Quinn Eastman

The challenges of graduate school

Biochemist Paul Doetsch’s recent appearance in a Science magazine feature on laboratory leadership led to a conversation with him about the challenges of graduate school.

He emphasized that scientific research is a team sport, and brilliance on the part of the lab head may not yield fruit without a productive relationship with the people in the lab. Doetsch suggested talking with Lydia Morris, a graduate student in the Genetics and Molecular Biology graduate program. Morris has been working in Doetsch’s lab for several years and is about to complete her degree. She has been examining the in vivo distribution of DNA repair proteins.

In this video, Morris and Doetsch talk about the differences between turn-the-crank and blue-sky projects, and the importance of backup projects, communications, high expectations and perseverance.

Posted on by Quinn Eastman in Cancer Leave a comment

The body’s anticancer defenses come in a variety of sizes

Sometimes you have to look at the whole picture, big and small.

Sarah Cork, PhD

That was the lesson that emerged from Winship Cancer Institute researcher Erwin Van Meir’s laboratory, highlighted in a recent paper in Oncogene. Van Meir’s team has been studying vasculostatin, a secreted protein that inhibits blood vessel growth by tumors (hence the name). Vasculostatin was discovered by Balveen Kaur, now at Ohio State, while she was in Van Meir’s lab.

Van Meir and his colleagues originally began studying vasculostatin because it is a product of a gene that brain tumors somehow silence or get rid of, and studying the obstacles our bodies throws in cancer’s way may be a good way to learn how to fight it via modern medicine. Eventually, it could form the basis for a treatment to prevent a tumor from attracting new blood vessels.

Vasculostatin is somewhat unique because it is a secreted fragment of a membrane-bound protein, called BAI1. BAI1 has an apparently separate function as an “engulfment receptor,” allowing the recognition and internalization of dying cells.

Most of the secreted vasculostatin is around 40 kilodaltons in size, not 120 as previously thought.

Graduate student Sarah Cork discovered that most of the vasculostatin protein being produced by cells is actually much smaller than what had been originally discovered. She and Van Meir were surprised to find that the smaller, cleaved form of the protein still has potent anti-angiogenic activity.

The researchers were using a technique where a mixture of proteins is separated within a gel by electric current, transferred to a polymer sheet, and probed with antibodies. The large proteins appear at the top and the small proteins at the bottom.

“Previously, we had been running the gels for a long time to detect large protein fragments, so missed out on what was happening with small fragments which run off the gel,” Van Meir says. “We were only looking at the top of the
gel, when the smaller form of vasculostatin was actually much more
abundant as you can see on the picture of a gel run for a shorter time.”

More broadly, Van Meir says that the finding adds to understanding about BAI1’s dual function in the brain and how vasculostatin (big or small) might be used in anticancer therapy.

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Fragile X protein: one toggle switch, many circuits

The fragile X protein — missing in the most common inherited form of intellectual disability — plays a central role in neurons and how they respond to external signals. Cell biologist Gary Bassell and his colleagues have been examining how the fragile X protein (FMRP) acts as a “toggle switch.”

Gary Bassell, PhD

FMRP controls the activity of several genes by holding on to the RNAs those genes encode. When neurons get an electrochemical signal from the outside, FMRP releases the RNAs, allowing the RNAs to be made into protein, and facilitating changes in the neurons linked to learning and memory.

The Bassell lab’s new paper in Journal of Neuroscience reveals the role of another player in this process. The first author is postdoctoral fellow Vijay Nalavadi.

The researchers show that neurons modify FMRP with ubiquitin, the cellular equivalent of a tag for trash pickup, after receiving an external signal. In general, cells attach ubiquitin to proteins so that the proteins get eaten up by the proteasome, the cellular trash disposal bin. Here, neurons are temporarily getting rid of FMRP, prolonging the effects of the external signal.

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Dye me anticancer yellow

Over the last few years, pathologist Keqiang Ye and his colleagues have displayed an uncanny talent for finding potentially useful medicinal compounds. Recently another example of this talent appeared in Journal of Biological Chemistry.

Keqiang Ye, PhD

Postdoctoral fellow Qi Qi is first author on the paper. Collaborators include Jeffrey Olson, Liya Wang, Hui Mao, Haian Fu, Suresh Ramalingam and Shi-Yong Sun at Emory and Paul Mischel at UCLA.

Qi and Ye were looking for compounds that could inhibit the growth of an especially aggressive form of brain cancer, glioblastoma with deletion in the tumor suppressor gene PTEN. Tumors with this deletion do not respond to currently available targeted therapies.

The researchers found that acridine yellow G, a fluorescent dye used to stain microscope slides, can inhibit the growth of this tumor:

Oral administration of this compound evidently decreases the tumor volumes in both subcutaneous and intracranial models and elongates the life span of brain tumor inoculated nude mice. It also displays potent antitumor effect against human lung cancers. Moreover, it significantly decreases cell proliferation and enhances apoptosis in tumors…

Optimization of this compound by improving its potency through medicinal chemistry modification might warrant a novel anticancer drug for malignant human cancers.

Ye’s team observed that acridine yellow G appears not to be toxic in rodents. However, the acridine family of compounds tends to intercalate (insert itself) into DNA and can promote DNA damage, so more toxicology studies are needed. Other acridine family compounds such as quinacrine have been used to treat bacterial infections and as antiinflammatory agents, they note.

A paramecium stained with acridine orange, which shows anticancer activity for tumors containing PTEN mutations

Posted on by Quinn Eastman in Cancer Leave a comment

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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