Fall 2013 GResearch

Revealing Research into What Resonates in Mass Marketing

L L A F VOL. 1

NO. 2

2013

A Striking Message

D I S COV E R I E S

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P R O G R E S S

At a Glance Nailing the Problem Longitudinal Study Sheds Unprecedented Light on Diabetes

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Springing into Action Radiation Oncologist Aims for High-Impact Cancer Research

GResearch is produced by the GRU Research Office and the Office of Communications and Marketing.

President Dr. Ricardo Azziz Provost Dr. Gretchen Caughman

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Editor Christine Hurley Deriso Design and Production P.J. Hayes Design Photographer Phil Jones Writers Toni Baker Christine Hurley Deriso Jennifer Hilliard Scott Steven Uhles

Š2013 Georgia Regents University

What Resonates in Mass Marketing?

A Neu Mind Schizophrenia Symptoms Eliminated in Animal Model

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Senior Vice President for Research Dr. Mark Hamrick Senior Vice President for Communications and Marketing David Brond

A Striking Message

Medieval Mission Studies Redeem Era’s Long-Tarnished Reputation

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Doing This Right Research Perpetuates Pioneering Role in Sickle Cell Treatment

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Advancement Update Carlos and Marguerite Mason Trust

FALL

Dear Readers, Synergy.

That’s the order of the day as Georgia Regents University’s stellar legacy begins unfolding in earnest.

The consolidation last year of Augusta State University and Georgia Health Sciences University has launched countless exciting opportunities Other synergistic examples abound For instance, Dr. Marcia Loda’s to synergize our in this edition of GResearch, as well. marketing research (see page 18) now-combined health For instance, Dr. Wendy Turner’s has vast implications for the many research into the medieval era, discoveries that spring from our Office sciences and liberal particularly the treatment of mental of Innovation Commercialization. The arts research missions. illness at the time (see page 28), implications also apply to health care This edition of professionals in general, most of whom has meshed with initiatives in GRU’s Departments of Psychology and are intimately involved in the business GResearch points to Psychiatry and Health Behavior to world; indeed, countless practitioners just a few sterling launch a new era of health humanities. are actually business owners. Loda’s examples.

Read also about updates in sickle well-honed insights, and those of her colleagues in the James M. Hull College of Business, can benefit each and every one of them.

Such synergy was on full display at GRU’s Innovation Summit 2013 Sept.

17-18 at Augusta’s Kroc Center. This free conference featured distinguished thought leaders sharing strategies to create, invent, market, and disseminate potentially life-changing innovations.

The summit taught new ways to think about the future as attendees networked with industry colleagues to turn good ideas into great products.

DR. MARK HAMRICK D I S COV E R I E S

cell and diabetes research, including a $10 million National Institutes of Health grant to continue a longitudinal study of heritable and environmental contributors to type 1 diabetes.

Has there ever been a more exciting time to be a member of the Georgia Regents University research community? I think not. u

Senior Vice President for Research

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P R O G R E S S

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Research

at a Glance

GEORGIA REGENTS UNIVERSITY

RESEARCH / FALL 2013

Estrogen Impact REMOVING THE OVARIES before menopause appears to leave more of the brain vulnerable to stroke and increase the risk of Alzheimer’s disease, researchers report.

Low doses of estrogen started right after surgery appear to reduce this vulnerability in an area of the brain that typically is not super-sensitive to stress, said Dr. Darrell Brann, Associate Director of the Institute of Molecular Medicine and Genetics.

This robust treatment response supports the “critical window” hypothesis of beginning low-dose estrogen replacement therapy right after ovaries are removed in younger women and continuing it until age 51, the median age of onset for menopause, Brann said.

Women who abruptly and prematurely lose estrogen from surgical menopause have a two-fold increase in cognitive decline and dementia.

“This is what the clinical studies indicate, and our animal studies looking at the underlying mechanisms back this up,” said Brann, corresponding author of the study in the journal Brain. “We wanted to find out why that is occurring. We suspect it’s due to the premature loss of estrogen.”

In an effort to mimic what occurs in women, Brann DR. LAWRENCE C. LAYMAN (LEFT) AND SAMUEL D. QUAYNOR and his colleagues looked at rats 10 weeks after removal of their estrogen-producing ovaries that were either immediately started on low-dose estrogen therapy, started therapy 10 weeks later, or never given estrogen.

When the researchers caused a stroke-like event in the brain’s hippocampus, a center of learning and memory, they found the rodents treated late or not at all experienced more brain damage, specifically to a region of the hippocampus called CA3 that is normally stroke-resistant. To make matters worse, untreated or late-treated rats also began an abnormal, robust production of Alzheimer’s disease-related proteins in the CA3 region.

Both problems appear associated with the increased production of free radicals in the brain. In fact, when the researchers blocked the excessive production, heightened stroke sensitivity and brain cell death in the CA3 region were reduced. Follow-up studies are needed to see if estrogen therapy also reduces sensitivity to the beta amyloid protein in the CA3 region, as they expect, Brann noted. u DRS. DARRELL BRANN (LEFT) AND QUAN-GUANG ZHANG

Faulty Reception A RECEPTOR MUTATION that essentially blocks estrogen’s action has been identified for the first time in a female, researchers report.

The 18-year-old’s delayed puberty suggested too little estrogen, but studies instead revealed sky-high levels, said Dr. Lawrence C. Layman, Chief of the MCG Section of Reproductive Endocrinology, Infertility and Genetics. “Her body totally ignores estrogen,” Layman said. “Even at levels that are 10 to 15 times normal, it has no effect.”

Genetic testing determined a mutation in estrogen receptor-α, which is essential to reproduction and bone health, researchers report in the New England Journal of Medicine. The mutation results in profound estrogen resistance in women, said Layman, an expert in delayed puberty and the

PCOS Clue

study’s corresponding author, noting implications for reproduction, breast development, and bone health.

Estrogen binding with this receptor alerts the brain to its presence. In this case, that didn’t happen, so estrogen built up in her blood, eventually dumping in her urine, said Samuel D. Quaynor, an M.D./Ph.D. student at GRU and the study’s first author.

To fully understand the impact of the receptor mutation, they plan a large-scale screening to see if other substances bind to its altered state. u

DR. RICARDO AZZIZ

A GROUP OF TINY, newly discovered RNA molecules with a big role in regulating gene expression appears to have a role as well in causing insulin resistance in women with polycystic ovary syndrome and, perhaps, in all women, researchers report.

“This is one of the first reports of a defect that may occur both in women who are insulin-resistant and, in particular, in women with PCOS,” said GRU President Ricardo Azziz, a reproductive endocrinologist. “Identifying this molecular mechanism helps us understand these common conditions better and points us toward targeted therapies to correct these problems.”

NORMAL OVARY

Research in the journal Diabetes indicates that high activity levels of a microRNA called miR-93 in fat cells impedes insulin’s use of glucose, contributing to PCOS, characterized by excess male hormone and an increased risk for insulin resistance.

Researchers found that PCOS patients over-expressed miR93 and under-expressed GLUT4, a key protein that regulates fat’s use of glucose for energy, according to Azziz, the study’s corresponding author. GLUT4 expression was lowest in the women with PCOS who also were insulin-resistant. The researchers also found the expression was low in insulinresistant members of the control group.

He and his colleagues also reported recently in DR. the Journal of AZZIZ RICARDO POLYCYSTIC OVARY Clinical Endocrinology & Metabolism that PCOS patients with the highest level of insulin resistance “appear to have a double defect in how glucose is controlled, which affects both the mechanisms that use insulin and those that do not.”

A better understanding of these processes, Azziz said, should yield better treatments. u

Discoveries in Progress

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Research

at a Glance

GEORGIA REGENTS UNIVERSITY

RESEARCH / FALL 2013

SAMUEL HERBERG (FROM LEFT), DRS. WILLIAM HILL AND CARLOS ISALES

Bone Cell Survival A SIGNALING MOLECULE that helps stem cells survive in the naturally low-oxygen environment inside the bone marrow may hold clues to cell survival in the face of age and disease, researchers report.

They hope the findings, reported in PLOS ONE, will result in better therapies to prevent bone loss in aging and enhance success of stem cell transplants.

They’ve found that inside the usual, oxygen-poor niche of mesenchymal stem cells, stromal cell-derived factor-1, or SDF-1, triggers a survival pathway called autophagy that keeps the cells on task, said Dr. William D. Hill, an MCG stem cell researcher and the study’s corresponding author.

SDF-1 appears to change its tune with age or disease, said Samuel Herberg, GRU graduate student and the study’s first author. The researchers believe that changes in the normal environment that come with age or illness, including diminished nutrition, prompt SDF-1’s shifting role.

“You put new cells in there and, all of the sudden, you put them in a neighborhood where they are being attacked,” Hill said. “If we can precondition the transplanted cells or modify the environment so they have higher levels of autophagy, they will survive that stress.”

Autophagy is the consummate green, survival pathway, where the cell perpetuates itself by essentially eating itself over and over again in the face of low food sources, other stress or needing to eliminate damaged or toxic product buildup. The researchers believe autophagy slows with age, so deadly trash starts piling up in and around cells.

“Your cells normally have a reminder to take out the trash,” said Dr. Carlos Isales, MCG endocrinologist and Clinical Director of the GRU Institute of Regenerative and Reparative Medicine.

“That reminder, SDF-1, becomes inconsistent as you get older, so rather than being an activator of the trash signal, it becomes an inhibitor.”

Herberg led efforts to genetically modify stem cells from mice to overexpress SDF-1 and control autophagy in their novel cells.

They found that while SDF-1 didn’t increase stem cell numbers, it protected stem cell hazards related to low oxygen and more by increasing autophagy while decreasing apoptosis.

“The success of stem cell transplants is mixed, and we think part of the problem is the environment the cells are put into,” said Isales. “Ultimately we want to find out the triggering event for aging what initiates this cascade. This new finding gives us a piece of the puzzle that helps us see the big picture.” u

Retina Remix SEVERAL GRU RESEARCHERS are pursuing disparate but related physiological processes to target the blinding disease, diabetic retinopathy.

Drs. William and Ruth Caldwell, Chairman of the Department of Pharmacology and Toxicology and a cell biologist in the Vascular Biology Center, respectively, are using a $2.2 million National Eye Institute grant to optimize the balance of the amino acid, L-arginine, and the enzyme, arginase, in hopes of staving off the disease.

DRS. RUTH AND WILLIAM CALDWELL

DR. MOHAMED AL-SHABRAWEY

Also, Dr. Manuela Bartoli, an MCG vision scientist, has a $1.8 million National Eye Institute grant to try to bolster the body’s endogenous system for dealing with free radicals, which is dramatically impacted by diabetes—one consequence of which can be diabetic retinopathy.

She theorizes that a selenium supplement could bolster the body’s thioredoxin system, which works to maintain a healthy level of free radicals by neutralizing the excess. GRU Graduate Student Folami Lamoke also is studying thioredoxin, supported by a National Eye Institute fellowship.

And Dr. Mohamed AlShabrawey, a Culver Vision Discovery Institute vision scientist, has a $1.8 million National Institutes of Health Grant to try to trick the retina into producing good fat instead of bad to slow the disease. u

DR. MANUELA BARTOLI

Discoveries in Progress

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Research

at a Glance

Kidney Cell Recovery

GEORGIA REGENTS UNIVERSITY

RESEARCH / FALL 2013

GRU RESEARCHERS may have found a way to block kidneydestroying inflammation and help damaged kidney cells recover.

In a related study, they report progress on a non-invasive method to assess how much kidney function has survived a serious bout of inflammation or a chronic problem such as high blood pressure.

The diagnostic tool could help physicians determine whether patients have enough kidney function left to benefit from treatment or whether dialysis or a transplant is in their future, said Dr. Michael P. Madaio, nephrologist and Chairman of the Department of Medicine.

If the kidneys can be saved, this approach could also aid optimal delivery of drugs directly to ailing kidney filters.

The researchers induced acute kidney inflammation, or nephritis, in mice, then gave them prostaglandin E2. The kidneys’ filtering units promptly recovered. “The cells got better and the kidneys got better,” said Madaio, corresponding author of the study in the American Journal of PhysiologyRenal Physiology.

While prostaglandins are better known as natural proinflammatory lipid compounds, prostaglandin E2 has an antiinflammatory effect. The researchers suspected—and found—it also had the bonus regenerative properties.

“We’ve already got numerous ways to block inflammation, but what we hope is the magic here is the ability to also help injured kidney cells recover,” Madaio said. u

Watsky Named Dean DR. MICHAEL P. MADAIO

DR. MITCHELL WATSKY, former Associate Dean for Graduate Studies at the University of Tennessee Health Science Center, has joined GRU as Dean of Graduate Studies.

Watsky also serves as Professor of Cellular Biology and Anatomy, continuing to direct his research program, which includes several grants from the National Institutes of Health to investigate corneal wound healing.

“Dr. Watsky’s passion and experience as a teacher, mentor, researcher, and administrator are precisely what we hoped to find in a Graduate Studies Dean,” said GRU Provost Gretchen Caughman.

As Associate Dean at UT, Watsky reorganized the university’s Interdisciplinary Basic Sciences Program. He focused on coordinating the graduate programs run out of the College of Medicine. He also coordinated the university’s graduate program with St. Jude Children’s Research Hospital.

Watsky earned his doctorate in physiology at the Medical College of Wisconsin and completed a postdoctoral fellowship in physiology and biophysics at the Mayo Foundation in Rochester, Minn. He holds a patent as a co-inventor for the artificial cornea. u

Kidney Injury Biomarker A GUIDANCE CUE that helps kidneys form may also be a red flag that they are in danger, researchers report.

Acute kidney injury, which affects about 6 percent of all hospitalized patients and up to 40 percent of cardiopulmonary bypass surgery patients, can lead to chronic kidney damage that may require dialysis or a kidney transplant, said Dr. Ganesan Ramesh, kidney pathologist in the MCG Vascular Biology Center. Within hours of injury, a significant amount of the protein semaphorin 3A is detectable in the urine, Ramesh and his colleagues report in the journal PLOS ONE. “Semaphorin 3A appears to be a sensitive biomarker that we believe will give a heads-up to kidney injury so that damage can be minimized and potentially reversed with rapid intervention,” said Ramesh, the study’s corresponding author.

Kidneys are particularly vulnerable to decreases in oxygen levels that may result from lifesaving strategies such as cardiopulmonary bypass and mechanical ventilation, Ramesh said. When they stop filtering properly, the body starts dumping both good and bad products into the urine.

Unknowns about semaphorin 3A include the role of the guidance cue in the healthy developed kidney and why its levels shoot up then drop down so dramatically with injury. Ramesh is working on an antibody that will screen specifically for semaphorin 3A. The study was funded by the National Institutes of Health. u

Nigerian Roots DR. ABIODUN AKINWUNTAN, Director of the GRU Driving Simulation Laboratory and Interim Associate Dean of Research for the College of Allied Health Sciences, has been named a Fulbright Foreign Scholar to improve physiotherapy education and research and the rehabilitation of neurologically impaired patients in his home country of Nigeria.

He will spend 10 months teaching and conducting research in the University of Lagos College of Medicine.

“There are many Nigerians abroad in academia and research who do fantastic work but aren’t able to return to help improve health care delivery,” said Akinwuntan,

DR. GANESAN RAMESH

a naturalized U.S. citizen. “This will enable me to use my knowledge and expertise to improve the country’s quality of physical therapy education and clinical rehabilitation. On a personal level, I welcome the opportunity to give back to my country of origin.”

The Fulbright Program, administered by the U.S. Department of State’s Bureau of Educational and Cultural Affairs, matches countries seeking expertise in certain areas with U.S. faculty and professionals who can provide it.

Akinwuntan’s award is the first granted to further physical therapy education and research in Nigeria. His research component will compare virtual reality-based rehabilitation with conventional strengthening and reaching exercises, aiming to optimize treatment of upper limbs after stroke. u

Discoveries in Progress

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RESEARCH / FALL 2013 GEORGIA REGENTS UNIVERSITY

Nailing the Problem Longitudinal Study Sheds Unprecedented Light on Diabetes

BY TONI BAKER

VIRGINIA HARRINGTON (from right) with sister Ella and parents Mike and Shannon

Big sister Ella says Virginia has the gene to randomly burst into song.

Virginia responds with a too-precious smile and the promise to just maybe demonstrate later. Ella retorts with a roll of her eyes.

No doubt Virginia and Ella both have some fabulous genes with their obvious smarts, quick smiles, long legs, and physical prowess.

For Ella, 10, that’s running the hills of beautiful, slightly rustic Cumming, Ga., with her dad, Mike Harrington, and maybe some soccer and basketball. Virginia, 8, is good at gymnastics— although Ella gives her mediocre reviews—and she has been dancing since she was 3. Mom, Shannon Harrington, is certain an Oscar lies in Virginia’s future.

Family Legacy

Just seven months ago, Shannon and Mike learned that Virginia’s life also will include type 1 diabetes. It was hardly great news, but it was not unexpected. When Virginia was born at Northside Hospital in Atlanta, Shannon was asked if she wanted her newborn tested for

high-risk genes for type 1 diabetes. She didn’t hesitate. The great-great-grandmother of the baby who now lay in her arms had type 1 and her daughter did as well. Both would die way too soon, mom at age 37 and her child just three weeks later at age 10.

It turns out that Virginia and her greatgreat-grandmother would have even more in common. Mattie May Baldwin Acton, an Augustan, would travel to Boston where Dr. Elliott P. Joslin, the first physician to specialize in diabetes, enrolled her in one of the first diabetes studies. Nearly 90 years later, that positive newborn blood test qualified Virginia for a truly unprecedented and massive study to determine how genes and environment work together to cause type 1 diabetes.

The Environmental Determinants of Diabetes in the Young (TEDDY) study is

Discoveries in Progress

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RESEARCH / FALL 2013

DR. JIN-XIONG SHE

Director, Center for Biotechnology and Genomic Medicine

following for 15 years nearly 9,000 children who, like Virginia, are genetically at risk.

Having just turned 11 itself, TEDDY is giving scientists a unique opportunity to parse which genetic mutations correlate with progression or lack of progression to type 1 diabetes, says Dr. Jin-Xiong She, Director of the Medical College of Georgia Center for Biotechnology and Genomic Medicine.

Fourteen is the peak age for diagnosis in the United States. It’s a lifelong condition that prevents the body from using the glucose from food as the energy source it’s intended to be. Instead, the immune system attacks the insulin-producing cells of the pancreas so it can’t produce the insulin required to use glucose. In the short term, children can grow thirsty, urinate frequently, lose weight, and are often tired and hungry.

Longer term, the disease damages the heart, blood vessels, kidneys, eyes, feet, nerves, pretty much everything. Oddly, it often goes undetected until children show up extremely ill at an emergency room. Insulin shots are required to help manage the now-destructive glucose.

Simply a Bad Disease

“It’s simply a bad disease with a tremendous impact on children and their families that we’d like to help destroy,” says She, who gathered with colleagues more than a decade ago to plan their attack. He is principal investigator for the Georgia and Florida consortium of the study, which also has centers in Colorado, Washington, Finland, Sweden, and Germany.

Since 2003, 424,788 newborns have been screened by the centers for two genes believed to put them at high risk for type 1 diabetes. Screening closed March 1, 2010, and the youngest child is now three, the oldest 9.

It’s a truly massive undertaking for science and families that seems to provide more pleasure than pain to both.

The children’s blood is examined regularly for signs of the immune system attack on their insulin-producing cells. The blood also provides a window into the activity of genes as parents keep detailed records of what their children eat and when they

get sick, stressed, or vaccinated.

Parents also provide samples of their local water supply and their child’s fingernail clippings and stool.

It’s this close scrutiny through the peak ages of disease development that is enabling the longitudinal perspective.

“We are looking at the genes, genetic expression, the proteins, and the small molecules called metabolites, which are the products of our metabolism,” says She, Georgia Research Alliance Eminent Scholar in Genomic Medicine, running through the sequence of how genes produce both good and bad results in the body.

The Big Picture

“We are using this information to correlate the progression or lack of progression of the disease with different molecular markers and environmental triggers to understand all the factors

contributing to the development of type 1 diabetes, as well as what factors can provide protection from disease progression,” he says.

They are identifying differences in gene expression between children showing signs of autoimmunity, children with diabetes, and those who do not get the disease.

Meet Sheridan Carrier. Like Virginia, the 7-year-old comes from a fabulous family of four, but her sister, Danielle, 4, appears a bit shyer than Virginia’s big sister. Mom Tracy Carrier calls Sheridan “Freckles” because of the cute display across her nose. A strong intellect is also crystal clear in this child, who prefers to sit at the grownup table when her extended family gathers in Jackson, S.C. At home in Evans, Ga., she is an active, inquisitive child who likes to go hunting with her father, Dan, and play with her two dogs.

“She’d rather be in camouflage than a dress,” says her mom, “and I am

perfectly okay with that.”

When Sheridan was born at GR Medical Center, her mother also was asked about having her firstborn’s blood tested for two high-risk genes for type 1. Like Virginia’s mother, Tracy, of course, thought of her family and the power of knowledge. But the nurse and GRU graduate, who works at GRU’s Children’s Hospital of Georgia caring for children with cancer, was also thinking of her patients as well as stories about the incredibly sick children admitted on the floor below with the initial diagnosis of type 1.

“If my little girl can help another little girl not have diabetes or help them cure it by seeing what she ate this time or didn’t eat that time or if her poop looks different... ,” Tracy says, trailing off. There’s also that little girl back home in Jackson who was chronically sick and later found to have type 1.

SHERIDAN CARRIER, with parents Dan and Tracy

Discoveries in Progress

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The Magic of TEDDY

Where Sheridan and Virginia differ is part of the magic of TEDDY. All the poop and clippings and diet and infection records are providing the heaps of information that will determine why this child with the genes gets the disease and that one doesn’t.

“This is a whole new way of doing genetic studies.

This is the beauty and the power of the TEDDY study and, ideally, how all diseases should be studied,” says She, a geneticist who recently received $10 million in National Institutes of Health funding to continue his studies for another five years.

“We really have to look at the genetic components and the environmental components together, because they are inseparable. The fact is the same gene can behave very differently in a different environment,” She says, citing factors such as diet, air quality, and immunization schedules.

Identical twins provide the perfect case study. Even with their identical genes, there is still only a 50 to 70 percent chance that if one twin gets type 1, the other will also get the multi-gene disorder. Even in the same household, they don’t eat exactly the same kind or amount of food or even breathe the exact same air.

“They are not the same person,” She says.

The percentages are a little more straightforward for a monogenic, or single-gene, disorder, such as cystic fibrosis or neurofibromatosis, but still not 100 percent, he says. Part of the reason is, when drilling down to myriad details like the complement of the immune system, there are variations that also explain why, for instance, only one twin is allergic to mold spores.

Complex and Complicated

In fact, one of the many things She believes TEDDY will prove is that this sort of exhaustive study is the only way to create a relatively comprehensive understanding of a disease’s mechanism. He inserts “relatively” because of the reality that they will never know it all. Even the most comprehensive study reflects that study population, gene pools evolve slightly, the environment changes constantly. “It is so complex,” he says.

While She and his colleagues worked for a full two years to optimally design TEDDY, the study itself has evolved. As examples, they have started analyzing other suspect genes, collecting saliva, and monitoring exercise levels. While activity level is more associated with type 2 diabetes, it has a tremendous general influence on the body, including affecting the immune response, She says. “That is why this is so complicated.”

This approach is a big departure from traditional genome-wide association studies, which compare genetic variations in people with and without a disease—a process that identified the genes now used for the TEDDY screening. “You are basically looking at the frequency of genes in patients versus controls,” She says of an approach that has been popular for about two decades. At least in type 1 diabetes, it appears the approach doesn’t work very well.

However, massive data continually generated

by TEDDY are enabling scientists to watch all the pertinent pieces play out: gene expression juxtaposed with environmental exposures and, ultimately, with disease or lack thereof.

VIRGINIA HARRINGTON

Watching it Unfold

“We are watching it unfold at all levels. We are finding the real players. This is going to allow us to better predict which children will develop type 1 diabetes and, ultimately, what we can do to prevent or better manage this disease.”

The geneticist is willing to predict that this megacomprehensive approach will yield dozens more highly relevant genes and possibly more than 100 with some impact on disease progression. He also predicts it will mean putting aside some of 40 genes considered players today. While he won’t speculate on what they are, he anticipates some consistent environmental factors as well, regardless of the gene complement, and that some may be controversial.

The complexity and dynamics of disease development is already playing out in Georgia where the scientists are finding slower progression rates to full-blown diseases than in other parts of the world.

Interestingly, Georgia children are at greater risk for celiac disease, another autoimmune disease affecting intestinal cells. This didn’t surprise researchers, considering the overlap in high-risk genes for the two conditions. However, it was a surprise to Virginia and her mom, who both found out they had antibodies presaging the disease.

Heads-Up

This heads-up that already is preventing celiac disease from fully developing in many children is the kind of prevention researchers hope TEDDY will also enable for type 1. When antibodies to glutamate, a marker for the disease, are found, parents are advised that their child needs to avoid the disease trigger gluten, a protein in wheat, barley, and rye that prompts an immune response in the small intestines.

One of the gazillion things they’ll be analyzing is what percentage of study participants actually develop full-blown celiac disease, but She and others suspect that number will be small.

For the primary target, type 1, he envisions a simple screening test of all babies will detect those with highrisk genes. They will be told the likely environmental triggers to avoid based on their gene complement.

For those who already have antibodies—foreboding a disease risk as high as 90 percent—more aggressive drug therapies to block progression likely will be in order. “I envision multiple opportunities for disease prevention,” She says. In fact, the massive data generated by TEDDY likely will identify treatment targets and aid drug development for just that purpose.

“I think the next five years are going to be very exciting,” he says.

To date, nearly 500 of TEDDY’s 9,000 enrollees, who are now an average age of about 5, have persistent evidence of antibodies to their own insulin-producing islet cells—evidence that their immune system is turning on those cells—and more than 100 of the children already have type 1 diabetes. Researchers estimate that both groups will double in size in the coming years.

A Godsend

Antibodies started showing up in Virginia when she was just a toddler enabling the family to prepare for the diagnosis that would come in March 2013. That morning, Virginia was just a little “off,” and her blood sugar proved to be sky high. Mom immediately called Leigh Steed, the Atlanta TEDDY Site Coordinator, whose cell phone number she has had for years. As always, Leigh told her what they needed to do and what to expect.

“I feel like the study was a godsend,” says Shannon.

“I am thankful we knew so early and that we did not have complications and that we are happy and healthy and learning to deal with daily management.”

Not unlike the TEDDY study, they have developed a protocol that works: Virginia tests her blood sugar level; Mom takes a look; they decide together what to eat; Mom counts the carbs; Virginia puts alcohol on her skin; and Mom gives the shot of insulin.

Back in Evans, Sheridan remains antibody-free.

While mom admits to a little angst every time the envelope comes with the latest results, Sheridan, who is well aware of the study’s purpose, is more concerned about whether she’ll be a dolphin trainer or a veterinarian when she grows up. B

Jinfiniti Biosciences LLC, a biotech company led by She and housed in GRU’s Life Sciences Business Development Center, is the genomics laboratory for TEDDY.

Discoveries in Progress

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RESEARCH / FALL 2013 GEORGIA REGENTS UNIVERSITY

DR. SPRING KONG

Cancer Researcher, GRU Cancer Center

Springing into Action BY STEVEN UHLES

“I want to cure cancer. I want to heal people. But I can’t heal everybody and I can’t cure everything. That’s why I chose lung cancer.

One person dies from lung cancer every three seconds. Curing that is impact.”

Radiation Oncologist Aims for High-Impact Cancer Research

D

r. Feng-Ming Kong, Spring to her friends and family, has spent the better part of her career fine-tuning the radiation oncologist’s approach to eliminating lung cancer.

As the daughter of a smoker and the granddaughter of a grandmother who died of esophageal cancer while Kong was in medical school, she made the decision based on the easiest of equations: How many lives could she affect? How many lives could she save?

“I want to cure cancer,” she says. “I want to heal people. But I can’t heal everybody and I can’t cure everything. That’s why I chose lung cancer.

“One person dies from lung cancer every three seconds,” she says, noting it is the leading cause of cancer death. “Curing that is impact.”

Pinpoint Accuracy Seated in her office in the GRU Cancer Center’s research facility, she lights up when asked about the possibilities inherent in radiation therapy. Recounting a cartoon depicting a patient getting radiation therapy without leaving the car, Kong says while the fastfood model isn’t yet available to the lung, thoracic, and esophageal patients she treats, it’s closer than many might imagine. She explains that patients who once required as many as 35 radiation treatments might now find one to five equally effective, thanks to functional imaging and molecular markers that target the disease site with pinpoint accuracy.

Kong has spent the past three years conducting both animal research and clinical trials to refine the process. Armed with a five-year, $2.2 million National Cancer Institute grant, she uses radioactive tracers or probes to study physiological activities within tissue indicating cancer, enabling non-invasive diagnosis and helping clinicians gauge the effectiveness of treatment. Her research has helped determine the biomarkers—key molecular or cellular events that help

Discoveries in Progress

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types, has implications for a variety of cancers. “The technology is important,” she says. “It’s much more precise. You can be so accurate and really target, really focus, on a specific area.”

Just Getting Started Earlier radiation therapies often destroyed the tissue surrounding tumor areas, she notes, making the cure almost as damaging as the disease. And while conceding the significant price tag associated with discipline—with specialized equipment sometimes running into the tens of millions of dollars— Kong says the outcome always justifies the expenditure.

“It’s true,” she says with a laugh. “I do get to work with the most expensive tools, the

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RESEARCH / FALL 2013

distinguish healthy from cancerous tissues—enabling her to use the technology to target the disease site with pinpoint accuracy.

She is also the principal investigator on a five-year, $750,000 Varian Medical Systems grant studying radiation therapy in patients with operable Stage I lung cancer.

“The goal is to improve tumor control and decrease radiation toxicity in lung cancer patients,” Kong says. “What we are doing is giving patients options. That affects everything. It affects how they heal. It affects the quality of life. They are spending less time here and more time at home.

That’s the way it should be.”

Kong says her research, while focused on very particular disease

DR. SPRING KONG

most expensive weapons. But I am also saving lives. That makes what we do worthwhile.” She also notes that the technology often precludes more invasive and timeintensive procedures, such as surgery.

Kong’s research has already been published in more than 80 peer-reviewed publications, and she is a reviewer for more than 10 professional journals— yet her work at the GRU Cancer Center has only just begun. Prior to her appointment in April as the inaugural Chairwoman of the Medical College of Georgia Department of Radiation Oncology and the GRU Cancer Center, Kong oversaw thoracic radiation oncology at the University of Michigan. She was attracted to the

GRU Cancer Center not only by the work being done by its scientists and clinicians, but also the potential she saw.

“It was [GRU Cancer Center Director Samir N.] Khleif and his vision that motivated me,” she says. “It still motivates me. The things he wants to do, the things he is working toward—National Cancer Institute designation—they are important. And what’s most important is his commitment to patient resources. That’s what I’m excited about.”

Meeting a Need She considers her research and clinical work well-suited to a Cancer Center in a growing and under-served region, noting that the need—and Georgia’s need to supplement its sole NCI-designated

cancer center—will only increase.

“The community is growing,” she says. “What we do is needed.”

She is eager to spread the word, particularly to patients who may fear treatment. “If we can help them understand exactly what it is we can do,” she says, “the business will take care of itself. The challenge won’t be attracting patients. It will be ensuring we serve all the patients we have.”

Although advances in radiation oncology are ongoing, Kong says she already has enough success stories to fill a book. She remembers a woman who refused surgery for lung cancer and, after radiation treatments, has been cancer-free for more than four years.

“She never stopped working,” Kong says. “In fact, a few weeks after her last treatment, she opened

a nursing home.”

She remembers a man whose esophageal cancer was so advanced that doctors estimated he would live less than a year.

That was nearly five years ago.

“They did surgery to check,” Kong says. “He was completely cancerfree.”

Yet another former patient, a man in 80s diagnosed with Stage III cancer, spends his days swimming and biking four years later.

Those are the stories, Kong says, that make her research and clinical practice so rewarding.

“Success, for us, is being able to build these long-term relationships. It gives us time to get to know the people that we really come to care about.” B

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RESEARCH / FALL 2013 GEORGIA REGENTS UNIVERSITY

A Striking Message Revealing Research into Mass Marketing Strategies BY CHRISTINE HURLEY DERISO

THIS IS A SUBLIMINAL MESSAGE What follows is the most compelling, intriguing, and memorable article you’ll ever read.

What’s that?

You say you’re not convinced?

You’ve already written off my message as completely lacking in credibility? You’re way too sophisticated to fall for blatant self-promotion? You can smell an oversold message a mile away?

Well, aren’t you a smarty-pants.

Actually, you are really smart—which is why professional communicators have to be even smarter, or at least try to be, in catching your attention.

A Georgia Regents University marketing expert has spent years dissecting both the science and art of advertising—actually, communication in general—to glean the most effective ways to sell—um, convey—a message. c onti nued

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“The medium that carries your message is vital, and the credibility of that medium impacts the credibility of your message,” says Dr. Marsha Loda, Assistant Professor of Marketing in GRU’s James M. Hull College of Business.

She has conducted reams of market research—both in the private sector and during her 12-year career in academia—to determine which sources people deem credible—and why. She also completed a dissertation at Clemson University determining that, regardless of the medium, publicity (perceived as non-biased information) is more effective than marketing in driving a message. Her GRU research is further refining her studies, including her surprising findings that not only the medium, but the sequencing of the information, is vitally important.

Of course, most people have a hard time articulating gut reactions to messaging, so she follows the money.

“I’ve studied four measurements: attitude, credibility, message strength, and purchase intent [the willingness to actually follow up on a message by buying the product],” Loda says.

The upshot? “If the first you hear of something is from a source you consider credible [say, the New York Times], that tends to stay with you,” says Loda. “But if your initial exposure to something is from a source you don’t consider credible, it can be hard to shake that first impression.”

Despite her decades of real-world experience— including serving as Executive Vice President at Archer/Malmo Advertising (serving clients such as FedEx, International Paper, and Kraft) and Director of Marketing for Harrah’s Entertainment (overseeing a staff of 42)—she has stumbled onto plenty of surprises.

For instance, considering the technological savvy of young people—the most sought-after consumers in the advertising world due to their potential for establishing lifelong buying patterns—“I totally expected the web to sweep everything” in terms of media credibility and message strength, Loda said.

But she was wrong. Perhaps because the Internet is a repository of every conceivable kind of message, ranging from credible to ridiculous, young people are more discriminating than she anticipated. And they haven’t abandoned print media. “The young-adult cohort is still reading magazines,” she says. “They love them and will spend good money for them and good quality time with the content.”

The most effective message, she has found, is one that people have stumbled onto in, say, a magazine article—a message that is then reinforced with advertising. But if the advertising comes first,

“People distrust ads, and they know an ad when they see one.”

DR. MARSHA LODA

Assistant Professor of Marketing

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the credibility is tainted. And advertisers should realize that their attempts at duplicity—for instance, disguising their ads in packages designed to look like non-biased journalism (think advertorials or infomercials)—are highly transparent. “People distrust ads,” Loda says, “and they know an ad when they see one.”

On the other hand, consumers are generally more susceptible to subtle approaches, such as product placement in films, so look for advertisers to become increasingly sneaky.

And although consumers are inherently skeptical about Internet information, a surefire way to sell a product or message is by creating a seemingly nonbiased buzz about it via vehicles such as social media or YouTube. For instance, a video of an astronaut freefalling 128,000 feet from a space capsule had tallied some 3.5 million hits on YouTube as of press time, exponentially bolstering the popularity of the product that sponsored the feat: energy drink Red Bull. “This is a great example of creating a message that goes viral, then seeps into the mainstream media,” Loda says.

Or consider the company Loda cites as a messenger extraordinaire: Apple. The company, she says, has perfected the sine qua non of advertising: generating non-biased publicity (for instance, newspaper articles reporting the new technology characterizing an upcoming product); creating a buzz on the Internet (Facebook fans champing at the bit for the product to come on the market, for example); then following up with high-quality advertising.

But all three elements can be tricky, Loda cautions. For instance, unpaid publicity is beyond the control of promoters. They can try to interest journalists

“Keeping up with trends is something I really emphasize in my classes.”

–DR. MARSHA LODA

in their message, but there’s no guarantee—and no guarantee the publicity will be positive. Likewise, promoters can’t bottle the magic that turns a message viral on the Internet or control the chatter of social media. And even the most predictable and controllable element—advertising—can be fraught with potential minefields.

For instance, Loda notes humor is a tried-and-true element in advertising (think dollarshaveclub.com’s wry and irreverent videos)—unless it backfires, say by offending or by being so clever that the product itself is outshone. (Quick: You know the commercials featuring a guy in a suit having droll conversations with cute kids in a classroom? If you can’t remember what product he’s promoting, consider the ads too witty by half.) Likewise, sex is generally a surefire advertising winner unless it’s too distracting and/or too irrelevant to the

product. (Anybody remember the company promoted in the ad featuring Paris Hilton washing a car and eating a burger in a bikini?)

But don’t write off an ad’s effectiveness just because it doesn’t happen to resonate with you, Loda says. “If you don’t like a sexy ad, you’re probably not a young guy and weren’t intended to like it,” she says.

And don’t write off formats that may seem passé, such as television commercials. “It is very hard, if not impossible, to become a household word if you don’t advertise on television,” she says.

As Loda’s research becomes fine-tuned, one of her greatest joys is sharing her expertise with her GRU students. “In the private sector, I worked with lots of young people just coming into the business world, and I tend to treat my students more like staff than undergraduate kids,” she says. Her real-world experience—such as helping transform the image of Memphis, Tenn., by promoting a Civil Rights museum at the site of Dr. Martin Luther King Jr.’s assassination or dramatically enhancing the economy of western North Carolina by marketing a Cherokee casino in the Great Smoky Mountains—adds immeasurably to her credibility, according to her students. (Loda was named the former Augusta State University’s 2008-09 Outstanding Teacher of the Year.)

“Dr. Loda could take a subject matter and directly relate it to something she encountered in her career,” says 2010 graduate Tyler D. Werrick. “That, along with her great sense of humor and strive to not only teach but build relationships with students, made her classes the most enjoyable during my undergraduate education.”

Recent graduate Christopher Marsh agrees. “Dr. Loda is among my favorite professors. She inspires and encourages her students to take an active role in their learning experience. After she would teach on a subject, she had us present on what we learned or found interesting about the topic. Some of my favorite classroom memories are

presenting in her class. You would be hard-pressed to find a student who does not enjoy her class.”

Says Loda, “Keeping up with trends is something I really emphasize in my classes. One class project is finding 20 emerging trends, then doing an ‘if . . . then’ analysis. For instance, if more dads are staying home to raise their children, then what kinds of products or services might be successful a few years down the road?”

And even in her career in academia, Loda continues to walk the walk, immersing herself in real-world learning experiences to ensure that her coursework is as relevant as possible. For instance, she is a graduate of Leadership Augusta, an Augusta Metro Chamber of Commerce program to hone leadership skills, and chaired its 2013 class.

Says 2013 Leadership Augusta graduate Cathleen Caldwell, GRU Director of Marketing, “Marsha was adored by our whole class. We would refer to her as Mother Marsha, as she always kept us on track. I have great respect for Marsha as a marketing professional, but also as a great leader. And it doesn’t hurt that she has a terrific personality and is tons of fun!”

Adds 2013 Leadership Augusta graduate Mickey Williford, GRU Director of Accreditation, “She planned the agendas, kept us in line, provoked our thinking regarding each month’s topic, and just inspired us to be active in the community through her own enthusiasm to make a difference.”

Loda loves not only capturing her students’ imaginations, but helping set their careers in motion.

“One of my students from last semester got an internship with J. Walter Thompson [the world’s fourth-largest advertising agency],” she says. “I am so excited for him.”

In addition to bolstering to the body of knowledge they’ll carry into their careers, she also emphasizes the basics. “It all comes down to quality,” she says. “All marketing can do is get people to trying something one time, and if you’re not selling a quality experience, they won’t come back a second time. Or if you don’t do research on the front end, you may be selling something nobody wants. If you don’t do the elbow grease on the front end, you could be reinforcing the problem.”

Passing along her expertise to future generations, she says, is more fun than launching a hundred public relations campaigns. Says Loda, “I get real satisfaction out of seeing them get the big picture.” B

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Schizophrenia Symptoms Eliminated in Animal Model BY TONI BAKER

he classic symptoms of schizophrenia are reversed when expression of an implicated gene returns to normal, scientists say.

The researchers genetically engineered mice so they could turn up levels of neuregulin-1 to mimic high levels found in some patients, then return levels to normal, said Dr. Lin Mei, Director of the Medical College of Georgia Institute of Molecular Medicine and Genetics.

They found that when elevated, mice were hyperactive, couldn’t remember what they had just learned and couldn’t ignore distracting background or white noise. When they returned neuregulin-1 levels to normal in adult mice, the schizophrenia-like symptoms went away, said Mei, corresponding author of the study in the journal Neuron.

Schizophrenia affects about 1 percent of the population, causing hallucinations, depression, and impaired thinking and social behavior.

Babies born to mothers who develop a severe infection, such as influenza or pneumonia, during pregnancy have a significantly increased risk of schizophrenia.

While schizophrenia is generally considered a developmental disease that surfaces in early adulthood, Mei and his colleagues found that even when they kept neuregulin-1 levels normal until adulthood, mice still exhibited schizophrenia-like symptoms once higher levels were expressed.

Without intervention, they developed symptoms at about the same age humans do.

“This shows that high levels of neuregulin-1 are a cause of schizophrenia, at least in mice, because when you turn them down, the behavior deficit disappears,” Mei said. “Our data certainly suggests that we can treat this cause by bringing down excessive levels of neuregulin-1 or blocking its pathologic effects.” c onti nued

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Schizophrenia is a spectrum disorder with multiple causes—most of which are unknown—that tends to run in families, and high neuregulin-1 levels have been found in only a minority of patients. To reduce neuregulin-1 levels in those individuals likely would require development of small molecules that could, for example, block the gene’s signaling pathways, Mei said.

Current therapies treat symptoms and generally focus on reducing the activity of two neurotransmitters since the bottom line is excessive communication between neurons.

The good news is it’s relatively easy to measure neuregulin-1 since blood levels appear to correlate well with brain levels. To genetically alter the mice, they put a copy of the neuregulin-1 gene into mouse DNA. Then, to make sure they could control the levels, they put in front of the DNA a binding protein for doxycycline, a stable analogue for the antibiotic tetracycline, which is infamous for staining teeth.

The mice are born expressing high levels of neuregulin-1, and giving the antibiotic restores normal levels. “If you don’t feed the mice tetracycline, the neuregulin-1 levels are always high,” said Mei, noting that endogenous levels of the gene are not affected.

High levels of neuregulin-1 appear to activate the kinase LIMK1, impairing release of the neurotransmitter glutamate and normal behavior. The LIMK1 connection identifies another target for intervention, Mei said.

Neuregulin-1 is essential for heart development as well as formation of myelin, the insulation around nerves. It’s among about 100 schizophrenia-associated genes identified through genome-wide association studies and has remained a consistent susceptibility gene using numerous other methods for examining the genetics of the disease. It’s also implicated in cancer.

Mei and his colleagues were the first to show neuregulin-1’s positive impact in the developed brain, reporting in Neuron in 2007 that it and its receptor,

GEORGIA REGENTS UNIVERSITY

RESEARCH / FALL 2013

DRS. LIN MEI, YONG-JUN CHEN, and DONG-MIN YIN

Molecular Medicine and Genetics

ErbB4, help maintain a healthy balance of excitement and inhibition by releasing GABA, a major inhibitory neurotransmitter, at the sight of inhibitory synapses, the communication paths between neurons. Years earlier, they showed the genes were also at excitatory synapses, where they also could quash activation. In 2009, the MCG researchers provided additional evidence of the role of neuregulin-1 in schizophrenia by selectively deleting the gene for its receptor, ErbB4, and creating another symptomatic mouse.

Drs. Dong-Min Yin and Yong-Jun Chen, postdoctoral fellows, are co-first authors. Yin has received a National Alliance for Research on Schizophrenia and Depression Young Investigator Award, and Chen is supported by an American Heart Association Postdoctoral Fellowship. Mei is a Georgia Research Alliance Eminent Scholar in Neuroscience.

The research was funded by the National Institutes of Health and the National Alliance for Research on Schizophrenia and Depression. B DR. ANTHONY O. AHMED

Brain-Training Much like physical exercise can re-chisel the body, researchers hope targeted mental workouts can sharpen the memory, focus, and function of adults with schizophrenia.

“Cognitive retraining has the potential to help in core attention, memory, and executive function,” said MCG Dean Peter F. Buckley, principal investigator on the e-CAeSar study underway at 11 sites nationally, sponsored by San Franciscobased Brain Plasticity Inc. and funded by the National Institute of Mental Health.

Study modules use a game-like approach to take advantage of the brain’s natural plasticity and improve the speed and accuracy of information processing. As participants get better, the pace of the game increases, with the goal of increasing brainprocessing speed. Participants play the games an hour daily for six months while controls use commercially available games for the same period.

Many schizophrenia symptoms appear to result from faulty wiring laid down during development that results in erratic communication and sensory overload. “There is the potential to DR. PETER F. BUCKLEY retrain areas of the brain that are faulty or encourage other areas of the brain to assist so that you maximize the cortical output of the brain,” said Buckley, who recently received the American Psychiatric Association Special Presidential Commendation for his contributions to psychiatry and academic medicine.

In a related study, brain-training computer games may help restore memory and competency to forensic psychiatry patients in state mental hospitals, researchers say.

Computer software to improve memory and thinking may be used with psychotherapy, medication, and other approaches to help these patients, said Dr. Anthony O. Ahmed, an MCG research psychologist.

Ahmed is among the first to explore the potential of cognitive remediation in patients confined to state mental hospitals after being found incompetent to stand trial or not guilty by reason of insanity. His work has earned him the Science to Practice Award from the Brain & Behavior Research Foundation and the Cognitive Remediation in Psychiatry Conference. B

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Medieval

Mission

BY CHRISTINE HURLEY DERISO

Studies Redeem Era’s Long-Tarnished Reputation

T

he big picture of the medieval era drew Dr. Wendy Turner in, but the details keep her coming back for more.

Details like the boy whose hands were chewed off after falling into a pigpen but grew up to be a tailor who sewed with his feet.

Or like the prisoner of war whose family received one tooth at a time as they scrambled for ransom money.

Or like the mentally ill man prescribed restful relaxation—including a personal musician to play soothing music as he slept. c onti nued

DR. WENDY TURNER

Professor of History; Interim Chairwoman, Dept. of English and Foreign Languages

Pieter Breugel, Netherlandish Proverbs, 1559

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Treasure Troves of Information Turner, Georgia Regents University Professor of History and Interim Chairwoman of the Department of English and Foreign Languages, fell in love with the medieval period as a college student and uncovers enough treasure troves in her research to keep the flame burning bright.

Having spent decades poring through trial transcripts, medical records, administrative documents, literature, personal letters, and other texts of the period (roughly the fifth to 15th centuries in post-Roman Empire Europe), her upshot is as pithy as it is surprising: the medieval era has gotten short shrift.

“Yes, there were things like slavery and torture,” she acknowledges, “but there were also a lot of people defending women’s rights, forming guilds, and doing a lot of very progressive things. As far back as the 11th century, you see loads of people traveling the world to study science, medicine, and math, swapping texts and learning new techniques.

Even alchemists were doing a lot of great things.

They’d come up with medical-grade alcohol by the 12th century, good grief!”

She attributes the bad rap to the snobbery of medieval Europeans’ descendants who followed in their footsteps while claiming to have trod new ground. “At the end of the medieval period was the Renaissance—the rebirth of classical ideas,” Turner says, “followed by the early modern period, which included the so-called Age of Reason. Their mindset was, ‘We are the enlightened ones.’ It was very egocentric.”

It was in stumbling onto inaccuracies and misconceptions that Turner vowed to set the record straight, publishing numerous articles and texts that shed new light into the practices, culture, and mindsets of the time. “I work from a series of fundamental questions,” she says.

“Why do humans treat one another the way they do? How do people understand? Why do people categorize the things around them—and how?”

Looking to Science

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She quickly uncovered much more progressivism and humanity than she anticipated.

For instance, she found a rigorously sciencebased approach to mental illness at the time.

“Those who treated patients, many of whom were priests, certainly were working within a really interesting construct of how the mind works,” she says. “Obviously the whole culture is colored by religious thought, but they were looking for physiological explanations. They were expecting science to be the answer.”

As is true today, their treatments often missed the mark—but not for lack of trying. Initial attempts at curing diseases such as schizophrenia, bipolar disease, depression, and anxiety usually focused on lifestyle changes regarding diet, sleep, or climate, for instance. Practitioners also acknowledged a spectrum of disease severity (no blanket assessments of “crazy”) and recognized symptomatic cycles. For instance, Thomas Aquinas noted periods of psychosis and lucidity in mentally incapacitated patients and counseled appealing to their logic during the latter.

Cornelis Bega, The Alchemist, 1663

c onti nued

Pieter Breugel, Netherlandish Proverbs, 1559

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Pick-Me-Ups and Slow-Me-Downs

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When lifestyle changes were ineffective in treating mental illness, “there were increasingly elaborate treatments based on humours, and some of it actually worked,” Turner says. “As the period progressed, you start to see more and more authoritative references: ‘So-and-so tried this, and it seemed to work.’

Or they’d sum up a collection of theories. The medieval period is also when you start to see more opiates prescribed as pick-meups or slow-me-downs. But the practitioners were careful: ‘Don’t give too much, or you’ll kill him.’

And some of the treatments modern physicians thought foolish,

such as using leeches and maggots for bloodletting, we’re starting to see again.”

In many ways, mental illness was less stigmatized than it is today, largely because of efforts to sustain the patient’s independence.

Intractable mental illness, for instance, often resulted in the patient being assigned a guardian or custodian to live with or near him and oversee matters related to his family, work, and estate. (Sexism rears its head at this point; although mental-illness treatments were generally gender-neutral, wives of mentally ill husbands fell under the supervision of the guardian.

Husbands of mentally ill wives, of

course, faced no such constraint.)

And mentally ill patients at the time often found a much more forgiving judicial system than many in today’s society. Legal transcripts from the time note extraordinary attention to context and extenuating circumstances.

“There was a sense of mental illness as symptoms of ‘thought sins,’” Turner says, “but if you read trial transcripts, it’s not like God comes up every other sentence.”

It wasn’t unusual for the mentally ill—or those affected by them, such as the case of a man who slayed his violent senile father in selfdefense—to be absolved of their crimes altogether.

Fascinating Detours Turner will publish a monograph later this year studying all aspects of mental health related to the period, from intellectual disabilities to psychotic disorders. “I analyze the terminology and treatment— long misunderstood as disordered and unreasoned, based purely on superstition and religious doctrine—to find that not only is the terminology ordered and reasonable within the confines of medieval medicine, but it was not based on superstition,” Turner says.

“The book is at its core a study of English wardship laws for those afflicted with mental disability, but in order to understand why England had such laws, I had to spend much of the work explaining mental health, the role of guardians, medical and religious understanding of mental health and why the wardship system came to an end.”

And, as has characterized Turner’s entire career, she often finds the detours as fascinating as the main path she travels. For instance, “I have hypothesized with the help of several colleagues in psychology that King Henry VI may have had genetic schizophrenia. Just before a collapse that left him comatose for 16 months, he began licensing alchemists to try to make money. I became fascinated with his desire to save his country from financial ruin while at the same time searching for a possible panacea. He quite possibly hoped for a cure.”

KING HENRY VI

Humpbacks and Prostitutes

KING RICHARD III

Turner also stumbled onto literature regarding King Richard III (whose skeletal remains were recently unearthed in England) belying Shakespeare’s characterization of him as a hideous humpback with a shriveled arm. “Letters indicate he was actually a great dancer,” Turner says, and the archaeological find confirmed that although he had scoliosis, he was considerably less disfigured than popularly believed.

Stories of commoners spark Turner’s interest as well, including that of an English prostitute who sued for damages after her maid was raped by a leper, which left the girl mentally incapacitated.

“Many things about this strike me as fascinating—a woman suing in court, especially if she’s considered less than respectable; asking for funds to defray the cost of her employee’s care; the [attacker’s] possible leprosy, the accusation of leprosy as a cause for mental collapse in a rape case; the mental incapacity of the victim; and the repercussions in society of such an event.”

Turner is also writing a monograph on the medical understanding of the brain in medieval England. “I discuss the three-ventricle theory,” she says, “which understood that the brain was divided into three sections: anterior, mid, and posterior—that corresponded to the three functions of the brain: perception, cogitation, and memory.”

Her research has attracted international renown; for instance, Turner helped found the Society for the Study of Medieval Disabilities, which now has 50 members worldwide and is connected with similar groups in England and Germany.

Her studies are having ripple effects right here on campus, as well. She is working with Medical College of Georgia Vice Dean for Academic Affairs Paul Wallach and Department of Psychology Chairman Michael Stefanek in synergizing university initiatives related to mental illness. Upcoming initiatives include a course in narrative medicine (communication skills to validate the patient’s experience and encourage physicians’ self-reflection) and a program to help mentally ill patients and practitioners share their stories in writing.

“We hope these narratives will enable people to walk alongside the patients, even if just in writing, and help health care providers begin to think about these issues in different ways. My dream is to have a whole center of health humanities.”

And to help redeem the medieval era’s reputation, while she’s at it.

“It wasn’t dark; it was a period of light,” Turner insists. “It’s the foundation of science and chemistry. Just look at medieval churches—wow. The engineering and artistry and construction involved were just incredible—and prior to mechanization! They did it all by hand. It’s crazy.”

That initiative, at the individual level, is what she finds most inspiring not only about the medieval period, but about humanity in general.

“The human spirit is remarkable,” she says, “and I don’t care what era we’re talking about.” B

15th-century depiction of a medieval hospital

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DOING this RIGHT

GEORGIA REGENTS UNIVERSITY

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Director, Comprehensive Sickle Cell Center

DR. ABDULLAH KUTLAR

Research Perpetuates GRU’s Pioneering Role in Sickle Cell Treatment

BY JENNIFER HILLIARD SCOTT

“Sometimes it’s just a dull, nagging ache. Other times it feels like getting run over by a Mack truck and then thrown in a meat grinder. Every time is different.”

–CLAYTON ANDREWS

C

enough for me to do anything about. Other times, it’s like layton Andrews often struggles to accurately describe the pain he’s lived with for as long as he it’s saying, ‘I’m gonna beat the crap out of you’ and I can’t ignore it.” can remember.

In fact, ignoring a small crisis often leads to a bigger “I just start feeling funny,” agrees Krystal one, landing him in a hospital bed—although that happens Stone. “I really can’t explain what it feels like. Sometimes less and less, he says. There isn’t much time for that these it’s sharp pains, sometimes it’s dull. It can start in my legs, days, after all. Life at “normal pace” keeps Andrews busy my back, my arms—anywhere.” enough. He works as a caseworker for the Department of Like 70,000 other Americans, Andrews and Stone both Family and Children Services; is working on his graduate have sickle cell disease, a genetic mutation of hemoglobin, degree; and is even busier being a dad to his four young the red blood cell component that delivers oxygen to cells children. throughout the body, causing them to take on a crescent “For me, it’s very much about living—not suffering— shape. That sickling causes episodes of intense pain, or with the disease,” he says. “I am very blessed.” “crises”—the hallmark of the disease. The effects of the The same is true for Stone. sickling also travel downstream throughout the body, “I have learned to manage my sickle cell pretty well by depriving blood vessels of oxygen. taking my meds,” she adds. “I literally forget that I have it No organ system is spared. sometimes.”

It is the second-most common genetic disorder and is most common among descendants of Africans and other populations where malaria is common—likely because The Past the mutation actually offers protective benefits against Part of what has allowed Andrews and Stone and other the disease. In this country, sickle cell disease affects patients like them to “live” with sickle cell disease instead approximately one in 500 blacks and one in 1,000-1,400 of suffer from it are regular visits and participation in Hispanics, according to the National Institutes of Health. clinical trials at the GRU Comprehensive Sickle Cell Center.

The disease is now routinely screened for in newborns Established in 1972, the center incorporates the work nationwide, thanks to Georgia Regents of basic scientists and clinicians, with University initiatives—a vital heads-up mulltidisciplinary teams approaching for symptoms that typically begin in sickle cell treatment from all angles— early childhood, as was true for Andrews patient care, research, and education. and Stone.

“We very much take an enterprise “I can remember being in middle wide, well-rounded approach to care school and waking up sick that here,” says Dr. Abdullah Kutlar, Director morning,” Stone says. “I took some of the center. “In order to advance care, pain medication and tried to ignore it it has to be that way. Our center is one because I didn’t want to miss school, of the strongest translational programs but it got progressively worse and they on campus.” ended up having to call an ambulance

Its beginnings can be traced to school. My friends were all so worried back more than five decades to the about me.” work of Dr. Titus H.J. Huisman, founder In both Stone and Andrews’ cases, of the GRU Sickle Cell Center, who both parents carried the trait—or discovered a large number of the recessed genetic abnormality—which approximately 700 known hemoglobin increases the chance of children having variants. “That discovery enticed the disease. One of Andrews’ three scientists from all over the world to siblings, older sister Shawn, also come to GRU, including me,” says DR. TITUS H.J. HUISMAN suffered from sickle cell and passed Kutlar, who came to GRU in 1984 and away at age 6. became Director of the center in 1994.

“My mom always tried to protect us when we were kids, “Sickle cell does not affect a large number of people, but I knew something was wrong,” Andrews recalls. Unlike and many of those people represent the medically his friends, as a child he hated running, playing outside, or underserved,” Kutlar says. “But there is so much to be playing sports because he tired so easily. done—so much unknown about the disease—and that has As he grew older, the disease began materializing in been key to much of the center’s success.” other ways.

Among those success stories is the groundbreaking “Sometimes it starts as abdominal pain, other times it Stroke Prevention Trial in Sickle Cell Anemia, or STOP, starts in the joints,” Andrews says. “Sometimes the pain studies by former GRU faculty Dr. Robert Adams. Adams is just there reminding me that I have this, but not bad led a research team that used transcranial Doppler

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ultrasound to identify pediatric sickle cell patients with narrow blood vessels in the brain, reducing their stroke risk by 90 percent by treating them with regular blood transfusions.

“Studies like those have really put us on the map in terms of sickle cell care,” Kutlar says. “The clinical support and research that our patients have access to have been a longstanding tradition in our fight against this disease.”

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The Present The current plan of attack is managing the disease’s sometimes crippling symptoms. Bone marrow transplants can cure the disease, but compatible donors are few and far between, as relatives of those with sickle cell often carry the trait themselves. Fewer than 200 successful transplants have been completed.

But Kutlar still wants better options than treating symptoms and managing crises.

The focus of current drug development should be on anti-sickling therapies, not pain reduction, Kutlar says.

“There is currently only one drug that reduces sickling, and we need more.”

That drug—hydroxyurea—increases fetal hemoglobin, which binds better to oxygen than its adult counterpart. In the womb, that gives a developing fetus better access to oxygen in a mother’s bloodstream. Unfortunately for sickle cell patients, fetal hemoglobin is nearly completely replaced by adult hemoglobin within the first six months of life.

Approved 15 years ago, hydroxyurea is still not widely used—probably due to side effects such as weight gain, massive reduction of red blood cells, and the corresponding suppression of bone marrow function. But its benefits, which include less damage to blood vessels and organs from sickled cells, outweigh the downsides, Kutlar says.

Other anti-sickling therapies are being tested and developed, including a derivative of thalidomide that increases fetal hemoglobin expression. Dr. Steffen E. Meiler, Vice Chairman of Research in the Medical College of Georgia Department of Anesthesiology and Perioperative Medicine, and a team of other GRU researchers laid the groundwork for the therapy.

The Future The future, physicians and researchers agree, is figuring out sickle cell disease at the molecular and genetic levels.

And several GRU researchers are attempting to do just that.

For instance, a recently announced $8.8 million National Institutes of Health grant is enabling Drs. Kutlar and Meiler, along with GRU colleagues Betty Pace and David Pollock, to study the roles of endothelin 1 in sickle cell patients, specifically regarding kidney disease, acute lung injury, and pain—all hallmark symptoms of the disease.

Excess endothelin, which constricts blood vessels, can cause conditions such as high blood pressure and heart

disease. The level is normally kept in check by nitric oxide and other physiological mechanisms. But the sickling in sickle cell disease also causes cells to break open and spill hemoglobin, which scoops up the nitric oxide.

Pollock, Regents Professor of Surgery and Associate Professor of Pharmacology/Toxicology and Physiology, has already shown that high levels of protein in the urine (an early clinical indicator of kidney disease) correlate with high levels of endothelin in the blood. He suspects

“Ideally, we could begin to treat babies earlier.

I want to put Dr. Kutlar out of business.”

–DR. BETTY PACE excess endothelin might also be linked to the unchecked inflammation in the liver and lungs seen in sickle cell patients.

The study will use antagonist drugs prescribed for pulmonary hypertension to block the endothelin receptor that activates excess vasoconstriction. Pollock will block that receptor in mouse kidneys in hopes of reducing damage from inflammation.

Kutlar will see if blocking the receptor helps reduce pain in sickle cell patients by reducing inflammation.

Meiler will focus on the lungs, seeing if blocking the receptor (and thereby reducing inflammation) reduces the risk of hypoxia, a side effect of sickle cell disease due to a lack of non-sickled red blood cells.

Meiler is also collaborating with researchers nationwide to correct the cell mutation by harvesting blood-generating stem cells from a sickle cell patient, repairing them with specially engineered genome-editing tools, then returning

them to the patient where they will ideally begin to produce normal red blood cells. “This has the potential to be curative,” Meiler says.

Pace, Tedesco Distinguished Chair in Pediatric Hematology/Oncology, is also working to identify how cells signal each other during drug-induced production of fetal hemoglobin, with an eye toward developing better drug targets for sickle cell disease.

“The hope is that we’ll find ways to control gene expression and target those genes to induce fetal hemoglobin,” Pace says. “Ideally, we could begin to treat babies earlier. I want to put Dr. Kutlar out of business.”

The GRU Sickle Cell Center is also leading an initiative enlisting primary care physicians to serve as “medical homes” for patients, which they hope will improve how patients are treated when a crisis lands them in the hospital, or—even better—preclude hospitalization in the first place.

“This is an exciting opportunity to really take on sickle cell disease from many angles: from ensuring that patients get regular medical care to improving hospital care to dissecting why patients respond to pain and analgesics differently,” Kutlar says.

Kutlar and Dr. Robert Gibson, a GRU occupational therapist and medical anthropologist, are co-principal investigators on the $7 million, five-year grant from the National Center on Minority Health and Health Disparities of the National Institutes of Health, which partners GRU with Morehouse University School of Medicine and University of Florida.

Major projects of the grant are: n Establishing programs to ensure proper health care for pediatric patients as they grow into adults. Researchers

will work with children age 12 to 17 to determine what they know, what they need to know, and how to optimally prepare them for disease implications in adulthood. n Helping build medical homes that provide comprehensive care using family medicine physicians and residents across Georgia who have received additional training in the disease. n Encouraging primary care doctors to specialize in sickle cell disease and enabling young scientists to work in laboratories of veteran scientists. n Helping physicians and hospitals statewide set up observation centers that keep sickle cell patients experiencing a pain crisis out of busy emergency departments where they might not receive proper pain relief. n Better understanding the genetic modifications behind variations in the frequency, intensity, and treatment of pain crises. Researchers believe their studies, which will include pain diaries kept by patients, will enable individualized pain treatment strategies that improve quality of life and avoid the mischaracterization of patients as drug seekers. n Researching, and ideally manipulating, the switch from fetal to adult hemoglobin—including by decoding signaliing that enables fetal hemoglobin production in adults..

“There are opportunities that exist here that don’t exist elsewhere,” Pace says. “There are tremendous opportunities to enhance bench research, mentor young faculty and create rich opportunities for scientific and clinical collaborations. GRU is a model and a leader on how to do this right.” right. B

NEW DIGS In late fall, the Comprehensive Sickle Cell Center is making a move across campus. Renovations are almost complete on the center’s new home in the Shepeard Building. The new center will boast nearly 4,000 square feet of office space, exam rooms, a conference room, and research storage. Most of the second floor will be converted for space for the center’s DNA lab and offices.

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Dear Readers, Georgia Regents University has enjoyed a long history of support from the Carlos and Marguerite Mason Trust. In fact, this year marks the 20th anniversary of an invaluable partnership marked by millions of dollars of investment.

The Mason Trust’s mission sounds deceptively simple: to improve organ transplantation for needy Georgia residents. Its investment in research and patient care, however, has been— and continues to be—quite extraordinary.

Most recently, GRU received approval for a grant of over $800,000 to support two translational studies building on GRU research,

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RESEARCH / FALL 2013

George Atkins, Chairman of the Advisory Committee, Carlos and Marguerite Mason Trust

largely funded by the Mason Trust, identifying ways to prevent rejection of transplanted organs.

Advancement Update The science, focused almost exclusively on kidney transplantation, has been groundbreaking, and to date, has been limited to testing in mice. This new funding supports continued testing in mice as well as miniswine.

The goal is clinical trials of innovative therapies that prolong kidney transplant survival, while reducing the need for extended therapy with costly and potentially harmful immunosuppressive drugs.

As one of the region’s leading academic kidney transplant

Chandler

Horuzsko

programs, GRU has performed more than 2,000 successful adult and pediatric kidney transplants since the first transplant surgery in 1968.

Our medical center houses one of only 10 kidney transplant programs recognized by HealthGrades and awarded the Kidney Transplant Excellence Award, and one of only 20 nationwide to receive a HealthGrades Transplant Excellence Award.

The researchers involved in the most recent Mason Trust proposal are some of the finest at GRU: Drs. Phillip Chandler,

Anatolij Horuzsko, Lei Huang, Andrew Mellor, Laura Mulloy, Todd Merchen, and Stan Nahman Jr. The Office of Advancement is proud to work alongside this outstanding team, some of whom we have worked with for years, to help articulate its complex ideas and research to prospective funders. As engaged partners of the Mason Trust, managed by WellsFargo in Atlanta, we stay abreast of its evolving priorities to ensure that our applications for funding are well-informed and closely aligned with its mission

Huang

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Mulloy

and goals. We help submit funding applications and help prepare the stewardship reports.

Also, for the past several years, we have hosted Mason Trust representatives during annual campus visits. A typical day includes presentations by our researchers, tours of transplantation areas, and meetings with key GRU administrators, including Medical College of Georgia Dean Peter F. Buckley and GRU President Ricardo Azziz.

This year’s grant

RALPH ALEE

provided a unique partnership opportunity. When the Mason Trust asked us to identify matching funds to further enhance the impact of its gift, Drs. Mulloy and Nahman secured a $300,000 private research grant from Dialysis Clinic Inc., by working with a former MCG Fellow who is now a medical director with one of the company’s clinics in South Carolina. This gift, along with others, helped us meet the challenge.

Working with researchers who understand the philanthropic process, who are committed to

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Nahman

partnering with Advancement to work with key donors, and who are fiercely devoted to stewarding gifts is a formula that has proven successful time and time again.

The immediate beneficiaries of this partnership are the citizens of Georgia who need transplant services; the long-term benefits of this advanced research are incalculable.

Partnering for better health—one opportunity at a time.

To learn how you can help, contact me at ralee@gru.edu or 706-721-4001. B

Associate Vice President for Major Gifts

ABOUT THE TRUST Marguerite Fugazzi Mason died in January 1991, leaving the bulk of her estate to the Carlos and Marguerite Mason Trust. The purpose of the trust, created in loving memory of her husband, Carlos Mason, is to improve the process of organ transplantation for Georgians through grants to Georgia 501(c)(3) organizations “first and primarily to enable them to provide needy persons who are residents of the state of Georgia with financial assistance when they require transplants of eyes, kidneys, hearts, and other human organs.”

Discoveries in Progress

39

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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.

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