Quinn Eastman

Big data with heart, for psychiatric disorders

Imagine someone undergoing treatment by a psychiatrist. How do we know the treatment is really working or should be modified?

To assess whether the patient’s condition is objectively improving, the doctor could ask him or her to take home a heart rate monitor and wear it continuously for 24 hours. An app connected to the monitor could then track how much the patient’s heart rate varies over time and how much the patient moves.

Heart rate variability can be used to monitor psychiatric disorders

MD/PhD student Erik Reinertsen is the first author on two papers in Physiological Measurement advancing this approach, working under the supervision of Gari Clifford, interim chair of Emory’s Department of Biomedical Informatics.

Clifford’s team has been evaluating heart rate variability and activity as a tool for monitoring both PTSD (post-traumatic stress disorder) and schizophrenia. Clifford says his team’s research is expanding to look at treatment-resistant depression and other mental health issues.

For clinical applications, Clifford emphasizes that his plans focus on tracking disease severity for patients who are already diagnosed, rather than screening for new diagnoses. His team is involved in much larger studies in which heart rate data is being combined with physical activity data from smart watches, body patches, and clinical questionnaires, as well as other behavioral and exposure data collected through smartphone usage patterns.

Intuitively, heart rate variability makes sense for monitoring PTSD, because one of the core symptoms is hyperarousal, along with flashbacks and avoidance or numbness. However, it turns out that the time that provides the most information is when heart rate is lowest and study participants are most likely asleep, or at their lowest ebb during the night.

Home sleep tests generate a ton of information, which can be mined. This approach also fits into a trend for wearable medical technology, recently highlighted in STAT by Max Blau (subscription needed).

The research on PTSD monitoring grows out of work by cardiologists Amit Shah and Viola Vaccarino on heart rate variability in PTSD-discordant twin veterans (2013 Biological Psychiatry paper). Shah and Vaccarino had found that low frequency heart rate variability is much less (49 percent less) in the twin with PTSD. Genetics influences heart rate variability quite a bit, so studying twins allows those factors to be accounted for. Read more

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Unlocking schizophrenia biology via genetics

Kristen Thomas, PhD, now a postdoctoral fellow at St Jude Children’s Research Hospital

Schizophrenia genetics and its complexities are beginning to yield to large genome-wide studies. One of the recently identified top risk loci, miR 137, can be seen as a master key that unlocks other doors. The Mir 137 locus encodes a micro RNA that regulated hundreds of other genes, and several of those are also linked to schizophrenia.

Earlier this month, Emory’s chair of cell biology Gary Bassell and former graduate student Kristen Thomas published a paper in Cell Reports analyzing how perturbing Mir 137 affects signaling in neurons. Inhibiting Mir 137 blocked neurons’ responses to neuregulin and BDNF, well-known growth factors.

“We think a particularly interesting aspect of our paper is that it links miR137, neuregulin and ErbB4 receptor: three molecules with known genetic risk for schizophrenia,” Bassell writes. Read more

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Brain circuitry linked to social connection and desire to cuddle

Guest post from Neuroscience graduate student Amielle Moreno.

Why do scientists know more about the brain during fear than love? Behaviors such as startling and freezing in response to a fearful stimulus are rapid, vary little between subjects, and are easy to interpret. Things get messy when individuals show variability. Social behavior, like intimate partner selection and mating, has a lot of variability. To researchers willing to explore the neuroscience of love and mating, the stage is set for major discoveries.

A recent research study published in Nature from the Liu and Young laboratories at Emory and Yerkes uncovered a dynamic conversation between two brain regions during intimate behavior. The new findings in prairie voles explore the brain connections behind social connections. Read more

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Drug discovery: Alzheimer’s and Parkinson’s spurred by same enzyme

Alzheimer’s disease and Parkinson’s disease are not the same. They affect different regions of the brain and have distinct genetic and environmental risk factors.

But at the biochemical level, these two neurodegenerative diseases start to look similar. That’s how Emory scientists led by Keqiang Ye, PhD, landed on a potential drug target for Parkinson’s.

Keqiang Ye, PhD

In both Alzheimer’s (AD) and Parkinson’s (PD), a sticky and sometimes toxic protein forms clumps in brain cells. In AD, the troublemaker inside cells is called tau, making up neurofibrillary tangles. In PD, the sticky protein is alpha-synuclein, forming Lewy bodies. Here is a thorough review of alpha-synuclein’s role in Parkinson’s disease.

Ye and his colleagues had previously identified an enzyme (asparagine endopeptidase or AEP) that trims tau in a way that makes it both more sticky and more toxic. In addition, they have found that AEP similarly processes beta-amyloid, another bad actor in Alzheimer’s, and drugs that inhibit AEP have beneficial effects in Alzheimer’s animal models.

In a new Nature Structural and Molecular Biology paper, Emory researchers show that AEP acts in the same way toward alpha-synuclein as it does toward tau.

“In Parkinson’s, alpha-synuclein behaves much like Tau in Alzheimer’s,” Ye says. “We reasoned that if AEP cuts Tau, it’s very likely that it will cut alpha-synuclein too.”

A particular chunk of alpha-synuclein produced by AEP’s scissors can be found in samples of brain tissue from patients with PD, but not in control samples, Ye’s team found.

In control brain samples AEP was confined to lysosomes, parts of the cell with a garbage disposal function. But in PD samples, AEP was leaking out of the lysosomes to the rest of the cell.

The researchers also observed that the chunk of alpha-synuclein generated by AEP is more likely to aggregate into clumps than the full length protein, and is more toxic when introduced into cells or mouse brains. In addition, alpha-synuclein mutated so that AEP can’t cut it is less toxic. Read more

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Winship summer scholars glimpse the future

Guest post from Megan McCall at Winship Cancer Institute. It is not very often that a high school student has the opportunity to work in a lab or clinic shadowing a world-renowned doctor, but for the past six weeks, ten Georgia high schoolers have done just that at Winship Cancer Institute.

Summer scholars in Medical Simulation Lab. Photo by Megan McCall.

The Summer Scholars Research Program, now in its 16th year, exposes students to a multitude of experiences, such as research from Winship’s top experts, lectures by doctors from a variety of specialties, and field trips to Grady Memorial Hospital and the Centers for Disease Control and Prevention. The students have also seen different parts of Emory’s campus through visits to the School of Medicine’s Medical Simulation Lab and the Health Sciences Research Library.

The SSRP pairs each student with an oncologist with whom they complete their own research project and get an in-depth look at a specific cancer specialty. The program will culminate on Friday (8:30 am to 12:30 pm, C5012) with the students presenting their projects to an audience of their peers, mentors, and the Winship community.

“Our goal with this program is to engage scholars at a young age and promote their interest in cancer research. I view this program as a critical part of my work and as a critical piece of Winship’s mission,” says program director Jonathon Cohen, MD. “The SSRP is a unique opportunity for Winship researchers to interact with some of the brightest young people out there, many of whom we hope to consider as colleagues in the future.”

The students attend weekly lectures with a wide array of speakers including oncologists, cancer survivors, and statisticians. Guest lecturer and 10-year cancer survivor Carolyn Higgins says, “It is wonderful to see such a fresh example of today’s future doctors.”

Posted on by Quinn Eastman in Cancer Leave a comment

Seeing the nuts and bolts of neurons

Cool photo alert! James Zheng’s lab at Emory is uncommonly good at making photos and movies showing how neurons remodel themselves. They recently published a paper in Journal of Cell Biology showing how dendritic spines, which are small protrusions on neurons, contain concentrated pools of G-actin.

Actin, the main component of cells’ internal skeletons, is a small sturdy protein that can form long strings or filaments. It comes in two forms: F-actin (filamentous) or G-actin (globular). It is not an exaggeration to call F- and G-actin neurons’ “nuts and bolts.”

Think of actin monomers like Lego bricks. They can lock together in regular structures, or they can slosh around in a jumble. If the cell wants to build something, it needs to grab some of that slosh (G-actin) and turn them into filaments. Remodeling involves breaking down the filaments.

At Lab Land’s request, postdoc and lead author Wenliang Lei picked out his favorite photos of neurons, which show F-actin in red and G-actin in green. Zheng’s lab has developed probes that specifically label the F- and G- forms. Where both forms are present, such as in the dendritic spines, an orange or yellow color appears.

Why care about actin and dendritic spines?

*The Journal of Cell Biology paper identified the protein profilin as stabilizing neurons’ pool of G-actin. Profilin is mutated in some cases of ALS (amyotrophic lateral sclerosis), although exactly how the mutations affect actin dynamics is now under investigation.

Read more

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Gene editing reverses Huntington’s in mouse model

Disrupting a problematic gene in brain cells can reverse Huntington’s disease pathology and motor symptoms in a mouse model of the inherited neurological disorder, Emory scientists report.

The researchers used CRISPR/Cas9 gene editing, delivered by a viral vector, to snip part of a gene producing toxic protein aggregates in the brains of 9-month old mice. Weeks later, where the vector was applied, aggregated proteins had almost disappeared. In addition, the motor abilities of the mice had improved, although not to the level of control mice.

The results were published June 19, 2017 in Journal of Clinical InvestigationEncouraging Tweet from Scripps MD/author Eric Topol.

The findings open up an avenue for treating Huntington’s as well as other inherited neurodegenerative diseases, although more testing of safety and long-term effects is needed, says senior author Xiao-Jiang Li, MD, PhD, distinguished professor of human genetics at Emory University School of Medicine.

Huntington’s disease is caused by a gene encoding a toxic protein (mutant huntingtin or mHTT) that causes brain cells to die. Symptoms commonly appear in mid-life and include uncontrolled movements, balance problems, mood swings and cognitive decline.

Touted widely for its potential, CRISPR/Cas9 gene editing has not been used to treat any neurodegenerative disease in humans. Several concerns need to be addressed before its use, such as effective delivery and the safety of tinkering with DNA in brain cells. A similar approach, but using a different technology (zinc finger nucleases), was reported for Huntington’s disease in 2012.  Read more

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Urine tests for prostate cancer could reduce biopsies

In the prostate cancer field, there has been a push to move beyond PSA testing. With urine tests, it may be possible to avoid biopsies for men with suspected prostate cancer.

Martin Sanda, MD is chair of urology and leads Winship’s prostate cancer program

With PSA testing to guide decisions, only one in five men is found via biopsy to have a cancer that is sufficiently aggressive (Gleason score of 7 or higher) to warrant treatment right away.

A recently published paper in JAMA Oncology from urologist Martin Sanda and colleagues in the NCI’s Early Detection Research Network shows the potential of urine testing. Sanda’s team reports that two prostate cancer RNA biomarkers detectable in urine (PCA3 and T2:ERG) could be combined to enhance their discriminatory power and reduce unnecessary biopsies by almost half.

The National Cancer Institute’s Cancer Currents blog has an extensive discussion of the JAMA Oncology paper. Read more

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Mitochondrial blindness — Newman’s Emory story

Neuro-ophthalmologist Nancy Newman’s 2017 Dean’s Distinguished Faculty Lecture and Award were unexpectedly timely. Her talk on Tuesday was a tour of her career and mitochondrial disorders affecting vision, culminating in a description of gene therapy clinical trials for the treatment of Leber’s hereditary optic neuropathy.

The sponsor of those studies, Gensight Biologics, recently presented preliminary data on a previous study of their gene therapy at the American Academy of Neurology meeting in April. Two larger trials (REVERSE and RESCUE) are ongoing.

Despite all the progress, there are still several puzzles connected with mitochondrial diseases affecting vision and particularly Leber’s, the first human disease linked to mitochondrial DNA mutations by Douglas Wallace at Emory in the 1980s.

Newman called Leber’s an “ideal laboratory” for studying mitochondrial diseases of vision, because deterioration of vision in Leber’s tends to happen to one eye first, presenting a window of opportunity to deliver treatment to the other eye. Read more

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IMSD program nurtures young scientists

Guest post from Megan McCall, who works at Winship Cancer Institute. Thanks Megan!

On a Thursday afternoon this past semester, a diverse group of 50 students were listening to a lecture on the art of storytelling by Eladio Abreu, a lecturer in the Biology department. This was an unusual topic for these students, but they sat enrapt, not distracted by cell phones or laptops.

Eladio Abreu, PhD

The weekly seminar was part of the Emory Initiative to Maximize Student Development (IMSD) program, aimed at the professional development of undergraduate and graduate students in STEM fields. What sets this program apart is its commitment to increase diversity in the biological, biomedical and behavioral sciences by nurturing students who may be underrepresented in these fields. IMSD’s associate director Amanda James says the program includes some of Emory’s strongest students.

The two-year, NIH-funded research program has three main goals: preparing undergraduate students for doctoral programs in STEM fields, nurturing graduate students during their matriculation into Emory’s Ph.D. programs and increasing diversity through mentoring. They accomplish these goals by connecting undergraduates and graduates through mentorship, seminars, and career coaching, says Keith Wilkinson, IMSD director and vice-chair of the Department of Biochemistry.

(from left) Lina Jowhar, Max Cornely, Chayla Vazquez, and Jamie Guillen at an Initiative to Maximize Student development meeting.

This meeting included updates from students on their summer research plans. Answers ranged from epidemiology research with a children’s hospital in Philadelphia, to influenza research at Johns Hopkins. In addition to weekly seminars, IMSD offers classes aimed at increasing success post-graduation, workshops for career development, and pathways to funded research, a rare commodity for undergraduates. Students who can’t do funded research may use resources that IMSD offers to find other opportunities.

Lina Jowhar is an undergraduate who started the program in her third year at Emory. She is engaged in research on cystic fibrosis, a genetic disorder of the lungs, and she values the weekly meetings, particularly Abreu’s lecture on the art of storytelling. “I love his interactive teaching style,” she says. “He was comfortable letting us know that he changed the examples in his PowerPoint to include Biggie and Tupac which showed me how important it is to connect with your audience.” Read more

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