Spring 2013 - GResearch

Researchers Explore Link Between Depression, Insomnia, Suicide

SPRING VOL. 1

NO. 1

2013 Conquering the Nightmare

Welcome to the inaugural edition of GResearch.

Our university has a 185-year history of contributing to a knowledge base that has improved life dramatically for countless citizens, but this year marks a milestone in which we take particular pride.

This is the year that Augusta State University and Georgia Health Sciences University consolidated to create what will be one of the most dynamic comprehensive research institutions in Georgia. The creation of Georgia Regents University has not simply combined the best elements of the former universities; it has created a whole that is greater than the sum of its parts.

Our ambitious vision requires that we not only stay current but also invent the future. We plan to innovate new models of research that promote discovery, double our extramural funding and number of funded investigators, and become the state’s second National Cancer Institutedesignated Cancer Center within the next eight years. We will innovate the yet to be. We will be an agent of change.

As you read the magazine, I think you will find we are well on our way toward our mission to become:

RICARDO AZZIZ, MD, MPH, MBA G E O R G I A

R E G E N T S

n An internationally recognized leader in health sciences research n A regional destination for undergraduate and graduate students seeking research opportunities in STEM (science/ technology/engineering/math) disciplines n A national center for entrepreneurship and innovation widely recognized for translating discovery into practical application Thank you for supporting our research mission, and enjoy the journey as we create countless new milestones to come. u

Professor, Obstetrics & Gynecology, Medicine and Medical Humanities; President, Georgia Regents University; CEO, Georgia Regents Health System

U N I V E R S I T Y

SPRING

Dear Readers, A quick perusal of this inaugural edition of GResearch should make one thing, above all others, exceedingly clear: Georgia Regents University is one busy place.

As President Ricardo Azziz articulated in his introductory letter, our research goals are lofty and our mission ambitious.

Our future is incredibly bright. But as we anticipate these great strides, we celebrate advances in cancer and depression; And new discoveries are past and current innovation commercialization unfolding every day.

Existing accomplishments initiatives that expedite lab findings strengths in biomedical research as well. Our to the bedside and marketplace; at GRU—cancer, neurologic university boasts research to help us better disease, cardiovascular disease— a proud tradition understand earthquakes; and are being supplemented with that includes emotional factors that guide voting growing initiatives in areas decisions, among other items. including public/preventive health, discoveries of beta How’s that for a broad body of regenerative/reparative medicine blocking drugs and work? And trust me, this list doesn’t and personalized medicine/ fertility treatments, even scratch the surface of what genomics. Add to that impressive among many other unfolds in our laboratories day in list the growing contributions of our innovations. and day out.

Summerville Campus researchers and you’ll have a sense of the vast scope and reach of our initiatives.

In fact, our research is unfolding much too rapidly and voluminously to accommodate synopsis in a single publication. But we hope this magazine will give you a sense of the stature, variety and impact that characterize our research mission.

The articles included in this magazine cover biomedical

DR. MARK HAMRICK D I S C O V E R I E S

As you learn more about our research mission, feel free to contact me for more information at 706-721-1958, mhamrick@gru.edu or www.gru.edu/research.

I welcome your enthusiasm, ideas and support. u

Senior Vice President for Research

I N

P R O G R E S S

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Research

at a Glance

GEORGIA REGENTS UNIVERSITY

RESEARCH / SPRING 2013

Making Memories FILTERING INFORMATION becomes more difficult with age and may impede learning, scientists report.

“When you are young, your brain is able to strengthen certain connections and weaken certain connections to make new memories,” said Dr. Joe Z. Tsien, neuroscientist and Co-Director of the GRU Brain & Behavior Discovery Institute.

It’s that critical weakening that appears hampered in the older brain, according to a study in the journal, Scientific Reports.

The NMDA receptor in the brain’s hippocampus is like a switch for regulating learning and memory, working through subunits called NR2A and NR2B. NR2B is expressed in higher percentages in children, optimizing learning and memory. The ratio shifts after puberty.

When Tsien and his colleagues genetically modified mice that mimic the adult ratio—more NR2A, less NR2B—they were surprised to find the rodents were still good at making strong connections and short-term memories but had an impaired ability

to weaken existing connections and to make new long-term memories as a result. It’s called information-sculpting, and adult ratios of NMDA receptor subunits don’t appear to be very good at it.

“If you only make synapses stronger and never get rid of the noise, it’s a problem,” said Tsien, the study’s corresponding author. Insufficient sculpting, at least in their mouse model, meant a reduced ability to remember things short-term. Both are impacted in Alzheimer’s and age-related dementia.

Tsien and his colleagues already have learned what happens when NR2B is overexpressed. He and East China Normal University researchers announced in 2009 the development

DR. JOE Z. TSIEN

of Hobbie-J, a smarter-than-average rat. A decade earlier, Tsien reported in the journal, Nature, the development of a smart mouse dubbed Doogie using the same techniques to over-express the NR2B gene in the hippocampus.

Doogie, Hobbie-J and their descendants have maintained superior memory as they age. Now Tsien is interested in following the NR2A over-expressing mouse to see what happens.

Tsien is the Georgia Research Alliance Eminent Scholar in Cognitive and Systems Neurobiology. The research was funded by the National Institutes of Health and the GRA. u

Bacterial Sleuthing WHEN A RED-CLAW CRAYFISH being studied by biology student Nuvonka Wilson developed a fatal necrotic wound, Wilson reworked her research to begin identifying the bacteria associated with the wound.

With the guidance of GRU Biology Professors Christopher Bates and Bruce Saul, “we were able to isolate and grow three distinct types of bacteria on nutrient-rich media,” said Wilson, who graduated last May. “We then utilized a battery of biochemical and physiological tests to narrow the bacteria to either a member of the genus Acidovorax, Vibrio, Pseudomonas stutzeri or Halomonas aquamarina.”

Wilson, who is now pursuing a degree in veterinary medicine, plans to complete the identification process by utilizing a polymerase chain reaction. She is also screening the bacteria for their susceptibility to various antibiotics. u

Aldosterone Alert INCREASED LEVELS of the hormone, aldosterone, in young black males correlate with an enlarged heart muscle, researchers say.

The findings indicate physicians may want to reach for aldosterone inhibitors early in their effort to control blood pressure and reduce cardiovascular risk in this population.

Their studies of a 191 teens showed that only in black males was higher aldosterone associated with impaired sodium excretion, increased blood pressure and enlargement of the left pumping chamber of the heart, said Dr. Gregory A. Harshfield, hypertension researcher at the GRU Institute of Public and Preventive Health.

“It’s a clear pathway and is consistent

with the idea that is the highest-risk group for developing earlier and more severe cases of hypertension,” Harshfield said. Increased sodium causes fluid retention, which can lead to hypertension and, ultimately, an enlarged pumping chamber of the heart (left ventricular hypertrophy).

Harshfield’s studies have shown that black males particularly have a problem with blood pressure returning to normal following stress because of an impaired ability to eliminate sodium.

“It might be a good idea to consider early on drugs that target aldosterone in these individuals,” said Diana G. Murro, a fourth-year MCG student and first author of the study in the journal Pediatric Nephrology. u

Diabetes Shake-Up DAILY SESSIONS of wholebody vibration may combat prediabetes in adolescents, dramatically reducing inflammation, average blood glucose levels and symptoms such as frequent urination, researchers report.

In mice that mimic overeating adolescents headed toward diabetes, 20 minutes of daily vibration for eight weeks restored a healthy balance of key pro- and antiinflammatory mediators and was better than prescription drugs at reducing levels of hemoglobin A1c, the most

accurate indicator of average blood glucose levels, said Dr. Jack C. Yu, Chief of the Section of Plastic and Reconstructive Surgery.

In normal mice, just four days of vibration also dramatically improved the ability to manage a huge glucose surge. Interestingly, vibration did not produce similar changes in older, healthy mice, Yu told researchers at the Third World Congress of Plastic Surgeons of Chinese Descent.

“This is our model: the average American teenager who eats too much,” said Yu. “The only way to burn fat is to exercise. We shake the bone for you rather than the body’s muscle shaking it. This is a highly efficient way to fool the bone into thinking we are exercising.”

Next steps include learning more about how vibration produces these

results and largescale studies to see if they hold true in adolescents.

Yu and Biomedical Engineer Karl H. Wenger developed the whole-body vibrator used for the animal studies. u

DR. JACK YU

Discoveries in Progress

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Research

at a Glance

GEORGIA REGENTS UNIVERSITY

RESEARCH / SPRING 2013

Relapse Red Flag BLOOD LEVELS of a protein that helps regulate inflammation may also serve as a red flag for relapse in some schizophrenia patients, researchers said.

“There are no good, objective measures of treatment efficacy or indicators for relapse,” said Dr. Brian Miller, a GRU psychiatrist specializing in schizophrenia.

Researchers hope monitoring levels of interleukin-6 can fill that gap and improve DR. BRIAN MILLER medication compliance. “We hope the upshot of our studies will lead to new treatment approaches and strategies for care,” Miller said. “We want to attack the disease from as many directions as possible.”

To get a better handle on how IL-6 levels correspond to disease status, they are looking at levels in blood samples taken multiple times over several years in 305 patients enrolled in a study comparing injectable to oral medication. They also are taking one-time measurements in 80 healthy people and comparing those to levels in 240 schizophrenics.

Miller received a five-year, $920,000 National Institute of Mental Health Mentored Patient-Oriented Research Career Development Award to measure IL-6 levels as a potential indicator of how well treatment is working to control disease in these vulnerable patients and whether they are headed for relapse. Mounting evidence suggests inflammation’s impact in schizophrenia.

Once patients can be identified, ideally with a blood test of their IL-6 levels, the next questions are which drugs to use and for how long. u

Assessing Estrogen Levels A RECENT GRU GRADUATE has found a cost-effective way to determine estrogen levels in waterways.

Skylar Hendricks, who graduated with a chemistry degree last spring, used gas chromatography-mass spectrometry to determine estrogen content in local waterways—a crucial step in gleaning its effects on species, including fish, livestock and humans, that use the water.

“I believe our ability to derivatize estrogen by using acetic anhydride and to analyze the derivative using gas chromatography-mass spectrometry was just as effective as using more high-tech equipment,” she said, noting it was considerably less expensive, as well.

Her undergraduate research was rewarded with a William A. Bloodworth Jr. Academic Recognition Day Scholar Award.

Hendricks is now earning a pharmacy doctorate. u

Brazilian Exchange

DR. R. CLINTON WEBB

THE DEPARTMENT OF PHYSIOLOGY has received a training grant from the Brazil Scientific Motility Society to advance the education of future scientists and scientific discovery.

The three-year, $186,200 grant supports the exchange of six GRU graduate students and postdoctoral fellows with the University of Säo Paulo-Ribeiräo Preto and enables Dr. R. Clinton Webb, department Chair, to spend six months in Brazil researching hypertension.

“Each institution offers outstanding and highly complementary research programs and scientific activities,” said Dr. Rita Tostes, a former MCG faculty member who coordinates the Brazilian university’s pharmacology group. “We are

delighted that the Brazil Scientific Mobility Award provides a funding mechanism for the training of our students and fellows.

Our mutual collaboration can only result in improved knowledge and better outcomes for hypertensive patients worldwide.”

The program also seeks to attract established scientists who are leaders in the priority areas of Scientists Without Borders, a public-private partnership conceived by the New York Academy of Sciences in conjunction with the United Nations’ Millennium Project to tackle the most pressing global development challenges.

This contract will focus on finding better ways to treat hypertension, which affects roughly half or more of the elderly in the United States and Brazil. u

Multidisciplinary Momentum SOME GRU SCIENTISTS have gotten a head start on the countless new multidisciplinary research avenues created by consolidation.

For instance, Dr. Jay Hedge, Assistant Professor of Ophthalmology, teamed with student Karin Hauffen last spring to analyze vision and perception in primates. Hauffen, a management information systems major, completed 180 hours in his lab as a computer programmer. His software included MATLAB, a program for algorithm development and data analysis, and Presentation, software used in psychological experiments.

“When I began interning in the lab, I had absolutely no experience with the software or hardware technologies used in Dr. Hegdé’s research,” Hauffen said. “Although it felt like a daunting task at first to write code for each experiment, Dr. Hegdé offered plenty of advice and helped make each project more manageable.”

The resulting research—including the simulation of morphogenesis and phylogenesis to study object recognition and perceptual learning in humans, was featured in the Journal of Visualized Experiments and PLoS ONE. The Hull College of Business named Hauffen a 2010-2011 Hull Scholar. u

DR. JAY HEDGE, right, with KARIN HAUFFEN

Discoveries in Progress

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Research

at a Glance

Deconstructing a Riot

GEORGIA REGENTS UNIVERSITY

RESEARCH / SPRING 2013

SEA STACHURA

A GRU COMMUNICATIONS Instructor is taking the scab off an old psychic wound in hopes of preventing such wounds in the future.

Sea Stachura’s project, Recovering History: Oral Histories of Augusta’s Forgotten 1970 Riot, recounts the events surrounding the May 11 riot that occurred in downtown Augusta following the death of Charles Oatman, a mentally challenged African American teen being held in a Richmond County Jail.

“I have always enjoyed researching how communities are affected by riots, and I had a personal interest in learning more about Augusta’s race riot,” said Stachura, whose work is funded by the Georgia Humanities Council. “I know this grant will help us raise awareness about this historical event that impacted the race relations within the city of Augusta.”

The project includes testimonials and presentations from Augustans who give firsthand accounts of the protest. These residents include Willie Mays, an mortician who received Oatman’s body; Grady Abrams, a former City Council member and community leader; Joe Bowden, a surgical resident on duty the night of the riot; William Coleman, a lawyer who represented those arrested in the riot; and Mallory Millender, Paine College Professor and Historian. u

Undergraduate Research Boost A GRU PARTNERSHIP with Savannah River Remediation, LLC will help fund supplies and equipment for undergraduate research projects in science and math.

The Savannah River Remediation, the Savannah River Site’s Liquid Waste contractor for the U.S. Department of Energy, donated $5,000 to the Center for Undergraduate Research and Scholarship.

“This will enable undergraduates to gain practical experience and knowledge required for the nuclear science fields,” said Dr. J. Andrew Hauger, Professor of Physics and Director of the center. “We are excited to have the support of SRR as we continue to groom producers of knowledge and not just consumers of knowledge.”

This is the second year SRR has given a grant to the center. u

DR. J. ANDREW HAUGER (left)

Mindful Matters

STEM Success

IN A MONASTERY tucked away in the small town of Moncks Corner, S.C., GRU Communications Instructor Will Bryant lived 44 days with Trappist monks to better understand contemplation and mindfulness.

Bryant observed the monks’ daily lives in hopes of developing practices that will help teachers and students increase their ability to focus in the classroom.

He is using these observations for his dissertation in the Educational Studies program at the University of North Carolina at Greensboro.

Bryant believes students can experience

academic success if they can be guided into focusing on the task at hand.

“Students and teachers have tremendous potential, but we are easily distracted by the internal dialogues occurring in our minds, making it difficult to ‘stay in the moment,’” said Bryant.

“When students and teachers become unfocused, we run the risk of education being less effective.”

He has already begun developing focusing techniques that can be used in the classrooms. u

A PARTNERSHIP between Automatic Data Processing Inc., one of the world’s largest providers of business outsourcing solutions, GRU, Paine College and Augusta Technical College was named a finalist in the category of Public-Private Partnership in the first annual STEM Education Awards competition sponsored by the Technology Association of Georgia.

The partnership was honored for its efforts to increase the number of graduates in the critical-demand areas of science, technology, engineering and mathematics, according to Dr. Cliff Gardiner, DR. CLIFF GARDINER Associate Dean in the College of Science and Mathematics.

“It was remarkable to be in the room with over 200 people, many from schools and universities supported by such corporate heavyweights as Cisco, IBM and Georgia Power,” Gardiner said about the awards ceremony.

Citing the partnership’s goal to raise awareness about the need for creative STEM initiatives statewide, he noted, “Many of the corporate professionals there were looking to fill critical positions within their respective companies, which shows the ever increasing need for STEM graduates.”

He added that a number of graduates from GRU, Augusta Tech and Paine have already been placed locally and most current math/science students express interest in remaining in Augusta after graduation.

“The payoff is local, regional, national and potentially international,” said Gardiner. u

Discoveries in Progress

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Research

at a Glance

GEORGIA REGENTS UNIVERSITY

RESEARCH / SPRING 2013

Impulse Control SCIENTISTS HAVE FOUND an early step in how the brain’s inhibitory cells get excited.

A natural balance of excitement and inhibition keeps the brain from firing electrical impulses randomly and excessively, resulting in problems such as schizophrenia and seizures. However, excitement is required to put on the brakes.

“When the inhibitory neuron is excited, its job is to suppress whatever activity it touches,” said Dr. Lin Mei, Director of the Institute of Molecular Medicine and Genetics and corresponding author of the study in Nature Neuroscience.

Mei and his colleagues found that the protein erbin, crucial to brain development, is critical to the excitement.

It was known that a protein on the cell surface called TARP gamma-2, also known as stargazing, interacts with a brain cell receptor

called AMPA, ensuring the receptor finds the cells surface. It is here that the receptor can be activated by the neurotransmitter glutamate.

AMPA receptor activation is essential to activation of the NMDA receptor, which allows cells to communicate, ultimately enabling learning and memory, Mei said. How TARP gamma-2 was DR. LIN MEI controlled was an unknown.

Inside the nucleus of inhibitory cells in areas of the brain that control learning and memory, the researchers found erbin interacts with TARP gamma-2, enabling it to survive. “If you do not have this mechanism, your stargazing becomes very unstable and your AMPA receptor cannot be on the surface, so this neuron is inactive,” Mei said. They also found that erbin is only

RED: inhibitor neurons; GREEN: excitatory neurons

in these inhibitory neurons, called interneurons. They’re already working on what they believe to be the counterpart for excitatory cells, which account for about 80 percent of brain cells.

“Interneurons basically control firing,” releasing GABA, a major inhibitory neurotransmitter, Mei said. They tone down or synchronize the activity of pyramidal cells, pyramid-shaped neurons that get both excitatory and inhibitory input, then make the call on what action to take.

When scientists ablated the erbin gene in mice or kept erbin from interacting with TARP gamma-2, a protein that helps anchor the AMPA receptor on the cell surface, TARP gamma-2, couldn’t do its job. The result was less receptors on the cell surface and hyperactive mice with impaired learning and memory.

Cell activity hinges on receptor activity, and receptors must be

Driving Fitness anchored on the cell surface to work. Ensuring AMPA receptors are strategically placed is a lifelong task since the busy receptors wear out and each brain cell has tons of them, Mei said.

In 2007, he and his colleagues reported in the journal, Neuron, two genes – neuregulin-1 and its receptor ErbB4 – that help maintain a healthy balance of excitement and inhibition by releasing GABA at the sight of inhibitory synapses, the communication paths between neurons. Years before, they showed the genes were also at excitatory synapses, where they also could quash activation. Both genes are involved in human development and implicated in schizophrenia and cancer.

Mei is a Georgia Research Alliance Eminent Scholar in Neuroscience. u

A SIMPLE, ACCURATE testing protocol to determine driving fitness in individuals with multiple sclerosis is the aim of a three-year GRU study.

Dr. Abiodun Akinwuntan, Interim Associate Dean for Research in the College of Allied Health Sciences, has received a $360,000 grant from the National Multiple Sclerosis Society for phase one of a study of MS patients at GRU and the Andrew C. Carlos MS Institute at the Shepherd Center in Atlanta.

“Multiple sclerosis is a progressive neurological disease that affects the ability to drive. In the early stages, it is possible for some patients to remain safe drivers; however, it is only a matter of time before the disease progresses to a level where driving is unsafe,” said Akinwuntan.

The accident rate for drivers with MS is estimated to be three times higher than that of similarly aged healthy individuals.

In an earlier study, Akinwuntan assessed 50 patients with relapsingremitting MS, the most common of four types, and determined that just five specific fitness-to-drive tests could predict pass or fail outcomes on a road test with 91 percent accuracy.

Current practices administer 15 to 22

DR. ABIODUN AKINWUNTAN tests that last up to three hours and cost as much as $450. The five psychometric off-road tests can be given in less than 45 minutes for approximately $150.

The new study hopes to validate those findings by including patients with all four types of MS, expanding the number of subjects to 180, and narrowing participation to those who score between 3 and 7 on the Expanded Disability Status Scale.

“Studies have shown that typically those who score below 2.5 are relatively good drivers and those above 7 are not to fit to drive,” Akinwuntan said. “So we are concentrating on those people in the middle who are starting to experience deficits that would affect their driving.”

A planned second phase of the NMSS study will focus on drivers’ training.

Running concurrent with phase one is a supplementary study funded by an Extramural Success Award from the GRU Research Institute to compare driving simulation training with Wii-based exercise training to determine the more effective treatment. Dr. Miriam Cortez-Cooper is coinvestigator. u

Seamless Education COORDINATION and communication are key in helping juveniles reintegrate into school following incarceration, according to a GRU researcher.

Under-prepared and underpaid teachers, lack of timely access to academic records, lack of curricular coordination and poor communication among the community, school and correctional facility all can stymie this population’s academic success, according to Kathy Hogan, Professor of Educational

Leadership, Counseling, and Special Education.

“Rather than making the child feel as if he is being moved out of a detention center into another prison-like setting, all of the organizations must work together to effectively meet the educational needs of that student,” Hogan said.

She recommends establishing a seamless transfer of educational records and services to and from schools and correctional facilities, developing

individualized transition plans and establishing a youth tracking system.

She also urges school systems to develop intervention programs that focus on structured learning, school achievement and job skills.

Hogan recently presented her research at the 2013 International Child and Adolescent Conference in Minneapolis. u

Discoveries in Progress

9

Taking a Shot at Cancer CLINICAL TRIALS ENSURE CUTTING-EDGE TREATMENT

GEORGIA REGENTS UNIVERSITY

RESEARCH / SPRING 2013

After Joyce Chavis of Aiken, S.C., underwent surgery and chemotherapy for stage IV colon cancer in 2009, her treatment went well—so well, she says, that there were no signs that the cancer would ever come back.

Until it did.

JOYCE CHAVIS

BY DANIELLE WONG MOORES

GRU Clinical Trials Patient

Last December, her doctor found that her cancer had metastasized to her liver.

Because Chavis was on blood thinners, she was no longer a candidate for a standard therapy combining chemotherapy and Avastin. Instead, her oncologist referred her to the Georgia Regents University Cancer Center’s new Phase I clinic.

The clinic and a new partner immunotherapy clinic are just two indications of the major changes spilling out of the center’s newly reinvigorated clinical trials program. And there’s much more to come, said Dr. Samir N. Khleif, who just completed his first year as Director of the GRU Cancer Center.

Khleif has articulated his goal of National Cancer Institute designation, making GRU’s only the second such center to be so designated in Georgia. Last year, Gov. Nathan Deal pledged $5 million in state funding to support the initiative—a major component of which is a vibrant clinical trials program, offering innovative treatments available nowhere else in the region.

“One of the roles of a cancer center— particularly one that is National Cancer Institutedesignated—is to provide not only research and not only clinical care, but the latest combinations of research and clinical care,” said Khleif. “That means clinical trials, which help us provide the latest and most advanced care to the region. They also help us better understand disease biology and the causes of disease and further understand how cancer therapies work and how we can make them better.”

* Read about Rixe’s business, SISENE Oncology, on page 30.

A True Phase I Program Three days after her doctor referred her to GRU Cancer Center, Chavis was talking to Dr. Asha Nayak, a medical oncologist who specializes in gastrointestinal cancers, and Dr. Olivier Rixe*, who joined GRU in 2012 as the cancer center’s Director of Experimental Therapeutics following similar roles at the University of Cincinnati and National Cancer Institute.

The Phase I clinic and the immunotherapy clinic were both established as clinical-trial portals for patients who have exhausted front-line options—and for physicians to refer to them.

Only about 10 to 15 academic centers across the country have dedicated Phase I programs, said Rixe.

“This is very innovative research testing new pathways that show

benefits for patients, with real Phase I experts, a dedicated clinical team and a connection with basic research to identify patients based on molecular characteristics,” he said. “And that’s just the tip of the iceberg in terms of what a Phase I program can offer.”

What is most important is that patients unable to undergo standard treatments can potentially see benefits from early drugs that may not be approved for worldwide use until five or 10 years from now. Chavis, for example, is taking part in a study looking at PD-L1 inhibitor—a drug that can potentially help her immune system recognize and fight the cancer cells in her liver.

Discoveries in Progress

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Targeted Therapies Research into immune therapies as well as molecular targeted agents—either alone or combined with standard treatments— started about 20 years ago. Today, this research is experiencing a wave of heightened interest nationally and internationally for its promise in arming the body itself to fight cancer with fewer, and less toxic, side effects than chemotherapy or radiation.

GEORGIA REGENTS UNIVERSITY

RESEARCH / SPRING 2013

The GRU Cancer Center is building on its expertise in this area, with the ultimate goal of personalized medicine, which would individualize treatment depending on patients’ specific biomarkers.

Some of that work has already started. The GRU Cancer Center is part of a multicenter Phase 3 vaccine study for patients with DR. OLIVIER RIXE

The vaccine already extends the life expectancy of certain men with prostate cancer by nearly 20 percent; preclinical animal studies in Khleif’s lab found that the drug combination led to a significant increase in survival and complete tumor regression in more than 50 percent of mice.

“It’s not about the Provenge,” explained Khleif, who first began researching vaccines about 20 years ago. “It’s a clinical trial combining a vaccine with two agents—one of which enhances further immune response with the vaccine, while the second prevents the inhibitory power of the tumor on the immune system. It’s about combining multiple strategies to achieve additional patient benefits.”

Director of Experimental Therapeutics

glioblastoma, a fast-growing and aggressive brain tumor.

The trial is testing a new cancer vaccine that targets the roughly 30 percent of patients with glioblastoma who have a genetic abnormality—a gene deletion known as EGFRvIII, said Rixe, who is overseeing the trial at GRU and has been involved in the early phase of development.

Patients with this gene deletion express a specific protein on the tumor’s surface—the marker that is recognized by the vaccine and that gives these patients an important advantage. “We have been involved in preliminary studies with the vaccine, and now this is the last round to test the strategy,” said Rixe. “The preliminary data from the earlier studies was very, very encouraging. While these results will need to be confirmed in large-scale studies here in the U.S., this is just one example of the very sophisticated and targeted studies we’re bringing to this region, with the hope of being able to change the outcome of these tumors.”

In addition, Khleif is the principal investigator on a clinical trial combining the prostate cancer vaccine Provenge with two other cancer-fighting drugs, CT-011 and cyclophosphamide.

DR. SAMIR N. KHLEIF

Innovative Clinical Trials georgiahealth.edu/cancer/trials or 888-658-0422

Homegrown Invention At about the same time that Khleif was doing his initial studies into cancer vaccines, Dr. David Munn, a pediatric oncologist and Associate Director of the university’s Cancer Immunotherapy Program, together with Dr. Andrew Mellor,

To date, the GRU Cancer Center has 90 phase I, II or III clinical trials open, with 12 new trials set to launch soon, focused on cancers that affect Georgia and the Southeast. These new trials include:

Director of the Immunotherapy Center, was making a significant finding of his own.

Certain enzymes send signals to the immune system that foreign objects—food, for example—are safe. Tumors, however, can evolve and mimic these signals to prevent the immune system from doing its job. “You don’t have to worry about the dumb tumors.

The immune system takes care of those,” said Munn. “The tumors that come to clinical attention are the ones that have figured out some way to activate those enzymes and elude the immune system.”

For example, an enzyme called IDO keeps the immune system from seeing a growing fetus as a foreign object. Munn hypothesized and confirmed that certain tumors use this same pathway to suppress immune response.

About 14 years ago, he and Mellor discovered a new drug in their GRU lab—called one-methyltryptophan, or 1-MT— that would reactivate the immune system so that it would recognize and attack cancerous tumors.

Director, Cancer Center

A Pilot Study to Test the Feasibility and Immunologic Impact of Sipuleucel-T (Provenge™) Administered with or without anti-PD-1 The trial is the first in the country mAb (CT-011) and Low Dose Cyclophosphamide to investigate prostate cancer in Men with Advanced treatment combining Provenge with Castrate-resistant two other cancer-fighting drugs, Prostate Cancer CT-011 and cyclophosphamide, and

looks to improve survival rates.

A Pilot study to test the feasibility of the combination of Gemcitabine and The treatment combines a anti-PD1 monoclonal antibody (CT-011) in the standard chemotherapy drug with treatment of resected a monoclonal antibody that may pancreatic cancer help the immune system fight

pancreatic cancer.

A Phase 1 Dose Escalation Study of BMS-982470 (Recombinant Interleukin-21, rIL-21) in Combination with BMS-936558 This Phase I study investigates the (Anti-PD-1) in Subjects combination and clinical benefits with Advanced or Metastatic Solid of two cancer drugs in patients Tumors with locally advanced or metastatic

cancer.

Phase III Study of Rindopepimut/GM-CSF in Patients With Newly Diagnosed Glioblastoma (ACT IV)

This study will investigate the efficacy and safety of an experimental cancer vaccine combined with the current standard in patients with recently diagnosed glioblastoma, a type of brain cancer, who have tumors that express the EGFR protein.

Discoveries in Progress

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After years of bench and animal studies, the drug founded in a GRU lab is going into clinical trials. While it still may be some years before the treatment could be approved in children (trials typically must first be conducted and proved in adult populations), one of Munn’s goals as a pediatric oncologist is to speed this process so that children most in need of these new treatments can benefit.

“We want to be able to enroll more pediatric patients into these early-phase clinical trials,” he said. “But what makes this more challenging is that no one center really has enough patients for early-phase clinical trials just in its own center. Our hope is to reach out to several large clinical programs and join our science with their enthusiasm for moving these trials into children.”

It’s the type of work that could take a lifetime, and said Munn with a smile, “It has. And what’s nice too is to have a local university cancer center offering something not invented in New York or elsewhere that trickled to us, but something that we actually invented here.”

That is the promise of clinical trials—that the research done today will benefit the patients of tomorrow. For her part, Chavis is optimistic—after all, she’s already seen what clinical trials can do: During her initial treatment for colon cancer, Chavis took a drug, now FDA-approved, that Rixe worked on developing earlier in his career.

And for Khleif, who once gave presentations titled “Taking a Shot at Cancer,” the exciting recent work in the vaccine field gives him hope that cancer treatments, one day soon, could be as simple as a shot. “I’m proud I stuck to it,” said Khleif. “It’s great to know now after this many years that this growing field is extremely important and one of the milestones in cancer treatment.” B

GEORGIA REGENTS UNIVERSITY

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Speedy Sequencing The GRU Cancer Center is now the only cancer research center in the state that can sequence the entire human genome in 24 hours for about $6,000—thanks to an upgrade in technology that researchers believe will allow them to develop more targeted therapies for cancer. Until very recently, the cost was more than $20,000 to sequence an individual genome.

Cancer researchers used to have to analyze individual genes—often many thousands of them in a process spanning several years—for mutations, scouring certain regions of the genome implicated in specific tumor types, said Lesleyann Hawthorn, a geneticist and Director of Shared Resources at the GRU Cancer Center. But over the past decade, years have morphed to weeks, and now hours, as technology has improved through a push by the scientific community for faster and less-expensive gene sequencing.

“Nationally, since 2001, scientists have been working toward sequencing the human genome within 24 hours and for under $1,000, and we are now approaching that,” said Hawthorn, noting that the first draft of the human genome took 13 years and $3 billion to sequence. “As a result, our researchers are now able to work more effectively in identifying specific mutations in hard-to-treat tumors, to help us develop treatments targeted to that particular person and tumor type.”

Along with the genome-sequencing upgrade, the GRU Cancer Center can now sequence single exomes—the protein coding part of the genome—on a single run of a new instrument called the MiSeq. All upgrades and new instrumentation were supported through a $2 million grant from the Georgia Research Alliance. u

Fear

Factor

Political Scientist Gleans Role of Emotions in Voter Behavior BY CHRISTINE HURLEY DERISO

Exuberance . . . incredulity . . . jubilation . . . misery . . . hope . . . despair.

These were among the emotions experienced by millions of Americans on the heels of the Nov. 6 presidential election.

The highly polarized reactions were intriguing in their own right, but a GRU Assistant Professor of Political Science was much more interested in voters’ emotions in the weeks and months before the election.

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“What do you want the public to look like in a democracy?” mused Dr. Kathleen Searles shortly after the election. “You hope they’re motivated by reason, but I’ve been struck by the disconnect of how we say that’s what we want, but we don’t act that way. We are an emotional electorate.”

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DR. KATHLEEN SEARLES

Assistant Professor of Political Science

Her growing body of research— starting with dissertation work at Washington State University studying the effects of fear and anger appeals in campaign ads on voters—seeks to tease out the psychology involved in political affiliation, both to better understand the electorate at large and to better understand ourselves.

She is finding increasing evidence that the thought process involved in voting is really a feeling process—which isn’t necessarily a bad thing, she hastens to add. “Emotion helps us navigate this very uncertain world,” she said. “We shouldn’t assume that intellectual shortcuts are necessarily bad.”

Humans are fed a constant stream of information from the moment of birth, she noted—now more than ever in this technological age—and the shortcuts prevent people from feeling overwhelmed or paralyzed with indecision. Therefore, it’s predictable and understandable that people who rally around one political issue will be more likely to support the entire platform of the party that supports it . . . or that an emotional affiliation with one party will trigger visceral emotions when that affiliation is threatened. This is why voters tend to justify their own candidates’ shortcomings while finding the shortcomings of their opponents inexcusable, Searles said.

That’s also why voters tend to seek out echo chambers, gravitating toward information that reinforces what they already believe. Any surprise, for instance, that Fox News viewers are also likely to listen to Rush Limbaugh? Or that those who read the Huffington Post likely eschew the Drudge Report?

This phenomenon—called selective exposing—also explains why emotional appeals to voters’ beliefs carry such resonance, Searles said, noting that this mindset applies to all voters. “Sophisticates—educated, wellinformed voters—are just as affected by angry or fearful ads as less-educated voters,” she said. “It’s not necessarily a bad thing; it just means you’re relating to your home team.”

And she adds that it requires no small measure of political awareness and sophistication to choose that home team in the first place. “Really, we find that voters [who are heavily invested in selective exposing] are more nuanced in their consumption of news and better-informed than we give them credit for,” she said.

Using grant funding from the American Political Science Association, Searles recently took her findings one step further. Having added to the body of evidence making it clear that emotions are integral to political behavior, she wondered if emotion could stir political involvement. She showed political ads to a group of GRU students, then determined which

The GOP, she said, has been more effective than Democrats in using emotional appeals to mobilize voters. “The conservatives found they have an upper hand in that area,” she said. “It helps to speak to people on more emotional terms.”

So how does she account for the election results?

“The problem wasn’t that Romney didn’t turn out his base,” she said. “The problem is his base is shrinking.

Looking back, we’ll say this was a realigning election. I think the GOP will have to revitalize, reframe and move away from some of the social issues that drag them down with women and minorities.”

Indeed, most political scientists gleaned the writing on the wall weeks, if not months, in advance of the election. “The media were incentivized to make it look like a really tight race, which it wasn’t,” Searles said.

Yet, largely because of the echo-chamber effect, she expects the electorate to continue to be polarized.

“Worldviews aren’t unshakable,” she said. “but if you’ve been raised by parents who offered a consistent political mindset, you’re likely to follow in their footsteps.”

And old tricks, she surmises, will continue to work. “I don’t think fear-based politics will ever not be effective; we’re hard-wired to respond to fear.

Politicians just need to be more savvy in appealing to people’s fears.”

Yet Searles does envision change on the horizon.

“I’m optimistic [that the electorate is becoming increasingly well-informed and sophisticated],” she said. “My students make me optimistic. They’re so savvy about seeking out information using technology.

They’re very nuanced.”

In addition to Searles’ plans to field this research with a larger, more representative sample, the next leg of her research involves how people choose their news sources in light of an ever-growing menu of choices. “Young people’s reality is all media all the time,” she said. “What does that mean for politics?”

The better people understand their own voting behavior—and that of society as a whole—the better their government is likely to be, Searles said. “I think it goes a long way to acknowledge [the emotional aspect of our decision-making],” she said. “It’s important to understand when emotion can facilitate political decision-making and when it becomes detrimental so that we can guard against the latter as much as possible.” B

“I don’t think fear-based politics

will ever not be effective.” emotion—fear or anger—made them more likely to make a political donation.

“We found that those already involved in the political process were more likely to donate when exposed to anger,” she said. “Those not involved were more likely to donate when exposed to fear.”

She’s still studying the results, but she theorizes that “the angry ads might have been just the push needed to get people to make a donation, while fear was more effective in getting people without much investment in politics involved in the first place.”

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CONQUERING THE

nig

ghtmare Researchers It’s a Explore Link Between Depression, Insomnia, Suicide BY TONI BAKER

gut-wrenching and potentially deadly trifecta.

Major depressive disorder of the magnitude that can wreck one’s life is among the nation’s most common mental disorders. The exhausting inability to sleep, called chronic insomnia, is most often a symptom of yet another problem, with about half of all cases related to a mental disorder such as depression. Suicide is a leading cause of death across all age groups, with the majority of suicides occurring in patients with an active psychiatric disorder, most commonly, major depressive disorder.

“These things layer on top of each other,” said Dr. W. Vaughn McCall, Chair of the Medical College of Georgia Department of Psychiatry and Health Behavior at Georgia Regents University.

“If you talk with depressed people, they really feel like they have failed at so many things. It goes something like, ‘My marriage is a mess, I hate my job, I can’t communicate with my kids, I can’t even sleep.’”

While the trigger may vary, the fact that depression, insomnia and suicidal thoughts feed on each other does not.

Patients with insomnia that persists over a year have a 30-fold increased risk of developing depression compared to

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the insomniac who gets treatment.

“That is like the risk of cigarette smoking for cancer: it’s huge,” McCall said.

His previous studies linked the intensity of insomnia symptoms and suicidal thoughts and established insomnia as predictive of suicidal thinking.

Now McCall and colleagues at Wake Forest University School of Medicine, the University of Louisville and Psychiatric Associates of North Carolina, have taken the next step, showing just how insomnia—and related sleepdisturbing nightmares—result in suicidal thoughts.

While a general sense of hopelessness is known to be a powerful predictor of suicide, the researchers suspected and found that insomnia leads to a very specific sense of hopelessness about ever getting another good

night’s sleep.

“If it were the exact same thing as a general sense of hopelessness, we would have nothing to report,” McCall said. “Rather, we found that what was really predicting suicidal thinking was all the negative thinking about your sleep. Having nightmares also was predictive of suicide. It’s fascinating, because what it tells you is we have discovered a new predictor for suicidal thinking.”

The negativity is pretty overwhelming. Patients start thinking if they don’t sleep soon that they will fall apart; that their immune systems will be irrevocably damaged; that their lives and health are in a tailspin that nothing can stop.

McCall already directly challenges

these negative thoughts, telling his patients that science disputes this conventional wisdom. His latest study in the Journal of Clinical Sleep Medicine, the journal of the American Academy of Sleep Medicine, supports this strategy as well as targeted therapies for nightmares. It also reminds physicians that when depressed patients start reporting increased sleep problems, it’s a good time to ask again about suicidal thoughts.

“Worsening insomnia is a red flag,” said McCall.

To pinpoint the relationship between insomnia and suicidal thoughts, the scientists used psychometric testing to objectively assess the mental state of 50 depressed patients age 20-80

The Study: Wake Forest University is assisting in statistical analysis for the study.

Individuals with sleep apnea and severe suicidal thoughts are excluded. Participants will be referred for outpatient management after the study.

For more information, contact Senior Research Assistant Mary Anne Riley at mriley1@gru.edu or 706-721-1011.

Insomnia Aids:

N Wake up at the same time every day.

N Don’t go to bed until you are sleepy.

N Avoid caffeine, alcoholic beverages and tobacco products.

N Exercise at least four hours before bedtime.

N Allow ample time to digest a meal before bedtime.

DR. W. VAUGHN MCCALL and Staff

being treated as an inpatient, outpatient or in the Emergency Department. More than half had attempted suicide and most were taking an anti-depressant. Testing enabled the researchers to filter out other suicide risks such as depression itself and home in on the relationship between insomnia and suicide risk, asking specific questions regarding those dysfunctional sleep beliefs such as: Do you think you will ever sleep again?

“It was this dysfunctional thinking, all these negative thoughts about sleep that was the mediating factor that explained why insomnia was linked to suicide,” said McCall, who started the study predicting that general hopelessness would be the obvious culprit. What he found instead was an intermediary: that hopelessness

Chair, Department of Psychiatry and Health Behavior, Medical College of Georgia

about sleep seemed to explain the association between insomnia, suicide and nightmares.

“People who have nightmares will tell you they are up and down all night. When they do sleep, it’s very restless and they feel tired when they wake up.”

In fact for many, broadly defined insomnia includes nightmares— and nightmares and dysfunctional thoughts about sleep and their lives generally go hand in hand. Lack of nighttime peace starts disrupting the daytime, potentially affecting everything from the general zest for life to libido. And it’s lonely.

“There is something peculiar about being awake and isolated in the middle of the night and feeling like your options are reduced,” McCall said. “You can’t just pick up the phone at 2 a.m. like you could at 2 p.m.”

Still, these patients have choices, and now he wants to know if one of the best ones is a sleeping pill.

“The more we look at it, the more it looks like insomnia by itself is a predictor of suicide. So the next question becomes: Why not treat insomnia strategically as a focus of care and see if that reduces suicidal thinking?” said McCall.

He’s principal investigator on a $1.2 million National Institute of Mental Health grant assessing patient response to this strategy.

The study at GRU, Duke University and the University of Wisconsin is enrolling 138 adults over four years. To help ensure their safety, all participants are receiving the anti-depressant fluoxetine for the eight-week trial while half also get the sedative hypnoticzolpidem.

If giving sleeping pills to insomniacs seems like just

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Magnetic Methodology common sense, consider that physicians are understandably concerned about giving sleeping pills to potentially suicidal patients. It goes back to the unfortunate trifecta. “We are faced very commonly with a patient who is not sleeping, is depressed, is suicidal and the treating physician is understandably concerned about giving that patient sleeping pills,” McCall said.

In fact, some sleep experts routinely condemn sleeping pills, saying the pills themselves are potentially deadly, independent of suicide. Other people with chronic insomnia never seek professional help, trying home or natural remedies while negative thoughts about sleep escalate. If they do seek medical care as problems mount, they may find themselves with a doctor hesitant or even adamantly opposed to hypnotics, McCall said.

But if McCall and his colleagues can show a direct link between insomnia treatment and reduced suicidal thinking, it could help mainstream targeted drug therapy as well as non-drug approaches such as the structured talk therapy McCall uses to target faulty thoughts such as, ‘I will never sleep again.’

They already have evidence that the intensity of insomnia correlates with the intensity of suicidal thoughts as well as a pilot study linking proactive hypnotic treatment to reduced suicidal thoughts. In fact, 31 studies have linked insomnia to suicidal thoughts, behavior or death. Still, suicide risk factors and prevention often overlook insomnia, McCall said.

Acknowledging the very vulnerable population under study, numerous safeguards are built into the research protocol, such as participants getting only one week’s supply of sleeping pills for the first two weeks, then getting a two-week supply if their suicidal thoughts stabilize.

Additionally, they are asked to take the drug shortly before going to bed and to allow eight hours for sleep.

Sleeping pills such as zolpidem accentuate the body’s normal mechanism for sleep by targeting GABA, a neurotransmitter that slows the brain’s metabolism, McCall noted. Existing antidepressants don’t affect GABA. Many over-the-counter sleep aids are essentially antihistamines; histamine is another neurotransmitter that helps keep you awake. In insomniacs, GABA tends to be underactive while histamine works overtime.

The question remains: Can these drugs help stop suicide?

“When a patient comes in and says, “I am depressed and I can’t sleep,’ what should you do about that? Is it better to treat the insomnia or not? That is what we are going to find out,” McCall said. B

W

hile powerful magnetic stimulation of the frontal lobe of the brain can alleviate symptoms of depression, those receiving the treatment did not report effects on sleep or arousal commonly seen with antidepressant medications, researchers say.

The finding resulted from a secondary analysis of a study of 301 patients at 23 sites comparing the anti-depressive effects of the Neuronetics Transcranial Magnetic Stimulation Therapy System (TMS) to sham (placebo) treatment in patients resistant to antidepressant medications.

TMS sessions were given for 40 minutes, five days a week for six weeks. Initial findings, published in the journal Biological Psychiatry in 2007, were the primary evidence in the Food and Drug Administration’s approval of TMS for depression.

The secondary review reaffirmed TMS’s effectiveness in depression but revealed no

differences in rates of insomnia or sleepiness among those who got actual and sham therapy. Patients in the treatment group were also no more likely to request medication for insomnia or anxiety.

“It’s important for us to understand the full range of the effects of any treatment we give,” said said Dr. Peter B. Rosenquist, Vice Chair of the Department of Psychiatry and Health Behavior and corresponding author of the study in the journal Psychiatric Research, noting that new findings will assuage worries of the sleep-related side effects associated with many antidepressants. u

Major depressive order is one of the most common mental disorders in the United States, affecting about 6.7 percent of adults in a 12-month period with about 30 percent of these cases classified as severe, according to the National Institute of Mental Health.

ECT Effectiveness

P

atients whose severe depression goes into remission for six months following electroconvulsive therapy report a quality of life similar to that of healthy individuals, researchers say.

Researchers looked at quality-of-life questionnaires filled out by more than 500 patients, rating themselves on topics such as physical function, pain, vitality and social function. About half the patients went into remission after ECT, and researchers completed their information-gathering, including pre- and post-ECT quality-of-life measures, on 64 patients who remained in remission at six months.

The patients had poor quality-of-life scores before ECT, reflecting a severity of disease that made them strong candidates for the therapy. Researchers compared those scores to depressed patients who did not receive ECT as well as a group of about 500 healthy individuals.

After therapy, the worst scores generally normalized. The not-so-great news was that not enough patients stayed in remission, notes Dr. Vaughn McCall, Chair of the Department of Psychiatry and Health Behavior, an expert in depression and ECT and corresponding author of the study in the Journal of Affective Disorders. “We need to look at different drug treatments for patients to prevent relapse.”

In fact, McCall and others have early evidence that ECT patients who also take antidepressants fare better.

Antidepressant use was not restricted in this study. “The other possibility is that there are some people who seem to respond to nothing but ECT and will need booster ECT sessions to stay well,” he said.

Study co-authors include Dr. David Reboussin, Wake Forest University School of Medicine; Dr. Joan Prudic, New York State Psychiatric Institute and Columbia University College of Physicians and Surgeons; Dr. Roger F. Haskett, University of Pittsburgh School of Medicine; Dr. Keith Isenberg, Washington University School of Medicine; Dr. Mark Olfson, New York State Psychiatric Institute; Dr. Peter B. Rosenquist, MCG at GRU; and Dr. Harold A. Sackeim, New York State Psychiatric Institute and Columbia University College of Physicians and Surgeons.

The research was supported by the National Institutes of Health, the U.S. Public Health Service, Wyeth Pharmaceuticals and MECTA Corp. u

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ON SOLID GROUND Physicist Crunches Numbers to Better Understand Earthquakes

GEORGIA REGENTS UNIVERSITY

RESEARCH / SPRING 2013

DR. CHRISTIAN POPPELIERS

BY CHRISTINE HURLEY DERISO

Associate Professor of Physics

When a 5.8-magnitude earthquake struck

the Piedmont area of Virginia on Aug. 23, 2011, Dr. Christian Poppeliers was among many within a 500-mile radius who felt it.

“Our building [on the Summerville Campus] started shaking, pictures started moving on the walls and [my colleagues and I] looked at each other wondering what in the world was going on,” he recalls.

Yet just a couple of miles up the road on the Health Sciences Campus, the ground stayed steady and those on the campus were blissfully unaware of the excitement.

“That’s a perfect example,” said Poppeliers, Associate Professor of Physics, of how quirky earthquake waves can be.

His love of physics, math and precision has compelled him to try to sort out the quirks— or at least make them more understandable.

Funded by a $78,000 National Science Foundation grant, Poppeliers is studying earthquakes on several different fronts. For one component of the study, he is placing seismic instruments—those that

measure ground motion—in two geologically disparate locations, determining how the terrain will affect their measurements. The locations are only 30 miles apart but might as well be on different continents for Poppeliers’ purposes.

One of the locations, on the Savannah River Site, is south of the Fall Line, a 5-mile-wide geographical swath that runs across Georgia northeastward from Columbus to Augusta. The Fall Line separates the Piedmont Plateau region from the coastal

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plain, and marks the boundary between very old, crystalline bedrock that formed deep in the crust and marine sedimentary materials that were deposited by former oceans.

“The geologic terrain is very different on either side of the Fall Line,” Poppeliers said. “Very old, crystalline bedrock is exposed at the surface north of the Fall Line, whereas south of the Fall Line, there are thousands of meters of unconsolidated sand, silt and clay overlying quite young sedimentary rocks.”

Seismologists have expended tremendous energy predicting and measuring earthquakes, “but nobody’s ever controlled for what’s underneath seismic instruments,” Poppeliers said. “This will be the first controlled seismic experiment to measure such an effect.”

Noting that the instruments “are fantastically sensitive” and will detect earthquake energy from thousands of miles away, he wants to compare the measurements of the two sets of instruments, determining the effects of the underlying geologic materials, and how this affects the

POPPELIERS takes seismic readings.

determination of parameters calculated from the measured seismic waves. “Does terrain affect the results?” he mused.

“There won’t be good results or bad results; we’ll just observ e, I think, very different things.”

Those differences, he thinks, will be highly instructive, minimizing the chance that “different scientists will get differe nt measurements from the same seismic activity,” a common occurrence today, Poppeliers said.

In a follow-up study, he plans to deploy the 14 instruments in a specific pattern that will allow him to test various instrument spacings. The goal is to determine the optimal instrument spacing to calculate a certain seismic parameter, called a seismic gradient. “The farther apart the instruments are, the less sensitive they are to noise, but the gradients that we calculate from them are less accurate,” he said. “I want to determine the sweet spot.”

As he pursues his efforts to make the measurements more precise, he is also studying the exact nature of the waves themselves. Earthquakes—which result when the earth’s plates shift suddenly, usually along a pre-existing break, or fault, in the earth’s crust—are simply the most extreme manifestation of an ongoing roiling beneath our feet. This is a good thing; should the roiling suddenly cease, “our planet would flatten and be covered in water. Earthquakes build mountains,” Poppeliers said.

He therefore has a healthy respect for the waves that churn relentlessly underground.

And he wants to understand them better.

Seismic waves, those most associated with earthquakes, are widely studied. But a subspecies of underground waves, rotational seismic waves, has been largely overlooked. “We rarely measure them; they’ve been considered inconsequential,” Poppeliers said. By putting them figuratively under the microscope, he hopes to glean previously overlooked information about earthquakes and the planet in general.

He is also working with Dr. Predrag Punosevac, Assistant Professor of Math, to produce mathematical equations enabling threedimensional seismic measurements, rather than the two-dimensional measurements currently available. “When we observe seismic waves,” he said, “we see a two-dimensional cross-section. When you formulate the right equations, you can open up a third dimension. We’ll still use the same seismic instruments, but the burial and processing technique will be different. Dr. Punosevac and I have identified a couple of key areas that need to be developed more rigorously. Once we nail the math, we’ll bury the

understand how the fault [causing an earthquake] actually ruptured,” he said. “I want to better understand the fault properties of an earthquake.”

He works extensively with undergraduate students in his research, hoping not only to infuse them with his expertise, but his passion. “Seismology is the most mathematical of all the geosciences,” he said. “It’s the physics of wave propagation and waves are naturally amenable to math.”

As the equations keep coming, he theorizes, the less shaky the science of seismology will be. B

“...our planet would flatten and be covered in water. Earthquakes build mountains,” Poppeliers said.

instruments and process the data using our new techniques.”

Poppeliers hopes his studies “will help us better

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Hatching Success: Incubator Nurtures Growth of Life Sciences Businesses

GEORGIA REGENTS UNIVERSITY

RESEARCH / SPRING 2013

DR. CHRIS McKINNEY

BY JENNIFER HILLIARD SCOTT

On the second floor of the Interdisciplinary Research Building at Georgia Regents University, through an unassuming set of double glass doors, lies a virtual pathway where science travels from discovery to the open market.

Director of the Life Sciences Business Development Center

It’s a place where researchers working to develop new drugs to treat the most aggressive cancers work down the hall from those who’ve figured out how an extract from green tea leaves can treat everything from dry mouth to fever blisters to dandruff. In nearby labs and offices, others are investigating how fish that grow to only 2 inches long can help determine the effectiveness of new therapeutics at treating degenerative diseases. And, another stone’s throw away, others work to develop new biomarkers for human disease.

In many ways, the Life Sciences Business Development Center, known as the incubator, is like a real incubator. It hatches viable companies from scientific discovery. It nurtures those companies by providing support services and a physical space to grow and mature. And, often, it protects those companies until they’re ready to brave a rapid-fire marketplace on their own.

“We offer scientists a different approach to incubation,” says Dr. Chris McKinney, GRU Associate Vice President of the Office of Innovation Commercialization and Director of the Life Sciences Business Development Center. “It’s not a rapid process where we bring them in, quickly mature them and then push them out the door. We are here to help them with every stage of what can be a lengthy process, from the bootstrap efforts of starting a company, to finding funding from angel investors, to getting them ready to function independently in the marketplace.”

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The incubator got its start nearly 10 years ago when former Georgia Gov. Sonny Perdue launched the Center of Innovation for Life Sciences with funding from OneGeorgia Authority. The mission – to centralize industry-related life sciences initiatives statewide –perfectly dovetailed with the mission of the state’s health sciences university: to improve health and reduce the burden of illness on society.

The center offers approximately 16,000 square feet of space that can house up to five entrepreneurial businesses. Individual units include a large wet lab, a separate clean room or culture room and two offices. Major scientific equipment is included as well. Business can also easily access the university’s Core Laboratories, which offer stateof-the-art scientific equipment and expertise.

“We offer them a riskreducing approach to growing business,” McKinney says. “Bio business startup us costly – purchasing equipment and real estate for lab space can add up quickly. With our space, those costs are minimized.”

But beyond the real estate, the incubator offers tenants much more, he says. “The incubator and the people housed in it serve as motivators and a source of morale. Here, startups are working around other startups. There is some camaraderie in that struggle – we all sort of become one big, extended family throughout the process.”

That process ultimately should include creating jobs, commercializing new products and services, increasing companies’ value, expanding the life sciences business base in Augusta and contributing to the economic prosperity of the state.

“We really aim to grow these companies organically, which is a process,” McKinney says.

“It’s like growing a Thanksgiving turkey instead of buying it off the shelf. We want to make the

company successful and then the investors come to you, instead of doing it the other way around and chasing investors up front. That process tends to take the focus away from what makes the business works. Our model is different because we are creating great ideas and helping people cook and grow those great ideas here. If they grow them here, they are likely to stay here and be huge economic drivers.”

Here’s a look at the incubator’s current tenants:

SISENE Oncology

S

ISENE Oncology, which develops therapies to treat the most aggressive forms of cancer, is the new kid on the incubator block. The company recently received a Venture Lab grant from the Georgia Research Alliance to help bring its operations to Georgia and develop a partnership with the GRU Cancer Center.

Dr. Olivier Rixe, Director of Experimental Therapeutics at the GRU Cancer Center, spent much of his early career studying under an international cancer pioneer. His mentor was French physician Jean Plouet, who co-discovered Vascular Endothelial Growth Factor protein, one of the main drug targets for cancer therapeutics.

The VEGF protein uses a specific pathway to signal the body to form new blood vessels from existing ones—an important process in transitioning tumors from dormant or benign states to malignant.

Drugs preventing that signal—called antioangiogenics—are standard treatment for many solid tumor cancers, Rixe says.

Plouet formed SISENE in 2007 in France, as an international biotech company focused on developing patented cancer drugs and ophthalmic therapies. While studying anti-angiogenesis pathways and targets before he died in 2008, Plouet discovered a new molecule with significant anti-tumor effects called NOV C-ter, which could be a

SISENE Oncology

DR. OLIVIER RIXE

Director of Experimental Therapeutics

new therapy for some of the most devastating cancers. malignant brain tumor, as well as other large solid The molecule acts on specific pathways to starve tumors, including lung and colorectal cancers. Rixe, as tumors and prevent the growth of new vessels, Chief Scientific Officer, leads the team, which includes without some of the toxic effects of current therapies. other GRU Cancer Center and SISENE scientists, as Because forming new well as researchers blood vessels is vital to from the National “NOV C-ter is a very exciting, normal body processes, Cancer Institute and the very promising new agent, and antiangiogenics can University of Cincinnati. complicate things like our objective is to bring this and “NOV C-ter is a very wound-healing, heart exciting, very promising other cutting-edge treatment to new agent, and our and kidney function, fetal development and the clinic, where they have the objective is to bring this reproduction. Side effects and other cutting-edge potential to improve the quality treatment to the clinic, of angiogenesis inhibitors can include problems where they have the of life and life expectancy.” with bleeding, blood potential to improve clots, hypertension and protein in the urine, according the quality of life and life expectancy,” Rixe says. “Our to the National Cancer Institute. hope is to move this drug into Phase I clinical trials by SISENE is developing a new drug therapy targeting 2014.” B glioblastoma multiform, the most common type of

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Jinfiniti Biosciences

GEORGIA REGENTS UNIVERSITY

RESEARCH / SPRING 2013

Recognizing an unmet need for the type of research he was doing, Dr. Jin-Xiong She founded Jinfiniti to offer a faster, cheaper way to process cell samples.

DR. JIN-XIONG SHE

Director of the Center for Biotechnmology

Jinfiniti Biosciences

Screening more than 450,000 newborns worldwide for genes that put them at risk for type 1 diabetes and following them for 15 years is, in a word, cumbersome. Enter robotics technology to speed up the process.

As principal investigator on a $10 million study called “The Environmental Determinants of Diabetes in the Young,” or TEDDY, She is piecing together genetic and environmental causes of the disease. Screening thousands of blood samples multiple times a year, he and his colleagues found no place that offered high-throughput scientific services on such a large scale.

“It is a wonderful High throughput uses robots, data-processing software and economic driver for this sensitive detectors to quickly conduct millions of “tests.” The process can rapidly identify active community, but more compounds, antibodies or genes than that, it supports that can illuminate starting points for drug design and for understanding commercialization the interaction or role of a particular and entrepreneurship, biochemical processes.

“There really was an unmet need,” something that is so says She, also Director of the GRU important. Biobusinesses Center for Biotechnology and Genomic Medicine. are the wave of the future.”

In 2010, She founded Jinfiniti Biosciences, LLC, to meet that need.

The company provides high-throughput scientific services including nucleic acid isolation, genomic analysis, antibody production, immunoassays, medicinal chemistry and toxicity evaluation for academic and pharmaceutical institutions. In its first two years, Jinfiniti had already secured two multi-year, multimillion-dollar contracts to isolate large numbers of RNA/DNA samples using an automated proprietary high-throughput platform that offers superior ability to process samples at high speed and low cost.

She’s short-term goal is providing those research services on a contract basis to pharmaceutical companies and large research programs, including the worldwide TEDDY program.

“It is a great way to provide our expertise and generate revenue, which we’ll use for further research and development,” She says.

“But our long-term goal is to help translate discoveries into clinical practice and ultimately improve people’s health.”

She and his 10 Jinfiniti colleagues are doing that by seeking biomarkers for human disease prediction and diagnosis. That could lead to more personalized drugs, which would better treat diseases such as diabetes and cancer.

It’s something She says wouldn’t be possible without the GRU incubator.

“Having that here is so important to career development,” She says. “Of course, it is a wonderful economic driver for this community, but more than that, it supports commercialization and entrepreneurship, something that is so important. Biobusinesses are the wave of the future.” B and Genomic Medicine

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Luminomics A small fish has the ability to illuminate what biology is capable of, according to Jeff Mumm, former head of Luminomics and a GRU biologist. “With the same general set of genetic tools, these animals can do something we can’t: regenerate lost cells and tissues.”

The key, he says, is figuring out how and leveraging that to create regenerative therapies for humans from existing drugs.

This company is harnessing a

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fish’s ability to regenerate cells into disease treatment.

As a postdoctoral fellow at Washington University in St. Louis, Mumm and his research partner, Eric Schroeter (now at Loyola University in Chicago). developed a technique that allowed them to eliminate specific cell types in zebrafish by adding a ‘prodrug’ to their water. Why zebrafish?

Because once the prodrug is removed, they can regenerate the lost cells. This simple technique facilitates the study of cellspecific regeneration, a new paradigm for most organ systems. The technique took a page from targeted cancer therapies, which work by directing bacterial enzymes to cancer cells, enzymes that convert otherwise innocuous prodrugs into cellkilling toxins. However, the mass killing effect typically used for cancer therapeutics was too broad for what they had in mind, Mumm says.

“Cancer-related toxins kill cells in and around the area, which is what you want for cancer because you don’t want to leave anything behind,” he says. “We were more interested in using this system in a cellspecific manner—to kill specific cells that are associated with degenerative disease.”

Luckily, Mumm and colleagues were able to find other prodrugs that have a much more targeted effect.

The system works by transgenically targeting the bacterial enzyme to specific cells like the insulin-producing cells of the pancreas, which are lost in diabetes. In addition, targeted cells express jellyfish proteins to light them up. Now, addition of prodrug not only destroys the targeted cells—through a process called inducible cellular ablation—but scientists can watch how zebrafish regenerate them in great detail.

“We quickly realized that idea was applicable to more things than we originally wanted to apply it to, including many high-profile degenerative disease, so we marched it over to the technology transfer office at Washington University.

They got us excited about the idea of starting a company.” Mumm and Schroeter worked with the university’s business school to develop a business plan and Luminomics was born. The company was actually incorporated in 2002, but wasn’t fully functioning until 2004. Mumm moved the company to the incubator at GRU in 2008.

The future of Luminomics, Mumm says, is based on using zebrafish to streamline drug screening, in particular large-scale screens to identify regeneration-promoting drugs. Drug screening is largely based on other animal models without much regenerative capacity. While those animals—particularly mice—have a genetic identity that is more like humans,

JEFF MUMM

“Upon realizing fish are really a rich disease modeling platform, we developed an automated screening system that facilitates evaluating up to about 200,000 fish per day,” he says. “The system is applicable to any light-based assay, thus particularly useful for monitoring the loss and regeneration of the cells we light up to model degenerative diseases.”

Mumm is working with Johns Hopkins University, which holds the largest repository of FDA-approved compounds in the country, with the idea that those drugs could be repurposed for new indications.

“The ultimate goal is finding a therapy that enables humans to regenerate lost cells,” he says. B

Luminomics

zebrafish have greater relevance for regenerative biology, according to Mumm.

“Fish have cells and proteins that do the same things in their bodies that they do in our—like make insulin. The individual pieces of the proteins can vary while the function remains the same.”

Because zebrafish develop functional body systems in about five days, Mumm and the Luminomics staff can model degenerative diseases in animals about the size of the head of a pin. This scale allows them to be applied directly to existing highthroughput screening platforms, platforms that allow researchers to quickly ascertain a drug’s effect.

Biologist and Founder, Luminomics

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Camellix Working to harness the power of ECGC – the component of green tea that suppresses the body’s inflammatory response, Dr. Stephen Hsu is developing better, natural treatments for illnesses, both common and rare. The company’s name is a combination of Camellia sinensis – the species of plant that

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produces green tea – and an “x,” which means “prescription.”

Stephen Hsu’s love affair with green tea began during less-than-lovely circumstances.

Working as a young boy on a rural farm in China during Mao Tse Tung’s Cultural Revolution, a normal day for him included raising pigs, growing rice and cultivating green tea leaves. What it didn’t include was running water.

“I was 16 years old and wasn’t given the opportunity to go to high school,” Hsu, head of Camellix and a GRU oral biologist, says. “I became very ill with a bad case of diarrhea for a very long time. The local farmers told me to drink this beverage and handed me water with a lot of the green tea plant leaves in it and I got better.”

Fast-forward nearly 20 years and Hsu has immigrated to the United States, earned his doctorate and is on the faculty in the GRU College of Dental Medicine, where he and his colleagues study oral cancer.

“I began to think back to my experiences on the farm and apply that to our study,” Hsu says. “It caused me to wonder, are there natural treatments that we were overlooking?”

The answer, Hsu says, was in the power of the green tea leaves that had cured him so long ago.

Specifically, the magic was in a component of green tea called ECGC, which helps suppress the body’s abnormal immune response.

What started as the study of green tea’s curative effects on cancer cells moved to other cells—in the skin, hair, salivary glands . . . just about any place in the body.

“The polyphenols, or ECGC, in the tea cleared the body of oxidative stress and protected against free radicals,” Hsu says. “It also led us to look at ECGC-regulated protein expressions that inhibited the body’s

“We have found that when viruses are exposed to modified polyphenols from green tea, they lose their ability to bind to cells."

DR. STEPHEN HSU

Camellix

inflammatory response. It prevented much of the damage cause by inflammation.”

Turning those lab discoveries into useful products seemed like a natural progression, he says.

In March 2012, Camellix launched its first green tea technology-based product— an over-the-counter all-natural chewing gum to treat dry mouth, the first consumer product released from the incubator. Those products were followed by dandruff and hair-loss shampoos and a treatment for fever blisters and cold sores.

But that, Hsu says, is the small part of the company. “What we really want to focus on is drug development,” he says. “We have found that when viruses are exposed to modified polyphenols from green tea, they lose their ability to find and infect cells.” Treatments capitalizing on that effect could yield preventions for herpes and HIV. “We all believe that natural products are the future for controlling diseases and chronic conditions, without toxic and harmful materials,” Hsu says. “But without the resources—the lab space, the credibility, the support from the university that the incubator has provided—none of it would be possible.” B

Oral Biologist and CEO, Camellix

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Dear Readers, Last April, Gov. Nathan Deal visited Georgia Regents University and signed important bills into law from the lobby of our cancer research building. This was much more than a symbolic gesture.

Gov. Deal is a vocal supporter of Georgia Regents University and our efforts to achieve National Cancer Institute designation for our cancer center. His budget last year included $5 million in cancer funding for GRU and, in his 2012 State of the State Address, he noted,

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“Georgians deserve a world-class, public medical university, and it will be a priority of this administration to have [GRU] among the top 50 nationally.�

The University System of Georgia Board of Regents is also in our corner. In August, the board voted to request $45 million in bond funding in fiscal year 2014 to help underwrite the cost of constructing a new, state-of-the-art $100 million cancer building on the health sciences campus.

This high level of state support has resulted in unprecedented momentum. Under the leadership of Dr. Samir Khleif, Director of the GRU Cancer Center, our team is rowing hard in the direction of building a world-class cancer center by:

FOSTERING collaborative research, LAUNCHING new models of care, CONDUCTING innovative clinical trials, IMPROVING the quality of life for people living with cancer and ENVISIONING the new facility that, with bond funding from the state of Georgia and vigorous financial support from individuals, corporations and foundations, will be the heart of a new comprehensive cancer complex at Georgia Regents University.

We are pursuing a bold, future-focused agenda. And in the months and years ahead, you’ll hear a lot about GRU becoming home to Georgia’s second NCI-designated cancer center. But as Khleif has observed, “It isn’t the NCI designation that matters most. It’s the process that leads to that designation. To get there, you build something extraordinary.”

How will you join us in building something truly extraordinary? We welcome your counsel, your time as volunteers and your actions as ambassadors for the Georgia Regents University Cancer Center. u

Susan Barcus Senior Vice President for Advancement and Alumni Affairs

GRU PRESIDENT RICARDO AZZIZ (left) with GEORGIA GOVERNOR NATHAN DEAL

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How to Donate To learn more about supporting the Georgia Regents University Cancer Center, please contact:

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Kathleen Luzier-Bogolea Director of Development GRU Cancer Center Office: 706-721-7398 Cell: 706-755-3957

Our mission is to provide leadership and excellence in teaching, discovery, clinical care and service as a student-centered comprehensive research university and academic health center with a wide range of programs from learning assistance through postdoctoral studies.

GResearch is produced by the Office of Communications and Marketing.

President Dr. Ricardo Azziz Provost Dr. Gretchen Caughman Senior Vice President for Research Dr. Mark Hamrick Senior Vice President for Communications and Marketing David Brond Editor Christine Hurley Deriso Photographer Phil Jones Writers Toni Baker Christine Hurley Deriso Danielle Wong Moores Jennifer Hilliard Scott

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www.gru.edu RESEARCH / SPRING 2013 Sniffing Out the Culprit GEORGIA REGENTS Health System physicians now have a quick, thorough method to identify the viruses and bacteria causing respiratory illness.

Within an hour, the technique, called polymerase chain reaction, determines which of 21 common viruses and bacteria are causing respiratory symptoms. Using a small nasal sample, PCR converts RNA to DNA and rapidly copies the DNA to determine the culprit, enabling targeted treatment. “Our goal is to get patients the most rapid, accurate diagnosis,� said Dr. Christine M. Litwin, Medical Director of Clinical Microbiology and Immunology.