Can blood from coronavirus survivors save the lives of others?

Donated blood from COVID-19 survivors could be an effective treatment in helping others fight the illness – and should be tested more broadly to see if it can “change the course of this pandemic,” two Emory pathologists say. The idea of using a component of survivors’ donated blood, or “convalescent plasma,” is that antibodies from patients who have recovered can be used in other people to help them defend against coronavirus. Emory pathologists John Roback, MD, Read more

Targeting metastasis through metabolism

Research from Adam Marcus’ and Mala Shanmugam’s labs was published Tuesday in Nature Communications – months after we wrote an article for Winship Cancer Institute’s magazine about it. So here it is again! At your last visit to the dentist, you may have been given a mouth rinse with the antiseptic chlorhexidine. Available over the counter, chlorhexidine is also washed over the skin to prepare someone for surgery. Winship researchers are now looking at chlorhexidine Read more

Immunotherapy combo achieves reservoir shrinkage in HIV model

Stimulating immune cells with two cancer immunotherapies together can shrink the size of the viral “reservoir” in SIV-infected nonhuman primates treated with antiviral drugs. Important implications for the quest to cure HIV, because reservoir shrinkage has not been achieved consistently Read more

Neuro

NINDS supporting Emory/UF work on myotonic dystrophy

A collaboration we wrote about back in 2017, between Emory cell biology chair Gary Bassell and University of Florida neurogeneticist Eric Wang, is taking off.

The National Institute of Neurological Disorders and Stroke has awarded Bassell’s and Wang’s laboratories $2.2 million over five years to examine the neuronal function of Muscleblind-like proteins, which play key roles in myotonic dystrophy.

Gary Bassell and Eric Wang have been collaborating on myotonic dystrophy research

The classic symptom for myotonic dystrophy is having trouble releasing one’s grip on a doorknob, but it is a multi-system disorder, caused by expanded DNA triplet or quadruplet repeats. RNA from the expanded repeats is thought to bind and sequester Muscleblind-like proteins, leading to an impaired process of RNA splicing.

Bassell says the project is expected to clarify how Muscleblind-like proteins regulate RNA localization in neurons and also identify therapeutic targets. In recent years, the DM research community has been paying increasing attention to neurologic symptoms.

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Traynelis lead researcher on CureGRIN/Chan Zuckerberg award

Congratulations to the CureGRIN Foundation, which was recently awarded a capacity-building grant from the Chan Zuckerberg Initiative’s Rare as One Network. The Chan Zuckerberg Initiative is giving 30 patient advocacy groups such as CureGRIN $450,000 each over two years.

CureGRIN works closely with Emory pharmacologist Stephen Traynelis, who has been investigating rare genetic disorders affecting NMDA receptors, which play key roles in memory, learning and neuronal development. When NMDA receptor function is perturbed by mutations, symptoms appear in infancy or early childhood, usually including epilepsy and developmental delay.

For the grant, Traynelis is named as the lead researcher for the CureGRIN Foundation, with Tim Benke of Children’s Hospital Colorado as lead clinician. Traynelis is director of the Center for Functional Evaluation of Rare Variants, which hosted a gathering at Emory Conference Center that brought together several GRIN-oriented patient advocacy groups in September 2019.

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Neurodegeneration accelerated by intestinal bacteria?

An influential theory about the anatomical trajectory of Parkinson’s disease is getting a microbial boost. The idea, first proposed by neuroanatomist Heiko Braak in 2003, is that pathology and neurodegeneration start in the intestines and then travel to the brain. See this article in Scientific American for background.

Illustration showing neurons with Lewy bodies, depicted as small red spheres, which are deposits of aggregated proteins in brain cells

Timothy Sampson, in Emory’s Department of Physiology, was first author on a recent paper in eLife, which explores the idea that prion-like proteins produced by intestinal bacteria can accelerate the aggregation of similar proteins found in our cells. The findings suggest that interventions targeting intestinal bacteria could modulate neurodegeneration.

Sampson, a former Emory graduate student who did postdoctoral work in Sarkis Mazmaniam’s lab at Caltech, says he will continue the project here. He and his colleagues were looking at the interaction between a bacterial protein called Curli – involved in adhesion + biofilms — and the aggregation-prone mammalian protein alpha-synuclein, known as a main component of the Lewy body clumps seen in Parkinson’s. The experiments were in a mouse model of Parkinson’s neurodegeneration, in which human alpha-synuclein is overproduced.

Looking ahead, Sampson says he is interested in what signals from the microbiome may trigger, accelerate or slow synuclein aggregation. He’s also looking at where in the GI tract synuclein begins to aggregate, possibly facilitated by particular cells in the intestine, and whether the observations with alpha-synuclein hold true for other proteins such as amyloid-beta in Alzheimer’s.

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More NMDA but less excitotoxicity? Now possible

Emory pharmacologists have discovered a new class of potential drugs that might allow them to have their cake and eat it too — with reference to NMDA receptors, important control sites in the brain for learning and memory.

Many researchers have wanted to enhance NMDA receptor signals to treat disorders such as schizophrenia. But at the same time, they need to avoid killing neurons with “excitotoxicity”, which comes from excess calcium entering the cell. Excitotoxicity is thought to be a major mechanism of cell death in stroke and traumatic brain injury.

Usually more sensitivity to NMDA activation and excess calcium go hand in hand. In a new Nature Chemical Biology paper, pharmacologist Stephen Traynelis and colleagues have identified a group of compounds that allow them to separate those two aspects of NMDA signaling.

These compounds appear to selectively decrease how much calcium (as opposed to sodium) flows through the NMDA ion channel. Traynelis says that the discovery opens up pharmacological possibilities for NMDA receptors similar to those for other receptor classes that are prominent drug targets, such as G-protein coupled receptors and acetylcholine receptors. With such receptors, the drugs are called “biased agonists” or “biased modulators” because they shift the balance of how the ion channel responds.

For NMDA receptors, how these newly identified compounds work on a molecular level needs to be explored, and could lead to the long-standing goal of NMDA-based neuroprotection for treatment of stroke/TBI, the authors note. Postdoc Riley Perszyk is first author, with cell biologist Gary Bassell and chemists Dennis Liotta and Lanny Liebeskind as co-authors.

Traynelis discussed this research in his Hodgkin Huxley Katz Prize Lecture to the Physiology 2019 conference in Scotland in December 2019 (the part about the new class of NMDA modulators starts at about 20 minutes).

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Probing visual memory at leisure

Emory Brain Health researchers have developed a computer program that passively assesses visual memory. An infrared eye tracker monitors eye movements, while the person being tested views a series of photos.

This approach, relatively unstrenuous for those whose memory is being assessed, is an alternative for the diagnosis of mild cognitive impairment or Alzheimer’s disease. It detects degeneration of the regions of the brain that govern visual memory (entorhinal cortex/hippocampus), which are some of the earliest to deteriorate.

The approach was published in Learning and Memory last year, but bioinformatics chair Gari Clifford discussed the project at a recent talk, and we felt it deserved more attention. First author Rafi Haque is a MD/PhD student in the Neuroscience program, with neurology chair/Goizueta ADRC director Allan Levey as senior author.

Eye tracking of people with MCI and Alzheimer’s shows they spend less time checking the new or missing element in the critical region of the photo, compared with healthy controls. Adapted from Haque et al 2019.

The entire test takes around 4 minutes on a standard 24 inch monitor (a follow-up publication on an iPad version is in the pipeline). Photos are presented twice a few minutes apart, and the second time, part of the photo is missing or new – see diagram above. Read more

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Setting the goalposts for ALS clinical trials

In the fight against a relentless neurodegenerative disease such as ALS (amyotrophic lateral sclerosis), a critical question for research is: what is the definition of success?

Emory neurologists, with advice from other experts, have created a new disability rating scale for ALS. This is a set of questions patients or their caregivers answer to gauge how much ALS is eroding someone’s ability to manage daily life. The researchers think it can become a resource for testing new treatments for ALS in clinical trials.

The research used to develop the new rating scale was published on December 30 in JAMA Neurology. The rating scale itself will be available on the Emory ALS Center web site.

ALS’s attack on motor neurons makes it progressively more difficult to accomplish tasks such as household chores, daily hygiene, and eventually speaking and eating. Some patients live a year or two after diagnosis, some live ten.

Christina Fournier, MD

“If our goal in clinical trials is to have that decline happen more slowly, how we measure it matters,” says lead author Christina Fournier, MD, assistant professor of neurology at Emory University School of Medicine and co-director of Emory’s ALS Center.

Update: see Fournier’s comments to Medscape/Reuters Health here.

The current standard outcome measure is the ALSFRS-R (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised). While widely accepted in the field, the ALSFRS-R has some uneven aspects, or nonlinear weighting, which become problems when it is used to determine drug approval.

One example: a patient’s score will decline 3 points if they change from climbing stairs normally to holding a handrail, and will decline the same amount if they change from normal dressing and hygiene to being unable to dress or perform hygiene tasks without assistance. So 3 points can represent small or large changes in their lives. Also, the ALSFRS-R can change depending on symptom management, rather than underlying biology.

To put this in perspective, the most recent drug to be approved by the FDA (edaravone) displayed an effect size of 2.5 points – and the same drug faced resistance from European regulators. According to the Wall Street Journal, about 20 drugs are in clinical testing for ALS and 5 are in the late stages of development. Read more

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Hedgehog pathway outside cilia

Emory geneticist Tamara Caspary is an expert on the Hedgehog pathway, critical for brain development. In particular, she and her colleagues have been studying a gene that is part of the Hedgehog pathway called Arl13b, which is mutated in Joubert syndrome, affecting development of the cerebellum and brain stem.

The Arl13b protein was known to be enriched in primary cilia, tiny hair-like cellular structures with a signaling/navigation function in neuronal development. However Caspary’s lab, in a collaboration with Frederic Charron’s group in Montreal, has found that Arl13b can also function outside cilia: in axons and growth cones.

The Hedgehog pathway has several roles, some in specifying what embryonic cells will become, and others in terms of guiding growing axons, the scientists conclude in their new paper in Cell Reports.

“Arl13b regulates Shh [Sonic Hedgehog] signaling through two mechanisms: a cilia-associated one to specify cell fate and a cilia localization-independent one to guide axons,” they write.  A related preprint, confirming Arl13b’s extra-ciliary role in mouse development, has been posted on bioRxiv.

 

 

 

 

 

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Opioids: crunching the Tweets

Posts on publicly available social media platforms such as Twitter contain a huge volume of information about the declared activities and transient whims of millions of people. Within this unruly pile of data, there may be clues that could help public health researchers track opioid users and issues affecting them.

Abeed Sarker from Emory’s Department of Biomedical Informatics recently published a paper in JAMA Network Open on his analysis of Twitter posts about opioid use. The paper was featured in Popular Science.

Sarker and colleagues from Penn trained a machine learning algorithm on a subset of posts about opioid use, so that the algorithm could analyze a larger body of tweets. They found that Twitter posts about opioids in Pennsylvania, classified by the algorithm, matched the rates of overdose deaths and rates of opioid use measured through national surveys. Their aim is to be able to spot patterns of overdoses faster than prescription drug monitoring programs.

“The findings suggest that automatic processing of social media data, combined with geospatial and temporal information, may provide close to real-time insights into the status and trajectory of the opioid epidemic,” the authors write.

Read more

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Stage fright: don’t get over it, get used to it

Stage fright: don’t get over it, get used to it, advises Emory neuroscientist Anwesha Banerjee in her recent talk at TEDx Decatur. Many can feel empathy with the situation Banerjee describes. It was her first public presentation eight years ago, facing “a room full of scientists, who for whatever reason, did not look very happy that day.”

“What if I fail in front of the crowd? What if everybody thinks I’m an idiot?”

That feeling of scrutiny might have an evolutionary relationship to the fear of being eaten by a predator, she speculates.

Through participating in Toastmasters International, she has made public speaking more of a habit. She contrasts the two parts of the brain: the amygdala, tuner of emotional responses, with the basal ganglia, director of habits.

“I still get stage fright,” she says. “In fact, I have it right now, thinking how all you predators might try to eat me up! But my brain pays less attention to it.”

Banerjee is a postdoctoral scientist in cell biologist Gary Bassell’s lab, studying myotonic dystrophy. In 2017, she was funded by the Myotonic Dystrophy Foundation to create a mouse model of the neurological/sleep symptoms of myotonic dystrophy.

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Designer drugs as tools for studying brain development in non-human primates

To investigate the functions of regions within the brain, developmental neuroscience studies have often relied on permanent lesions. As an alternative to permanent lesions, scientists at Yerkes National Primate Research Center sought to test whether chemogenetic techniques could be applied to produce a transient inhibition of the amygdala, well known for regulating emotional responses, in infant non-human primates.

Their findings were recently published online by eNeuro, an open access journal of the Society for Neuroscience.

Amygdala — image from NIMH

Chemogenetics is a way of engineering cells so that they selectively respond to designer drugs, which have minimal effects elsewhere in the brain. It involves injection of a viral vector carrying genes encoding receptors responsive to the designer drug – in this case, clozapine-N-oxide, a metabolite of the antipsychotic clozapine. The technique has mostly been tested in rodents.

“This proof-of-principle study is the first to demonstrate that chemogenetic tools can be used in young infant nonhuman primates to address developmental behavioral neuroscience questions,” says Jessica Raper, PhD, first author of the eNeuro paper and a research associate at Yerkes. “Considering its reversibility and reduced invasiveness, this technique holds promise for developmental studies in which more invasive techniques cannot be employed.” Read more

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