Category Archives: Neuroscience/mental health

Neuroscience/mental health

Q&A: How the Brain Activity Map came together—and what its proponents hope to achieve

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{credit}Laura Luongo{/credit}

It was a single tweet. On 12 February, after US President Barack Obama made a subtle nod to a new neuroscience project in his annual State of the Union address, Francis Collins, director of the country’s National Institutes of Health (NIH), posted on the @NIHDirector Twitter feed: “Obama mentions the #NIH Brain Activity Map in #SOTU.” Instantly, scientists were buzzing with rumors that the Brain Activity Map could be the next moon shot, with a budget and timeline similar to the Human Genome Project.

The brain map began as a brief white paper and has grown into a large—and still largely undefined—collaboration of several government agencies, nonprofit foundations and private companies. As the stakeholders describe in a commentary slated to be published later this month, the goal of the initiative is to understand how thousands of neurons work in concert to control behavior and trigger disease. Miyoung Chun, vice president for science programs at The Kavli Foundation in Oxnard, California, has been developing the project since the beginning and is the self-described “glue” between its many diverse stakeholders. Chun (pictured) spoke with Virginia Hughes about the evolution of the project and what it might mean for biomedicine.

Were you surprised that President Obama mentioned the Brain Activity Map during his speech?

Absolutely. I had no idea that he was going to mention the project. All of us scientists who have been working so hard and talking about this issue for the past 18 months, we were writing emails to each other, we were calling each other, shouting, jumping. We were like, “Wow, he knows about this project? That’s amazing!”

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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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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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‘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.”

Depression has become leading cause of disability burden amongst US and Canadian teens

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The recent tragedy in Newtown, Connecticut, perpetrated by 20 year-old Adam Lanza, has intensified the discussion about how mental health is handled and documented in the US. Officials have not provided information about Lanza’s motivation and state of mind, and many are rightfully quick to point out that it is wrong to equate mental illness with the fatal sociopathic actions of a small group of individuals. The conversation about access to mental health care should, however, take into account new data showing an increasing contribution of mental and behavioral disorders to deterioration in the health-related quality of life among teenagers in the US and Canada over the last two decades, and increases elsewhere around the globe.

The estimation of ‘years lived with disabilities’, or YLDs, is used as a collective metric to determine how much a particular disorder deprives the population of healthy years of life during a particular window of time. In 2010 just as in 1990, depression ranked as the number two contributor of YLDs, affecting 4% of the global population, eclipsed only by back pain that affected almost 10% of population worldwide. Among 10 to 14 year olds, the top contributor worldwide is iron deficiency. Asthma had been the largest contributor to YLDs for youths in that age range in the US and Canada in 1990, but the study published in The Lancet on Thursday led by researchers at the Institute of Health Metrics and Evaluation (IHME) at the University of Washington in Seattle showed that depression surpassed asthma to claim the number one spot in this group in 2010. Among this cohort, the collective number of ‘years lost to disability’ grew from about 140,000 in 1990 to almost 180,000 in 2010, a 30% increase. Notably, global figures for the same age group show that the number of years lost to disability from depression grew from 4.9 million in 1990 to 5.5 million in 2010, a 13% increase as shown in the graphs below.

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Newly identified compound can thwart protein implicated in Parkinson’s disease

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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 dean of 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 in Nature Medicine showed 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:

Image courtesy of Shutterstock

Lithium experiment in ‘Down syndrome’ mice casts light on human trials

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Worldwide, one in about 1,000 newborns is diagnosed with Down syndrome, a genetic disorder predominantly caused by an extra copy of chromosome 21—also known as trisomy 21—and in countries such as the US the number of children affected by the condition appears to be increasing. No medicines can currently treat the memory and learning impairments seen in Down syndrome; a new study published today in the Journal of Clinical Investigation could offer insight into the cellular pathways to target to improve cognitive function.

In the study, Italian researchers report that a one-month lithium treatment promotes the growth of new neurons in the hippocampus and improves cognitive functions in an animal model of Down syndrome. The team, led by neuroscientist Laura Gasparini at the Italian Institute of Technology in Genoa, took advantage of the fact that mice with an extra copy of chromosome 16 demonstrate cognitive impairment and neuronal dysfunction similar to that seen in trisomy 21. “We hypothesized that stimulating the growth of new neurons in this mouse model will benefit cognitive function in Down syndrome,” Gasparini says.

The scientists gave the genetically engineered mice lithium—a drug already used to treat mood disorders in people. Previous studies, including one in 2010 in these mice, have shown that lithium increases the production of new brain cells in a region know as the hippocampus, which has a key role in memory. In their experiment, Gasparini and her colleagues measured the expression of a marker, doublecortin (DCX), which is present on the surface of newly formed neurons.

At the end of the one month treatment, the ‘Down syndrome’ mice who received lithium had approximately 3,500 cells in the hippocampus expressing DCX, about the same number as that seen in healthy mice without the condition. By comparison, those mice with the trisomy mutation that received saline solution only had about 1,500 cells expressing DCX, indicating that they had about 40% fewer newly formed neurons. Additionally, trisomic mice that received lithium treatment performed much better than their untreated counterparts on the behavioral assessments designed to test their contextual learning by fear conditioning, spatial memory and object discrimination.

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Sangamo tries its hand with zinc fingers for Huntington’s

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NEW ORLEANS — Sangamo BioSciences, the Richmond, California company that has sped ahead with engineered ‘zinc fingers’, is pointing to these proteins as a powerful tools in treating an ever-increasing list of illnesses. Clinicians at the Glandular Disease Research Clinic in San Antonio, Texas, began testing Sangamo’s first therapeutic in 2006, in individuals with diabetic neuropathy, but this was halted in 2011 at the end of phase 2 clinical trials because there was insufficient evidence of its efficacy. At present, the company is involved in on-going clinical trials of zinc fingers for glioblastoma and HIV. It hopes to eventually add Huntington’s disease to that roster, thanks to encouraging data from tests on cells. But the ease of applying the zinc finger approach to diseases affecting the brain presents a more challenging endeavor.

At the root of Huntington’s disease is a specific type of mutation, called a trinucleotide repeat expansion, in the Huntingtin (Htt) gene. The normal Htt gene contains up to 28 copies of the nucleotide sequence CAG, but this expands to more than 40 copies in the disease-causing allele. As a result of the expanded repeat, insoluble clumps of the Huntingtin protein accumulate inside neurons, causing cell death that leads to uncontrollable movements, dementia and, ultimately, death. Patients with between 28 and 35 repeats are unaffected, while those with between 36 and 40 have a form of the disease with reduced penetrance.

In animal models, reducing mutant Htt protein levels prevents disease progression and reverses some symptoms. However, most therapeutic approaches in development lower both versions of the huntingtin protein (the one produced by the normal gene, and the one made by the mutated gene). This has raised concerns about their safety for human use, because the normal protein has important, albeit as yet unknown, cellular function.

To overcome this, Sangamo researchers have developed zinc finger transcriptional repressors that specifically target the mutant Htt allele and block its expression while preserving near-normal expression levels of the normal allele. Zinc fingers are naturally occurring protein segments that recognize and bind to specific DNA sequences, typically regulating the output of a given gene. Using genetic engineering, the Sangamo researchers designed zinc finger proteins containing a DNA-binding site that recognizes the prolonged tricnucleotide repeat found in the mutant Htt gene. They then fused this binding site to a protein domain that recruits other molecules that zip closed the chromosomal region containing the Htt gene with the expanded repeat—thus hindering production of mutated huntingtin protein.

In a recent experiment in a lab dish, the group added the engineered zinc fingers to fibroblast cells obtained from six people with Huntington’s disease. This lowered production of the mutant protein by more than 90%, while reducing the amount of the normal protein by just 10% or less, the researchers reported at the annual meeting of the Society for Neuroscience, held here this week. “There was very potent discrimination between the mutant and normal alleles in cells from all six patients, even though each contained mutant alleles of different lengths,” explains Phillip Gregory*, chief scientific officer at Sangamo BioSciences. “The next step is to make that sure they operate at a broad range of doses, and then we need to move into animal studies of efficacy and safety.”

This is the first attempt to apply the zinc finger approach to Huntington’s disease, and the researchers eventually aim to deliver genes for the zinc finger proteins directly into the brain using adeno-associated viral vectors*, which are already being used to successfully deliver therapeutic genes into the brains of people with Parkinson’s disease in clinical trials.

“This is very promising and exciting work,” says Sarah Tabrizi, a professor at the Institute of Neurology in London, who was not involved in the study, “but it’s still at a very early and exploratory stage, and it’s a big jump going from cells in culture to the human brain.” One challenge is that targeting viral vectors to specified brain areas and then ensuring their proper distribution is difficult, and this is further complicated by the fact that Huntington’s disease begins in deep brain structures before spreading to the cerebral cortex. “Distributing the vector will be a challenge,” Tabrizi says, “but I don’t think it’s insurmountable.”

*Correction: The first version of this post incorrectly stated that the chief scientific officer at Sagamo BioSciences is Phillip Gordon, and that Sangamo are planning to use adenovirus vectors to deliver therapeutic genes into the brain.

First US stem cell trial for autistic children launches today

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Families with autistic children must navigate a condition where questions outnumber the answers, and therapies remain sparse and largely ineffective. A clinical trial being conducted by the Sutter Neuroscience Institute in Sacramento, California to address this situation began recruiting participants today for a highly experimental stem cell therapy for autism. The institute plans to find 30 autistic children between ages 2 and 7 with cord blood banked at the privately-run Cord Blood Registry, located about 100 miles west of the institute.

Already one other clinical trial, with 37 total participants between ages 3 and 12 years old, has been completed in China. The researchers affiliated with Beike Biotechnology in Shenzhen, the firm that sponsored the study, have not yet published any papers from that the trial, which used stem cells from donated cord blood. Mexican researchers are currently recruiting kids for yet another type of autism stem cell trial that will harvest cells from the participant’s fat tissue.

But for each of these officially registered trials, many more undocumented stem cell therapy treatments take place for clients who are willing to pay enough. “Our research is important because many people are going to foreign countries and spending a lot of money on therapy that may not be valid,” says Michael Chez, a pediatric neurologist and lead investigator of the study at Sutter.

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Laboratory dye repurposed against protein clumps found in Huntington’s disease

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A compound already sitting on the shelves of biomedical laboratories and emergency room supply closets seems to interrupt the formation of neurodegenerative protein clumps found in Huntington’s disease, according to a preliminary animal study published today in the Journal of Neuroscience.

This versatile agent, called methylene blue, gets a mention in medical literature as early as 1897 and was used to treat, at one time or another, ailments ranging from malaria to cyanide poisoning. The US Food and Drug Administration has never formally approved it as a therapy for any illnesses. But that fact hasn’t stopped biomedical researchers from tinkering with the agent’s apparent ability to improve cognitive function. And although the new paper out today relies on a Huntington’s disease model in flies and mice, scientists are hopeful. “Because of existing knowledge of methylene blue and the fact that it’s not harmful to humans, I would hope that progress toward clinical trials could go relatively quickly,” says Leslie Thompson, a neurobiologist at University of California–Irvine and lead author on the new study.

Huntington’s disease occurs when the C-A-G sequence of DNA base pairs repeat too often on the HTT gene, resulting in an abnormally long version of the huntingtin protein, that therefore folds incorrectly and forms clumps in the brain. The illness usually begins to affect people in their 30s and 40s, causing movement problems and early death. No drug is currently available to stop the disease from progressing.

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