Warren symposium follows legacy of geneticist giant

If we want to understand how the brain creates memories, and how genetic disorders distort the brain’s machinery, then the fragile X gene is an ideal place to start. That’s why the Stephen T. Warren Memorial Symposium, taking place November 28-29 at Emory, will be a significant event for those interested in neuroscience and genetics. Stephen T. Warren, 1953-2021 Warren, the founding chair of Emory’s Department of Human Genetics, led an international team that discovered Read more

Mutations in V-ATPase proton pump implicated in epilepsy syndrome

Why and how disrupting V-ATPase function leads to epilepsy, researchers are just starting to figure Read more

Tracing the start of COVID-19 in GA

At a time when COVID-19 appears to be receding in much of Georgia, it’s worth revisiting the start of the pandemic in early 2020. Emory virologist Anne Piantadosi and colleagues have a paper in Viral Evolution on the earliest SARS-CoV-2 genetic sequences detected in Georgia. Analyzing relationships between those virus sequences and samples from other states and countries can give us an idea about where the first COVID-19 infections in Georgia came from. We can draw Read more

Lab management: leading by example

Paul Doetsch, PhD

Cancer researcher Paul Doetsch is a prominent voice in a recent feature in Science magazine’s Careers section. The article gives scientists who are setting up their laboratories advice on how to manage their laboratories and lead by example.

Doetsch holds a distinguished chair of cancer research and is associate director for basic research at Winship Cancer Institute. His research on how cells handle DNA damage has provided insights into mechanisms of tumor formation and antibiotic resistance. His lab includes five graduate students, two senior postdocs and one technical specialist.

From the article:

Doetsch says that he tries to maintain a lab culture that provides technicians, students, postdocs, and research faculty a sense of “ownership” of their projects and to give the message everyone is making a significant contribution to the research enterprise, regardless of their specific title or role.
“I make it a point to walk around my lab several times a day to chat with my group and hold individual weekly research meetings with each member to get an update of their progress and provide them with direct, constructive feedback on their activities,” he says. “I always strongly encourage everyone to discuss their results and other issues affecting their project with their lab colleagues and to not hesitate to disagree with me when necessary.”

Author Emma Hitt was herself a graduate student at Emory.

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The face behind a case

Last week Emory posted a news item about a case report published in the American Journal of Human Genetics. The paper described how geneticists at Emory, in cooperation with Sanford Burnham Medical Research Institute in San Diego, used “whole exome sequencing” — a sort of executive summary scan of the genome — to find the cause of a metabolic disease in a young boy.

The case was an illustration of the trend of whole exome sequencing, which is starting to enter clinical practice as a diagnostic technology. A photo of the patient, courtesy of his parents and Sanford Burnham, is a powerful reminder that within every case report, there’s a real person’s history.

Courtesy of Heather Buschman

“Over the years, we’ve come to know many families and their kids with glycosylation disorders. Here we can tell them their boy is a true ‘trail-blazer’ for this new disease,” says Hudson Freeze, director of the Genetic Disease program at Sanford Burnham. “Their smiles—that’s our bonus checks.”

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What is the default mode network?

Welcome to what could become a regular feature on the Emory Health Now blog: explaining a word or phrase that is connected with research going on at Emory.

What is the default mode network?
This is a concept that grew out of brain imaging studies, using techniques such as functional magnetic resonance imaging. The default mode network consists of regions of the brain that are active when someone is not doing anything in particular, especially something requiring focused attention. More fancifully: it’s what daydreaming looks like.

The default mode network includes the medial prefrontal cortex (MPFC) and the posterior cingulate cortex (PCC).

Researchers at Emory and elsewhere have been looking at whether the DMN’s activity and its links to other areas of the brain are changed in disorders such as schizophrenia, autism, depression and post-traumatic stress disorder.

For example, Xiaoping Hu, director of Emory’s Biomedical Imaging Technology Center, and his colleagues have investigated how the default mode network’s activity is modified in individuals with prenatal alcohol exposure and prenatal cocaine exposure. They also have probed how the DMN’s activity is shut down by anesthesia.

At the Atlanta Veterans Affairs Medical Center, Erica Duncan and her colleagues have examined the DMN in people with schizophrenia. They found (as have other groups) that individuals with schizophrenia appear to have difficulty shutting down the DMN and focusing on a task, as well as having a different pattern of connections within the DMN.

Yerkes investigator Lary Walker recently wrote about research connecting metabolic activity in the default mode network with the burden of amyloid in Alzheimer’s disease.

The DMN is made up of several regions of the brain, most prominently the posterior cingulate cortex (PCC) and medial prefrontal cortex (MPFC). Other regions such as the inferior parietal lobule, lateral temporal cortex, and hippocampal formation including parahippocampus are also considered part of the DMN. Note: these regions can also be engaged in other tasks besides daydreaming or introspection.

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Strengthening bone with silica nanoparticles

Tiny particles of silicon dioxide – essentially, extremely fine sand — can strengthen bones when introduced into animals, researchers at Emory University School of Medicine have discovered.

The particles stimulate the generation of bone-forming cells and inhibit other cells that break down bone. The findings could someday form the basis for an alternative treatment for osteoporosis.

The results were published recently in the journal Nanomedicine.

The paper represents a collaboration between the laboratories of George Beck and Neale Weitzmann, both in the Division of Endocrinology, Metabolism and Lipids. The project started when Jin-Kyu Lee, now at Seoul National University, came to Beck’s lab with silica nanoparticles he had developed that contained fluorescent dyes. This allowed researchers to track the particles within the body and within cells.

In the laboratory, the nanoparticles stimulate the generation of bone-forming osteoblasts and inhibit the maturation of bone-remodeling osteoclasts. Beck says that the particles’ properties seem to depend on their size (50 nanometers wide) and shape, because larger particles don’t have the same effects. The nanoparticles appear to work by being taken up by the cells and then by inhibiting NF-kB, a molecule that controls inflammation.

Silicon is a trace element in the diet of most people. Scientists have known for several years that dietary silicon is linked to strong bones, but how silicon influences bone growth has remained unclear: it could become physically incorporated into bone, or it could provide signals to the cells that make up bone. To be sure, silica nanoparticles may be acting in a way that is different than dietary silicon.

The particles’ ability to stimulate osteoblasts distinguish them from bisphosphonates, the most common drugs now used to treat osteoporosis, Beck says. Bisphosphonates only inhibit bone breakdown and do not stimulate bone formation.

The Emory team has found that injecting silica nanoparticles can increase the bone density of young mice by roughly 15 percent over six weeks, augmenting the increases coming from adolescent growth.

To test the particles’ potential for use with humans, the researchers are examining whether injection is the best way to deliver the nanoparticles, and whether long-term toxicity is an issue. Inhalation of larger particles of silica dust, an occupational hazard for miners and construction workers, can result in the lung disease silicosis. However, silicosis arises because the lungs can’t absorb and remove the larger dust particles. Since cells clearly can take up the nanoparticles (see video), it is possible that they will not induce the body to respond similarly.

Emory has applied for patents on this technology. A presentation by Emory’s Office of Technology Transfer is available here.

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Making “death receptor” anticancer drugs live up to their name

Cancer cells have an array of built-in self-destruct buttons called death receptors. A drug that targets death receptors sounds like a promising concept, and death receptor-targeting drugs have been under development by several biotech companies. Unfortunately, so far results in clinical trials have been disappointing, because cancer cells appear to develop resistance pathways.

Death receptor-targeting drugs under development include: drozitumab, mapatumumab, lexatumumab, AMG655, dulanermin.

Winship Cancer Institute researcher Shi-Yong Sun, PhD and colleagues have a paper in Journal of Biological Chemistry that may help pick the tumors that are most likely to be vulnerable to death receptor-targeting drugs. This could help clinical researchers identify potential successes ahead of time and maximize chances of a good response for patients.

Postdoctoral fellow Youtake Oh is the first author. Winship deputy director Fadlo Khuri, MD and Taofeek Owonikoko, MD, PhD, co-chair of Winship’s clinical and translational research committee, are co-authors. Khuri’s 2010 presentation on death receptor drugs and lung cancer is available here (PDF).

Sun’s team shows that mutations in the cancer-driving genes Ras and B-Raf both induce cancer cells to make more of one of the death receptors (death receptor 5). In addition, they show that cancer cells with mutations in Ras or B-Raf tend to be more vulnerable to drugs that target death receptor 5.

Shi-Yong Sun, PhD

These mutations are known to be more common in some types of cancer. For example, roughly half of melanomas have mutations in B-Raf. Vemurafenib, a drug that inhibits mutated B-Raf, was approved in August 2011 for the treatment of melanoma. K-ras mutations are similarly abundant in lung cancer.

The selection and targeting of tumors via their specific mutations is a growing trend. Sun says lung, colon and pancreatic cancer are all cancer types where Ras and Raf mutations are common enough to become useful biomarkers. In lung cancer, Sun’s team’s results could be especially welcome news because, as a 2009 review concluded:

Recent studies indicate that patients with mutant KRAS tumors fail to benefit from adjuvant chemotherapy, and their disease does not respond to EGFR inhibitors. There is a dire need for therapies specifically for patients with KRAS mutant NSCLC.

 

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New molecular target in dystonia

Emory researchers led by pharmacologist Ellen Hess have identified a new molecular target in dystonia. Their findings, recently published in the Journal of Pharmacology and Experimental Therapeutics, could help doctors find drugs for treating the movement disorder.

Ellen Hess, PhD

Dystonia gives sufferers involuntary muscle contractions that cause rigid, twisting movements and abnormal postures. It is the third most common movement disorder, after tremor and Parkinson’s disease. Neurologists can sometimes use drugs to address the symptoms of dystonia but there is no cure.

A 2008 review by Hess (PDF) concludes that compared with other neurological disorders, “our understanding of the biology and potential treatments for dystonia is in its infancy.” Still, scientists have known for a while that the cerebellum, a region of the brain that regulates movement, is involved.

“We focused on the cerebellum because studies in patients with dystonia often show that this part of the brain is more active, when examined by MRI,” Hess says. “The abnormal overactivity of the cerebellum is seen in patients with all different types of dystonia, so it seems to be a common hotspot. Our goal was to understand what might be causing the overactivity in mice because if we can stop the overactivity, we might be able to stop the dystonia.”

Hess and her colleagues discovered that drugs that stimulate AMPA receptors induce dystonia when introduced into the mouse cerebellum. Their results suggest that drugs that act in reverse, blocking AMPA receptors, could be used to treat dystonia.

Postdoctoral fellow Xueliang Fan is the first author of the paper. Emory neurologist H.A. Jinnah, director of a NIH-supported network of clinical research sites focusing on dystonia, is a co-author.

AMPA receptors are a subset of glutamate receptors, a large group of “receiver dishes” for excitatory signals in the brain. Fan performed a variety of experiments to show that AMPA receptor activity plays a specific role in generating dystonia. For example, drugs that affect other types of glutamate receptors did not induce dystonia. AMPA receptor blockers can also reduce dystonia in a genetic model, the “tottering” mouse.

Although pharmaceutical companies have already been testing AMPA receptor blockers as potential antiseizure drugs, caution is in order. AMPA receptor stimulators/ enhancers (or “ampakines”) have been identified as potential enhancers of learning and memory, so AMPA receptor blockers may interfere with those processes.

“Our results suggest that reducing AMPA receptor activity could help alleviate dystonia but we still have a lot of work to do before we know whether blocking AMPA receptor activity in patients will really help,” Hess says. “Since there aren’t many drugs that act at AMPA receptors, one of our goals is to identify drugs that change the ‘downstream’ effects of AMPA receptor activation. For example, we may be able to find other drug classes that change neuronal activity in the same way that AMPA receptor blockade changes activity.”

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Emory Cardiologist Helps Rank Top Diets

Laurence Sperling, MD

It’s a new year and shedding pounds is at the top of the resolution list for many Americans. To help dieters lose weight and jump start healthier eating habits, Emory Heart & Vascular Center cardiologist Laurence Sperling, MD served on a U.S. News & World Report panel evaluating some of the country’s most popular diets.

The rankings, released today, include U.S. News’ second annual list of Best Diets, featuring its first-ever ranking of Easiest Diets to Follow. It includes six other rankings first assessed and published in 2011: Best Diets Overall, Best Commercial Diet Plans, Best Weight-Loss Diets, Best Diets for Healthy Eating, Best Diabetes Diets, and Best Heart-Healthy Diets.

According to U.S. News, dieters who choose a diet at or near the top of the new Easiest Diets to Follow list are more likely to succeed in staying on their diet for the long haul. Weight Watchers took the top spot on that list, followed by Jenny Craig, the Mediterranean Diet, Slim-Fast and Volumetrics.

The five new diets added for 2012 are the Abs Diet, Biggest Loser Diet, Dukan Diet, Flat Belly Diet, and Macrobiotic Diet.

Big winners across the rankings included:

  • DASH Diet: ranked #1 in Best Diets Overall, Best Diets for Healthy Eating, and Best Diabetes Diets (tie)
  • Weight Watchers: ranked #1 in Best Weight-Loss Diets, Best Commercial Diet Plans, and Easiest Diets to Follow
  • Biggest Loser Diet: ranked #1 in Best Diabetes Diets (tie)
  • Ornish Diet: ranked #1 in Best Heart-Healthy Diets

To create the rankings, U.S. News turned to Sperling and the same 22 experts for Best Diets 2012 as it did for Best Diets 2011. The panel, which included nutritionists, dietitians, cardiologists and diabetologists, reviewed 25 popular diet profiles that were developed by reporters and editors at U.S. News.

“I can’t say enough about their commitment and hard work,” said Avery Comarow, U.S. News Health Rankings Editor. “They enabled us to provide meaningful, evidence-based rankings.”

Sperling is a professor of medicine at Emory University School of Medicine and director of Emory’s Center for Heart Disease Prevention.

For a complete list of the new diet rankings, please visit:

http://health.usnews.com/best-diet

 

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mTOR inhibitors gaining favor for breast cancer treatment

This week, breast cancer researchers have been reporting encouraging clinical trial results with the drug everolimus at the San Antonio Breast Cancer Symposium. Everolimus is a mTOR inhibitor, first approved by the FDA for treatment of kidney cancer and then for post-transplant control of the immune system.

Ruth O’Regan, MD, director of the Translational Breast Cancer Research Program at Winship Cancer Institute, has led clinical studies of everolimus in breast cancer and has championed the strategy of combining mTOR inhibitors with current treatments for breast cancer.

She recently explained the rationale to the NCI Cancer Bulletin:

She views the combination therapy as a potential alternative to chemotherapy for treating ER-positive advanced breast cancer when hormonal therapies have stopped working.

When resistance to hormonal therapies occurs, Dr. O’Regan explained, additional signaling pathways become activated. Unlike chemotherapy, which targets rapidly dividing cells, mTOR inhibitors are an example of the kind of treatment that may block growth-promoting signaling pathways.

Currently, Winship researchers are examining a combination involving everolimus and the EGFR inhibitor lapatinib for “triple-negative” breast cancer, a particularly aggressive and difficult-to-treat variety.

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DNA copying problems explain muscular dystrophy mutations

Geneticist Madhuri Hegde and her colleagues have a paper in the journal Genome Researchthat addresses the question: where do copy number variations come from?

Madhuri Hegde, PhD

Copy number variations (CNVs), which are deletions or duplications of small parts of the genome, have been the subject of genetic research for a long time. But only in the last few years has it become clear that copy number variations are where the action is for complex diseases such as autism and schizophrenia. Geneticists studying these diseases are shifting their focus from short, common mutations (often, single nucleotide polymorphisms or SNPs) to looking at rarer variants such as CNVs. A 2009 discussion of this trend with Steve Warren and Brad Pearce can be found here.

Hegde is the Scientific Director of the Department of Human Genetics’ clinical laboratory. Postdoctoral fellow Arun Ankala is the first author. In the new paper, Ankala and Hegde examine rearrangements in patients’ genomes that arose in 62 clinical cases of Duchenne’s muscular dystrophy and several other diseases. Mutations in the DMD gene are responsible for Duchenne’s muscular dystrophy.

The pattern of the rearrangement hints what events took place in the cell beforehand, and hint that a problem took place during replication of the DNA. The signature is a tandem duplication of a short segment next to a large deletion, indicating how the DNA was repaired.

The authors note that the DMD locus is especially prone to these types of problems because it is much larger than other gene loci. The gene is actually the longest human gene known on the DNA level, covering 2.4 megabases (0.08 percent of the genome.)

Replication origins are where the DNA copying machinery in the cell starts unwinding and copying the DNA. Bacterial circular chromosomes have just one replication origin. In contrast, humans have thousands of replication origins spread across our chromosomes. In the discussion, the authors suggest that DNA copying problems may also explain duplications and historically embedded rearrangements of the genome.

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A twist on epigenetic therapy vs cancer

Epigenetic therapies against cancer have attracted considerable attention in recent years. But many of the drugs currently being studied as epigenetic anticancer therapies may have indiscriminate effects. A recent paper in Cancer Research from brain cancer researcher Erwin Van Meir’s laboratory highlights a different type of target within cancer cells that may be more selective. Postdoctoral fellow Dan Zhu is the first author of the paper.

Erwin Van Meir, PhD

The basic idea for epigenetic therapy is to focus on how cancer cells’ DNA is wrapped instead of the mutations in the DNA. Cancer cells often have aberrant patterns of methylation or chromatin modifications. Methylation is a punctuation-like modification of DNA that usually shuts genes off, and chromatin is the term describing DNA when it is clothed by proteins such as histones, a form of packaging that determines whether a gene is on or off.

In contrast to mutations that are hard-wired in the DNA, changes in cancer cells’ methylation or chromatin may be reversible with certain drug treatments. But a puzzle remains: if a drug wipes away methylation indiscriminately, that might turn on an oncogene just as much as it might restore a tumor suppressor gene.

The ability of an inhibitor of methylation to treat cancer may depend on cell type and context, explains chromatin/methylation expert and co-author Paula Vertino. She points out that one well-known methylation inhibitor, azacytidine (Vidaza), is a standard treatment for myelodysplastic syndrome, but the strategy of blanket-inhibition of methylation can’t be expected to work for all cancers. A similar challenge exists for agents that target histone acetylation in a global fashion.

Epigenetic therapies seek to modify how DNA is packaged in the cell.

Van Meir’s laboratory has been studying a tumor suppressor protein called BAI1 (brain angiogenesis inhibitor 1), which prevents tumor and blood vessel growth. BAI1 is produced by brain cells naturally, but is often silenced epigenetically in glioblastoma cells. His team found that azacytidine de-represses the BAI1 gene.

Methylation won’t turn a gene off without the help of a set of proteins that bind preferentially to methylated DNA. These proteins are what recognize the methylation state of a given gene and recruit repressive chromatin. Zhu and colleagues in Van Meir’s group found that one particular methyl-binding protein, MBD2, is overproduced in glioblastoma and is enriched on the BAI1 gene.

“Taken together, our results suggest that MBD2 overexpression during gliomagenesis may drive tumor growth by suppressing the anti-angiogenic activity of a key tumor suppressor. These findings have therapeutic implications since inhibiting MBD2 could offer a strategy to reactivate BAI1 and suppress glioma pathobiology,” the authors write.

By itself, MBD2 appears to be dispensable, since mice seem to be able to develop and survive without it. Not having it even seems to push back against tumor formation in the intestine, for example. Targeting MBD2 may represent an alternative way to steer away from cancer cells’ altered state.

Van Meir cautions: “We need to have a better understanding of all the genes that are turned on or off by silencing MBD2 in a given cancer before we can envision to use this approach for therapy.”

Vertino and Steven Hunter, both at Emory, are co-authors on the paper. The work was supported by grants from the NIH and the Southeastern Brain Tumor Foundation and the Emory University Research Council.

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