terça-feira, 18 de outubro de 2011


Education: Inspiration for informatics

Nature
 
478,
 
143–145
 
(2011)
 
doi:10.1038/nj7367-143a
Published online
 
This article was originally published in the journal Nature
Trainees in bioinformatics and computational biology should seek depth of knowledge over breadth.
This January, Alexander Sczyrba and his colleagues published what was at the time the largest metagenome ever assembled (M. Hess et al. Science 331,463–467; 2011). Collecting and collating genetic material from environmental samples is always a challenge; in this case, the metagenome came from parts of a cow's stomach, and contained more than 27,000 biomass-degrading genes and 15 microbe genomes. It totalled 268 gigabases. “We had to develop new algorithms to run analyses on computer clusters, or clouds, as using traditional methods would have taken 80 years on a single computer,” says Sczyrba.
Sczyrba wants to focus his career on similar complex, leading-edge analyses. But the path hasn't been straightforward; when he was looking for a postdoc in 2008, it was tough to find institutions that could generate or analyse such large data sets. He landed a post at the US Department of Energy Joint Genome Institute (JGI) in Walnut Creek, California: a large-scale sequencing facility that offered access to data, computing resources and brain power. In 2010 alone, the JGI sequenced 170 metagenomes.
J. ENDICOTT/IMAGES.COM/CORBIS
Soon, however, big sequencing centres won't be the only sources of data. “With next-generation sequencing, everybody can produce sequences; it's the analysis that is getting more important,” says Sczyrba. Modern biologists need to be able to manage large data sets and explore new computational tools.

Finding a path

Qualified candidates are hard to find, say recruiters in both industry and academia. That may be because, so far, there hasn't been a typical career path for bioinformaticians or computational biologists. “Often we find that it's the people motivated to simply roll up their sleeves and figure out on their own how to work with these data that have the strongest skills,” says Jim Bristow, deputy director of programmes at the JGI. As more departments are established, the often circuitous routes once required to attain such skills will probably be replaced by more direct paths. The challenge is finding a training programme that will help researchers to keep pace in a rapidly changing, technology-driven field.
By conventional definitions, bioinformaticians develop new ways to acquire, organize and analyse biological data, whereas computational biologists develop mathematical models or simulation techniques to work out the data's biological significance. But these lines are blurring, and departments and training programmes are both proliferating and combining the fields.
“The demand for computational-biology training that we have today is way more than was expected a decade ago,” says Burkhard Rost, president of the International Society for Computational Biology, which is based in La Jolla, California.

Not just skin deep

The most obvious training route — pursuing an undergraduate degree in bioinformatics — isn't necessarily the best for a budding researcher. Some undergraduate programmes fail to provide the depth of knowledge sought by employers. “Often these trainees come with great-looking CVs, but when we press them on what they are capable of doing, they tend to be rather weak,” says Nick Goldman, research and training coordinator at the European Bioinformatics Institute in Hinxton, UK. Goldman is most impressed by applicants who have actively pursued training in both informatics and the area of research in which they're interested — for example, someone with a computing degree who has done a molecular-biology project (see 'Talent checklist').
Box 1: Basic skills: Talent checklist
  • Be at least conversant in the broad range of disciplines contributing to bioinformatics — from statistics to molecular biology to computer science.
  • Most work, especially in industry, is done in teams, so communication skills are always in demand.
  • Get experience in handling massive data sets. Learn to parse data or run analyses in parallel — using, for example, cloud computing.
  • Learn to write programmes in software languages such as Perl or R.
  • Cultivate a deep knowledge of at least one area of biology. V.G.
Expand
Goldman says that students should be wary of learning about only the latest software or genome-mining tool, without gaining a full understanding of the biological topics. Recruiters want savvy scientists who understand technology's ability to address questions. Steve Cleaver, head of quantitative biology at Novartis Institutes for BioMedical Research in Cambridge, Massachusetts, says that the key to a sustainable career in the field is the ability to turn a scientific question into a statistical hypothesis. “But those who can ride the tech waves are well positioned to find career success,” he adds. Without a doubt, he adds, the next generation of biologists will be more conversant in bioinformatics. “It's all about cross-training — getting the appropriate training in both analytical science and biology during graduate school to make a meaningful contribution,” says Cleaver.
Picking a programme with comprehensive training modules in statistics, computer science and/or biology can be an effective strategy. But Søren Brunak, director of the Center for Biological Sequence Analysis at the Technical University of Denmark in Lyngby, says that researchers should avoid training programmes that focus on just a few data types. With the expansion in high-throughput sequencing of genomes, proteins and metabolites, programmes that focus on a single area, such as genomics, don't adequately prepare students for the job market, says Brunak. “Analyses conducted now are much more reliant on combinations of data types — for example, combining molecular-level data with patient records — than they were before,” he notes.
D. E. GILBERT
Alexander Sczyrba: "We don't know where we'll be in ten years because the technologies and ideas are moving so fast".
Aspiring principal investigators can go one step further to find the best graduate training for the career they want, by deciding whether to focus on developing tools, such as algorithms to analyse data, or applying those tools to turn data into knowledge. “The most important decision a trainee can make is what kind of research programme they want to build,” says Robert Murphy, founding director of a computational-biology PhD programme run jointly between the University of Pittsburgh in Pennsylvania and Carnegie Mellon University, also in Pittsburgh.
The University of California, Los Angeles (UCLA), has a bioinformatics PhD programme designed to shape the tool developers. It accepts only candidates who demonstrate a core strength in an analytical field such as computer science or maths, or have a dual degree combining one of these fields with biology. Christopher Lee, director of the programme, says that many bioinformatics courses are affiliated with data-rich biology labs on campus, supplying the students needed to tackle a flood of data. They often lack, however, the matrix of expertise necessary to conduct innovative analyses. Lee hopes that the UCLA programme will foster such expertise.
A few graduate training programmes, notably those at the Netherlands Bioinformatics Center in Nijmegen, cater to students with backgrounds in either computer science or biology. “We want to train the tool shapers as well as the people more into applying the tools in a biological setting,” says Celia van Gelder, the centre's education project leader. “Over the past 10–20 years, the field of biology has become more computational, with bioinformatics serving as an interdisciplinary field that links researchers who can't otherwise readily talk to one another.” The scope of work is widening, she says. As a result, demand for bioinformatics training continues to increase across Europe — with greater emphasis placed on data analysis at all levels. “We produce trainees who have multidisciplinary training in molecular-biology principles as well as algorithms to deal with data,” says Jaap Heringa, the centre's scientific director for bioinformatics education. “Things move so fast in bioinformatics, we are constantly innovating our courses,” he adds. Murphy agrees; Carnegie Mellon and the University of Pittsburgh offer in-depth training. “We are pretty clear in the application materials that our programme is not for people who want to get enough of a smattering of computational biology to get a job,” says Murphy.

Expanding options

M. VAN ZWAM
Celia van Gelder: "We want to train the tool shapers as well as the people more into applying the tools".
This trend towards creating more comprehensive, interdisciplinary training programmes has gained momentum at biology strongholds in the United States. In July 2010, Dartmouth Medical School in Hanover, New Hampshire, established the Institute for Quantitative Biological Sciences in nearby Lebanon. Its graduate offerings combine modules in bioinformatics, biostatistics and epidemiology. “We have created what we think is a model of the future — training computational-biology students to speak multiple languages beyond bioinformatics,” says the centre's director, Jason Moore. He adds that the key is assuming complexity rather than simplicity when approaching a problem.
In August, Moore secured funding to create a US National Institutes of Health (NIH) Center for Biomedical Research Excellence, through which he will mentor five early-career bioinformatics faculty members, to be recruited over the next 3–4 years. After two years of learning how to secure competitive funding, among other things, trainees will be required to submit an application for an R01 grant, the NIH's main funding mechanism. “We really want to provide a well rounded education so that our new recruits can secure funding for — and conduct — well designed studies in computational biology,” says Moore.
Other medical schools are also taking the plunge. Duke University School of Medicine in Durham, North Carolina, formed its Department of Biostatistics and Bioinformatics in 2000. This year, it opens its first master's programme, says Elizabeth Delong, chair of the department.
And in September, the University of Michigan Medical School in Ann Arbor established a computational-medicine and bioinformatics department to help attract new faculty members and trainees. In June, Emory University School of Medicine in Atlanta, Georgia, launched a biomedical-informatics department with the goal of combining expertise in imaging, computer science and biology to improve patient care. It will recruit four or five researchers over the next few years. “Our particular strength is training computer scientists who want to transition into biomedical informatics, and bringing them together with clinicians to use informatics to treat disease,” says department chair Joel Saltz.
Qualified postdocs remain in demand. “It can be very difficult for individual investigators to hire a postdoc in bioinformatics,” says Tom Tullius, interim chair of the bioinformatics programme at Boston University in Massachusetts. He attributes the paucity of candidates in part to efforts over the past several years to build large teams at high-powered institutes — such as the Broad Institute in Cambridge, Massachusetts, or the Wellcome Trust Sanger Institute in Cambridge, UK — leaving smaller labs struggling to find talent. The growth of training programmes could ease this.
Now sequencing centres won't be the sole providers of data, individual researchers, particularly at medical centres, will have ample data to fuel research and training. “We've passed out of the period of genome projects where there were amazing public data raining down from the heavens; it's now possible to do exciting work without being associated with data-generating centres,” says Lee.
Sczyrba, who begins a junior faculty position in metagenomics at the University of Bielefeld Center for Biotechnology in Germany this autumn, says that unpredictability is what makes the discipline so exciting. “We don't know where we will be in ten years because the technologies and ideas are moving so fast,” he says. As Cleaver notes: “Perhaps the best career strategy is to stay flexible and curious.”

Author information

Affiliations

  1. Virginia Gewin is a freelance writer in Portland, Oregon.


Structural basis for a [4Fe-3S] cluster in the oxygen-tolerant membrane-bound [NiFe]-hydrogenase

Nature
 
(2011)
 
doi:10.1038/nature10504
Received
 
 
Accepted
 
 
Published online
 
Membrane-bound respiratory [NiFe]-hydrogenase (MBH), a H2-uptake enzyme found in the periplasmic space of bacteria, catalyses the oxidation of dihydrogen: H2 right arrow 2H+ + 2e− (ref. 1). In contrast to the well-studied O2-sensitive[NiFe]-hydrogenases (referred to as the standard enzymes), MBH has an O2-tolerant H2 oxidation activity2, 3, 4; however, the mechanism of O2 tolerance is unclear5. Here we report the crystal structures of Hydrogenovibrio marinusMBH in three different redox conditions at resolutions between 1.18 and 1.32 Å. We find that the proximal iron-sulphur (Fe-S) cluster of MBH has a[4Fe-3S] structure coordinated by six cysteine residues—in contrast to the[4Fe-4S] cubane structure coordinated by four cysteine residues found in the proximal Fe-S cluster of the standard enzymes—and that an amide nitrogen of the polypeptide backbone is deprotonated and additionally coordinates the cluster when chemically oxidized, thus stabilizing the superoxidized state of the cluster. The structure of MBH is very similar to that of the O2-sensitive standard enzymes except for the proximal Fe-S cluster. Our results give a reasonable explanation why the O2tolerance of MBH is attributable to the unique proximal Fe-S cluster; we propose that the cluster is not only a component of the electron transfer for the catalytic cycle, but that it also donates two electrons and one proton crucial for the appropriate reduction of O2 in preventing the formation of an unready, inactive state of the enzyme.

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Published online 18 October 2011 | Nature | doi:10.1038/news.2011.598
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Pentagon cultural analyst helped with interrogations

'Experiment' raises alarm among social scientists.
Human TerrainThe US Army's Human Terrain System programme embeds civilian social scientists with Army units.Photo by Marco Di Lauro/Getty Images
The Pentagon's forays into social science — what the military calls "human terrain" — have raised ethics concerns among academics. But now, a cultural analyst working as a contractor for the military has said that she helped to interrogate detainees in Afghanistan.
Cultural expertise was "key in the support I was providing to the interrogator to develop a relationship with the detainee", said Julia Bowers, principal senior analyst for human terrain at SCIA, a company based in Tampa, Florida, that provides socio-cultural services for the military and intelligence community, at a conference in San Antonio, Texas, on 16 October.
"Typically human-terrain analysis is more of a human data-gathering and mapping approach," Bowers said, but in this job, her remit was more to help the interrogator to gain the detainee's trust. The programme was experimental and ran "for just a few months", she said.
Bowers worked with the US Central Command's human terrain analysis branch, which is separate from the army's Human Terrain System (HTS), a better known programme that embeds social scientists within the military. Both, however, are designed to provide the military with better cultural understanding and expertise.
The HTS, started in 2006, actively recruits from academia and now has 31 teams deployed in Afghanistan. It was initially embraced by senior Pentagon officials, including former defence secretary Robert Gates, but has been dogged by controversy after the injury and death of several social scientists.
In one of the more dramatic incidents, a team member was convicted of manslaughter for killing an Afghan detainee who had set a social scientist on fire. The social scientist later died of her wounds.
The Human Terrain Analysis Branch, by contrast, has kept a much lower profile, though it is also uses social science to collect cultural and ethnographic information for the military in Afghanistan and around the region.

Levels of advice

The American Anthropological Association in Arlington, Virginia, has a rapid response network of individuals dedicated to advising the organisation on the ethical concerns of anthropologists working with the military. The network was faced with the interrogation issue early on, says Hugh Gusterson, an anthropologist at George Mason University in Fairfax, Virginia, who is part of the network. But the issue then was whether they should advise on interrogation policy, not whether anthropologists should actually participate in interrogations.
"Advising people on how to extract information from people who don't want information extracted, that is the antithesis of what the anthropological encounter is supposed to look like," says Gusterson. "It's inherently unethical to me."

Published online 18 October 2011 | Nature | doi:10.1038/news.2011.601
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Malaria vaccine one step closer to approval

Trial results are promising, but marred by poor efficacy against severe forms of the disease.
vaccineThe RTS,S malaria vaccine shows promise, but the efficacy is lower than was hoped.David Poland, PATH Malaria Vaccine Initiative
The world's leading candidate for a malaria vaccine has cleared another hoop on the way to widespread use, proponents say. But the vaccine's low efficacy against severe forms of the disease have disappointed some experts. The latest findings from a Phase III clinical trial in thousands of African children appear today in the New England Journal of Medicine1.
This vaccine against thePlasmodium falciparumparasite — called RTS,S/AS01 and funded by GlaxoSmithKline and the PATH Malaria Vaccine Initiative — has carried the hopes of many since rising to the fore in the race to develop a malaria vaccine. If approved by regulators, it would be the first vaccine against malaria, and the first against a parasitic disease, notes Vasee Moorthy, who studies malaria at the World Health Organization's (WHO) Initiative for Vaccine Research.
Beginning in March 2009, 15,460 children split into two age groups — 6–12 weeks or 5–17 months — were given either the vaccine or a control. In the first 6,000 children aged 5–17 months, the vaccine had an efficacy against clinical malaria of around 50%. The efficacy of the vaccine against severe malaria in this same group was around 45%.
"The results of this study represent a major scientific achievement, for which WHO congratulates the vaccine development partnership," says Moorthy. "These promising results are in line with the earlier results seen in Phase 2 studies. Malaria has never had a vaccine get this far."

Half-full, or half-empty?

Not all experts are quite as optimistic. The vaccine's overall efficacy against severe malaria in all age groups was around 31%. This was disappointing to researchers — previous, smaller trials had suggested that the vaccine would prove to be more effective against the severe form of the disease than against the clinical definition - a temperature of 37.5°C or higher and significant P. falciparium in the blood.
Adrian Hill, director of the Jenner Institute in Oxford, UK, which develops vaccines against global diseases, says it is a great step that the trial has been done in a large number of children. But "overall, it's really disappointing in terms of what we had hoped", he says, adding that the low efficacy for severe malaria "really is a problem".
Kim Mulholland, a professor of child health and vaccinology at the London School of Hygiene and Tropical Medicine, says that although the low numbers are surprising and "quite disappointing", researchers should not necessarily rule out RTS,S. The vaccine's higher efficacy in older children is much more promising, he says. "Forty-five per cent of a pretty common condition is something that's really worth going for."
But Tsiri Agbenyega, head of the Malaria Research Unit at Komfo Anokye Hospital in Kumasi, Ghana and chairman of the RTS,S Clinical Trials Partnership Committee, remains optimistic. "Obviously one would want to have a higher efficacy when it comes to severe disease, but we're still hoping we can improve on the vaccine as we go along with the trials."

Enduring questions

Thomas Smith, who studies the epidemiology of malaria at the Swiss Tropical Institute in Basel, says it may be premature to say exactly what the efficacy is based on this early data from the trial, which is still ongoing.
"For me, the main question is how long the efficacy is going to last," he says. "The duration of efficacy is something we're uncertain about. We should see this as a very positive step in that it's the first time a malaria vaccine has made it so far. [But] we shouldn't assume this is going to be widely deployed."
In a year, the study team will have finished collecting and processing the vaccine efficacy data for clinical and severe malaria in the younger group.
The WHO will assess the potential for the vaccine to prevent the spread of malaria when the full trial results come out in 2014. "Depending on the results, WHO may be able to issue a recommendation for use of RTS,S as early as 2015," says Moorthy. 

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  • #28263
    Very Interesting Article on Vaccine for Malaria.
    Each year, there are more than 225 million cases of malaria, killing around 781,000 people each year according to the World Health Organization's 2010 World Malaria Report, 2.23% of deaths worldwide. Ninety percent of malaria-related deaths occur in sub-Saharan Africa, with the majority being in young children. Malaria is commonly associated with poverty, and can indeed be a cause of poverty and a major hindrance to economic development.
    A variety of antimalarial medications are available. Severe malaria is treated with intravenous or intramuscular quinine or, since the mid-2000s, the artemisinin derivative artesunate, which is superior to quinine in both children and adults. Resistance has developed to several antimalarial drugs, most notably chloroquine.
    The challenge of producing a widely available vaccine that provides a high level of protection for a sustained period is eluding and the vaccine against the Plasmodium falciparum parasite — called RTS,S/AS01 and funded by GlaxoSmithKline and the PATH Malaria Vaccine Initiative will help to control the Malaria.

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Published online 18 October 2011 | Nature | doi:10.1038/478294a
News

US row threatens Chinese links

Dispute intensifies over a ban on some types of scientific cooperation with China.
When US presidential science adviser John Holdren hosted a dinner and meetings between US and Chinese science officials in May, he must have known it would lead to a high-level stand-off. That came to pass on 11 October, when the Govern­ment Accountability Office (GAO), an arm of Congress, concluded in a report that those activities violated legislation banning scientific cooperation with China by NASA and by the White House Office of Science and Technology Policy (OSTP), which Holdren directs.
Frank Wolf (Republican, Virginia), the congressman who chairs the subcommittee that funds science agencies including the OSTP and NASA, inserted the ban into a spending bill that was passed last spring. Now, backed by the GAO report, he has asked the US Department of Justice to rein in Holdren's China-related activities; if the department refuses to do so, the matter could end up in the courts.
“This has potential to cut off collaboration with a country on a rapidly rising science trajectory.”
Holdren — armed with a memo from the justice department saying that he has the right to conduct diplomacy on behalf of US President Barack Obama, even without congressional approval — is showing no signs of backing down. Yet science-policy experts say that the dispute has the potential to cast a cloud over joint academic and commercial research efforts between the two economic superpowers. "This has potential to cut off collaboration with a country on a rapidly rising science and technology trajectory," says Richard P. Suttmeier, a retired expert on Chinese science policy based in Keene Valley, New York.
Relations between the United States and China have their roots in a historic 1972 visit to Beijing by US president Richard Nixon. That led to a 1979 agreement between the two govern­ments for cooperation on scientific activities. Suttmeier estimates that US agencies now have more than 30 agreements on scientific cooperation with their equivalents in the Chinese government. The US National Science Foundation (NSF) opened an office in Beijing in 2006, and the US Department of Energy founded a US$150-million Clean Energy Research Center with China in 2009. Chinese researchers are now more likely to collaborate and co-author papers with scientists from the United States than with those from any other country.
"I don't understand the motivation for trying to cut off something of benefit to both sides," says Martin Briggs, a hydrogeology graduate student at Syracuse University in New York, who spent two months at Fudan University in Shanghai on a fellowship funded by the NSF to learn about water quality.
Wolf's spokesman Daniel Scandling says that the congressman sought to ban NASA and the OSTP from fostering relations with China after NASA administrator Charles Bolden visited the country last year and invited Chinese officials to visit NASA facilities in return. "Congressman Wolf is deeply concerned by China's spying and theft of technology and doesn't think it is wise to give the Chinese access to advanced space technologies," Scandling says.

Published online 18 October 2011 | Nature | doi:10.1038/478295a
News

No quick fix for Haiti cholera

As outbreak enters its second year, relief bodies move to roll out vaccine for the first time.
Until clean water and sanitation are readily available in Haiti, cholera outbreaks will continue.Until clean water and sanitation are readily available in Haiti, cholera outbreaks will continue.J. Silva/Reuters
A year after cholera broke out in the aftermath of the January 2010 Haiti earthquake, the epidemic has disappeared from the headlines, but it continues to wreak a deadly toll. Mortality rates remain high in some areas, but donor funding for front-line response teams is drying up, even as a newly approved vaccine offers a glimmer of hope.
The epidemic has already caused almost half a million cases, half of which have required hospitalization. Haiti's health ministry says that roughly 6,500 people have died from their infections — a figure widely believed to be an underestimate.
The Pan American Health Organization (PAHO) in Washington DC expects the epidemic to ease partially, but nonetheless predicts a further 250,000 cases next year, says Peter Graaff, the PAHO/World Health Organization (WHO) representative in Haiti.
Shanchol, a vaccine approved by the WHO for worldwide use on 29 September, could brighten the outlook. It was developed by the International Vaccine Institute in Seoul with support from the Bill & Melinda Gates Foundation, and is produced by Shantha Biotechnics in Hyderabad, India, a subsidiary of vaccine company Sanofi Pasteur. Two groups of non-governmental organizations (NGOs) operating in Haiti now intend to include the vaccine in their own emergency responses to cholera.
At US$1.85 a dose, Shanchol is cheaper than the only other currently available cholera vaccine — Dukoral, made by Crucell, based in Leiden, the Netherlands. Shanchol is also given orally, and requires fewer doses in children under six, who are among the most vulnerable to cholera. The vaccine's benefits "are really clear for the outbreak contexts in which MSF works", says Julia Hill, vaccines policy adviser at Médecins Sans Frontières (MSF), also called Doctors Without Borders, in Geneva, Switzerland.
MSF has one of the largest ongoing emergency-response operations in Haiti, treating as many as one-third of all reported cholera cases. It intends to begin vaccinating with Shanchol soon in Haiti; it is also considering a vaccination campaign in West and Central Africa, where cholera is currently resurging. MSF has yet to finalize details of its campaign, but will probably focus vaccination efforts on vulnerable groups, such as people in remote rural areas, who lack timely access to treatments.
Because mountainous communities can often be reached only after half-a-day's journey on foot, "a whole village can be infected before help arrives", says Michel Van Herp, an epidemiologist in the MSF office in Brussels. Van Herp oversaw MSF's field response at the start of the epidemic, when as many as 9% of cases resulted in fatalities. In the capital, Port-au-Prince, that figure has now been brought down below 1%, but in remote rural areas, death rates as high as 5–10% persist, he says.
A separate campaign aims to vaccinate 100,000 vulnerable Haitians using 200,000 doses of Shanchol. That effort will be carried out jointly by GHESKIO, an NGO based in Port-au-Prince, and Partners in Health (PIH), a non-profit organization in Boston, Massachusetts, that is affiliated with health groups at Harvard University in Cambridge, Massachusetts. The group intends to launch its campaign in January 2012, says Louise Ivers, a senior adviser to PIH working in Haiti. The lack of clean water and sanitation in Haiti, and the poor prospects for improving that infrastructure in the near future, makes for a "compelling argument" to use cholera vaccines, she says.
The WHO opposed vaccination during the chaos of the initial cholera outbreak in Haiti; Claire-Lise Chaignat, coordinator of the WHO's Global Task Force on Cholera Control, argued at the time that the logistics would have been impossible to manage (see Nature 468,483–484; 2010). But the chaos has subsided, and the peaks in numbers of cholera cases are coming less frequently, so the WHO now supports targeted vaccination in Haiti, says Chaignat.
Eventually, the Haitian government will have to assume responsibility and run its own vaccination programmes, but persuading them to do so could be tough, warns Van Herp — not least because there is little economic or political interest in the rural target communities that might benefit most. Van Herp and other experts also warn that cholera vaccination is no panacea. The focus of relief efforts must be on rehydrating the dangerously ill with a cheap and highly effective oral solution of glucose and salts, he says. Building infrastructure to provide clean water and sanitation is the only way to prevent cholera in the long term.
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