribute to significant advances in the coming years. “We''ve messed around with genes in a rather blind, sort of non-predictive process,” said Scott Jackson, a plant genomics expert at Purdue University (West Lafayette, IN, USA), who headed the team that decoded the soybean genome (Schmutz et al, 2010). “Having a full genome sequence, having all the genes underlying all the traits in whatever plant organism you''re looking at, makes it less blind. You can determine which genes affect the trait and it has the potential to make it a more predictive process where you can take specific genes in combinations and you can predict what the outcome might be. I think that''s where the real revolution in plant breeding is going to come.”Nevertheless, the main problem that could hold back this revolution is a lack of trained people in academia and the private sector. Ted Crosbie, Head of Plant Breeding at Monsanto (St Louis, MO, USA), commented at the national Plant Breeding Coordinating Committee meeting in 2008 that “[w]e, in the plant breeding industry, face a number of challenges. More plant breeders are reaching retirement age at a time when the need for plant breeders has never been greater […] We need to renew our nation''s capacity for plant breeding.”“…with the new [genomic] technologies, the whole subject of plant breeding has come back into the limelight”Dry bean breeder James Kelly, a professor of crop and soil sciences at Michigan State University (East Lansing, MI, USA), said while there has been a disconnect between public breeders and genomics researchers, new federal grants are designed to increase collaboration.In the meantime, developing countries such as India and China have been filling the gap. “China is putting a huge amount of effort into agriculture. They actually know the importance of food. They have plant breeders all over the place,” Wehner said. “The US is starting to fall behind. And now, agricultural companies are looking around wondering—where are we going to get our plant breeders?”To address the problem, major agriculture companies have begun to fund fellowships to train new plant breeders. Thus far, Buckler said, these efforts have had only a small impact. He noted that 500 new PhDs a year are needed just in maize breeding. “It''s not uncommon for the big companies like Monsanto, Pioneer and Syngenta to spend money on training, on endowing chairs at universities,” Flavell said. “It''s good PR, but they''re serious about the need for breeders.”The US government has also taken some measures to alleviate the problem. Congress decided to establish the US National Institute of Food and Agriculture (Washington, DC, USA) under the auspices of the US Department of Agriculture to make more efficient use of research money, advance the application of plant science and attract new students to plant breeding (see the interview with Roger Beachy in this issue, pp 504–507). Another approach is to use distance education to train breeders, such as technicians who want to advance their careers, in certificate programmes rather than master''s or doctorate programmes.“If [breeding] is not done in universities in the public sector, where is it done?”…“If [breeding] is not done in universities in the public sector, where is it done?” Flavell asked about the future of public breeding. “I can wax lyrical and perhaps be perceived as being over the top, but if we''re going to manage this planet on getting more food out of less land, this has to be almost one of the highest things that has got to be taken care of by government.” Wehner added, “The public in the developed world thinks food magically appears in grocery stores. There is no civilization without agriculture. Without plant breeders to work on improving our crops, civilization is at risk.”     

The puzzle of sympatry. Recent evidence supports the notion of sympatric speciation--the rise of new species in the same location--but the reasons for this phenomenon remain elusive

Sympatric speciation—the rise of new species in the absence of geographical barriers—remains a puzzle for evolutionary biologists. Though the evidence for sympatric speciation itself is mounting, an underlying genetic explanation remains elusive.For centuries, the greatest puzzle in biology was how to account for the sheer variety of life. In his 1859 landmark book, On the Origin of Species, Charles Darwin (1809–1882) finally supplied an answer: his grand theory of evolution explained how the process of natural selection, acting on the substrate of genetic mutations, could gradually produce new organisms that are better adapted to their environment. It is easy to see how adaptation to a given environment can differentiate organisms that are geographically separated; different environmental conditions exert different selective pressures on organisms and, over time, the selection of mutations creates different species—a process that is known as allopatric speciation.It is more difficult to explain how new and different species can arise within the same environment. Although Darwin never used the term sympatric speciation for this process, he did describe the formation of new species in the absence of geographical separation. “I can bring a considerable catalogue of facts,” he argued, “showing that within the same area, varieties of the same animal can long remain distinct, from haunting different stations, from breeding at slightly different seasons, or from varieties of the same kind preferring to pair together” (Darwin, 1859).It is more difficult to explain how new and different species can arise within the same environmentIn the 1920s and 1930s, however, allopatric speciation and the role of geographical isolation became the focus of speciation research. Among those leading the charge was Ernst Mayr (1904–2005), a young evolutionary biologist, who would go on to influence generations of biologists with his later work in the field. William Baker, head of palm research at the Royal Botanic Gardens, Kew in Richmond, UK, described Mayr as “one of the key figures to crush sympatric speciation.” Frank Sulloway, a Darwin Scholar at the Institute of Personality and Social Research at the University of California, Berkeley, USA, similarly asserted that Mayr''s scepticism about sympatry was central to his career.The debate about sympatric and allopatric speciation has livened up since Mayr''s death…Since Mayr''s death in 2005, however, several publications have challenged the notion that sympatric speciation is a rare exception to the rule of allopatry. These papers describe examples of both plants and animals that have undergone speciation in the same location, with no apparent geographical barriers to explain their separation. In these instances, a single ancestral population has diverged to the extent that the two new species cannot produce viable offspring, despite the fact that their ranges overlap. The debate about sympatric and allopatric speciation has livened up since Mayr''s death, as Mayr''s influence over the field has waned and as new tools and technologies in molecular biology have become available.Sulloway, who studied with Mayr at Harvard University, in the late 1960s and early 1970s, notes that Mayr''s background in natural history and years of fieldwork in New Guinea and the Solomon Islands contributed to his perception that the bulk of the data supported allopatry. “Ernst''s early career was in many ways built around that argument. It wasn''t the only important idea he had, but he was one of the strong proponents of it. When an intellectual stance exists where most people seem to have gotten it wrong, there is a tendency to sort of lay down the law,” Sulloway said.Sulloway also explained that Mayr “felt that botanists had basically led Darwin astray because there is so much evidence of polyploidy in plants and Darwin turned in large part to the study of botany and geographical distribution in drawing evidence in The Origin.” Indeed, polyploidization is common in plants and can lead to ‘instantaneous'' speciation without geographical barriers.In February 2006, the journal Nature simultaneously published two papers that described sympatric speciation in animals and plants, reopening the debate. Axel Meyer, a zoologist and evolutionary biologist at the University of Konstanz, Germany, demonstrated with his colleagues that sympatric speciation has occurred in cichlid fish in Lake Apoyo, Nicaragua (Barluenga et al, 2006). The researchers claimed that the ancestral fish only seeded the crater lake once; from this, new species have evolved that are distinct and reproductively isolated. Meyer''s paper was broadly supported, even by critics of sympatric speciation, perhaps because Mayr himself endorsed sympatric speciation among the cichlids in his 2001 book What Evolution Is. “[Mayr] told me that in the case of our crater lake cichlids, the onus of showing that it''s not sympatric speciation lies with the people who strongly believe in only allopatric speciation,” Meyer said.…several scientists involved in the debate think that molecular biology could help to eventually resolve the issueThe other paper in Nature—by Vincent Savolainen, a molecular systematist at Imperial College, London, UK, and colleagues—described the sympatric speciation of Howea palms on Lord Howe Island (Fig 1), a minute Pacific island paradise (Savolainen et al, 2006a). Savolainen''s research had originally focused on plant diversity in the gesneriad family—the best known example of which is the African violet—while he was in Brazil for the Geneva Botanical Garden, Switzerland. However, he realized that he would never be able prove the occurrence of sympatry within a continent. “It might happen on a continent,” he explained, “but people will always argue that maybe they were separated and got together after. […] I had to go to an isolated piece of the world and that''s why I started to look at islands.”Open in a separate windowFigure 1Lord Howe Island. Photo: Ian Hutton.He eventually heard about Lord Howe Island, which is situated just off the east coast of Australia, has an area of 56 km² and is known for its abundance of endemic palms (Sidebar A). The palms, Savolainen said, were an ideal focus for sympatric research: “Palms are not the most diverse group of plants in the world, so we could make a phylogeny of all the related species of palms in the Indian Ocean, southeast Asia and so on.”…the next challenges will be to determine which genes are responsible for speciation, and whether sympatric speciation is common

Sidebar A | Research in paradise

Alexander Papadopulos is no Tarzan of the Apes, but he has spent a couple months over the past two years aloft in palm trees hugging rugged mountainsides on Lord Howe Island, a Pacific island paradise and UNESCO World Heritage site.Papadopulos—who is finishing his doctorate at Imperial College London, UK—said the views are breathtaking, but the work is hard and a bit treacherous as he moves from branch to branch. “At times, it can be quite hairy. Often you''re looking over a 600-, 700-metre drop without a huge amount to hold onto,” he said. “There''s such dense vegetation on most of the steep parts of the island. You''re actually climbing between trees. There are times when you''re completely unsupported.”Papadopulos typically spends around 10 hours a day in the field, carrying a backpack and utility belt with a digital camera, a trowel to collect soil samples, a first-aid kit, a field notebook, food and water, specimen bags, tags to label specimens, a GPS device and more. After several days in the field, he spends a day working in a well-equipped field lab and sleeping in the quarters that were built by the Lord Howe governing board to accommodate the scientists who visit the island on various projects. Papadopulos is studying Lord Howe''s flora, which includes more than 200 plant species, about half of which are indigenous.Vincent Savolainen said it takes a lot of planning to get materials to Lord Howe: the two-hour flight from Sydney is on a small plane, with only about a dozen passengers on board and limited space for equipment. Extra gear—from gardening equipment to silica gel and wood for boxes in which to dry wet specimens—arrives via other flights or by boat, to serve the needs of the various scientists on the team, including botanists, evolutionary biologists and ecologists.Savolainen praised the well-stocked researcher station for visiting scientists. It is run by the island board and situated near the palm nursery. It includes one room for the lab and another with bunks. “There is electricity and even email,” he said. Papadoupulos said only in the past year has the internet service been adequate to accommodate video calls back home.Ian Hutton, a Lord Howe-based naturalist and author, who has lived on the island since 1980, said the island authorities set limits on not only the number of residents—350—but also the number of visitors at one time—400—as well as banning cats, to protect birds such as the flightless wood hen. He praised the Imperial/Kew group: “They''re world leaders in their field. And they''re what I call ‘Gentlemen Botanists''. They''re very nice people, they engage the locals here. Sometimes researchers might come here, and they''re just interested in what they''re doing and they don''t want to share what they''re doing. Not so with these people. Savolainen said his research helps the locals: “The genetics that we do on the island are not only useful to understand big questions about evolution, but we also always provide feedback to help in its conservation efforts.”Yet, in Savolainen''s opinion, Mayr''s influential views made it difficult to obtain research funding. “Mayr was a powerful figure and he dismissed sympatric speciation in textbooks. People were not too keen to put money on this,” Savolainen explained. Eventually, the Leverhulme Trust (London, UK) gave Savolainen and Baker £70,000 between 2003–2005 to get the research moving. “It was enough to do the basic genetics and to send a research assistant for six months to the island to do a lot of natural history work,” Savolainen said. Once the initial results had been processed, the project received a further £337,000 from the British Natural Environment Research Council in 2008, and €2.5 million from the European Research Council in 2009.From the data collected on Lord Howe Island, Savolainen and his team constructed a dated phylogenetic tree showing that the two endemic species of the palm Howea (Arecaceae; Fig 2) are sister taxa. From their tree, the researchers were able to establish that the two species—one with a thatch of leaves and one with curly leaves—diverged long after the island was formed 6.9 million years ago. Even where they are found in close proximity, the two species cannot interbreed as they flower at different times.Open in a separate windowFigure 2The two species of Howea palm. (A) Howea fosteriana (Kentia palm). (B) Howea belmoreana. Photos: William Baker, Royal Botanical Gardens, Kew, Richmond, UK.According to the researchers, the palm speciation probably occurred owing to the different soil types in which the plants grow. Baker explained that there are two soil types on Lord Howe—the older volcanic soil and the younger calcareous soils. The Kentia palm grows in both, whereas the curly variety is restricted to the volcanic soil. These soil types are closely intercalated—fingers and lenses of calcareous soils intrude into the volcanic soils in lowland Lord Howe Island. “You can step over a geological boundary and the palms in the forest can change completely, but they remain extremely close to each other,” Baker said. “What''s more, the palms are wind-pollinated, producing vast amounts of pollen that blows all over the place during the flowering season—people even get pollen allergies there because there is so much of the stuff.” According to Savolainen, that the two species have different flowering times is a “way of having isolation so that they don''t reproduce with each other […] this is a mechanism that evolved to allow other species to diverge in situ on a few square kilometres.”According to Baker, the absence of a causative link has not been demonstrated between the different soils and the altered flowering times, “but we have suggested that at the time of speciation, perhaps when calcareous soils first appeared, an environmental effect may have altered the flowering time of palms colonising the new soil, potentially causing non-random mating and kicking off speciation. This is just a hypothesis—we need to do a lot more fieldwork to get to the bottom of this,” he said. What is clear is that this is not allopatric speciation, as “the micro-scale differentiation in geology and soil type cannot create geographical isolation”, said Baker.…although molecular data will add to the debate, it will not settle it aloneThe results of the palm research caused something of a splash in evolutionary biology, although the study was not without its critics. Tod Stuessy, Chair of the Department of Systematic and Evolutionary Botany at the University of Vienna, Austria, has dealt with similar issues of divergence on Chile''s Juan Fernández Islands—also known as the Robinson Crusoe Islands—in the South Pacific. From his research, he points out that on old islands, large ecological areas that once separated species—and caused allopatric speciation—could have since disappeared, diluting the argument for sympatry. “There are a lot of cases [in the Juan Fernández Islands] where you have closely related species occurring in the same place on an island, even in the same valley. We never considered that they had sympatric origins because we were always impressed by how much the island had been modified through time,” Stuessy said. “What [the Lord Howe researchers] really didn''t consider was that Lord Howe Island could have changed a lot over time since the origins of the species in question.” It has also been argued that one of the palm species on Lord Howe Island might have evolved allopatrically on a now-sunken island in the same oceanic region.In their response to a letter from Stuessy, Savolainen and colleagues argued that erosion on the island has been mainly coastal and equal from all sides. “Consequently, Quaternary calcarenite deposits, which created divergent ecological selection pressures conducive to Howea species divergence, have formed evenly around the island; these are so closely intercalated with volcanic rocks that allopatric speciation due to ecogeographic isolation, as Stuessy proposes, is unrealistic” (Savolainen et al, 2006b). Their rebuttal has found support in the field. Evolutionary biologist Loren Rieseberg at the University of British Columbia in Vancouver, Canada, said: “Basically, you have two sister species found on a very small island in the middle of the ocean. It''s hard to see how one could argue anything other than they evolved there. To me, it would be hard to come up with a better case.”Whatever the reality, several scientists involved in the debate think that molecular biology could help to eventually resolve the issue. Savolainen said that the next challenges will be to determine which genes are responsible for speciation, and whether sympatric speciation is common. New sequencing techniques should enable the team to obtain a complete genomic sequence for the palms. Savolainen said that next-generation sequencing is “a total revolution.” By using sequencing, he explained that the team, “want to basically dissect exactly what genes are involved and what has happened […] Is it very special on Lord Howe and for this palm, or is [sympatric speciation] a more general phenomenon? This is a big question now. I think now we''ve found places like Lord Howe and [have] tools like the next-gen sequencing, we can actually get the answer.”Determining whether sympatric speciation occurs in animal species will prove equally challenging, according to Meyer. His own lab, among others, is already looking for ‘speciation genes'', but this remains a tricky challenge. “Genetic models […] argue that two traits (one for ecological specialisation and another for mate choice, based on those ecological differences) need to become tightly linked on one chromosome (so that they don''t get separated, often by segregation or crossing over). The problem is that the genetic basis for most ecologically relevant traits are not known, so it would be very hard to look for them,” Meyer explained. “But, that is about to change […] because of next-generation sequencing and genomics more generally.”Many researchers who knew Mayr personally think he would have enjoyed the challenge to his viewsOthers are more cautious. “In some situations, such as on isolated oceanic islands, or in crater lakes, molecular phylogenetic information can provide strong evidence of sympatric speciation. It also is possible, in theory, to use molecular data to estimate the timing of gene flow, which could help settle the debate,” Rieseberg said. However, he cautioned that although molecular data will add to the debate, it will not settle it alone. “We will still need information from historical biogeography, natural history, phylogeny, and theory, etc. to move things forward.”Many researchers who knew Mayr personally think he would have enjoyed the challenge to his views. “I can only imagine that it would''ve been great fun to engage directly with him [on sympatry on Lord Howe],” Baker said. “It''s a shame that he wasn''t alive to comment on [our paper].” In fact, Mayr was not really as opposed to sympatric speciation as some think. “If one is of the opinion that Mayr opposed all forms of sympatric speciation, well then this looks like a big swing back the other way,” Sulloway commented. “But if one reads Mayr carefully, one sees that he was actually interested in potential exceptions and, as best he could, chronicled which ones he thought were the best candidates.”Mayr''s opinions aside, many biologists today have stronger feelings against sympatric speciation than he did himself in his later years, Meyer added. “I think that Ernst was more open to the idea of sympatric speciation later in his life. He got ‘softer'' on this during the last two of his ten decades of life that I knew him. I was close to him personally and I think that he was much less dogmatic than he is often made out to be […] So, I don''t think that he is spinning in his grave.” Mayr once told Sulloway that he liked to take strong stances, precisely so that other researchers would be motivated to try to prove him wrong. “If they eventually succeeded in doing so, Mayr felt that science was all the better for it.”? Open in a separate windowAlex Papadopulos and Ian Hutton doing fieldwork on a very precarious ridge on top of Mt. Gower. Photo: William Baker, Royal Botanical Gardens, Kew, Richmond, UK.     

Vaccine outlooks

After negative publicity and a series of setbacks over HIV/AIDS and influenza, the prospects for research on new vaccines are improvingVaccine research is at a crossroads between renewed optimism created by fundamental scientific advances, and pessimism from a series of scientific and publicity setbacks over the past decade. Early successes in the field against acute viral diseases, such as smallpox and polio, raised hopes that more serious infectious diseases could be controlled or even eradicated by vaccination, just as it was once thought that penicillin would eradicate major bacterial diseases such as tuberculosis and leprosy....it became clear that many viruses were much tougher nuts to crack in terms of vaccine development...However, it became clear that many viruses were much tougher nuts to crack in terms of vaccine development than had been thought, and it also emerged that not all vaccines were equally safe. Indeed, mounting concerns over the safety of vaccines culminated in the infamous Wakefield paper published in the Lancet in 1998 that associated the MMR vaccine—against measles, mumps and rubella—with autism and inflammatory bowel disease in children. After several studies failed to reproduce these results, the Lancet eventually retracted this paper in 2010, but not before considerable damage had been done to public confidence in vaccination as a whole. Other factors have also sapped confidence in the field—notably the continuing failure to develop an effective vaccine against HIV/AIDS, 15 years after the first hopeful reports that a breakthrough might be imminent (Gorse et al, 1995).Researchers have since developed a string of HIV/AIDS vaccine candidates, some of which have entered clinical trials, but none of which have been sufficiently efficient and safe. The gloom has deepened further after the failure of a vaccine candidate developed by the pharmaceutical company Merck in 2007, that had high hopes for success. This vaccine, called V520, used a weakened adenovirus that carries three HIV genes, to stimulate host production of T cells that it was hoped would kill HIV-infected cells. Early small trials had detected cellular immune responses, but these largely failed to materialize in a subsequent phase II clinical trial. The recombinant vaccine triggered a rapid immune response against itself that actually impaired the T-cell response against the HIV antigens. As a result, the trial was halted in September 2007 (Anon, 2007).Controversially, it has since been suggested that V520 rendered some individuals more liable to subsequent infection, although views on this finding are polarized. According to Steven Patterson, a research fellow specializing in HIV at Imperial College, London, “there was a greater incidence of infection in those individuals who had immunity to adenovirus type 5 before vaccination. Some scientists argue that the numbers [of people who suffered infection during the trial] are relatively low, the results represent a statistical anomaly and that the effect gradually disappeared, suggesting that it was not a real effect. Others, including ourselves, think that in adenovirus type 5-immune individuals the vector activated pre-existing memory CD4 cells migrate to mucosal tissue. Then, because the virus preferentially replicates in activated CD4 T cells and the number of HIV susceptible cells is increased at the site of HIV infection, there is an increase in the number of infections. With time the activated cells return to a resting state which would explain why the effect of adenovirus vaccination gradually disappeared.”Whatever the truth in this case, it highlighted the setbacks in HIV/AIDS research and increased negative sentiments both among the public and, more crucially, funding agencies. “The devastating impact of HIV and its lethality have placed research on vaccines and other preventative measures under an unfamiliar spotlight,” said Colonel Jerome Kim, HIV vaccines product manager for the US Army from the Walter Reed Army Institute of Research. “This has tended to exaggerate both the incremental successes and failures of HIV-1 vaccine research.”The devastating impact of HIV and its lethality have placed research on vaccines and other preventative measures under an unfamiliar spotlightThis might have contributed to a decline in public funding that has been combined with a continuing lack of investment from the private sector (AVERT, 2010). More worryingly, there have been signs that governments are withdrawing funding from vaccine research (Médecins Sans Frontières, 2009). In fact, the US government—through the National Institutes of Health—and the Bill and Melinda Gates Foundation—the charitable trust established in 1994 by Microsoft founder Bill Gates—accounted for 79% of the world''s US$868 million funding for HIV/AIDS vaccine research in 2008 (HIV Vaccines and Microbicides Resource Tracking Working Group, 2010).Other areas of vaccination research have also contributed to negative sentiments towards the field. A universal vaccine against influenza has proved similarly elusive, given the mutability of the virus. The recent swine flu pandemic—the severity of which fell short of many pessimistic expectations—left many governments having spent huge sums on vaccines that they never needed. Furthermore, had swine flu become as virulent as it might have, these vaccine stockpiles might still have been only partially effective.More worryingly, there have been signs that governments are withdrawing funding from vaccine researchAll of these factors are fuelling groups who are opposed to vaccine research for various reasons, according to Joachim Hombach, at the World Health Organization''s Initiative for Vaccine Research in Geneva. “There are certain groups, particularly in the industrialised world, that have an anti-vaccine attitude, and these kinds of cases find very fertile ground there,” he said, referring in particular to the Lancet MMR article. “There is also a different story relating to general attitudes towards acceptance of absolutely no risk associated with vaccines or other medical interventions.” This risk-averse culture exposes vaccines to public scrutiny when side effects occur during trials or afterwards, and has even been spreading to developing countries. “This creates a challenging climate for vaccine research,” said Hombach.There are still strong grounds for optimism, as huge strides have been made in understanding the relationship between viruses and the immune response, which is more subtle and diverse than has been previously appreciated. In a sense, diseases such as polio represent the low-hanging fruit in the orchard of infectious disease; early successes in vaccine development have perhaps created a false sense of optimism. “Diseases that are more chronic, where you have a very delicate balance between the pathogen and the immune response, are very difficult to prevent with vaccines,” Hombach said. “HIV is not the only one and there is also TB for instance, which is quite difficult. It is much easier to develop vaccines against acute diseases.”There is accordingly a need to educate the public about these difficulties, commented Tomáš Hanke, Nuffield professor of medicine specializing in HIV research at Oxford University. “Public confidence is a matter of public education and understanding of the process of scientific discovery,” he said. “The more challenging the aim is, the more explaining the public needs.”Researchers disagree about the major problems hindering the development of new vaccines. In the case of HIV, Kim identified the elimination of CD4⁺ helper T cells by the virus as one of the major problems, because these cells are at the centre of immune control and influence the activities of other cells. It is this disabling of helper T cells that weakens the immune response to other diseases in those who have AIDS.Patterson believes that the greatest problem is the virus''s mutability. “The ability of the virus to quickly mutate and escape from responses that are mounted against specific domains of the virus that are recognized by the immune system is, I think, the major hurdle that we need to overcome,” he said. This is one reason why the traditional strategy of inducing protective antibodies by administering an attenuated virus has not worked for HIV.There are two further problems. First, important regions of the HIV virus are shielded by sugars and second, although antibodies that disable a broad range of HIV viruses have been identified, these tend to be produced too late in the immune response, when infection is already well established. For this reason, there has been increased focus on T-cell vaccines that can recognize and kill infected cells, rather than on efforts to prevent infection in the first place. Crucially though, as Patterson pointed out, this approach still faces the problem of mutation, because this can enable the virus to escape recognition by T cells.This, in turn, suggests that vaccines must target regions of the virus that are well conserved. “A normal T cell immune response tends to be against a small number of so-called dominant epitopes and in the case of HIV these are often against the more variable regions the virus can afford to mutate without any cost to itself,” Patterson explained. “To avoid immune escape, we probably need to induce a T cell response against a number of conserved virus epitopes that the virus could not afford to mutate without severely impairing its replication capacity. I believe this aim is achievable.”While the battle against HIV/AIDS has been catching most of the headlines, a lesser known viral disease, dengue, has been rising quickly up the research agendaMore fundamental research at the molecular level is needed to achieve this goal. Robin Weiss, professor of viral oncology at University College London, leads one team who are trying to identify antigens or targets that might one day become useful in vaccine design. Weiss does not claim to be near an imminent breakthrough, but he believes that a major step might be made soon towards developing a broad-spectrum vaccine that could prevent HIV infection in the first place. The problem, as Weiss pointed out, is not that individuals with HIV fail to produce antibodies, but that HIV elicits too many different ones, nearly all of which are ineffective. Only a few HIV-infected individuals produce potent antibodies and even then, these are often in insufficient concentrations. Now that the crystal structure of the potent antibodies has been defined, this vital molecular information could be used to design new vaccines that elicit production of these antibodies in the host.Valuable information has also come from a US Army sponsored clinical trial in Thailand that studied more than 16,000 healthy individuals between 2003 and 2006. A vaccine containing genetically engineered versions of three HIV genes was used, with an inert form of the bird virus canary pox as the vector. In December 2009, the sponsors reported that the rate of HIV infection among volunteers who received the experimental vaccine was 31% lower than among those who received a placebo (Rerks-Ngarm et al, 2009). “[The trial] showed, for the first time, that a vaccine is able to reduce the risk of HIV infection in humans,” said Kim. “Although our results were modest, they are providing a great deal of information to inform the field. For example, the protection appeared highest at 6–12 months based on post-hoc analysis. If we can sustain or increase this effect, that would be a great accomplishment.”While the battle against HIV/AIDS has been catching most of the headlines, a lesser known viral disease, dengue fever, has been rising quickly up the research agenda. Dengue fever is caused by four related strains of flavivirus that are transmitted by mosquitoes. The disease affects 50–100 million people annually, mostly in urban tropical areas, where an estimated 2.5 billion are at risk (Webster et al, 2009), largely because of growing urban populations. Attempts to develop a vaccine have been inhibited by the host immune response to the vaccine, according to Sarah Rowland-Jones, professor of immunology at the Weatherall Institute of Molecular Medicine in Oxford, UK. “It is a tough target for vaccine development principally because of the possibility that immune mechanisms contribute to pathogenesis, so researchers have to be particularly careful that a dengue vaccine does not make disease more likely because of the kind of immune response it stimulates, rather than leading to protection from infection,” she said.The fact that there are four viruses is another problem, especially as a vaccine protecting against one might actually prime individuals for another serotype. “The best hypothesis for severe dengue is that following a first infection, an individual gains immunity against that serotype but becomes more prone to a second infection with a different serotype,” said Jeremy Farrar, Director of the Wellcome Unit in Vietnam and a professor of tropical medicine at Oxford University. “With that second infection against another serotype, more severe disease develops. Obviously this makes vaccine development difficult as one worries individuals will be ‘primed'' by the vaccine and, when they get a natural infection will have more severe disease.”...the effect of each nucleotide change on virus activity is very small, but the cumulative impact of hundreds of such changes causes strong attenuationHowever, Farrar believes this problem has been fixed with the new generation of ‘chimeric vaccines'' that offer protection against all four serotypes. These are based on an exisiting vaccine against the related disease yellow fever, incorporating a part of the dengue virus that triggers an immune response. This chimeric approach has the potential to be extended to develop vaccines against other diseases.This begs the question of why a dengue virus vaccine has not been developed already, given that the related yellow fever vaccine has been available for years. Part of the reason is that dengue is a tougher target, involving four serotypes, but it is also because its mortality is much lower than the 50% rate of yellow fever. “Dengue hasn''t been top of the agenda because it hasn''t caused so much mortality, but there is a lot of morbidity, and it puts a lot of stress on health authorities and has an epidemic potential,” Hombach said. For this reason it has received more funding recently, with phase III clinical trials likely to begin soon, according to Farrar.An entirely different approach for engineering vaccines might also be emerging. Traditional vaccines use mutated virus strains with limited replication abilities, in order to stimulate the immune system. The main drawback of this approach is that many attenuated strains fail to elicit adequate immunity, and it takes a long time to develop such strains. However, Eckard Wimmer and colleagues at Stony Brook University in New York, have developed a computer-aided approach to create attenuated strains without changing the composition and amino-acid sequence of the virus''s proteins (Mueller et al, 2010).They exploit the redundancy of the genetic code; 64 codons code for just 20 amino acids. As most amino acids are coded for by several codons, it is possible to introduce single-nucleotide changes without altering which proteins are expressed, thereby retaining all antigens that might generate an adaptive immune response. Crucially, however, this alters the expression of some genes, which reduces the ability of the virus to replicate. As Wimmer pointed out, the effect of each nucleotide change on virus activity is very small, but the cumulative impact of hundreds of such changes causes strong attenuation. “We call this ‘death by a thousand cuts'',” he said.Moreover, subsequent natural mutations will probably change only one or two of these nucleotide substitutions back to the original, so the chance that the virus will regain its former virulence is very small. The greatest advantage of this approach, however, is speed. “Clearly, such recoded genomes can only be produced by chemical synthesis,” said Wimmer. “They can be designed rapidly—much faster than any other live vaccine that was isolated after long trials of selection.” This, argues Wimmer, makes the approach ideal for countering emerging pandemics when time is short, especially those caused by influenza. Indeed, Wimmer has demonstrated his approach by designing an influenza vaccine (Mueller et al, 2010).Even if this synthetic approach can generate new vaccine candidates more quickly, it will still require development time and clinical trials to assess their efficacy and safety—as is the case for other emerging techniques. New knowledge and new technologies are filtering through to vaccine development; while the disappointments of the past have provided valuable lessons.     

Lipid rafts make for slippery platforms

What''s in a raft? Although cell membranes are certainly not homogeneous mixtures of lipids and proteins, almost all aspects of lipid rafts—how to define them, their size, composition, lifetime, and biological relevance—remain controversial. The answers will shape our views of signaling and of membrane dynamics.In the influential “fluid mosaic” model of Singer and Nicolson, a “mosaic” of integral transmembrane proteins floats about in a “fluid” sea of lipids (Singer and Nicolson, 1972). More recently, researchers have shifted to a view in which membrane lipids are not randomly distributed, but instead show local heterogeneity. One might imagine this as a two-dimensional projection of a lava lamp, with different types of greasy globules in constant motion, endlessly separating and rejoining into distinct but transient domains. These domains are now referred to under the general heading of lipid rafts and domains, a subset of which are the morphologically identifiable “caveolae.”The study of lipid domains has exploded since the debut of the “raft hypothesis” only about fifteen years ago. This torrent of research notwithstanding, there remains heated discussion concerning matters as fundamental as what lipid domains look like—a discussion that peaked but reached little in the way of resolution at a recent conference (Euroconference on Microdomains, Lipid Rafts, and Caveolae; Tomar, Portugal, May 17–22, 2003). Regardless of their actual form, evidence is mounting that lipid rafts are essential participants in signal transduction, membrane and protein sorting, and the pathogenesis of several human diseases.     

Academic labour shortages. A lack of trained scientists could slow down research in Europe

A shortage of skilled science labour in Europe could hold back research progress. The EU will increase science funding to address the problem, but real long-term measures need to start in schools, not universities.Scientists have always warned about the doom of research that could result from a shortage of students and skilled labour in the biomedical sciences. In the past, this apocalyptic vision of empty laboratories and unclaimed research grants has seemed improbable, but some national research councils and the European Union (EU) itself now seem to think that we may be on the brink of a genuine science labour crisis in Europe. This possibility, and its potential effects on economic growth, has proven sufficiently convincing for the European Commission (EC) to propose a 45% increase to its seven-year research and development budget of 45%—from €55 billion, provided under the Framework Programme (FP7), to €80 billion—for a new strategic programme for research and innovation called Horizon 2020 that will start in 2014.This bold proposal to drastically increase research funding, which comes at a time when many other budgets are being frozen or cut, was rigorously defended in May 2012 by the EU ministers responsible for science and innovation, against critics who argued that such a massive increase could not be justified given the deepening economic crisis across the EU. So far, the EU seems to be holding to the line that it has to invest more into research if Europe is to compete globally through technological innovation underpinned by scientific research.Europe is caught in a pincer movement between its principle competitors—the USA and Japan, which are both increasing their research budgets way ahead of inflation—and the emerging economies of China, India, Brazil and Russia, which are quickly closing from behind. The main argument for the Horizon 2020 funding boost came from a study commissioned by the EU [1], which led the EC to claim that Europe faces an “innovation emergency” because its businesses are falling behind US and Japanese rivals in terms of investment and new patents. As Martin Lange, Policy Officer for Marie Curie Actions—an EU fellowship programme for scientists—pointed out, “China, India and Brazil have started to rapidly catch up with the EU by improving their performance seven per cent, three per cent and one per cent faster than the EU year on year over the last five years.”According to Lange, Europe''s innovation gap equates to a shortage of around 1 million researchers across the EU, including a large number in chemistry and the life sciences. This raises fundamental issues of science recruitment and retention that a budget increase alone cannot address. The situation has also been confused by the economic crisis, which has led to the position where many graduates are unemployed, and yet there is still an acute shortage of specialist skills in areas vital to research.This is a particularly serious issue in the UK, where around 2,000 researcher jobs were lost following the closure of pharmaceutical company Pfizer''s R&D facility in Kent, announced in February 2011. “The travails of Pfizer have affected the UK recruitment market,” explained Charlie Ball, graduate labour market specialist at the UK''s Higher Education Careers Services Unit. The closure has contributed to high unemployment among graduates, particularly chemists, who tend to be employed in pharmaceutical research in the UK. “Even among people with chemistry doctorates, the unemployment rate is higher than the average,” he said.The issue for chemists, at least in the UK, is not a skills shortage, but a skills mismatch. Ball identified analytical chemistry as one area without enough skilled people, despite the availability of chemists with other specialties. He attributes part of the problem to the pharmaceutical industry''s inability to communicate its requirements to universities and graduates, although he concedes that doing so can be challenging. “One issue is that industry is changing so quickly that it is genuinely difficult to say that in three or four years time we will need people with specific skills,” Ball explained.So far, the EU seems to be holding to the line that it has to invest more into research […] to compete globally through technological innovation underpinned by scientific researchAlongside this shortage of analytical skills, the UK Medical Research Council (MRC) has identified a lack of people with practical research knowledge, and in particular of experience working with animals, as a major factor holding back fundamental and pre-clinical biomedical research in the country. It has responded by encouraging applications from non-UK and even non-EU candidates for doctoral studentships that it funds, in cases where there is a scarcity of suitable UK applicants.But, the underlying problem common to the whole of Europe is more fundamental, at least according to Bengt Norden, Professor of Physical Chemistry at the University of Gothenburg in Sweden. The issue is not a shortage of intellectual capital, Norden argues, but a growing lack of investment into training chemists, which in turn undermines life sciences research. Similarly to many other physical chemists, Norden has worked mainly in biology, where he has applied his expertise in molecular recognition and function to DNA recombination and membrane translocation mechanisms. He therefore views a particularly acute recruitment and retention crisis in chemistry as being a drag on both fundamental and applied research across the life sciences. “The recruitment crisis is severe,” Norden said. “While a small rill of genuinely devoted‘young amateur scientists‘ still may sustain the recruitment chain, there is a general drain of interest in science in general and chemistry in particular.” He attributes this in part to sort of a ‘chemophobia'', resulting from the association of chemistry with environmental pollution or foul odours, but he also blames ignorant politicians and other public figures for their negative attitude towards chemistry. “A former Swedish Prime Minister, Goran Persson, claimed that ‘his political goal was to make Sweden completely free from chemicals'',” Norden explained by way of example.Scientists themselves also need to do a better job of countering the negative perceptions of chemistry and science, perhaps by highlighting the contribution that chemistry is already making to clearing up pollution. Chemistry has been crucial to the development of microorganisms that can be used to break down organic pollutants in industrial waste, or clear up accidental spillage during transport. In fact, chemistry has specifically addressed the two major challenges involved: the risk that genetically engineered microorganisms could threaten the wider environment if they escape, and the problem that the microorganisms themselves can be poisoned if the concentration of pollutants is too high.A team at the University of Buenos Aires in Argentina has solved both problems by developing a material comprising an alginate bead surrounded by a silica gel [2]. This container houses a fungus that produces enzymes that break up a variety of organic pollutants. The pores of the hydrogel can limit the intake of toxic compounds from the polluted surroundings, thus controlling the level of toxicity experienced by the fungus, whilst the fungus itself is encapsulated inside the unit and cannot escape. Norden and others believe that if such examples were given more publicity, they would both improve the reputation of chemistry and science in general, and help to enthuse school students at a formative age.…Europe''s innovation gap equates to a shortage of around 1 million researchers across the EU, including a large number in chemistry and the life sciencesUnfortunately, this is not happening in schools, according to Norden, where the curriculum is failing both to enthuse pupils through practical work, and to inform them of the value of chemistry across society: “school chemistry neither stimulates curiosity nor does it promote understanding of what is most important to everybody,” he said. “It should be realized that well-taught chemistry is a necessary tool for dealing with everyday problems, at home or at work, and in the environment, relating to function of medicines, as well as what is poisonous and what is less noxious. As it is, all chemicals are presented simply as poisons.”Norden believes that a broader cultural element also tends to explain the particular shortage of analytical skills in chemistry. He believes that young people are more inclined than ever before to weigh up the probable rewards of a chosen profession in relation to the effort involved. “There seems to be a ‘cost–benefit'' aspect that young people apply when choosing an academic career: science, including maths, is too hard in relation to the jobs that eventually are available in research,” he explained. This ‘cost–benefit'' factor might not deter people from studying subjects up to university level, but can divert them into careers that pay a lot more. Ball believes that there is also an issue of esteem, in that people tend to gravitate towards careers where they feel valued. “Our most able graduates don''t see parity in esteem between research and other professions being represented by the salary they are paid,” he explained. “That is an issue that needs to be resolved, and it is not just about money, but working hard to convince these graduates that there is a worthwhile career in research.”Our most able graduates don''t see parity in esteem between research and other professions being represented by the salary they are paid,Lange suggests that it would be much easier to persuade the best graduates to stay in science if they were able to pursue their ideas free from bureaucracy or other constraints. This was a main reason to start the Marie Curie Actions programme of which Lange is a part, and which will be continued under Horizon 2020 with a new name, Marie Skłodowska-Curie Actions, and an increased budget. “The Marie Curie Actions have been applying a bottom-up principle, allowing researchers to freely choose their topic of research,” Lange explained. “The principle of ‘individual-driven mobility'' that is used in the Individual Fellowships empowers researchers to make their own choices about the scientific topic of their work, as well as their host institutions. […] It is a clear win–win situation for both sides: researchers are more satisfied because they are given the opportunity to take their careers in their own hands, while universities and research organizations value top-class scientists coming from abroad to work at their institutes.”Lange also noted that although Marie Curie Fellows choose their own research subjects, they tend to pursue topics that are relevant to societal needs because they want to find work afterwards. “More than 50% of the FP7 Marie Curie budget has been dedicated to research that can be directly related to the current societal challenges, such as an ageing population, climate change, energy shortage, food and water supply and health,” he said. “This demonstrates that researchers are acting in a responsible way. Even though they have the freedom to choose their own research topics, they still address problems that concern society in general.” In addition, Marie Curie Actions also encourages engagement with the public, feeding back into the wider campaign to draw more people into science careers. “Communicating science to the general public will be of importance as well, if we want to attract more young people to science,” Lange said. “Recently, the Marie Curie Actions started encouraging their Fellows to engage in outreach activities. In addition, we have just launched a call for the Marie Curie Prize, where one of the three Prize categories will be ‘Communicating Science''.”Another important element of the EU''s strategy to stimulate innovative cutting edge research is the European Research Council (ERC). It was the first pan-European funding body for front-line research across the sciences, with a budget of €7.5 billion for the FP7 period of 2007–2013, and has been widely heralded as a success. As a result, the ERC is set to receive an even bigger percentage increase than other departments within Horizon 2020 for the period 2014–2020, with a provisional budget of €13.2 billion.Leading scientists, such as Nobel laureate Jean-Marie Lehn, from Strasbourg University in France, believe that the ERC has made a substantial contribution to innovative research and, as a result, has boosted the reputation of European science. “The ERC has done a fantastic job which is quite independent of pressures from the outside,” he said. “It is good to hear that taking risks is regarded as important.” Lehn also highlighted the importance of making it clear that there are plenty of opportunities in research beyond those funded, and therefore dictated, by the big pharmaceutical companies. “There is chemistry outside big pharma, and life beyond return on investment,” he said. Lehn agreed that there must be a blend between blue sky and goal-oriented research, even if there is an argument over what the blend and goals should be.…the ERC has made a substantial contribution to innovative research and, as a result, has boosted the reputation of European scienceThere is growing optimism that Europe''s main funding bodies, including the national research councils of individual countries, have not only recognized the recruitment problem, but are taking significant steps to address it. Even so, there is still work to be done to improve the image of science and to engage students through more stimulating teaching. Chemistry in particular would benefit from broader measures to attract young people to science. Ultimately, the success of such initiatives will have much broader effects in the life sciences and drug development.     

A systems genetics approach provides a bridge from discovered genetic variants to biological pathways in rheumatoid arthritis

Genome-wide association studies (GWAS) have yielded novel genetic loci underlying common diseases. We propose a systems genetics approach to utilize these discoveries for better understanding of the genetic architecture of rheumatoid arthritis (RA). Current evidence of genetic associations with RA was sought through PubMed and the NHGRI GWAS catalog. The associations of 15 single nucleotide polymorphisms and HLA-DRB1 alleles were confirmed in 1,287 cases and 1,500 controls of Japanese subjects. Among these, HLA-DRB1 alleles and eight SNPs showed significant associations and all but one of the variants had the same direction of effect as identified in the previous studies, indicating that the genetic risk factors underlying RA are shared across populations. By receiver operating characteristic curve analysis, the area under the curve (AUC) for the genetic risk score based on the selected variants was 68.4%. For seropositive RA patients only, the AUC improved to 70.9%, indicating good but suboptimal predictive ability. A simulation study shows that more than 200 additional loci with similar effect size as recent GWAS findings or 20 rare variants with intermediate effects are needed to achieve AUC = 80.0%. We performed the random walk with restart (RWR) algorithm to prioritize genes for future mapping studies. The performance of the algorithm was confirmed by leave-one-out cross-validation. The RWR algorithm pointed to ZAP70 in the first rank, in which mutation causes RA-like autoimmune arthritis in mice. By applying the hierarchical clustering method to a subnetwork comprising RA-associated genes and top-ranked genes by the RWR, we found three functional modules relevant to RA etiology: “leukocyte activation and differentiation”, “pattern-recognition receptor signaling pathway”, and “chemokines and their receptors”.These results suggest that the systems genetics approach is useful to find directions of future mapping strategies to illuminate biological pathways.     

Evolvement of uniformity and volatility in the stressed global financial village

Background

In the current era of strong worldwide market couplings the global financial village became highly prone to systemic collapses, events that can rapidly sweep throughout the entire village.

Methodology/Principal Findings

We present a new methodology to assess and quantify inter-market relations. The approach is based on the correlations between the market index, the index volatility, the market Index Cohesive Force and the meta-correlations (correlations between the intra-correlations.) We investigated the relations between six important world markets—U.S., U.K., Germany, Japan, China and India—from January 2000 until December 2010. We found that while the developed “western” markets (U.S., U.K., Germany) are highly correlated, the interdependencies between these markets and the developing “eastern” markets (India and China) are volatile and with noticeable maxima at times of global world events. The Japanese market switches “identity”—it switches between periods of high meta-correlations with the “western” markets and periods when it behaves more similarly to the “eastern” markets.

Conclusions/Significance

The methodological framework presented here provides a way to quantify the evolvement of interdependencies in the global market, evaluate a world financial network and quantify changes in the world inter market relations. Such changes can be used as precursors to the agitation of the global financial village. Hence, the new approach can help to develop a sensitive “financial seismograph” to detect early signs of global financial crises so they can be treated before they develop into worldwide events.     

Endpiece: Three different talks

ObjectivesTo characterise the information needs of family doctors by collecting the questions they asked about patient care during consultations and to classify these in ways that would be useful to developers of knowledge bases.DesignObservational study in which investigators visited doctors for two half days and collected their questions. Taxonomies were developed to characterise the clinical topic and generic type of information sought for each question.SettingEastern Iowa.ParticipantsRandom sample of 103 family doctors.ResultsParticipants asked a total of 1101 questions. Questions about drug prescribing, obstetrics and gynaecology, and adult infectious disease were most common and comprised 36% of all questions. The taxonomy of generic questions included 69 categories; the three most common types, comprising 24% of all questions, were “What is the cause of symptom X?” “What is the dose of drug X?” and “How should I manage disease or finding X?” Answers to most questions (702, 64%) were not immediately pursued, but, of those pursued, most (318, 80%) were answered. Doctors spent an average of less than 2 minutes pursuing an answer, and they used readily available print and human resources. Only two questions led to a formal literature search.ConclusionsFamily doctors in this study did not pursue answers to most of their questions. Questions about patient care can be organised into a limited number of generic types, which could help guide the efforts of knowledge base developers.

Key messages

• Questions that doctors have about the care of their patients could help guide the content of medical information sources and medical training
• In this study of US family doctors, participants frequently had questions about patient care but did not pursue answers to most questions (64%)
• On average, participants spent less than 2 minutes seeking an answer to a question
• The most common resources used to answer questions included textbooks and colleagues; formal literature searches were rarely performed
• The most common generic questions were “What is the cause of symptom X?” “What is the dose of drug X?” and “How should I manage disease or finding X?”

     

The concept of disease.

The connotations of the term “a disease” were investigated by studying the ways in which both medical and non-medical people used the word. A list of common diagnostic terms was read slowly to groups of non-medical academic staff of a university, secondary-school students, medical academics, and family practitioners, who then indicated whether they thought each word referred to disease.All groups rated illnesses due to infections as diseases, but the doctors, and particularly the general practitioners, were more generous in accepting as diseases the terms for non-infectious conditions. Apart from the nature of the cause, the most influential factor in determining whether or not an illness was considered to be a disease was the importance of the doctor in diagnosis and treatment.These findings provide further evidence that there is ambiguity about the meaning of the term disease. To the layman a disease seems to be a living agency that causes illness. Doctors have obviously accepted more heterogeneous defining characteristics but remain reluctant to adopt unequivocally nominalist ways of thought. The position is not unlike that in the physical sciences, in which there is a good precedent for distinguishing between the formal scientific and the everyday uses of terms such as “force” and “power.”