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.”
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.
This year has proven to be a veritable cliff-hanger for the world of biomedicine. At the same time that the US government stands poised on the brink of the so-called ‘fiscal cliff’, pharmaceutical companies are stumbling with the industry’s ‘patent cliff’ and academic researchers face the looming ‘funding cliff’. But not everything in 2012 was so dire, with dozens of new drugs to hit worldwide markets and countless discoveries made to enable the next generation of medicines. What follows are a set of ‘Cliff’s notes’ to the year that was for the field.
Sergey Brin, the co-founder of Google, has an increased risk of developing Parkinson’s disease because he harbors a mutation in a protein called Leucine-rich repeat kinase 2, or LRRK2. The protein is viewed as a promising drug target to treat Parkinson’s, a progressive neurological disorder, but it’s not possible to track LRRK2 activity in the brain, making the search for targeted therapies against the disease challenging. In a new study, researchers now provide evidence for a way to measure LRRK2 activity—and a new compound that can block the damaging effects of the protein in rodent neurons.
“This study is important because the authors showed that specific mutations in LRRK2 activate it and cause damage to nerve cells. This finding can now provide opportunities to monitor the effects of LRRK2 inhibitors in cells and animals,” says Howard Federoff, executive deanof Georgetown University’s School of Medicine in Washington, DC, who was not involved in the study.
Parkinson’s disease affects approximately 10 million people worldwide by impairing motor functioning caused by the death of dopamine-secreting neurons in the brain. Mutations in LRRK2 are the most common cause of familial Parkinson’s disease, accounting for about 2% of all patients with Parkinson’s. Specific mutations in LRRK2 increase its enzyme activity. A 2006 study in Nature Neuroscience revealed that mutations affecting LRRK2 activity can damage mouse nerve cells grown in culture. A 2010 study published inNature Medicineshowed that inhibiting LRRK2 can prevent some of the symptoms of Parkinson’s disease in a mouse model. However, an understanding of how LRRK2 causes neuronal damage remained elusive.
Today, reporting in Science Translational Medicine, a collaborative team led by neurologist Haitao Zhu and chemist Don Kirkpatrick at biotech powerhouse Genentech, based in South San Francisco, California, identified several abnormalities in mutated LRRK2 at a site of the protein known as serine 1292 that make it more active—and thereby more toxic to neurons. The identification of serine 1292 allowed the researchers to develop an antibody that could bind to the protein, allowing them to build an assay that measured the amount and activity of LRRK2.
Subsequently, the researchers found that the amount of LRRK2 with this serine 1292 modification—specifically, the addition of a molecule known as a phosphate group—was ten times higher in cells taken from the brains of mice genetically engineered to carry mutated LRRK2 compared to that seen in normal mice.
The scientists also developed a molecular screening approach to test hundreds of potential LRRK2 inhibitors. In the end, they identified one such compound, G1023, which completely removed the bound phosphate group in mutated LRRK2. G1023 protected embryonic neurons taken from mice with the LRRK2 mutation, returning the growth rate of these cells to the same level as that seen in cells taken from healthy mice.
“The serine 1292 site is highly conserved through evolution from worms to humans, suggesting that it is very important for the function of LRRK2 and can be used as a starting point in drug discovery to prioritize compounds that are selective, potent, and brain-penetrable,” says Zhu.
“We still don’t know if this inhibitor molecule will be protective in an animal, but now they are well prepared to do these studies,” says Federoff. Zhu and Kirkpatrick agree that the next step, now that they have an inhibitor, is to test its efficacy in an animal model, as a necessary first step to evaluate whether to ultimately go forward with a human clinical trial.
Here’s a look back at where the search was in 2010 when the Nature Medicine story came out:
Testing fetal DNA for fine-scale copy number variations can reveal more genetic defects than standard karyotyping methods that look for genetic abnormalities in developing fetuses on a whole-chromosome level, according to the largest clinical trial of its kind.
“These findings will undoubtedly cause many clinical and laboratory geneticists to consider whether chromosomal microarrays should be recommended as a first-tiered prenatal diagnostic test,” says Cynthia Morton, director of cytogenetics at the Brigham and Women’s Hospital in Boston, who was not involved in the trial.
Karyotypic staining analyzes the composition and structure of chromosomes to reveal abnormal changes in chromosome number and shape that are commonly implicated in disease. This technique is currently the gold standard for detecting prenatal genetic defects, but is far from perfect. Karyotyping routinely misses small genetic aberrations and the method only works on cultured cells. To overcome these limitations, researchers have recently turned to a method known as ‘array-comparative genomic hybridization’, which relies on a small chip embedded with millions of molecular probes that recognize particular genomic DNA regions and pinpoint genetic abnormalities too small to be detected by current methods. And as an added bonus, it works on any tissue, living or dead.
Such ‘chromosomal microarrays’ have historically only been used in small scale studies for prenatal diagnostics. But now, a team led by Ronald Wapner, director of Maternal Fetal Medicine at the Columbia University Medical Center (CUMC) in New York, has tested fetal DNA from more than 4,400 expectant mothers at 29 centers across the US using both standard karyotyping and chromosomal microarrays. Microarray analysis, the researchers found, detected chromosomal deletions or duplications in 6% of cases in a group that was flagged as structurally abnormal by ultrasound but scored normal by karyotyping and also revealed genetic abnormalities in about 2% cases missed by karyotyping in another group with advanced maternal age.
“The advantage of microarrays is their high resolution and sensitivity, which allows detection of events at the level of genes, as opposed to the level of chromosomes for karyotyping,” says Wapner, who published the results today in the New England Journal of Medicine (NEJM).
Also today in NEJM, a team led by Uma Reddy, an obstetrician-gynecologistat the US National Institute of Child Health and Human Development in Bethesda, Maryland, compared the ability of microarrays and karyotyping to diagnose the cause of more than 500 stillbirths. Because of the challenges associated with culturing tissue from a dead fetus, karyotyping failed to give results in 30% of cases, whereas microarrays, which don’t require live cells, yielded a genetic culprit in 87% of stillbirth cases. “With microarrays, you are more likely to obtain a result, which is important for families waiting for answers,” says Reddy.
Genetic analysis has confirmed that the cases of SARS-like viral disease that made headlines this fall—first killing a Saudi Arabian man in June and then sickening a Qatari man in September—were the result of a single coronavirus strain that made the leap from bats to humans.
“These two individuals were exposed to the same virus that was harbored in bats in the Saudi Arabian peninsula,” says Ralph Baric, a microbiologist at University of North Carolina–Chapel Hill who was not involved in the work.
A team led by Ron Fouchier, a virologist at the Erasmus Medical Center in the Netherlands, sequenced all 30,000 nucleotides of the new virus’ genome. Reporting today in mBio, the researchers found that the virus is most closely related to two coronaviruses found in bats, one from vesper bats and another from pipstrelle bats. The finding mirrors earlierdiscoveries that bats often serve as reservoirs and likely sources of coronaviruses for people. It also validates preliminary molecular details reported earlier this month in the New England Journal of Medicine.
In unpublished material disclosed in a press release to accompany the mBio paper, Fouchier and his colleagues additionally found that the isolates from the first two men infected with the virus differed by only 99 nucleotides, indicating that the two viruses are the same species. Genetic data from a third viral isolate taken from another Saudi Arabian man who earlier this month came down with what scientists think is the same coronavirus are not yet available.
It could be worse
Although it’s still too early to make definitive statements, Baric says that the novel coronavirus—dubbed HCoV EMC/2012—does not appear to be transmissible between people, which distinguishes it from the virus responsible for severe acute respiratory syndrome (SARS) that spread between thousands of people a decade ago, killing around 10% of those infected. “If it were as transmissible as SARS, it would be much more dangerous,” he says.
BOSTON — With so many topnotch research proposals seeking funding but only limited grant money to go around, deciding which among the best of the best projects to support is no easy task. What if you have a number of equally commendable applications and you don’t know how to break the tie? Usually, a panel of experts will weigh the merits of the various projects and come to some consensus behind closed doors. But in an unconventional twist, the Brigham and Women’s Hospital (BWH) has opted to let the general public act as scientific judge and jury.
After six weeks of online voting and nearly 6,500 votescast,the decision was in. Today, the Harvard-affiliated hospital announced that a project designed to explore how best to integrate genomic sequencing into routine medical care for healthy newborns had won the inaugural BRIght Futures Prize. The project’s leader, clinical geneticist Robert Green, and his team received a $100,000 research grant from the BWH’s Biomedical Research Institute (BRI).
“I’m not sure if there’s any other example where an academic institution has allowed the public to decide to whom they’ll give some of their hard-earned, hard-raised research money,” says Jacqueline Slavik, executive director of the BRI.
“Our goal was really to engage the Brigham community at large,” adds Lesley Solomon, director of strategy and innovation at the institute. “We want the world to know about the breadth and depth of the research that goes on here.”
It may sound akin to a popularity contest, but Slavik and Solomon are quick to point out that all three finalists for the prize had gone through a rigorous, behind-the-scenes, peer-reviewed vetting process before reaching the final stage. Review committees with expertise in personalized medicine and systems immunology—the two subject areas for which the BRI solicited proposals for the prize—winnowed the list of applicants down to a series of semifinalists. Each selected applicant made an in-person pitch to the BRI’s Research Oversight Committee, which ultimately chose the three proposals that were presented to the public. The three finalists then worked together with the hospital’s public affairs team to create a series of videos and brief nontechnical descriptions about the projects that were hosted on the voting site.
“It’s a new way of trying to decide who gets the money when you have equally meritorious projects,” says Slavik. “We could flip a coin,” she quips. Instead, by engaging the public, “we achieve several goals at once,” without sacrificing scientific rigor.
It’s got to be quite a competition when the winner can boast solving a family’s medical mystery, but those are the bragging rights the clinical genetics division at Brigham and Women’s Hospital captured when it won Boston Children’s Hospital’s first CLARITY contest (short for Children’s Leadership Award for the Reliable Interpretation and appropriate Transmission of Your genomic information).
In January, the Children’s Hospital put out the call for submissions, asking participants to help determine the unknown genetic root cause of illness in three children. The teams could sequence the genomes of the children and their parents, and were tasked with interpreting the information. The ultimate aim of the competition was to shed light on how data from whole genome sequences can be made most useful in a clinical setting (see ‘Genomics contest underscores challenges of personalized medicine‘).
There was a “real question of whether these technologies are ready for prime-time clinical applications,” says Isaac Kohane, an endocrinologist at Children’s Hospital. “What these teams have demonstrated is that going from end to end—from a genome sequence to a clinical readable report—can be turned into a routine process.”
Of the 23 teams submitting entries, three were able to identify both mutations in the titin and GJB2 genes that, respectively, explained the muscle weakness and hearing impairment afflicting one of the youngsters, a sixth grader. The Brigham and Women’s team provided the most insight on these points, winning the $15,000 top prize. Meanwhile, a team from University of Iowa in Iowa City was awarded $5,000 as a finalist for their approach to communicating unexpected genetic results, which they based on patient preferences. A German team (with representatives from the gene sequencing companies Genomatix and CeGaT, as well as the Institute of Pathology at the University of Bonn) also received $5,000 as a finalist for flagging all likely genetic mutations in the three cases.
The Children’s Hospital team behind the contest plans to publish a paper comparing and contrasting the various approaches taken by the entrants in the contest, according to Kohane. The hope is that this information from the contest will help inform procedures in the gene sequencing field. They’re also planning a second challenge, focused on cancer genomes, to carry on their efforts of helping understand how to process the large data sets and communicate the information to patients.
Using gene therapy, a team of researchers for the first time successfully restored normal hearing to mice born deaf due to a missing protein, according to a study published today in the journal Neuron. This finding could be music to the ears of people whose congenital hearing loss is caused by genetic mutations that may prevent tiny inner ear hairs from interacting with neurotransmitters that are necessary for hearing. In the current experiment, mice recovered full hearing for an average of seven weeks, with two of 19 mice maintaining it for as long as one and a half years. “I was completely shocked,” says lead author Lawrence Lustig, director of the Douglas Grant Cochlear Implant Center at the University of California, San Francisco. “The hearing looked almost completely normal and you couldn’t tell these were rescued mice.”
Richard Smith, a geneticist at Iowa State University in Iowa City who was not involved in the study, says that the findings offer hope for the estimated 12,000 infants, or 0.3 % of all babies born each year in the US, with severe-to-moderate hearing loss in one or both ears. “A hearing aid or cochlear implant doesn’t correct hearing in the same way that eyeglasses correct sight,” Smith explains. “Those devices only aid in hearing—hence the need for alternative treatments.”
Previous studies have introduced genes that cause deafness into mice and then applied gene therapy to remedy the problem, thereby using an artificial congenital hearing loss animal model. By comparison, the current study tested the approach using mice born without the Vglut3 mouse gene—which produces the protein known as vesicular glutamate transporter-3 (VGLUT3). Without this protein, the inner ear cells could not release the neurotransmitter glutamate, which carries sound signals to the brain. The researchers injected a harmless virus called adeno-associated virus type 1 (AAV1), which carried a working copy of Vglut3, into the ears of some animals one day after birth and in others almost two weeks post-delivery. They confirmed that both groups of treated mice could hear based on electrical signals picked up by electrodes attached to the scalp during an auditory brainstem response test. During that test, inner ear hairs send signals through the auditory pathway which goes through the brainstem. The control group of mice with this mutation received no injections and showed no response on hearing tests.
Lustig believes his study is a big step towards clinical trials—possibly in as soon as five years—to test gene therapy for congenital hearing loss in humans. But there’s one potential drawback to the study: the mouse gene Lustig used does not correlate with the same behavior of the mutant human gene SLC17A8. While a mutation in this gene in humans causes high-frequency hearing loss in adulthood, no studies have linked it yet to congenital deafness in people.
The researchers used the Vglut3 gene because they already had these knockout mice available in their lab. Smith says the choice was understandable and doesn’t take away from the significance of the study. “Gene therapy is complicated and very expensive and so you want to choose a model you have on hand already,” he adds.
Today’s study comes on the heels of a recommendation from a committee within the European Medical Agency to approve a gene therapy for people who lack an enzyme that breaks down fat in the body. Other companies, such as GenVec and Novartis, which are mentioned in earlier Nature Medicine coverage on hearing loss, continue to work on gene therapy that seeks to repair sensory hair cells in the inner ear.
The burgeoning field of do-it-yourself biomedical research got a major endorsement this week when the genetic testing heavyweight 23andMeannounced it had bought the community health site CureTogether for an undisclosed sum.
With CureTogether, a social networking site that enables users to conduct their own research studies by sharing and aggregating health information, California-based 23andMe appears to be getting serious about expanding its efforts in the Web-based, participant-driven research arena.
Already, peer-reviewed studies involving 23andMe’s 150,000 customers have yielded novel genetic insights into Parkinson’s disease, hypothyroidism and common traits such as freckling. CureTogether’s infrastructure and user base—which span some 500 medical conditions—should only make such patient-driven research easier.
“There are tremendous opportunities for our members and for future research by integrating the 23andMe and the CureTogether platforms and phenotypic data,” CureTogether cofounder Daniel Reda, who will now serve as 23andMe’s senior product manager, said in a statement.
23andMe will face competition, though. PatientsLikeMe, Quantified Self and DIYgenomics are just a few of the community portals that now facilitate crowdsourced biomedical research. “Participatory health initiatives are becoming part of the public health ecosystem,” Melanie Swan, the founder of DIYgenomics, wrote in a study published earlier this year the Journal of Medical Internet Research.
Two years ago, Nature Medicine profiled one such participatory health startup called Genomera (see ‘Personalized investigation’ from our September 2010 issue). At the time, chief executive Greg Biggers was just developing the Palo Alto, California-based company’s platforms. But in the intervening years, Biggers has been busy tweaking the cloud-based software, testifying before the Presidential Commission for the Study of Bioethical Issues about amateurs participating in research and helping academics, as well as lay users, run analyses on his website.
Now, Biggers says his goal of a prospective, longitudinal study that can yield scientifically valid results has almost been achieved. Currently, the site hosts an ongoing study that is examining the effects of whole-fat butter on human cognition. (Biggers declined to share more details from the study on his beta site.)
“Since the first study we helped orchestrate [on vitamin B metabolism], we have proven two important items,” he says. “That participant-driven research is credible and productive, and that Internet study operations bring efficiency and scale to the world of health research.”
That’s a message that still has some skeptics in the ivory towers of most universities, but it doesn’t seem to have escaped 23andMe.
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. 
but it’s not possible to track LRRK2 activity in the brain, making the search for targeted therapies against the disease challenging. In a new study, researchers now provide evidence for a way to measure LRRK2 activity—and a new compound that can block the damaging effects of the protein in rodent neurons.
