Monthly Archives: January 2013

Gene sequencing yields breakthrough for children with rare Parkinson’s-like disorder

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Doctors can now use a person’s genetic sequence as the basis for rational drug selection—a sign of how far personalized genomics has come in recent years. A case report published today in the New England Journal of Medicine illustrates the strength of this approach.

The paper describes an extended Saudi Arabian family in which many young siblings suffered from a Parkinson’s-like condition affecting their movement. The children had normal levels of neurotransmitters dopamine and serotonin in their spinal fluid, suggesting they should have been healthy. The unique circumstances prompted researchers to use the latest advances in genomic sequencing to identify a mutation in the SLC18A2 gene, which encodes the protein vesicular monoamine transporter 2, or VMAT2, as the cause of the disease.

A team led by Berge Minassian, a neurologist at the Hospital for Sick Children in Toronto, successfully pinpointed the mutation and treated the symptoms in these siblings. “I am certain that in the next few years patients walking into children’s hospitals will have their whole genomes sequenced,” says Minassian. Until now, magnetic resonance imaging (MRI) has been the primary diagnostic tool for people with neurological diseases.

The study’s initial patient was a 16-year-old girl first diagnosed with muscle weakness when she was just four months old. She sat for the first time when she was two and a half years old, began crawling at four and walking—and only with difficulty—at the very late age of 13. Her symptoms resembled Parkinson’s disease, but all her metabolic and MRI tests came back normal. Doctors also ran tests on her 2-year-old sister who suffered from similar symptoms and a red flag showed up in the toddler’s urine, where dopamine levels were below average. The physicians then gave the 16-year-old and her three younger siblings levodopa-carbidopa, a dopamine precursor used to treat Parkinson’s. They were puzzled, though, when the conditions worsened in all four.

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Proposal to overhaul disease’s name could boost awareness and funding

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There’s an idea in linguistics known as the Whorfian hypothesis. It proposes that language is inexorably linked with how we perceive and think about the world. The classic argument is this: an Inuit person, possessing different names for snow, has the ability to think about, and even see, subtle differences in snow that speakers of some other languages do not.

Could the same apply to biomedicine?

Last week, a panel convened by the US National Institutes of Health (NIH) released a series of recommendations about how best to study and diagnose a common hormonal disorder in women known as polycystic ovary syndrome (PCOS). At the top of their list: a call for a name change.

It might seem counterintuitive that a name could be critical to scientific investigation. After all, a disease such as PCOS, which affects one in ten women of reproductive age and is a major cause of infertility, is still just that—no more or less common, no more or less severe, regardless of the name. Still, the semantics of a particular moniker can have potential repercussions, from levels of research funding to how patients find the right doctor.

PCOS affects an estimated five million women in the US and encompasses a range of symptoms, including high levels of the male hormone androgen, insulin-resistance, an increased risk of type 2 diabetes, abnormal hair growth and growths on the ovaries. However, little is known about the underlying causal mechanisms of the disease. As a result, there are currently no cures, only treatments for symptoms. Combined with the fact that many women express only some of these symptoms, the diagnostic criteria for PCOS are still under debate.

A distraction and an impediment

Late last year, the NIH called for an independent panel—four experts not involved in PCOS research—to assess this issue. Over the course of the December 2012 workshop, the panelists soon came to a realization: “We believe the name ‘PCOS’ is a distraction and an impediment to progress.  It causes confusion and is a barrier to effective education of clinicians and communication with the public and research funders,” panel member Robert Rizza, executive dean for research at the Mayo Clinic in Rochester, Minnesota, said in a teleconference last week unveiling the committee’s findings.

After reviewing the current state of research and different diagnosing standards, Rizza and his colleagues concluded that the presence of “polycystic ovary”—which is actually a misnomer, as the numerous ‘cysts’ on the ovary are really immature eggs known as follicles—is not sufficient to diagnose PCOS. Some women with excess follicular growth show no signs of having the disease; others show some combination of symptoms but have no ovarian abnormalities.

In their report, the panelists agreed with the relatively-contentious ‘Rotterdam criteria‘, which require patients to have two out of three major symptoms—increased androgen levels, irregular periods, and “polycystic ovary”—for a diagnosis. Therefore, they wrote, “It is time to expeditiously assign a name that reflects the complex metabolic, hypothalamic, pituitary, ovarian and adrenal interactions that characterize the syndrome,” and not just focus on one particular symptom. But being outsiders to PCOS research, they declined to propose a new name.

“Our feeling was that this was the right time to rebrand,” panelist Timothy Johnson, chair of the department of obstetrics and gynecology at the University of Michigan Medical School in Ann Arbor, told Nature Medicine. “The new name would really make people think about the disease in a broader way, do research in a broader way and get a broader range of funding.”

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Blue-sky HIV test chip will upload results to the cloud

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In Rwanda, the most densely populated country in Africa, there are approximately 190,000 people living with HIV, with electronic records facilitating care for over 90,000 of them. However, many thousands of HIV-infected people there who don’t have access to health centers remain undiagnosed.

It’s exactly this type of situation that Samuel Sia hopes to ameliorate. Sia, a biomedical engineer, and his team at Columbia University in New York have combined the portability of mobile technology with the detection potential of enzyme-linked antibodies to create a fully automated and portable microfluidic device dubbed the ‘mChip’. The scientists tested the device on serum, plasma and blood samples from over 200 HIV-infected individuals in Rwanda and published their findings in this month’s issue of Clinical Chemistry.

The device uses blood from a finger prick, similar to that employed by a glucose meter, which is automatically loaded onto a small fluidics chip that contains HIV-specific antibodies and reagents needed to perform an enzyme-linked immunosorbent assay, or ELISA. ELISA is the most sensitive and commonly used laboratory diagnostic for HIV, and historically has taken hours and sometimes days to provide a result. The mChip device, however, produces a result in just 15 minutes. Sia says that this shortened testing time does not sacrifice the specificity and sensitivity of the mChip, as it was 100% accurate in detecting HIV positive samples and 99% accurate in distinguishing HIV negative samples in the pilot study.

“This is a novel device and the diagnostic field is likely to move in this direction in coming years,” says Bharat Parekh, a laboratory chief at the US Center for Disease Control’s Division of Global HIV/AIDS in Atlanta, Georgia, who works on developing rapid HIV testing.

To Sia’s knowledge, the mChip device is the first rapid HIV test that uses cell phone network or satellite connectivity to automatically synchronize test results with patient health records anywhere in the world. “Now, with a single push of a button, there is automation not only from the sample to the result, but to the synchronization of data to the cloud,” Sia says, referring to the data repository that doctors can access. “This automation is very important because it minimizes user error and user variability.”

The HIV diagnostics realm has seen other user-friendly devices recently. Last July, the FDA approved OraQuick, manufactured the Pennsylvania-based OraSure Technologies, as the first in-home mouth swab HIV testing kit. According to Sia, though, when “there is a weakly positive sample [that’s] where you can’t tell.” In a head to head comparison of the mChip, OraQuick, and a standard laboratory HIV ELISA using a commercial panel of 23 HIV samples, the mChip correctly detected all 17 HIV positive and six weakly positive samples, whereas OraQuick missed the six weakly positive samples, with four registering as false negative and two as indeterminate. Weakly positive samples, such as those from recent HIV infections, can constitute 0.3% to 3% of HIV-infected patients in high-risk populations.

Parekh cautions that it is too early to say if the device will make a major impact for the developing world. There are several rapid tests currently in use that do not require any electrical power source and can be performed anywhere by properly trained personnel.

But Sia emphasizes that another advantage of the chip is that it can look for multiple diseases at once. “The real power is [that] one finger prick can give you multiple rapid test results, making it cheaper and more convenient.” Sia and his team published a paper in Nature Medicine in February 2011 that used an early prototype of the mChip to simultaneously diagnose HIV and syphilis in 67 samples collected in Rwanda, giving 100% and 94% sensitivity and 95% and 76% specificity, respectively.

For a closer look at the prototype, check out our video about that 2011 paper:

Image: Shutterstock

Clinical trial begins for rare and fatal illness nicknamed “childhood Alzheimer’s”

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Addison and Cassidy Hempel are seven-year-old identical twins who are among only about 500 people in the world with an extremely rare but fatal neurological disease that gradually destroys the young mind and body. The US Food and Drug Administration (FDA) has not approved any therapies for this rare disease, known as Niemann-Pick disease type C1 (NPC). So under normal circumstances, Addi and Cassi would not live through adolescence. But that fate is not yet sealed because in 2010 they became the first children in the world to start receiving injections of an experimental drug called cyclodextrin.

In an effort to bring this treatment to other children with NPC, the US National Institutes of Health (NIH) announced on 23 January that scientists at its National Center for Advancing Translational Science (NCATS) will begin a phase 1 clinical trial to evaluate the safety and effectiveness of cyclodextrin in nine other NPC patients. Both NCATS and its clinical trial partner, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), are based in Bethesda, Maryland.

Charles Vite, a veterinary neurologist at the University of Pennsylvania in Philadelphia who has tested cyclodextrin in a feline model of NPC, says the the drug “shows clear improvements in the animal model” above and beyond other compounds scientists have tried. “It’s very exciting because this drug has the potential to be successful in children.”

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EDITORIAL: A long pause

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A version of this editorial appears in the February 2013 issue of Nature Medicine.

Last January, scientists voluntarily imposed a pause on research that could lead to the generation of highly pathogenic avian influenza viruses with increased transmissibility to mammals. Now, new restrictions currently under debate further risk stalling progress in avian flu research.

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In late 2011, a firestorm erupted around two papers under peer review on highly pathogenic avian influenza (HPAI) H5N1 viruses. Both identified mutations that would permit airborne transmission of the viruses to ferrets. Although the viruses were not highly pathogenic in the ferrets, the papers sparked concerns that the mutant H5N1 viruses might have pandemic potential.

The concerns are not unwarranted given the history of H5N1 infections. The case fatality rate due to H5N1 in humans exceeds 50%, yet only 610 infections have been recorded since 2003, in part because of its low capacity for human-to-human transmission. However, there is fear that avian influenza could acquire the mutations necessary to rapidly transmit among humans, similar to seasonal influenza. Therefore, a better understanding of the mutations necessary to facilitate transmission of H5N1 in mammals and their effects on the fitness of the virus is considered by many to be crucial in developing countermeasures in the event of an avian flu pandemic.

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Anonymity not guaranteed: Identity of personal genomic DNA revealed by Web search

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A few decades ago, people might have looked at you funny if you asked them to publicly share the intimate details of their personal lives—where they live, their age, what they had for dinner a few nights ago, photos of their children and more. However, between Facebook, Google, LinkedIn and the rest, it’s almost a trivial matter to find out people’s private details today. And soon, a new study suggests, your entire genome could get added to that list of personal information so easily found online—whether you want it or not.

“The issue is the current status of privacy,” says Yaniv Erlich, a geneticist at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, who led the research. “We need [sponsors of genomic studies] to be respectful to participants, to tell them the truth: that someone can identify you.”

To lift the mask off of genomic data that had been seemingly stripped of identifying information, Erlich and his team focused on the Y-chromosome, typically passed along with surnames from fathers to sons. Genetic ancestry services such as FamilyTreeDNA and Ancestry.com allow customers to trace their paternal genealogy through an analysis of a series of genetic markers known as short tandem repeats on the Y-chromosome (Y-STRs). As a free service, many of these companies also share their large databases of Y-STRs, with accompanying surnames and built-in search engines, to the public. Since demographic information, including year of birth and state of residency, are often included in published scientific reports, and can also be linked to surname records on sites such as such as PeopleFinders.com or USApeople-search.com, it proved relatively straightforward for Erlich and his colleagues to narrow the identity of DNA contributors down to small lists of likely suspects.

As an example, they tested their procedure on 10 ‘anonymous’ personal genomes, taken from the 1000Genomes project and the European Nucleotide Archive. They recovered surnames for half of these men with a high probability of accuracy. After an internet search, they identified not only the individuals to whom the genomes belonged, but their entire family trees. The findings were published today in Science.

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A universal problem: One virologist’s 20-year effort to challenge an imperfect flu test

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{credit}Bindu Marathe{/credit}

Recent headlines have promised that a ‘universal flu vaccine’ may be within reach, pointing to antibodies that offer broad protection in animal studies. But the scientists behind this effort had to first overcome great skepticism from their peers—as well as an imperfect laboratory test. Hannah Hoag reports on one virologist’s 20-year effort to challenge the tenets of the field.

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Influenza is the Lady Gaga of viruses: it reinvents itself each year, often in unexpected ways. But the flu virus is far more dangerous than an infectious tune. Although the flu usually manifests as a mild illness, the virus kills as many as 500,000 people worldwide each year, and it continues to provide a challenge from a vaccination standpoint. Whereas most vaccines for illnesses such as measles or polio offer years or decades of protection, influenza vaccines tend to work for only one season. The relentless refashioning means new influenza vaccines must be routinely reformulated, all at a cost to consumers and global health systems of more than $4 billion each year.

A new type of vaccine could be on the way. In the past few years, a flurry of papers has provided firm evidence of antibodies capable of neutralizing multiple subtypes of the influenza virus. Immunologists say that isolating such antibodies is the first step toward the creation of a universal influenza vaccine that protects against seasonal flu year after year—and possibly prevents hundreds of millions of deaths when the next influenza pandemic sweeps across the globe. Several such universal flu vaccines are already in early human clinical testing. But convincing the biology community of the existence and potential of such antibodies was an uphill battle, and one complicated by a ‘gold standard’ test that masked the key findings.

Yoshinobu Okuno, who has chased the dream of a universal antibody against flu since 1989, knows these challenges well. Okuno, a virologist at Osaka University in Japan, is now viewed by many experts in the field as an important and early champion of the idea. Yet his discovery two decades ago of a broad-acting antibody called C179 didn’t make waves at the time. “People didn’t pay attention to it,” says Ian Wilson, a structural biologist at the Scripps Research Institute in La Jolla, California. “In those days, most people weren’t thinking about broadly neutralizing antibodies that you could develop for flu.”

The very test that prompted Okuno to look for these special antibodies—a tool known as the hemagglutination inhibition assay—tripped up the efforts of others in the field. In hindsight, the fault in the assay provides a cautionary tale of how the shortcomings of a test can mean that biomedical researchers miss what they are not looking for.

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An ingestible pill-sized device offers a 3D view of the esophagus

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Almost everyone gets occasional heartburn, that painful sensation in the chest or throat caused by the reflux of stomach acid back into the esophagus. When it happens too frequently, however, such as in patients with gastroesophageal reflux disease, it can result in a condition known as Barrett’s esophagus. An estimated 3 million Americans suffer from this disorder, where the tissue that lines the esophagus accumulates abnormal changes over time, increasing the risk for esophageal cancer.

Barrett’s esophagus often goes undiagnosed because it causes minor or nonexistent symptoms, and because of the procedure required to identify it. Currently, doctors must sedate a patient, insert a long, flexible camera known as an endoscope down the esophagus to look for abnormal tissue, and then cut off a small piece for analysis in a laboratory. The procedure is invasive, expensive and uncomfortable.

Now, researchers at the Massachusetts General Hospital (MGH) in Boston have invented a tethered, pill-sized endoscope that that allows doctors to construct an image of a person’s esophagus in microscopic detail within a few minutes—and all without anesthesia, intense training or causing pain. Their work was published today in Nature Medicine.

“A lot of people have reflux but don’t feel the pain of heartburn,” says MGH pathologist Gary Tearney, who led the study. These patients are at high risk for developing cancer, because they usually have no reason to get their esophagus inspected. “[Our device] really opens up screening to many more people,” Tearney says.

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Better labeling aimed to spur development of abuse-resistant painkillers

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Prescription opioid pain relievers such as codeine and oxycodone are among the most widely abused drugs in the US. The country’s Centers for Disease Control and Prevention (CDC) estimated that in 2010 around 12 million Americans aged 12 or older used this class of drugs for nonmedical purposes, at a cost of up to $72.5 billion in direct healthcare expenses. Worse, the CDC estimates that around 15,000 fatalities occur each year due to overdoses from these meds, a number comparable to the total number of annual murders nationwide.

In response to this growing public health crisis, the US Food and Drug Administration (FDA) yesterday released a draft guidance detailing how the agency plans to evaluate new opioid pain relievers with special formulations designed to reduce abuse. Importantly, it gave pharmaceutical companies labeling guidelines.

“Our goal here is to encourage the development of abuse deterrent formulations that work to reduce abuse in the real world, in the community. The intent of this guidance is to incentivize that, to encourage the development of that science,” said Douglas Throckmorton, deputy director of the FDA’s Center for Drug Evaluation and Research, in a conference call to reporters.

Drugs with abuse-deterrent properties have already been developed and sold on the market. For example, Endo Pharmaceuticals of Chadds Ford, Pennsylvania, sells a tablet called Opana ER that releases its active painkilling ingredient slowly over time and is harder to abuse by crushing or snorting. But Endo is not allowed to include any permutation of the term “abuse-deterrent” on the drug’s label, a major issue for a company that’s trying to differentiate its product from the pharmacopeia of other painkillers. Last year, Endo went so far as to sue the FDA to prevent a generic version of their drug’s older, non-abuse-deterrent formulation from entering the market. The generic was ultimately approved, but the timing and language of yesterday’s draft guidance should help mitigate some of the concerns raised by Endo going forward.

Despite the added clarity for drugmakers, questions remain for the health care industry as to whether doctors will ultimately prescribe the abuse-resistant painkillers, not to mention whether health insurers and patients will be willing to pay for their higher premiums next to the cheaper generic—and tamperable—alternatives.

Nathaniel Katz, president of Analgesic Solutions, a Massachusetts-based consulting firm, believes there are obvious incentives. “[Doctors] want to always prescribe the safer product,” he says. For health insurers, “from a pure financial perspective, prescription opioid abuse is a huge problem. They will increasingly recognize that, and recognize there’s a financial return on investment.”

That just leaves patients. Many people seeking pain relief, especially those who do not identify as at-risk for abuse issues, will probably not accept higher co-pays when much cheaper but abusable options are still available. Katz sees a simple solution to that problem: “Eventually the idea is perhaps that the option will no longer be available to them,” he says. As yet, however, the FDA hasn’t taken that option off the table.

Image: Ondřej Karlík, Wikimedia Commons

‘FlyWalker’ tracks insect feet, could advance Parkinson’s research

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They may have wings, but fruit flies spend plenty of time on their feet. And these insects, also known as Drosophila, are a standard animal model for studying neurodegenerative diseases, such as Parkinson’s and even Alzhiemer’s.

Often, scientists will create fruit flies that contain the same genetic mutations as seen in these disorders to see how the DNA changes affect the insects. Yet, for all the complex genetic tools they employ, the way of measuring the resulting motor defects remain crude: A researcher will knock the flies in a vial down to the bottom with a quick tap, and then wait to see how long it takes for the insects to climb to the top. (For an example, go to 2:28 into this video on LRRK2 animal models of Parkinson’s.)

Now, reporting in eLife, a team at Columbia University in New York has developed a more accurate and sophisticated way to quantify such movement. They first videotape a fly walking, and then, using computer software that can spot the individual footpads of the insect and mark when these each hit the surface. With this data, they can calculate the insects’ walking speed, distance covered and overall gait.

In the paper, the authors looked at sensory-deprived flies and showed that inactivation of sensory neurons in the insects’ legs led to defects in step precision but did not affect coordination between the legs. They call the program FlyWalker.

Similar technology already exists for tracking the movements of lab rodents. But as Ronald Calabrese of Emory University in Atlanta notes in an accompany commentary, “the Columbia team is the first to scale it down to fly-like dimensions.”

With so many metrics being teased apart by the new algorithm, Columbia’s César Mendes, a postdoc in Richard Mann’s lab who led the research, expects scientists who use the technique to discover new things about their diseases of interest, such as how an ailment worsens over time. “This method is good if you want to see a progressive phenotype and to see subtle changes as time goes by and the disease phenotype gets more aggravated,” he says.

“I really foresee that you will see flies that start to have some [movement] defects that have not been seen before, and hopefully we’ll be able to correlate some phenotypes to particular groups of neurons or to particular circuits,” Mendes told Nature Medicine. “I’m very curious to see what we’re going to have in the future.”