March for Science ATL: photos

Emory scientists and supporters of science were out in substantial numbers Saturday at the March for Science Atlanta in Candler Park. March organizers, many of whom came from the Emory research community, say they want to continue their advocacy momentum and community-building after the event’s Read more

How race + TBI experience affect views of informed consent

The upcoming HBO movie of The Immortal Life of Henrietta Lacks reminds us that biomedical research has a complex legacy, when it comes to informed consent and people of color. A paper from Emory investigators touches on related issues important for conduct of clinical research Read more

Fecal transplant replants microbial garden

Emory physicians explain how FMT (fecal microbiota transplant) restores microbial balance when someone’s internal garden has been Read more

Neuro

Maturing brain flips function of amygdala in regulating stress hormones

In contrast to evidence that the amygdala stimulates stress responses in adults, researchers at Yerkes National Primate Research Center, Emory University have found that the amygdala has an inhibitory effect on stress hormones during the early development of nonhuman primates.

The results are published this week in Journal of Neuroscience.

The amygdala is a region of the brain known to be important for responses to threatening situations and learning about threats. Alterations in the amygdala have been reported in psychiatric disorders such as depression, anxiety disorders like PTSD, schizophrenia and autism spectrum disorder. However, much of what is known about the amygdala comes from research on adults.

“Our findings fit into an emerging theme in neuroscience research: that during childhood, there is a switch in amygdala function and connectivity with other brain regions, particularly the prefrontal cortex,” says Mar Sanchez, PhD, neuroscience researcher at Yerkes and associate professor of psychiatry and behavioral sciences at Emory University School of Medicine. The first author of the paper is postdoctoral fellow Jessica Raper, PhD.

Some notable links on the amygdala:

*An effort to correct simplistic views of amygdala as the “fear center” of the brain

*Collection of papers mentioning patient SM, an adult human with an amygdala lesion

*Recent Nature Neuroscience paper on amygdala’s role in appetite control

*Evidence for changing amygdala-prefrontal connectivity in humans during development Read more

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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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Debunking detour to DNA

Debunking the idea that most humans only use 10 percent of our brains, which is a starting point for the Scarlett Johansson/Luc Besson movie Lucy, was popular last week.
Many media outlets and popular Web sites took on this task. Emory’s Krish Sathian – known for his work on rehabilitation, how the brain processes sensory experiences and how we understand metaphors – does an able job of it in the video below.

But a related question is still a matter of debate: how much of our DNA do we “use”? This is an important question for geneticists because it seeks to define the most productive mutation hunting grounds.

A study published in PLOS Genetics last week concluded that just 8.2 percent of the human genome is constrained during evolution and is likely to be “functional”. The press release on this paper pointed out sharply that this contrasts with the more expansive analysis from the multinational ENCODE project, which assigned some biochemical function to 80 percent of the human genome.

Read more

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Anti-inflammatory drug prevents neuron loss in Parkinson’s model

A lot of evidence has piled up suggesting that inflammation plays a big role in the progression of Parkinson’s.

Immune system genes are linked to disease risk. People who regularly take NSAIDs such as ibuprofen have lower risk. Microglia, the immune system’s ambassadors to the brain, have been observed in PD patients.

Malu Tansey and her postdoc CJ Barnum make a convincing case for an anti-inflammatory — specifically, anti-TNF– therapy to Parkinson’s. They’ve been working with the Michael J. Fox Foundation for Parkinson’s Research to push this promising approach forward. Please check it out.

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Rare disease diagnosis, accelerated by social media

Seth Mnookin’s long piece in the New Yorker, on how social media accelerated the diagnosis of several children with a rare genetic disorder, is getting a lot of praise this week. This is the same story that was on CNN.com in March, titled “Kids who don’t cry”, and that Emory Genetics Laboratory director Madhuri Hedge mentioned as a recent diagnostic success for the technique of whole exome sequencing.

Briefly: parents of or doctors treating several children with a previously unknown metabolic disorder, with multiple symptoms — absent tear production, developmental delay, movement deficits, digestive problems etc — found each other via Internet searches/blog posts. The problems were traced back to mutations in the NGLY1 gene.

Emory geneticists Michael Gambello, Melanie Jones (now at the Greenwood Genetic Center in South Carolina) and Hegde are co-authors on the Genetics in Medicine paper that lays everything out scientifically.

Gambello, Jones and Hegde were responsible for sequencing the DNA of a North Georgia family (they live in Jackson County), whose members are mentioned in Mnookin’s piece. The Gambello lab is developing an animal model of NGLY1 deficiency and is studying the mechanisms of how NGLY1 deficiency affects brain development.

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Parkinson’s drug discovery: visit the dopamine container store

In a recent PNAS paper, Gary Miller and colleagues at Rollins School of Public Health outline a potential therapeutic approach to Parkinson’s disease that I’m going to call the Container Store approach.

If you have a mess in your kitchen or basement workshop, you might need more or better containers to hold your tools. Analogously, problems in Parkinson’s disease can be traced back to a lack of effective containers for the brain communication chemical dopamine.

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Beyond the usual suspects among Alzheimer’s proteins

If you’ve been paying attention to Alzheimer’s disease research, you’ve probably read a lot about beta-amyloid. It’s a toxic protein fragment that dominates the plaques that appear in the brains of people with Alzheimer’s. Many experimental therapies for Alzheimer’s target beta-amyloid, but so far, they’ve not proven effective.

That could be for several reasons. Maybe those treatments started too late to make a difference. But an increasing number of Alzheimer’s researchers are starting to reconsider the field’s emphasis on amyloid. Nature News has a feature this week explaining how the spotlight is shifting to the protein ApoE, encoded by the gene whose variation is responsible for the top genetic risk factor for Alzheimer’s.

In line with this trend, Emory’s Alzheimer’s Disease Research Center recently received a five-year, $7.2 million grant to go beyond the usual suspects like beta-amyloid. Emory will lead several universities in a project to comprehensively examine proteins altered in Alzheimer’s. You’ve heard of the Cancer Genome Atlas? Think of this as the Alzheimer’s Proteome Atlas, potentially addressing the same kind of questions about which changes are the drivers and which are the passengers.

Emory’s back-to-basics proteomics approach has already yielded some scientific fruit, uncovering changes in proteins involved in RNA splicing and processing. Also, the Nature feature also has some background on a clinical trial called TOMMORROW, which Emory’s ADRC is participating in.

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Monitoring the brain’s temperature

It’s been a little while since we had an Intriguing Image. This video illustrates a surgical technique for the treatment of medication-resistant temporal lobe epilepsy.

In this procedure, which is designed to minimize cognitive side effects, the surgeon carefully uses a laser probe to heat and ablate the regions of the brain doctors think are important for seizures. Magnetic resonance imaging allows the temperature in the brain to be precisely monitored. The video was provided by Robert Gross, MD, PhD, and accompanies an upcoming paper in the journal Neurosurgery. More discussion of this procedure here and here.

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Progesterone could become tool vs glioblastoma

The hormone progesterone could become part of therapy against the most aggressive form of brain cancer. High concentrations of progesterone kill glioblastoma cells and inhibit tumor growth when the tumors are implanted in mice, researchers have found.

The results were recently published in the Journal of Steroid Biochemistry and Molecular Biology.

Glioblastoma is the most common and the most aggressive form of brain cancer in adults, with average survival after diagnosis of around 15 months. Surgery, radiation and chemotherapy do prolong survival by several months, but targeted therapies, which have been effective with other forms of cancer, have not lengthened survival in patients fighting glioblastoma.

The lead author of the current paper is assistant professor of emergency medicine Fahim Atif, PhD. The findings with glioblastoma came out of Emory researchers’ work on progesterone as therapy for traumatic brain injury and more recently, stroke. Atif, Donald Stein and their colleagues have been studying progesterone for the treatment of traumatic brain injury for more than two decades, prompted by Stein’s initial observation that females recover from brain injury more readily than males. There is a similar tilt in glioblastoma as well: primary glioblastoma develops three times more frequently in males compared to females.

These results could pave the way for the use of progesterone against glioblastoma in a human clinical trial, perhaps in combination with standard-of-care therapeutic agents such as temozolomide. However, Stein says that more experiments are necessary with grafts of human tumor cells into animal brains first. His team identified a factor that may be important for clinical trial design: progesterone was not toxic to all glioblastoma cell lines, and its toxicity may depend on whether the tumor suppressor gene p53 is mutated.

Atif, Stein, and colleague Seema Yousuf found that low, physiological doses of progesterone stimulate the growth of glioblastoma tumor cells, but higher doses kill the tumor cells while remaining nontoxic for healthy cells. Similar effects have been seen with the progesterone antagonist RU486, but the authors cite evidence that progesterone is less toxic to healthy cells. Progesterone has also been found to inhibit growth of neuroblastoma cells (neuroblastoma is the most common cancer in infants), as well as breast, ovarian and colon cancers in cell culture and animal models.

 

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Valproate: epigenetic solvent

Oncologist Johann Brandes and colleagues from Winship Cancer Institute have a recent study on the preventive effects of valproate, now prescribed for epilepsy and bipolar disorder, against head and neck cancer.

Published in Cancer, it was a clever example of number crunching, using data from the Veterans’ Administration. If you want to know about the anticancer effects of a widely used drug, check who’s already taking it for another reason (25,000 veterans were taking it). The results suggest that valproate – OR a drug that works with a similar mechanism – might be used to prevent head and neck cancer in patients who are at high risk. Also see this related paper from Brandes and colleagues on chemoprevention in lung cancer.

However, any examination of valproate should take into account neurologist Kim Meador’s work on antiepileptic drugs taken by pregnant women — he was at Emory for several years but recently moved to Stanford. His work with the NEAD study definitively showed that valproate, taken during pregnancy, increases the risk of birth defects and intellectual disability in children.

There’s even more about valproate: it might help tone-deaf adults learn to differentiate musical tones, according to one study. It has been used to enhance the reprogramming of somatic cells into induced pluripotent stem cells. It seems that valproate just shakes things up, turning on genes that have been off, erasing decisions that cells have already made.

Valproate is a tricky drug, with several modes of action: it blocks sodium channels, enhances the effects of the inhibitory neurotransmitter GABA, and inhibits histone deacetylases. Although the first two may be contributing to the antiepileptic effects, the last one may be contributing to longer-lasting changes. Histone deacetylases are a way a cell keeps genes turned off; inhibit them and you loosen things up, allowing the remodeling of chromatin and unearthing genes that were silenced.

In tumors, genes that prevent runaway growth are silenced. It may be that valproate is loosening chromatin enough to allow the growth control machinery to reemerge, although the effects observed in the Brandes paper are specific for head and neck cancer, and not other forms of cancer. The data suggest that valproate has a preventive effect with respect to smoking-related cancers and not viral-related cancers.

With adults at high risk of cancer recurrence, side effects from valproate may be more acceptable than in other situations. Even so, with follow-up research, it may be possible to isolate where the anticancer effects of valproate come from – that is, which histone deacetylase in particular is responsible – find a more specific drug, and avoid potential broad side effects.

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