Earlier this month, Indian regulatory authorities granted conditional approval to the country’s first homegrown drug, a malaria-fighting pill that combines a new synthetic form of artemisinin with an older antimalarial compound called piperaquine. If the decision is ratified by the country’s Central Drugs Standard Control Organization, the new drug — developed from start to finish by the New Delhi-based pharmaceutical company Ranbaxy Laboratories — will add to doctors’ armament of artemisinin-based combination therapies (ACTs), the World Health Organization’s medicine of choice for tackling the parasite. Yet with so many options, the question is: which ACT is actually best at treating the infectious disease?

A study comparing four ACTs should go a long way to answering that question. In a randomized clinical trial involving more than 4,100 newly infected children at 12 sites across seven sub-Saharan African countries, three widely-used artemisinin variants proved equally effective at ridding youngsters of the malaria parasite. All three ACTs cleared the infection in more than 95% of trial participants up to 63 days post-treatment. But a fourth combo drug — a newer antimalarial that combines chlorproguanil, dapsone and artesunate — proved only around 85% effective, and was removed from the study after its maker, London-based GlaxoSmithKline, pulled it from the market in 2008 because of adverse effects. The results were published today in PLoS Medicine.

“This should reassure people that these are good drugs that are highly effective and well tolerated and that we should get them to people that need them,” says Nicholas White, a malaria epidemiologist at the University of Oxford in the UK, who was not involved in the study.

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Treating costly conditions such as Alzheimer’s disease may soon collapse healthcare systems around the world, yet companies hesitate to invest in the long, large clinical trials required to discover disease-modifying therapies. New incentives are necessary to turn this tide.

Although there is some disagreement about the right therapeutic target to combat Alzhemer’s disease—whether it’s β-amyloid, tau phosphorylation or something else—there is overwhelming agreement about how to address many of the other problems that plague this field.

If you were to conduct a poll of Alzheimer’s researchers, virtually all would agree that current clinical testing of potential new therapies starts too late, after the brain is severely damaged by the disease. They would also agree that early diagnosis and biomarkers predictive of clinical progression are crucial for combating the disease.

Incorporating these views into clinical-trial design would certainly result in better trials, but such trials would also be very large and very long. Longitudinal studies are beginning to identify people at risk to develop Alzheimer’s disease: subjects with subtle cognitive or biochemical changes who, years later, will go on to develop the pathology. But validating these markers in a clinical trial will require the trial to start as early as a decade before the onset of the disease, when the presumptive biomarkers start to appear and before brain damage has advanced too far. More importantly, as biomarkers only help identify people at risk, a fraction of whom ultimately won’t develop Alzheimer’s, the trial would have to include thousands of patients to allow for these ‘false positives’ and still pick up a statistically significant therapeutic signal. Such a trial would be prohibitively expensive.

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By Sarah C P Williams

Most laboratory mice, when meeting new cagemates, will sniff the strangers thoroughly. But the mice in Matthew Anderson’s lab instead sit alone, licking their paws repetitively. They ignore other mice, avoid new toys and rarely make noise. Taken together, the abnormalities closely resemble the behavioral symptoms seen in people with autism, a disorder that has been proven difficult to accurately recapitulate in animal models—until recently.

“When I first started working on this, I really wondered whether we’d be able to study autism in a mouse,” says Anderson, a neuroscientist at the Beth Israel Deaconess Medical Center in Boston. “But these mice act just like you would expect with autism. I was pleasantly surprised.”

Mouse models for autism first started to emerge around ten years ago. And as researchers have discovered more genes linked to the disease, they have continued to generate more mouse models that are collectively providing the field with a window into the brain structure, neuron function and cellular pathways associated with autism, as well as a platform for testing new drugs. But as more models emerge, it has become increasingly clear that the field needs standardized behavioral assays to compare the effects of the different genetic mutations more clearly. “All these mice have been tested in different labs using different paradigms,” says Daniel Geschwind, a neurogeneticist at the University of California–Los Angeles. “People bandy about repetitive behavior, for example, but what some folks call repetitive behavior is different than what others call repetitive behavior.”

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Image: courtesy of Philip Renna/Cold Spring Harbor Laboratory

This past spring, Christian Schaaf sat back and watched seven-year-old Lily play in his office at the Baylor College of Medicine in Houston. She looked just like any other girl her age, he recalls, but she didn’t seek interaction or even eye contact in the way a child normally would. Instead, she communed with a corner of the room, excitably hopping and flapping her arms as if that spot held a treat too great to bear. Without peering into the file in front of him, Schaaf knew what afflicted Lily. “I’ve seen enough children that when I see someone with autism, I have a high suspicion for it,” he says.

Lily (not her real name) and her mother didn’t come to Schaaf’s office that day for a diagnosis; a psychiatrist had already detected autism after her fourth birthday. They visited Schaaf, a clinical geneticist, to search her genome using a chromosomal microarray. The technology can find duplications or deletions of small segments of DNA, known as copy-number variants (CNVs), to pinpoint the genetic aberration that might have caused the disorder. Lily’s parents hoped that a genetic diagnosis would help them better understand and treat her specific form of autism—and, ultimately, help her get the services she needs to have the best chance at adult independence.

Such genetic tests for autism have only become available in the last few years. But, owing to high demand, autism testing has expanded from research centers to private companies. In the US, six companies now offer laboratory-developed tests to doctors that specifically target the developmental disorder, searching the genome for either irregular CNVs or single-nucleotide polymorphisms (SNPs) that could explain the symptoms. And these tests aren’t cheap: a microarray costs, on average, $1,500, and that’s without the bells and whistles such as doctor visits and additional gene sequencing. Although the tests themselves aren’t therapeutic, they represent the leading edge of a deeper genetic understanding of autism that could lead to targeted therapies—a market that UK-based research publisher Global Data expects to top $5 billion in the US in 2018, according to an October report.

For the most part, the diagnosis of autism remains the domain of psychiatrists, who do so on the basis of a range of symptoms, including delayed speech, repetitive behaviors and social withdrawal. These abnormalities remain difficult to detect until a child is around four years of age or older, which is unfortunate because receiving therapy from age two can improve outcomes for youngsters with developmental disabilities. “The earlier the diagnosis, the earlier you can start some type of interventional therapy,” says Stephen Scherer, director of the Centre for Applied Genomics at Toronto’s Hospital for Sick Children.

The diagnostic holy grail is a molecular test that can pinpoint the disorder at birth to hook children into therapies straightaway. Just a few decades ago, this suggestion would have sounded ludicrous. From the 1950s through the 1970s, doctors thought autism resulted from poor parenting and social conditioning by ‘refrigerator mothers’, so called for parents supposedly being cold with their kids. “Now there has been a paradigm shift,” says Schaaf. “We think that 80–90% of what causes autism is really the genetics."

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It’s an understatement to say that HPV has made headlines in recent weeks, but there’s another way the virus might be hitting home. While a clinic-based DNA test for the virus received regulatory approval in the US in 2000, researchers are now exploring the possibility of at-home testing to screen for the pathogen.

The first randomized controlled trial of self-sampling for human papillomavirus (HPV), published today in The Lancet, ultimately found that this tool picked up more premalignant cervical cancers than in-clinic pap smears in women in poor regions of Mexico. The study, the largest to date with more than 20,000 participants, suggests that at-home testing could be a good solution for women living in areas where hospitals are few and far between.

“The main goal was to see which approach was the most sensitive in detecting the most cancers, and really find out what might be the indications of use for this test in terms of effectiveness,” says paper author and trial organizer Attila Lorincz, a molecular epidemiologist at Barts and The London School of Medicine and Dentistry.

In a study of more than 20,000 women, Lorincz and his colleagues randomly invited half to either self-collect a tiny amount of cervical cells by swab, advised by a visiting clinician, for DNA testing or to pop into a clinic for a pap smear to look for abnormal cell growth associated with cervical cancer, called cervical intraepithelial neoplasia (CIN). Of those invited in each respective group, 98% and 87% accepted, suggesting that women were more willing to undergo testing at home.

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With the US Congress largely in a state of ineffectual paralysis, President Barack Obama has turned to his executive authority to get things done. Last week, he signed an executive order that will shorten the time it takes to turn federally-funded research into commercial products. And this afternoon, he pushed through an executive action aimed at tackling the current drug shortages affecting patients, doctors, clinical trials and biomedical researchers nationwide.

There are currently more than 200 drugs and biologics in short supply — a record high up from just 56 five years ago. To bring that number down, Obama’s order directs the US Food and Drug Administration (FDA) to demand better shortage reporting from drug manufacturers, to expedite any applications that could bring drug production back on track and to communicate any reports of price gouging on the drugs out there to the Justice Department.

“It’s encouraging to see this level of engagement,” says Kasey Thompson, the vice president of policy at the American Society of Health-System Pharmacists in Bethesda, Maryland. “Is it going to solve drug shortages tomorrow? Probably not. But directing the FDA and the Department of Justice in particular to describe the grey market more thoroughly is important.”

Before Obama’s pen even graced the paper, however, the FDA was already beginning to lay the blame elsewhere. This morning, agency commissioner Margaret Hamburg published an open letter addressed to drug manufacturers, noting that more than half of all drug shortages last year were caused by problems at the manufacturing plants themselves. Thus, she argued, industry needs to uphold quality standards rather than expect the FDA to pick up the production pieces. “The American public counts on companies like yours to ensure drug quality and safety, so that patient care is not compromised,” Hamburg wrote.

Erin Fox, manager of the University of Utah’s Drug Information Service in Salt Lake City, agrees that industry needs to speak up to recover from the drug shortages. “We don’t know why companies are having manufacturing problems in the first place,” she says. “The chief difficulty in trying to solve this crisis is that we don’t have a full understanding of the problems at hand.”

Image: via Flickr user US Mission Canada under Creative Commons licensing

Hearts under stress need to work harder, and cardiac cells bulk up to facilitate this output. But healthy heart cell growth, caused by exercise or pregnancy, occurs by a different mechanism than so-called pathological growth, induced by heart attack or high blood pressure.

To better understand the difference, and possibly to uncover a way to preferentially encourage healthy growth, cardiologist Leslie Leinwand of the University of Colorado in Boulder studied Burmese python hearts, which balloon by 40% after the snakes’ monthly meal without incurring harm. In a paper published today in Science, Leinwand and her colleagues identified a mixture of three fatty acids in the pythons’ blood that were activated during cardiac growth: myristic, palmitic, and palmitoleic acids. And, when she injected them into mice, their hearts exhibited healthy growth — although they expanded by less than 10%.

The next step is to study whether this fatty acid mixture can heal or treat diseased mouse hearts and then, eventually, human. “The question is whether this growth is truly physiological and is it going to help the heart function better,” says Rong Tian, who studies cardiovascular metabolism at the University of Washington in Seattle.

Image: Burmese python digesting, courtesy of Stephen M. Secor

Diseases that disproportionally afflict the world’s poor provide few incentives for profit-seeking drug companies. In the past couple years, collaborative patent sharing schemes have popped up to remedy this by helping drugmakers develop low-cost medicines for less developed nations. Last year, for example, UNITAID launched the Medicines Patent Pool (MPP), which focuses on HIV drugs.

Yesterday, the World Intellectual Property Organization (WIPO), a Geneva-based arm of the United Nations, unveiled its Re:Search database, a new open-access resource aimed at tackling malaria, tuberculosis and neglected tropical diseases. The database was launched in partnership with the Washington, DC-based non-profit BIO Ventures for Global Health (BVGH). Since 2009, BVGH has administered the Pool for Open Innovation against Neglected Tropical Diseases formed by the British drug giant GlaxoSmithKline.

But organizers hope that Re:Search will grow to ultimately supplant that database. Like GlaxoSmithKline’s effort, WIPO’s resource compiles intellectual property beyond patents, including assets related to many steps in the drug development process, such as research tools, manufacturing technology, as well as both experimental and marketed compounds. However, it is far more extensive, as eight major pharmaceutical companies and a dozen non-profit research organizations from around the world have contributed. The database is available to all scientists and drugmakers free of charge as long as they agree that any therapies stemming from the information are sold at cost of production to the UN’s list of the 48 least developed countries in the world.

Stephen Maurer, who studies innovation and science policy at the University of California–Berkeley School of Law, thinks that sharing non-patented proprietary information, previously held hostage by institutions, is the database’s major contribution. “This is a good first step in terms of getting out of this problem that intellectual property does nothing for the developing world,” he says.

However, Michelle Childs, director of policy and advocacy at Médecins Sans Frontières’ Campaign for Access to Essential Medicines in Geneva, worries that by only making drugs available to the most impoverished nations, Re:Search — like other patent pools before it — could leave out people in middle-income countries who can’t afford full-price meds (see Nat. Med. 17, 1023–1023, 2011).

“Restricting access to the least developed countries is just ignoring where people with neglected tropical diseases live,” Childs says. “By agreeing to licensing terms that have such an unacceptably limited geographical scope, the UN — a norm setting agency — is setting a bad precedent for future licensing arrangements.”

And without concrete targets, some experts worry whether the initiative will actually deliver on its stated goal of promoting the development of new drugs, vaccines and diagnostics. “Statements of goodwill made in good faith are not good enough,” says MPP head Ellen t’ Hoen. “Actual action needs to be put behind it.”

In 1988, health groups and governments around the world launched the Global Polio Eradication Initiative (GPEI), a public-private partnership aimed at eradicating the poliovirus by 2000. That year has come and gone, and still the contagious virus plagues many parts of the world, with ongoing outbreaks in China, Pakistan and Madagascar, just to name a few countries.

The program has made great progress over the past 23 years, though. For example, the number of polio infections worldwide has decreased by more than 99% since 1988, with only around 1,350 cases of wild polio in 20 countries last year. Buoyed by that success, in June 2010 the GPEI published a new strategic plan, laying out guidelines to terminate polio in two of four endemic countries (Afghanistan, India, Nigeria and Pakistan) by the end of 2011 and to end wild polio transmission in countries that had active outbreaks in 2009 by 2012.

But the end is not yet in sight, according to an independent evaluation of the strategic plan published earlier this month. Virus control in India has made great strides, the new report notes, with only one case reported in 2011 thus far — a considerable accomplishment considering that, less than a decade ago, India accounted for 85% of polio cases worldwide. However, Afghanistan and Nigeria, two of the three remaining endemic countries, have had more cases in the first nine months of this year than in 2010 altogether. Several other countries targeted by the plan have also seen more cases to date this year compared to this time in 2010. Additionally, polio had popped up in countries where it had previously been eradicated — notably China, which went polio-free for 11 years until this summer.

With so little progress, the report concludes that “the GPEI is not on track to interrupt polio transmission by the end of 2012 as it planned to.”

Problems with the GPEI “run so deep,” the report continues, “that nobody should believe that ‘more time’ is the solution to them.” Instead, the evaluation recommends that the program should receive higher priority — in other word, more funding. But is throwing more money at the problem really going to wipe out polio for good? As we’ve noted many times before in the pages of Nature Medicine, millions have been invested to make polio history, but the virus remains. On this World Polio Day, shouldn’t we be searching for novel solutions?

Image: Oral polio vaccination in Guinea in 2009. By Julien Harneis via flickr under Creative Commons

On Tuesday, highly-anticipated preliminary results from a phase 3 clinical trial of the RTS,S vaccine against malaria found that vaccinated young children had a 56% lower risk of developing the infection. The vaccine’s maker, London’s GlaxoSmithKline (GSK), has been involved with the vaccine since the early 1980s. But its history goes back further to mouse research conducted at New York University (NYU) in the 1960s. Yet, despite a half century of research into malaria vaccines and numerous clinical trials, laboratory models of the disease have changed little — a fact that experts say could be hindering the development of new vaccines.

“The mouse models have not been very predictive,” says Jean Langhorne, an immunopathologist at the MRC National Institute for Medical Research in London. “They’re very good at telling us what vaccines don’t work, but not very good at telling us what vaccines should work.”

When NYU immunologist Ruth Nussenzweig started her hunt for malaria vaccines in the 1960s, mouse models for the disease were brand new. The parasite that causes malaria in humans, Plasmodium falciparum, does not naturally infect mice, so researchers were at a loss for how to study even malaria’s basic immunology. In the 1950s, scientists traveled to the Congo to collect parasites related to malaria from tree-dwelling African thicket rats, and then adapted them to infect mice in the lab. And, thus, scientists developed the mouse model first used for RTS,S: a lab mouse artificially infected with Plasmodium berghei.

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