Exosomes as potential biomarkers of radiation exposure

Exosomes = potential biomarkers of radiation in the Read more

Before the cardiologist goes nuclear w/ stress #AHA17

Measuring troponin in CAD patients before embarking on stress testing may provide Read more

Virus hunting season open

Previously unknown viruses, identified by Winship + UCSF scientists, come from a patient with a melanoma that had metastasized to the Read more

Atlanta Clinical and Translational Science Institute

Threading the RSV needle: live attenuated vaccine effective in animals

Crafting a vaccine against RSV (respiratory syncytial virus) has been a minefield for 50 years, but scientists believe they have found the right balance.

A 3-D rendering of a live-attenuated respiratory syncytial virus (RSV) particle, captured in a near-to-native state by cryo-electron tomography. Surface glycoproteins (yellow) are anchored on the viral membrane (cyan), with ribonucleoprotein complexes inside (red). Image courtesy of Zunlong Ke and Elizabeth Wright.

Researchers at Emory University School of Medicine and Children’s Healthcare of Atlanta have engineered a version of RSV that is highly attenuated – weakened in its ability to cause disease – yet potent in its ability to induce protective antibodies.

The researchers examined the engineered virus using cryo-electron microscopy and cryo-electron tomography techniques, and showed that it is structurally very similar to wild type virus. When used as a vaccine, it can protect mice and cotton rats from RSV infection.

The results were published this morning in Nature Communications.

“Our paper shows that it’s possible to attenuate RSV without losing any immunogenicity,” says senior author Martin Moore, PhD, associate professor of pediatrics at Emory University School of Medicine and a Children’s Healthcare of Atlanta Research Scholar. “This is a promising live-attenuated vaccine candidate that merits further investigation clinically.”

The next steps for this vaccine are to produce a clinical grade lot and conduct a phase 1 study of safety and immunogenicity in infants, Moore says. Read more

Posted on by Quinn Eastman in Immunology Leave a comment

Deep dive into NMDA receptor variation

The study of human genetics has often focused on mutations that cause disease. When it comes to genetic variations in healthy people, scientists knew they were out there, but didn’t have a full picture of their extent. That is changing with the emergence of resources such as the Exome Aggregation Consortium or ExAC, which combines sequences for the protein-coding parts of the genome from more than 60,000 people into a database that continues to expand.

ajhg-fig-2-092016

Rare mutations in the NMDA receptor genes cause epilepsy (GRIN2A) or intellectual disability (GRIN2B). Shown in blue are agonist binding domains of the receptors, where several disease-causing mutations can be found.

At Emory, the labs of Stephen Traynelis and Hongjie Yuan have published an analysis of ExAC data, focusing on the genes encoding two NMDA receptor subunits, GRIN2A and GRIN2B. These receptors are central to signaling between brain cells, and rare mutations in the corresponding genes cause epilepsy (GRIN2A) or intellectual disability (GRIN2B). GRIN2B mutations have also been linked with autism spectrum disorder.

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Steve Traynelis and Hongjie Yuan

The new paper in the American Journal of Human Genetics makes a deep dive into ExAC data to explore the link between normal variation in the healthy population and regions of the proteins that harbor disease-causing mutations.

In addition, the paper provides a detailed look at how 25 mutations that were identified in individuals with neurologic disease actually affect the receptors. For some patients, this insight could potentially guide anticonvulsant treatment with a repurposed Alzheimer’s medication. Also included are three new mutations from patients identified by whole exome sequencing, one in GRIN2A and two in GRIN2B.

“This is one of the first analyses like this, where we’re mapping the spectrum of variation in a gene onto the structure of the corresponding protein,” says Traynelis, PhD, professor of pharmacology at Emory University School of Medicine. “We’re able to see that the disease mutations cluster where variation among the healthy population disappears.”

Heat map of agonist binding domain for GRIN2A.

Heat map of agonist binding domain for GRIN2A. From Swanger et al AJHG (2016).

Postdoctoral fellow Sharon Swanger, PhD is first author of the paper, and Yuan, MD, PhD, assistant professor of pharmacology, is co-senior author.

It’s not always obvious, looking at the sequence of a given mutation, how it’s going to affect NMDA receptor function. Only introducing the altered gene into cells and studying protein function in the lab provides that information, Traynelis says.

NMDA receptors are complicated machines: mutations can affect how well they bind their ligands (glutamate and glycine), how they open and shut, or how they are processed onto the cell surface. On top of that complexity, mutations that make the receptors either stronger or weaker can both lead the brain into difficulty; within each gene, both types of mutation are associated with similar disorders. With some GRIN2A mutations, the functional changes identified in the lab were quite strong, but the effect on the brain was less dramatic (mild intellectual disability or speech disorder), suggesting that other genetic factors contribute to outcomes.

Clinical relevance

Traynelis and Yuan previously collaborated with the NIH’s Undiagnosed Disease Program to show that the Alzheimer’s medication memantine can be repurposed as an anticonvulsant, for a child with intractable epilepsy coming from a mutation in the GRIN2A gene. (Nature Communications, Annals of Clinical and Translational Neurology)

Memantine is an NMDA receptor antagonist, aimed at counteracting the overactivation of the receptor caused by the mutation. Memantine has also been used to treat children with epilepsy associated with mutations in the related GRIN2D gene. However, memantine doesn’t work on all activating mutations, and could have effects on the unmutated NMDA receptors in the brain as well. Traynelis reports that his clinical colleagues are developing guidelines for physicians on the use of memantine for children with GRIN gene mutations.

This study and related investigations were supported by funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD082373), the National Institute of Neurological Disorders and Stroke (R24NS092989), the Atlanta Clinical & Translational Science Institute (UL1TR000454), and CURE Epilepsy: Citizens United for Research in Epilepsy.

 

Posted on by Quinn Eastman in Neuro 2 Comments

Following lupus troublemaker cells, via DNA barcodes

People with systemic lupus erythematosus can experience a variety of symptoms, such as fatigue, joint pain, skin rashes and kidney problems. Often the symptoms come and go in episodes called flares. In lupus, the immune system goes haywire and produces antibodies that are directed against the body itself.

The immune system can produce many types of antibodies, directed against infectious viruses (good) or against human proteins as in lupus (harmful). Each antibody-secreting cell carries a DNA rearrangement that reflects the makeup of its antibody product. Scientists can use the DNA to identify and track that cell, like reading a bar code on an item in a supermarket.

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Iñaki Sanz, MD is a Georgia Research Alliance Eminent Scholar, director of the Lowance Center for Human Immunology and head of the Rheumatology division in the Department of Medicine.

Postdoc Chris Tipton, GRA Eminent Scholar Iñaki Sanz and colleagues at Emory have been using these DNA bar codes to investigate some fundamental questions about lupus: where do the autoantibody-producing cells come from? Are they all the same?

Their findings were published in Nature Immunology in May, and a News and Views commentary on the paper calls it “a quantum advance in the understanding of the origin of the autoreactive B cells.” It’s an example of how next-generation sequencing technology is deepening our understanding of autoimmune diseases.

The Emory team obtained blood samples from eight patients experiencing lupus flares and compared them to eight healthy people who had recently been vaccinated against influenza or tetanus.

When the immune system is responding to something it’s seen before, like when someone receives a booster vaccine, the bar codes of the antibody-producing cells look quite similar to each other. A set of just a few antibody-producing cells multiply and expand, making what looks like clones. In contrast, the researchers found that in lupus, many different cells are producing antibodies. Some of the expanded sets of cells are producing antibodies against infectious agents.

“We expected to see an expansion of the cells that produce autoantibodies, but instead we saw a very broad expansion of cells with all types of specificities,” Tipton says.

To use a Star Wars analogy: a booster vaccine response looks like the Clone Wars (oligoclonal — only a few kinds of monsters), but a lupus flare looks like a visit to Mos Eisley cantina (polyclonal — many monsters). Read more

Posted on by Quinn Eastman in Immunology Leave a comment

Subset of plasma cells display immune ‘historical record’

You may have read about recent research, published in Science, describing a technique for revealing which viruses have infected someone by scanning antiviral antibodies in the blood.

Emory immunologists have identified corresponding cells in which long-lived antibody production resides. A subset of plasma cells keep a catalog of how an adult’s immune system responded to infections decades ago, in childhood encounters with measles or mumps viruses.

The results, published Tuesday, July 14 in Immunity, could provide vaccine designers with a goalpost when aiming for long-lasting antibody production.

“If you’re developing a vaccine, you want to fill up this compartment with cells that respond to your target antigen,” says co-senior author F. Eun-Hyung Lee, MD, assistant professor of medicine at Emory University School of Medicine and director of Emory Healthcare’s Asthma, Allergy and Immunology program.

The findings could advance investigation of autoimmune diseases such as lupus erythematosus or rheumatoid arthritis, by better defining the cells that produce auto-reactive antibodies.

Lee says that her team’s research on plasma cells in humans provided insights unavailable from mice, since mice don’t live as long and their plasma cells also have a different pattern of protein markers. More here.

Posted on by Quinn Eastman in Immunology Leave a comment

Personalized Medicine Day in Georgia

Governor Nathan Deal was joined by Ambassador Andrew Young, Georgia State Representative Calvin Smyre and Leroy Hood, founder of the Institute of Systems Biology, in formally proclaiming September 1, 2011 Personalized Medicine Awareness Day in the State of Georgia.

Georgia Governor Nathan Deal presents Morehouse School of Medicine’s Dean and Executive Vice President, Valerie Montgomery Rice, MD, with a state proclamation declaring Sept. 1, 2011 Personalized Medicine Awareness Day in Georgia.

The event at Morehouse School of Medicine (MSM) was sponsored by Georgia Bio; the Atlanta Clinical & Translational Science Institute (ACTSI, which is funded by the NIH and led by Emory University with partners MSM and Georgia Tech); and Iverson Genetics, Inc.

“The collaboration within the ACTSI between these three research universities is an important undertaking and an example of how it should be done,” remarked Governor Deal as he kicked off the day’s program.

A visionary in the personalized medicine field, Dr. Hood developed the DNA gene sequencer and synthesizer and the protein synthesizer and sequencer – four instruments that paved the way for the successful mapping of the human genome.

During his keynote address he proposed a revolution in medicine.  P4 Medicine – Predictive, Preventive, Personalized and Participatory – is a proactive (instead of a reactive) approach to medicine. The paradigm change will drive radical changes in science.

For P4 medicine to succeed, a cross-disciplinary culture with team science and new approaches to educating scientists, as is done through the ACTSI, has to take place. Dr. Hood predicts the human genome will be part of individual medical records in 10 years.

Leroy Hood, MD, PhD

“The vision of P4 medicine is that each patient will be surrounded by a virtual cloud of billions of data points. Advances in science and technology will reduce this enormous data dimensionality to simple hypotheses about human health and disease,” says Hood.

“The ultimate outcome is to create individualized patient disease models that are predictive and actionable. The shift to P4 Medicine will also require societal changes.”

Personalized Medicine Awareness Day celebrated the first-of-its-kind personalized medicine study, approved by the Centers for Medicare and Medicaid Services. The study will determine the utility of genetic testing in calculating doses and reducing the incidence of adverse events associated with the initiation of Warfarin therapy. Warfarin is the world’s leading anti-blood clotting drug.

Researchers hope the study will provide data to demonstrate that individualizing treatment can improve patient safety and reduce healthcare costs, says Dean Sproles, CEO of Iverson Genetics, Inc., which is collaborating in the study with MSM and the ACTSI.

Governor Deal congratulated the ACTSI for leading the landmark Warfarin study with Iverson and is “proud that Georgia will be leading the effort.”

The Warfarin Study is led by ACTSI Senior Co-Principal Investigator Elizabeth Ofili, MD, MPH, director of the Clinical Research Center, chief of cardiology and associate dean for clinical research at MSM, and will engage 50 sites across the country and 7,000 participants. The first participant was recently enrolled at Grady Memorial Hospital.

“This study should help us understand how to use each patient’s genetic information to deliver a safer and more effective dose,” says Ofili.

Sproles noted, “The study is evidence of the growing role of genetics in helping doctors to develop optimal individual treatments for their patients.”

A panel including Emory medical leaders David Stephens, Fred Sanfilippo and Kenneth Brigham discussed and addressed questions like how to communicate ‘big science’ to the individual, how to move genetic testing to medical outcomes and who owns genome data.

“Personalized Medicine is the future,” stated Governor Deal. The presence of Governor Deal, Ambassador Young and Representative Smyre is a sign that policymakers are beginning to recognize that personalized medicine is not just a vision for better healthcare; it has the power to improve health and reduce healthcare costs.

Posted on by Holly Korschun in Uncategorized 1 Comment

Dr. Kutner Receives Award for Excellence in Public Health

Michael Kutner

Michael Kutner, PhD, the recipient of the 2011 Charles R. Hatcher, Jr, MD Award

The Rollins School of Public Health is on a 35-year trajectory that dreams are only made of. What began as a small working group tasked with formulating a strategic plan for Emory’s school of public health, evolved into a Masters of Community Health program (MCH) and degree in 1975. Finally, in 1990, Emory approved the public health school, the university’s first new school in 71 years. Michael Kutner, PhD has been there every step of the way, and as a result is the recipient of the 2011 Charles R. Hatcher, Jr, MD Award. The award honors faculty members from Emory’s Woodruff Health Sciences Center who, through their lifetime of work, exemplify excellence in public health.

For 40 years, Dr. Kutner has played a key role in building the school of public health and advancing programs of research across the Woodruff Health Sciences Center.  He joined Emory’s School of Medicine in 1971, was a key figure on that small planning group for a school of public health, and served as Interim Chair of the medical school’s Department of Statistics and Biometry in 1986.

When Dr. Hatcher and the Board of Trustees approved the creation of the Emory University School of Public Health in 1990, Dr. Kutner was appointed the inaugural Associate Dean for Academic Affairs.  As he has stated on numerous occasions that subsequent events after this appointment “went way beyond our wildest dreams.”

He played a major role in creating the organizational structure of the school—curriculum, strategic faculty and chair recruitments, committees, policies and procedures—and for securing its initial accreditation.

Dr. Kutner always carried public health with him. In 1994, he served as Chair of the Department of Biostatistics and Epidemiology at the Cleveland Clinic Foundation, and returned to the Rollins School of Public Health in 2000.  In 2004, he was named Rollins Professor and Chair of the Department of Biostatistics and Bioinformatics, where he served until 2009.

Throughout his Emory career, Dr. Kutner has provided critical support for biomedical research.  He developed the Biostatistics Consulting Center, collaborated with scores of investigators, and has co-authored over 150 articles in leading health and medical journals.   He is former Director for Biostatistics, Epidemiology and Research Design for the Atlanta Clinical and Translational Science Institute and is currently the Biostatistics Core Director for the Center for AIDS Research.  He is known around the world for his widely adopted textbooks, Applied Linear Regression Models and Applied Linear Statistical Models.

Dr. Kutner’s lifetime contributions to research, teaching and mentoring are not only legendary, but they give integrity and energy to public health and to Emory. On April 5th, the Woodruff Health Sciences Center and the Rollins School of Public Health will celebrate Dr. Kutner’s distinguished career with a reception in the RSPH Klamon Room at 4 p.m.

RSVP to Nancy Sterk at nsterk@emory.edu.

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Microsoft Life Sciences Award recognizes ACTSI innovation

Microsoft Corp. recently selected the Atlanta Clinical and Translational Science Institute (ACTSI) for a 2010 Life Sciences Innovation Award. The award recognized the ACTSI’s Biomedical Informatics Program for implementing the Thermo Scientific Nautilus Laboratory Information System (LIMS) across ACTSI laboratories.

The ACTSI is a partnership of Emory University, Morehouse School of Medicine and Georgia Institute of Technology, along with other community partners and collaborators. It is one of 46 medical research institutes working to enhance translational research in the United States and is supported by the Clinical and Translational Science Award program, National Institutes of Health, National Center for Research Resources.
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Posted on by Holly Korschun in Uncategorized Leave a comment

NIH director visits Emory, Atlanta Clinical & Translational Science Institute

David Stephens, MD, Jim Wagner, PhD, Earl Lewis, PhD, Francis Collins, MD, PhD

Dr. Francis Collins, director of the National Institutes of Health, and chief of staff Dr. Kathy Hudson, paid a daylong visit to Emory’s Woodruff Health Sciences Center, including Yerkes National Primate Research Center, and Morehouse School of Medicine on April 14.

The purpose of Collins’ visit was to view the activities of the Atlanta Clinical and Translational Science Institute, one of 46 national CTSAs funded by the NIH through the National Center for Research Resources (NCRR).  Collins also will visit CTSAs at Duke, UNC, and Vanderbilt in the future.

Collins asked that his visit focus on “how CTSAs are enabling science.” It was an opportunity for the ACTSI, a partnership among Emory, Morehouse School of Medicine, Georgia Institute of Technology and others, including Children’s Healthcare of Atlanta, Georgia Research Alliance, Georgia BIO, Kaiser Permanente, CDC, the Atlanta VA Medical Center and the Grady Health System, to showcase the unique contributions the ACTSI makes to enabling clinical and translational research.

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