Peeling away pancreatic cancers' defenses

A combination immunotherapy approach that gets through pancreatic cancers’ extra Read more

Immune cell activation in severe COVID-19 resembles lupus

In severe cases of COVID-19, Emory researchers have been observing an exuberant activation of B cells, resembling acute flares in systemic lupus erythematosus (SLE), an autoimmune disease. The findings point towards tests that could separate some COVID-19 patients who need immune-calming therapies from others who may not. It also may begin to explain why some people infected with SARS-CoV-2 produce abundant antibodies against the virus, yet experience poor outcomes. The results were published online on Oct. Read more

Muscle cell boundaries: some assembly required

The worm C elegans gives insight into muscle cell assembly + architecture Read more

autism

Fragile X: $8 million NIH grant supports next-generation neuroscience

Supported by a $8 million, five-year grant, an Emory-led team of scientists plans to investigate new therapeutic approaches to fragile X syndrome, the most common inherited intellectual disability and a major single-gene cause of autism.

Fragile X research represents a doorway to a better understanding of autism, and learning and memory. The field has made strides in recent years. Researchers have a good understanding of the functions of the FMR1 gene, which is silenced in fragile X syndrome.

Still, clinical trials based on that understanding have been unsuccessful, highlighting limitations of current mouse models. Researchers say the answer is to use “organoid” cultures that mimic the developing human brain.

The new grant continues support for the Emory Fragile X Center, first funded by the National Institutes of Health in 1997. The Center’s research program includes scientists from Emory as well as Stanford, New York University, Penn and the University of Southern California. The Emory Center will be one of three funded by the National Institutes of Health; the others are at Baylor College of Medicine and Cincinnati Children’s Hospital Medical Center.

The co-directors for the Emory Fragile X Center are Peng Jin, PhD, chair of human genetics, and Stephen Warren, PhD, William Patterson Timmie professor and chair emeritus of human genetics. In the 1980s and 1990s, Warren led an international team that discovered the FMR1 gene and the mechanism of trinucleotide repeat expansion that silences the gene. This explained fragile X syndrome’s distinctive inheritance pattern, first identified by Emory geneticist Stephanie Sherman, PhD.

“Fragile X research is a consistent strength for Emory, stretching across several departments, based on groundbreaking work from Steve and Stephanie,” Jin says. “Now we have an opportunity to apply the knowledge we and our colleagues have gained to test the next generation of treatments.”

Fragile X researchers from three Emory departments, following COVID-19 spacing guidelines in the laboratory. From left to right: Peng Jin, Gary Bassell, Zhexing Wen and Nisha Raj.

Looking ahead, a key element of the Center’s research will involve studying the human brain in “disease in a dish” models, says Gary Bassell, PhD, chair of cell biology. Nisha Raj, PhD, a postdoctoral fellow in Bassell’s lab, has been studying how FMR1 regulates localized protein synthesis at the brain’s synapses.

“What we’re learning is that there may be different RNA targets in human and mouse cells,” he says. “There’s a clear need to regroup and incorporate human cells into the research.”

Microscope images of fragile X human brain organoids, courtesy of Zhexing Wen. Green represents cytoplasmic Nestin while red represents nuclear Sox2; both are markers for neural progenitor cells.
Microscope image of fragile X human brain organoids, courtesy of Zhexing Wen. Green represents cytoplasmic Nestin while red represents nuclear Sox2; both are markers for neural progenitor cells. 

Center investigator Zhexing Wen, PhD, has developed techniques for culturing brain organoids (image above), which reproduce features of human brain development in miniature. Wen, assistant professor of psychiatry and behavioral sciences, cell biology and neurology at Emory, has used organoids to model other disorders, such as schizophrenia and Alzheimer’s disease. 

The organoids are formed from human brain cells, coming from induced pluripotent stem cells, which are in turn derived from patient-donated tissues. Emory’s Laboratory of Translational Cell Biology, directed by Bassell, has developed several lines of induced pluripotent stem cells from fragile X syndrome patients.

“All of the investigators are sharing these valuable resources and collaborating on multiple projects,” Bassell says.

Principal investigators in the Emory Fragile X Center are Jin, Warren, Bassell, and Wen, along with Eric Klann, PhD at New York University, Lu Chen, PhD, and 2013 Nobel Prize winner Thomas Südhof, MD. Chen and Südhof are neuroscientists at Stanford.

Co-investigators include biostatistician Hao Wu, PhD and geneticist Emily Allen, PhD at Emory, neuroscientist Guo-li Ming, MD, PhD, at University of Pennsylvania, and biomedical engineer Dong Song, PhD, at University of Southern California.
 
Allen, Warren and Jin are part of an additional grant to Baylor, Emory and University of Michigan investigators, who are focusing on FXTAS (fragile X-associated tremor-ataxia syndrome) and FXPOI (fragile X-associated primary ovarian insufficiency). These are conditions that affect people with fragile X premutations.

Fragile X syndrome is caused by a genetic duplication on the X chromosome, a “triplet repeat” in which a portion of the gene (CGG) gets repeated again and again. Fragile X syndrome affects about one child in 5,000, and is more common and more severe in boys. It often causes mild to moderate intellectual disabilities as well as behavioral and learning challenges. About a third of children affected have characteristics of autism, such as problems with eye contact, social anxiety, and delayed speech. 
 
The award for the Emory Fragile X Center is administered by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, with funding from the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke.

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Fragile X files — expanded

A genetic disorder caused by silencing of a gene on the X chromosome, fragile X syndrome affects about one child in 5,000, and is more common and more severe in boys. It often causes mild to moderate intellectual disabilities as well as behavioral and learning challenges.

Amy Talboy, MD

The gene responsible for fragile X syndrome, the most common inherited form of intellectual disability, was identified more than 25 years ago. Emory genetics chair Stephen Warren played a major role in achieving that milestone. His work led to insights into the molecular details of learning and memory, and nationwide clinical trials — which have a more complicated story.

Treating the molecular basis of a neurodevelopmental disorder, instead of simply addressing symptoms, is a lofty goal – one that remains unfulfilled. Now a new study, supported by the National Institute of Neurological Disorders and Stroke, is reviving a pharmacological strategy that Warren had a hand in developing.

“This is a very well thought out approach to studying changes in language and learning in children who are difficult to test,” says Amy Talboy, medical director of Emory’s Down Syndrome and Fragile X clinics, who is an investigator in the NINDS study. “It could change how we conduct these types of studies in the future.” Read more

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MSCs: what’s in a name?

At a recent symposium of cellular therapies held by the Department of Pediatrics, we noticed something. Scientists do not have consistent language to talk about a type of cells called “mesenchymal stem cells” or “mesenchymal stromal cells.” Within the same symposium, some researchers used the first term, and others used the second.

Guest speaker Joanne Kurtzberg from Duke discussed the potential use of MSCs to treat autism spectrum disorder, cerebral palsy, and hypoxic-ischemic encephalopathy. Exciting stuff, although the outcomes of the clinical studies underway are still uncertain. In these studies, the mesenchymal stromal cells (the language Kurtzberg used) are derived from umbilical cord blood, not adult tissues.

Nomenclature matters, because a recent editorial in Nature calls for the term “stem cell” not to be used for mesenchymal (whatever) cells. They are often isolated from bone marrow or fat. MSCs are thought have the potential to become cells such as fibroblasts, cartilage, bone and fat. But most of their therapeutic effects appear to come from the growth factors and RNA-containing exosomes they secrete, rather than their ability to directly replace cells in damaged tissues.

The Nature editorial argues that “wildly varying reports have helped MSCs to acquire a near-magical, all-things-to-all-people quality in the media and in the public mind,” and calls for better characterization of the cells and more rigor in clinical studies.

At Emory, gastroenterologist Subra Kugathasan talked about his experience with MSCs in inflammatory bowel diseases. Hematologist Edwin Horwitz discussed his past work with MSCs on osteogenesis imperfecta. And Georgia Tech-based biomedical engineer Krishnendu Roy pointed out the need to reduce costs and scale up, especially if MSCs start to be used at a higher volume.

Several of the speakers were supported by the Marcus Foundation, which has a long-established interest in autism, stroke, cerebral palsy and other neurological conditions.

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Oxytocin receptor levels predict comforting behavior in prairie voles

Different levels of a receptor for a hormone involved in social bonding may explain individual variation in offering comfort during stressful situations. Like humans, animals console each other in times of distress: monkeys hug and kiss, and prairie voles groom each other.

James Burkett, PhD

James Burkett, PhD

Emory postdoc James Burkett described his research on voles at a press conference on “The Neuroscience of Emotion and Social Behavior” at the Society for Neuroscience meeting in San Diego on Sunday. Here are Video (Burkett’s part is roughly from 4:50 to 9:00) and the scientific abstract.

Burkett’s presentation, on oxytocin-dependent comforting behavior in prairie voles, outlined an extension of his graduate work with Larry Young at Yerkes National Primate Research Center, which was published in Science in January 2016 and impressed oxytocin skeptic Ed Yong. Burkett, now in Gary Miller’s laboratory at Rollins School of Public Health, also masterminded a Reddit “Ask me anything” in February.

The rest of the Society for Neuroscience press release:

Previous research indicates oxytocin—a hormone that promotes social and maternal bonding—acts in the anterior cingulate cortex (ACC) of the prairie vole brain to encourage consoling behavior. In humans, the ACC activates when people see others in pain. Some degree of personal distress motivates comforting behaviors, but too much actually makes animals (including humans, chimpanzees, and rats) less likely to offer comfort.

Read more

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Revisiting landmark folate-autism study

Geneticist Joe Cubells is doing some monumental work re-examining a Chinese study of folic acid supplementation during pregnancy and its impact on autism risk. He is also the Medical Director at the Emory Autism Center. Please see SFARI to check it out.

 

 

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Socialization relative strength in fragile X longitudinal study

A study published in Pediatrics this week tracks “adaptive behavior” as children and adolescents with fragile X syndrome are growing up. This is the largest longitudinal study to date in fragile X, which is the leading inherited cause of intellectual disability and the leading single-gene risk factor for autism spectrum disorder.

Adaptive behavior covers a range of everyday social and practical skills, including communication, socialization, and completing tasks of daily living such as getting dressed. In this study, socialization emerged as a relative strength in boys with fragile X, in that it did not decline as much as the other two domains of adaptive behavior measured: communication and daily living skills.

The lead author of the paper is Cheryl Klaiman, formerly of the Stanford University Center for Interdisciplinary Brain Sciences, now senior psychologist at Marcus Autism Center.

The “socialization as relative strength in fragile X” findings meshes with a growing awareness in the autism field, summarized nicely here by Jessica Wright at the Simons Foundation Autism Research Initiative, that fragile X syndrome symptoms are often distinct from those in autism spectrum disorder.

One key distinction between the disorders, for example, is in social interactions. Children with autism and those with fragile X syndrome both shy away from social contact, have trouble making friends and avert their gaze when people look at them.

But children with fragile X syndrome often sneak a peek when the other person turns his back, researchers say. Children with autism, in contrast, seem mostly uninterested in social interactions.

“Children with fragile X syndrome all have very severe social anxiety that plays a big role in the perception that they have autism,” says Stephen Warren, professor of human genetics at Emory University School of Medicine in Atlanta. “They are actually interested in their environment; they are just very shy and anxious about it.”

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Personalized molecular medicine part 2

This is a continuation of the post from last week on the early-onset epilepsy patient, whom doctors were able to devise an individualized treatment for. The treatment was based on Emory research on the molecular effects of a mutation in the patient’s GRIN2A gene, discovered through whole exome sequencing.*

For this patient, investigators were able to find the Ray Ban Baratas cause for a previously difficult to diagnose case, and then use a medication usually used for Alzheimer’s disease (memantine) to reduce his seizure frequency.

Last week, I posed the question: how often do we move from a disease-causing mutation to tailored treatment? Read more

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Fragile X clinical trial update

A recent issue of Emory Health magazine had an article describing the progress of clinical trials for fragile X syndrome, the most common inherited cause of intellectual disability. The article included interviews with the parents of a boy, Samuel McKinnon, who is participating in one of the phase III clinical trials here at Emory.

Last week, results for the phase II study for the same medication were published in Science Translational Medicine. The drug, called STX209 or arbaclofen, is one of the first designed to treat the molecular changes in the brain caused by fragile X syndrome. STX209 shows some promise in its ability to reduce social withdrawal, a key symptom of fragile X syndrome.

In one case, a boy was able to attend his birthday party for the first time in his life. In the past, he had been too shy and couldn’t tolerate hearing people sing Happy Birthday to You, the study’s lead author Elizabeth Berry-Kravis, MD, PhD from Rush University, told USA Today.

These results have generated excitement among autism researchers and specialists, because a fraction of individuals with fragile X mutations have autism and the same drug strategy may be able to address deficits in other forms of autism.

Some caveats:
1. Autism and fragile X are not the same thing.
2. This was a phase II study, the phase III results are yet to come.
3. The study authors are up front about saying that the “primary endpoint” (irritability) showed no difference between drug and placebo.

A team led by Emory genetics chair Steve Warren identified the gene responsible for fragile X in 1991, and Emory scientists have been important players in figuring out its effects on the brain.

Warren and colleague Mika Kinoshita are co-authors on a companion paper in STM on treatment of fragile X mice. A thoughtful review piece in the same issue of STM lays out current issues in developing therapies for “childhood disorders of the synapse.”

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Autism linked to hundreds of spontaneous genetic mutations

Emory genetic researchers Daniel Moreno De Luca, Christa Lese Martin and David Ledbetter were part of a team that produced a landmark result in autism genetics. The team identified hundreds of regions of the genome where spontaneous mutations are implicated in autism. Spontaneous mutations are those that arise for the first time in an individual, rather than being inherited from parents.

Christa Lese Martin, PhD

The team was led by Matthew State at Yale, and their results were published in the journal Neuron. Moreno De Luca discussed the topic in Spanish on a recent edition of the NPR program Science Friday. The June 10 segment was focused on autism genetics.

The team made an intriguing finding on a segment of chromosome 7. Deletion of the region is associated with Williams syndrome, where individuals can exhibit “striking verbal abilities, highly social personalities and an affinity for music.” Duplication of the same region, they found, is associated with autism.

Daniel Moreno De Luca, MD MSc

Companion studies also shed light on the question of why boys are more likely to develop autism than girls, and begin to outline a network of genes whose activity is altered in the brains of individuals with autism.

Ledbetter is now chief scientific officer at Geisinger Health in Pennsylvania.

 

 

 

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Links between autism and epilepsy

An article in the April 2011 issue of Nature Medicine highlights the mechanistic overlap between autism and epilepsy.

By studying how rare genetic conditions known to coincide with both epilepsy and autism—such as Rett syndrome, fragile X syndrome and tuberous sclerosis—unfold at an early age, neuroscientists are finding that both disorders may alter some of the same neural receptors, signaling molecules and proteins involved in the development of brain cell synapses.

Gary Bassell, PhD

Emory cell biologist Gary Bassell and his colleagues have been taking exactly this approach. Recently they published a paper in Journal of Neuroscience, showing that the protein missing in fragile X syndrome, FMRP, regulates expression of an ion channel linked to epilepsy. This could provide a partial explanation for the link between fragile X syndrome and epilepsy.

The Nature Medicine article also mentions a drug strategy, targeting the mTOR pathway, which Bassell’s group has been exploring with fragile X syndrome.

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