Pharma backs latest attempt at a global health R&D treaty

The World Health Organization (WHO) kicks off its annual meeting in Geneva next Monday, and one of the most contentious issues on the agenda will undoubtedly be a proposed agreement to fund the development of drugs for diseases that overwhelmingly afflict the world’s poor. The proposal, outlined today in PLoS Medicine, would require the WHO’s 193 member states to commit to increase government funding for global health initiatives from the $3 billion or so spent worldwide today to more than $6 billion annually in the near-future.

To raise that money, the authors of the report, which include global health economists, industry executives and patent experts from the WHO’s Consultative Expert Working Group on Research and Development (CEWG), call for every member nation to contribute at least 0.01% of its gross domestic product (GDP) for research and development (R&D) into neglected diseases—a percentage currently paid by only one country: the US.

“Money is the new focus of this debate,” says James Love, an advocate for affordable medicines and director of Knowledge Ecology International, a social justice nonprofit based in Washington, DC. “Now that it’s about funding, governments have to start talking to each other.”

Importantly, big pharma appears to be on-board—which may pave the way for successful passage of the treaty at next week’s World Health Assembly. “We’re hearing from industry a need to reform the current system,” says CEWG chair John-Arne Røttingen, a health economist at the University of Oslo’s Institute for Health and Society who coauthored the report. Similar proposals were put forward by coalitions of member states and non-governmental organizations in 2005 and 2009, but both efforts failed to even make it to a vote after drug companies lobbied hard against proposed patent reforms that would have opened the door to more generics for a wide variety of medicines. In contrast, the current draft treaty only calls for less patent protection of treatments for diseases commonly found in the developing world, such as malaria, Chagas disease and dengue fever.

Paul Herrling, head of corporate research at Basel-based Novartis and a member of the CEWG, also notes that the proposed convention includes some incentives for the pharmaceutical industry. For example, it aims to arrange sustainable financing for companies to further develop early-stage products for neglected and tropical diseases that the firms already have in their pipelines. “Industry is willing to contribute resources to early stage R&D,” Herrling says. “But to bring those products all the way to the market, they need more than private donors can give.”

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One in six cancer cases are caused by preventable infection, study finds

You can’t catch cancer, or so many think. Cancer is considered a non-communicable disease by the World Health Organization, but among cancer’s many causes are viruses that can travel from person to person, and, if infection persists, lead to tumor growth. For example, the human pappilomavirus (HPV) often triggers cervical, anal and other cancers, which has prompted public health agencies to push mass vaccine campaigns for boys and girls alike (see ‘The value of HPV vaccination’).

The importance of making such prevention available around the world was made startlingly clear today in a study published online in The Lancet Oncology, which estimates that of the 12.7 million new cases of cancer in 2008, fully 16% were caused by infections. The vast majority of those cancer cases were caused by one of four pathogens: HPV, Helicobacter pylori and the hepatitis B and C viruses. Although infections by all these pathogens can be prevented with vaccines or treated with simple antibiotics, they nonetheless caused close to 2 million cases of gastric, liver and cervical cancer.

Today’s findings point to “a very large potential for cancer prevention by preventing infectious causes of cancer,” Goodarz Danaei, an epidemiologist at the Harvard School of Public Health in Boston who wrote an accompanying commentary, told Nature Medicine.

To determine the role of infection in causing cancer worldwide, the paper’s authors analyzed incidence, prevalence and mortality data for 27 cancers in 184 countries. Senior author Catherine de Martel says the findings published today are particularly important for developing countries, where approximately 25% of cancers are caused by infection. The most severely hit, the authors found, was sub-Saharan Africa, where nearly 1 in 3 cases of cancer are caused by preventable or treatable infection.

“This study highlights the need for cancer control priorities to be set in light of the burden of infection-related cancers, particularly in the low- and middle-income countries,” says de Martell, an epidemiologist at the International Agency for Research on Cancer in Lyon, France.

Artist’s rendering of HPV courtesy of Michael Taylor via Shutterstock

‘The Vagina Catalogues’ show a microbiome in flux, sometimes daily

When the vaginal microbiome gets out of whack, it causes an uncomfortable, often chronic condition known as bacterial vaginosis, which is associated with pregnancy complications such as premature birth as well as a heightened risk of contracting sexually transmitted diseases. But finding ways to return the disrupted vaginal microbiome to its normal, healthy state has proven difficult because nobody knows what ‘normal’ really means.

As Nature Medicine reported in a July 2011 news feature, a team of scientists at the University of Maryland School of Medicine in Baltimore had found that there are many naturally occurring versions of the microbiome, in part because the bacteria present in a woman’s vagina may vary according to her ethnicity. In a paper published today in the journal Science Translational Medicine, the same team goes on to show that although ethnicity can predict the make up of a the vaginal microbiome over a lifetime, in individual women this bacterial community can change dramatically within a matter of days—often without causing any effects on health.

To characterize this microbial variability, the scientists recruited 32 healthy volunteers for a labor-intensive study. The women enrolled, half of whom were black and half of whom were white, self-sampled vaginal swabs twice a week for more than three months and sent them off to the lab of lead author Jacques Ravel and his collaborator, Larry Forney of the University of Idaho in Moscow. There, biologists sequenced the genomes of the bacteria present in the samples to determine the relative abundance of, for example, the common bacteria species Lactobaccilus or Anaerococcus. For each woman, a picture emerged of a unique and surprisingly mercurial bacterial community. “There has been an assumption that microbiomes are stable over time,” says Forney. “But we found that over the course of just a few days, the entire microbial community could change in a given woman.”

These findings could help biologists develop personalized treatments for bacterial vaginosis, yeast infections and other conditions in which the microbiome is disturbed. “Right now, the antibiotic and probiotic treatments that exist for these diseases work for some women but not for others, and that’s because we don’t understand the environment we’re trying to treat,” says Forney. The hope, he and his colleagues say, is that these findings will lead to new treatments tailored to specific groups of women.

To move toward that goal, they have already begun enrolling more than 160 women to take daily vaginal samples for a larger, more rigorous study of how the various ‘normal’ microbiomes they identified in today’s paper change when a healthy woman develops a vaginal infection. “We need to start rethinking the idea of personalized treatment for diseases of the vagina,” says Ravel.

To read ‘The Vagina Catalogues’ click here.

Artwork by Alyssa Grenning

Is Chuck Schumer going to blunt US cannabinoid research?

The press conference last Friday held by two New York state assemblymen was no doubt timed to coincide with observance of the 4/20 celebratory day in cannabis counterculture: On 20 April the duo announced a bill that would make New York the 41st state to deem possession or sale of the active ingredients in so-called ‘synthetic marijuana’ drugs a crime punishable by jail time. The drugs in question—known to the mostly teenagers who like to smoke them as K2, Spice, Killer Buzzz, Blaze and Mr. Nice Guy—are mixtures of herbs such as oregano laced with laboratory-produced cannabinoids, a class of chemicals that also includes marijuana’s psychoactive component, tetrahydrocannabinol (THC).

The dangers of synthetic cannabinoids are clear. A study published this month in Pediatrics documented more than 4,000 US hospital cases in which teens who used K2 and other drugs required emergency intervention for symptoms such as a dangerously rapid heart rate. But medical researchers warn that the march toward nationwide criminalization that started with a 2010 Kansas law banning three synthetic cannabinoids has already begun to stifle research on the chemicals, which are known to stimulate appetite and ameliorate nausea and pain. “It would be a disaster if they criminalized all synthetic cannabinoids,” says pharmacologist Nathan Lents at the City University of New York. “We already have to jump through hoops to do our research. These substances clearly have untapped potential as therapies.”

Therapeutic benefits aside, momentum is growing for broad criminalization not only among states but at the federal level. A US Senate bill introduced last March by Charles Schumer, a Democrat from New York, would criminalize all synthetic cannabinoids nationwide. “That would be so traumatic,” explains Lents, “because that law classifies all cannabinoids as schedule 1 drugs.” A ‘schedule 1’ drug has no known medical use, and so is very tightly controlled by the federal government. A researcher conducting experiments with any schedule 1 substance must submit protocols signed by the president of his university to the US Drug Enforcement Agency in order to obtain small amounts of the chemical, which then must be kept locked in a safe when not in use, and must fill out mountains of paperwork accounting for the chemical’s use in experiments. Lents says requiring researchers to jump through such hoops chokes research and draws already spare funding away from cannabinoid labs. “There’s already not a lot of political will because these substances are seen as somehow morally reprehensible. A schedule 1 designation would make it even harder to study them.”

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With even Europe falling behind, can WHO meet new goals for measles?

Perhaps it takes falling behind to know that you have to get ahead: shortly after The Lancet released a report today saying the World Health Organization had failed to meet its 2010 goal for global measles reduction, the WHO announced that it has a new, more ambitious target of eliminating measles and rubella—also known as German measles—in at least five of six global regions by 2020. The expanded goals come as Europe, despite its historically strong public health systems, is struggling to recover from more than 26,000 measles cases in 2011, a number on-par with developing countries such as Nigeria and Somalia.

As Europe redoubles its own immunization efforts at home, the WHO now must vaccinate an estimated 19 million children in India and sub-Saharan Africa if it hopes to meet the new 2020 target. “We have already seen India scaling up its efforts,” Jean-Marie Okwo-Bele, director of immunization at the WHO in Geneva, said at a teleconference this morning announcing the new goal. “The new [WHO] plan provides a good roadmap to eliminate measles by 2020.”

Measles is a highly contagious virus that can become airborne, making it crucial that virtually everyone in a region undergo vaccination if the disease is to be eliminated. It can spread rapidly to anyone who is not immune, often leading to death in children under five. The first vaccine against measles came in 1971, and it now costs as little as two cents per dose in developing countries. But as the European outbreak highlights, vaccine cost and availability are not the only barriers to getting people immunized. “Cultural and religious beliefs play a huge role in whether children receive the vaccine, both in Europe and elsewhere,” says Rebecca Martin, director of the global immunization division at the US Centers for Disease Control and Prevention (CDC) in Atlanta. She says one reason so many young Europeans are now susceptible to measles was false perception over the past fifteen years that the vaccine raised the risk of autism.

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MRSA’s killing potential explained, providing a new drug target to halt the superbug

Since it first arose more than 50 years ago, the methicillin-resistant staph infection known as MRSA has ravaged hospital wards around the globe, causing untreatable, often lethal, infections in people already weakened by disease. As with most cases of antibiotic resistance, the rise of the first MRSA bacteria was the fault of humans. The Staphylococcus aureus bacterium, which causes everything from respiratory infections to meningitis, mutated to become resistant to all the first-line drugs used to treat it—first penicillin, and later methicillin and other drugs known as beta-lactams.

But the story doesn’t end there. Since 1959, the drug-resistant superbugs have taken on many guises, evolving into five major lineages worldwide, each with slightly different genes that make the pathogens particularly deadly. Yet, how each strain’s killing power arose largely remains a mystery. Now, a paper published today in Nature Medicine takes a step toward explaining the killing mechanism of one particular strain from China. By sorting through a decade’s worth of superbugs isolated from Chinese hospitals, the authors have identified a resistance gene encoded by a mobile genetic element that helps S. aureus multiply in the noses, throats and lungs of susceptible patients.

“This is very exciting,” says study author Michael Otto, chief of the Pathogen Molecular Genetics Section at the US National Institute of Allergy and Infectious Diseases in Bethesda, Maryland. “This gene is a critical determinant how dangerous MRSA is to patients.”

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Database to help doctors grasp disease risk of duplications the genome

Copy number variations, in which a section of DNA is duplicated or deleted, have been a boon for geneticists hoping to explain the chromosomal causes of everything from autism to schizophrenia to colon cancer. CNVs that are deletions can be helpful in diagnosing a handful of developmental disorders and birth defects such as DiGeorge syndrome, an illness affecting skull formation in which a portion of chromosome 22 is missing. But when doctors find a CNV that is a duplication, they have difficulty knowing exactly which disorder their patient might have as a single duplicated region can cover multiple genes. For example, the clinical significance of rare duplication CNVs of the region including the gene DCLK2, which has been implicated in attention deficit hyperactivity disorder (ADHD), are often missed by lab technicians and physicians.

A new database has begun to change that, allowing doctors to input and access all of the tested mutations within a CNV. The free International Standards for Cytogenomic Arrays (ISCA) database, which currently includes the results of 30,000 CNV tests and is housed at the US National Center for Biotechnology Information in Bethesda, is described in the May issue of Clinical Genetics, and has already drawn more than 800 users. Using the database, “a doctor or lab technician can see all the genes in a CNV,” says geneticist and senior author Christa Martin of Emory University in Atlanta.

What’s more, the database includes a rating system to help physicians estimate how likely genes within an observed CNV are to cause disease. Each CNV is ranked by expert groups on the basis of seven criteria, including the number of mutations reported in people with the CNV, mutational mechanisms and patterns of inheritance. The ratings for CNVs go from 0 (no evidence it causes disease) to 3 (sufficient evidence to predict disease). Surprisingly, “before now, there was not a formal process to rate CNV pathogenicity,” says Martin. “It made analyzing [CNV microarray] data very confusing for doctors. This database begins to fix that problem.”

The ISCA database may become even more important in the future. Preliminary data from a multicenter study presented in February at the Society for Maternal-Fetal Medicine meeting in Dallas indicated that microarray testing detects fetal abnormalities than the current standard karyotype test misses. Helping parents make decisions based on prenatal CNV testing will require the use of a database. “It’s no longer an option for doctors to just avoid CNVs because they’re too complicated to analyze,” says Martin. “Physicians will have to start using the new database tools available to them.”

Photo courtesy of Shutterstock

FoldIt game’s next play: crowdsourcing better drug design

Two years ago, FoldIt made headlines, lots of them, when players of the online protein-folding video game took three weeks to solve the three dimensional structure of a simian retroviral protein that is used in animal models of HIV, but whose structure had eluded biochemists for more than a decade. Seth Cooper, the game’s co-creator, captured the attention of the crowd at the TEDMED medical technology conference in Washington, DC by recounting how thousands of players competed in that FoldIt challenge despite the lack of prize money or prestige. He even brought on-stage the winner, a beaming British lab technician named Mimi Minet whose identity had not been previously disclosed to the public.

But the hidden news, the ‘Easter egg’, so to speak, was that Cooper and his collaborators are updating FoldIt to leverage the power of online gaming to create new proteins—enzymes that could form the basis of novel drugs or improve how they are manufactured. This freshly expanded enzyme design platform for FoldIt saw initial success in January, when gamers using an early version created a blueprint for an enzyme that lab tests indicate speeds up a type of biosynthetic reaction used in the production of a variety of drugs—including the cholesterol medication lovastatin—by almost 2,000%.

“We’ve moved beyond just determining structures in nature,” Cooper, who is based at the University of Washington’s Center for Game Science in Seattle, told Nature Medicine. “We’re able to use the game to design brand new therapeutic enzymes.” He says players are now working on the ground-up design of a protein that would act as an inhibitor of the influenza A virus, and he expects to expand the drug development uses of the game to small molecule design within the next year.

Designing small molecules, which are not composed amino acid chains as proteins are, but still function according to their 3D folded shape, requires that Cooper and his team in Seattle add to the chemical building blocks available to FoldIt players. “To build proteins, players can swap out amino acids in a protein,” he explains, “and there are only 26 amino acids, so compiling the building blocks players will need is easy.”

For example, players can swap a tryptophan for a cysteine in the active site of a potential flu inhibitor and see how it changes the protein’s stability and its interaction with target proteins on the surface of the flu virus. But in order to design small molecules, FoldIt will need a new toolbox of organic subcomponents such as rings and chains of carbon that players can then piece together into larger molecules, adding functional groups like alcohols or sulfurs to create novel small molecule chemicals. Since there the number of organic subcomponents is virtually infinite, creating such a library is daunting, but “we’re hopeful that we’ll have a small molecule in the next year,” says Cooper.

Global health advocates eye Ryan budget plan with concern

At a panel discussion on Monday organized by the national research advocacy group Research!America and hosted at the New York Academy of Sciences, speakers aired their concerns about the proposed 2013 US federal budget, which they say threatens to cut both grants for primary research and spending on foreign aid.

“Under Paul Ryan’s plan, the number of grants available for global health research would be reduced dramatically over the next decade,” Nita Lowey, a Democratic congresswoman representing the suburbs of New York City, said at the conference. The plan of Wisconsin Republican Paul Ryan would keep the 2013 budget for the US National Institutes of Health (NIH) flat, and could decrease funding for basic research grants and for foreign aid between 2014 and 2024 by an unknown amount determined by a “review of the long-term budget outlook every 5 years”, as part of a larger goal to reduce federal spending by $261 billion.

Representatives from New York’s Global Alliance for TB Drug Development and the International AIDS Vaccine Initiative and Geneva-based Drugs for Neglected Diseases Initiative, agreed that the success of their initiatives relies on the US Congress passing greater federal funding for global health. “Without federal funding we’d have a lot less of the basic knowledge of disease mechanisms, which we in the pharmaceutical industry apply to develop drugs,” explained Pol Vandenbroucke, vice president of development for emerging markets at New York’s Pfizer, who said even private players in the global health community rely on government spending.

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Fledgling Pakistani group looks to train medical students in research

A recent Nature Medicine opinion article that called on the UK to fund more research opportunities for medical students resonated thousands of miles away. Pakistani medical students are now also asking their government to put more money toward educating young physician-researchers.

The need for funding support is, in part, a by product of substantial interest in such training. Since its founding in January 2011, the Pakistan Medical Students’ Research Society (PMSRS) has quickly swelled to more than 500 members. “Two years ago there was very little guidance for students, and opportunities for students to actually conduct research were basically nonexistent,” says Akhtar Amin, president of PMSRS and a third year medical student at Dow University of Health Sciences in Karachi. “Our organization is helping to change this, but we need the financial support of our government.”

In the past two years PMSRS has focused primarily on organizing free symposia on topics related to research careers, such as manuscript writing, presenting scientific data, experimental design and bioinformatics. They say the 17 symposia given so far have attracted more than 800 students, some of whom are located remotely and watch the presentations as internet broadcasts.

Those medical students based in Karachi are also paired by the organization with research mentors. “Funding would allow us to expand the mentor program,” says PMSRS adviser and research mentor Asif Qureshi, a physician and research associate at Dow University of Health Sciences. Qureshi notes that only 80 students have been paired with research mentors, in part because lack of resources makes it difficult to get the word out.

The organization’s primary domestic target for future funding is the Pakistan Medical Research Council, which is the country’s equivalent to the US National Institutes of Health. But the PMSRS also hopes to look outside its borders to make international resources available to Pakistani medical students. “We recently organized an online course collaborating with Indian medical students,” says Qureshi, who says such partnerships with countries where biomedical research is highly funded will be fruitful for students in his homeland.

To that end, he hopes that in the future PMSRS will be able to provide travel grants for Pakistani students doing research fellowships in the US and elsewhere. “Studying research abroad gives a big boost to students,” says Amin, who says he has been accepted to a summer research program at Johns Hopkins in Baltimore this summer. “We need more money to help make those connections.”