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School of Medicine



A new palliative care program
Mutant plants to the rescue
Gleevec for smallpox?
Nanotechnology funds for cancer
Treating (and preventing) injuries in Mozambique
Bernstein wins Novartis Prize
New blood vessels in the heart, thanks to gene transfer

A big breakthrough in curing diabetes, with the help of pigs and monkeys
Clues about ketogenic diet and seizures

Cystic fibrosis has an older face
On the rebound: more clues to bone loss
More than happiness: the science behind satisfaction
Why response to therapy varies in rheumatoid arthritis
Mental health for the homeless
Trials against cancer
Time for a commercial break: incentive to invest in new technologies
Faculty Leadership
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A new palliative care program has been established at both Emory and Emory Crawford Long hospitals, focusing on alleviating suffering and improving quality of life for patients who have a serious illness. Palliative care not only relieves both the physical and non-physical suffering that accompanies serious illnesses but also addresses mental health and spiritual needs.
     Staffed by internal medicine physicians and co-directed by hospitalists Stephanie Grossman and Melissa Mahoney, who are board certified in palliative care, the program is part of a rapidly growing trend in health care. Not to be confused with hospice care, palliative care is appropriate for patients in any stage of illness, not just for those approaching the end of life. The team includes physicians, nurses, social workers, chaplains, and pharmacists.
     Grady Hospital also has a palliative care clinic for cancer patients, funded by a $200,000 grant from the Lance Armstrong Foundation.
  Mutant plants to the rescue

  Global warming may have met its match. Emory researchers have discovered a mutant enzyme that could enable plants to use and convert carbon dioxide to sugar (3-phospho-glycolate) more quickly, effectively removing more greenhouse gases from the atmosphere.
     During photosynthesis, plants and some bacteria convert sunlight and carbon dioxide into usable chemical energy—a process that relies on an enzyme called RuBisCO. While RuBisCO is the most abundant enzyme in the world, it is one of the least efficient.
     “All life pretty much depends on the function of this enzyme,” says biochemist Ichiro Matsumura. “It actually has had billions of years to improve but remains about a thousand times slower than most other enzymes. Plants have to make tons of it just to stay alive.”
     For decades, scientists have struggled to engineer a variant of the enzyme that would more quickly convert carbon dioxide. For the Emory study, Matsumura and colleagues used a process called directed evolution, which involved mutating genes, inserting them into bacteria (in this case E. coli), and screening for the fastest and most efficient enzymes produced by the mutant genes.
     Matsumura’s team then added genes encoding RuBisCO to E. coli to enable the bacteria to change carbon dioxide into consumable energy. They then added mutated RuBisCO gene to the modified E. coli. The mutations of the fastest-growing strains caused a 500% increase in RuBisCO expression.
     “We are excited because such large changes could potentially lead to faster plant growth,” says Matsumura. More plants using and converting carbon dioxide more quickly means less pollution and greenhouse gases.
  Gleevec for smallpox?

  The hallmark anti-cancer drug Gleevec may be effective in controlling smallpox infections or treating the complications caused by smallpox vaccines. Emory scientists administered Gleevec to mice and infected them with lethal doses of the poxvirus used to vaccinate against smallpox. They found that the drug reduced dissemination of the virus and the mice survived. The Emory investigators, led by pathology researcher Daniel Kalman, tested Gleevec against poxviruses after their discoveries about how the viruses interact with host cells on a molecular level. The virus particles become encased in an envelope that helps them evade the immune system, then travel to the cell’s surface, where the enveloped viruses hijack host-cell proteins, which allow them to detach and spread to other cells.
     Kalman and colleagues speculated that Gleevec might be effective against poxvirus without eliciting drug resistance because it inhibits the host cell molecule, rather than the viral molecule. “It would be hard for the virus to overcome blockade of a host cell factor because it would have to completely change its virulence program,” says Kalman. He believes the concept of using anti-cancer drugs to treat microbial infections may prove to be more generally applicable. “Many pathogens use host molecules as part of their pathogenic program,” he says.
Nanotechnology funds for cancer

The National Cancer Institute (NCI) has selected Emory and Georgia Tech as one of seven National Centers of Cancer Nanotechnology Excellence. The Emory-Georgia Tech Nanotechnology Center for Personalized and Predictive Oncology will function as a discovery accelerator to integrate nanotechnology into personalized cancer treatments and early detection.
     With the new designation, Emory and Georgia Tech now have one of the largest federally funded programs in the United States in this arena. The NCI grant is expected to reach $19 to $20 million over a five-year period.
     Nanotechnology is research and technology at the atomic, molecular, or macromolecular levels, where particles are measured with a nanometer equivalent to one-billionth of a meter (or 100,000 times smaller than the width of a single strand of human hair). It offers promise for earlier cancer detection, personalized diagnostics for targeted treatment, and creation of new drugs for metastatic cancers.
     “Nanotechnology will eventually apply to all cancers,” says Bill Todd, CEO of the Georgia Cancer Coaltion (GCC). “However, this grant is focusing on breast and prostate cancers, which represent compelling challenges in cancer research.”
     The center’s director, Shuming Nie, an Emory faculty member and GCC Scholar, is leading collaborative research to develop several kinds of nanoparticle probes, including quantum dots, which are luminescent nanoparticles that can be chemically bound to biologic particles such as antibodies or proteins. Such dots therefore can act as markers to study protein interactions in live cells or to detect diseased cells.
     Jonathan Simons, outgoing director of the Winship Cancer Institute, is co-principal investigator of the grant.
     This NIH support came on the heels of other major NIH awards, including one for $11.5 million, again to Emory and Georgia Tech, to Gang Bao and colleagues, who are using nanostructured probes to detect cardiovascular plaques.
Treating (and preventing) injuries in Mozambique

If a motorist is hurt in a car crash in Mozambique, it is likely that the first person to tend to his or her injuries will be a bystander or a taxi cab driver.
    EMS systems like those that exist in the United States to aid accident victims are “far beyond the reach of most low-income countries,” says Scott Sasser, assistant professor of emergency medicine. “What they need are simple and sustainable strategies for improving prehospital care.”
     While much of the attention in global health assistance is geared toward disease prevention and treatment, WHO estimates that 5 million people worldwide die of injuries each year—largely in developing nations.
    Sasser, emergency medicine physician David Wright, and surgeon Jana MacLeod have received a five-year, $675,000 grant from the Fogarty International Center of the NIH to establish an injury control program in Mozambique.
     “When I did ward rounds at the Central Hospital Maputo, I discovered that 60% of the patients we saw that morning were admitted with an injury-related diagnosis,” says MacLeod. “For the general surgeon in such an environment, up-to-date knowledge about appropriate evidence-based trauma care is essential. Also, injury prevention will have a significant impact because of the relative volumes of injury, compared with other types of admissions to the Maputo hospital.”
     Mozambique was selected as the site of the program—which Sasser hopes will become a model for other African nations—because, according to WHO, its government was prepared to support efforts to reduce its “injury epidemic.” Through a partnership between Emory and Mozambique’s University Eduardo Mondlane, academic and clinical core medical faculty in Mozambique will be trained in the principles of public health, research methods, ethical principles, and safety promotion.
     Sasser also is working with WHO and the City Council of Maputo to improve prehospital care within the city. His efforts are based on the recently published WHO monograph, “Prehospital Trauma Care Systems,” of which he was lead editor.
     “Instead of buying 50 new ambulances that can’t be maintained or providing advanced training that existing technology can’t support, we look at what can be done,” says Sasser, “such as teaching basic first aid to interested community members.”
     The Fogarty grant will support the training of 10 fellows from Mozambique in trauma and injury control. The fellows, mostly clinicians, will spend their first year in Africa completing coursework, followed by stints at Emory’s Rollins School of Public Health and the University of South Africa, returning to Mozambique to put methods into practice. —Mary Loftus
  Bernstein wins Novartis Prize

  Emory pathologist Kenneth Bernstein was the 2005 co-recipient of the Novartis Prize from the American Heart Association, marking the second consecutive year that an Emory faculty member has won the award. In 2004, the award, which honors contributors to advancing knowledge of hypertension, vascular disease, and cardiovascular disease, went to Emory cardiologist David Harrison.
     Bernstein and his colleagues have been responsible for a number of important discoveries about the link between the kidneys, blood pressure, and cardiovascular function, including cloning and characterizing the gene for the receptor for angiotensin II, the central component of the process of blood pressure control.


  New blood vessels in the heart, thanks to gene transfer

  Emory Crawford Long Hospital is one of 32 sites participating in a national study of experimental gene transfer designed to stimulate new blood vessel growth in the heart. Researchers hope this new treatment will restore blood flow to ischemic areas of the heart in patients with severe angina due to coronary artery disease and who have few or no remaining treatment options.
     The procedure involves injecting a special gene directly into the heart muscle in six places through a specialized catheter. The goal is for the gene to provide the heart with instructions to grow new blood vessels.
     The results of earlier phase 1 and 2 trials have been encouraging, according to cardiologist Henry Liberman, who leads the study.


A big breakthrough in curing diabetes, with help of pigs and monkeys

Islet cell xenotransplantation presents a promising near-term solution to the problem of critically low islet cell supply for people with type 1 diabetes. Researchers from the Emory Transplant Center have transplanted insulin-producing neonatal porcine islet cells harvested by University of Alberta (Canada) researchers into diabetic rhesus macaque monkeys, restoring the monkeys’ glucose control and resulting in sustained insulin independence.
     Islet cell transplantation has successfully reversed type 1 diabetes in humans, but the availability of islet cells limits use of this procedure in reaching more than 1 million Americans with the disease. Each year, only 3,000 to 4,000 donor pancreases are available, and each can produce enough islet cells for, at most, only one transplant. “We must find new donor sources to allow large-scale application of islet cell transplantation in humans,” says Emory transplant researcher Chris Larsen.
     Published in February in Nature Medicine, this research also examines the effectiveness of a costimulation blockade-based regimen developed by Larsen and his colleague Thomas Pearson, which has fewer toxic side effects than currently used immunosuppressive regimens.
     Belatacept is a key ingredient in the costimulation blockade that selectively blocks the second of two cell signals the body needs to trigger an immune response. This regimen is less complex than the immunosuppressant compounds used in previous research, and its simplicity will make it more applicable in clinical use.
     In addition, Emory researchers addressed concerns of the possibility of cross-species disease transmission as a result of xenotransplantation. After extensive testing, they found no evidence of transmission of porcine endogenous retroviruses between the porcine cells and the transplant animals. The use of nonhuman primates was critical for testing cross-species viral transmission due to their close genetic link to humans, according to Larsen.
    The next step is to prove porcine islet cells can be a source for human transplantation and to verify the safety of the transplant procedures, a process researchers hope to begin in the next three to five years.


  Clues about ketogenic diet and seizures

  Physicians have long prescribed a high-fat, calorie-restricted ketogenic diet to prevent childhood epileptic seizures that are unresponsive to drugs, but until now no one has understood why the diet works. New studies at Emory show that the diet alters the expression of genes involved in energy metabolism in the brain, which in turn helps stabilize the function of neurons exposed to the challenges of epileptic seizures.
     To identify which genes might be involved in this process, the Emory research team, led by pharmacology chair Raymond Dingledine, used microarray gene chips to examine changes in gene expression for more than 7,000 rat genes. They focused on the hippocampus, finding more than 500 genes that correlated with treatment with the ketogenic diet, including genes involved in energy metabolism.
     To test whether energy reserves in hippocampal neurons were enhanced with the diet, they counted the number of mitochondria within cells, using electron microscopy. They found that ketogenic diet treatment significantly increased the number of mitochondria per unit area in the hippocampus and concluded that the diet enhances energy production in the hippocampus and may lead to improved neuronal stability.
     The researchers also tested whether brain tissue affected by the diet would be better able to withstand metabolic changes associated with seizures, such as lowered glucose levels, because of enhanced energy reserves. They found that synaptic communication in rats on the ketogenic diet was more resistant to low glucose levels.
     This new knowledge could lead to the development of more effective drug treatments for epilepsy and brain damage. The researchers also believe that the ketogenic diet should be studied as a possible treatment for neurodegenerative disorders such as Alzheimer’s or Parkinson’s diseases.


  Cystic fibrosis has an older face

  The median age of cystic fibrosis patients has risen from 14 in 1969 to 35 in 2004, with almost 40% of today’s patients already 18 or older. The Cystic Fibrosis Adult Program at Emory is the only one in Atlanta geared to the needs of adults living with the disease, which affects 30,000 people in the United States. The program is comprehensive, assembling pulmonologists, gastroenterologists, nutritionists, respiratory therapists, and others to serve more than 140 adults—the oldest of which is now in his mid-60s. A multi-pronged translational research program including studies on antioxidant production and lung inflammation and the role of pollution and ultraviolet light exposure helps researchers test multiple hypotheses simultaneously to further increase the life span of those with cystic fibrosis, says Arlene Stecenko, who directs the center and its research. Center faculty also are examining the potential for gene therapy and determining the molecular makeup of some 900 mutations of the cystic fibrosis gene and its functions.  
  On the rebound: more clues to bone loss

  Osteoporosis may be caused by a “thymic rebound” resulting from estrogen deficiency and increased production of the protein IL-7, according to research led by Garland Herndon Professor of Medicine Robert Pacifici and published in the Nov. 2 online edition of Proceedings of the National Academy of Sciences.
     The research is based on earlier findings suggesting a link between estrogen deficiency and an increase in the number and activity of T cells. Increased T cell activity also leads to increased levels of TNF, which helps ward off infections but causes bone loss.
     The Emory team discovered a cause for the increase in T cells and TNF production: reactivation of the thymus, which is where T cells finish developing after differentiating from stem cells in the bone marrow. The findings suggest a direct link between the functioning of the thymus and bone loss.
     Scientists have long believed that the thymus is inactive after childhood, but Pacifici and his colleagues found otherwise. Their data in mouse models (and there is similar evidence in humans, says Pacifici) showed that with estrogen deficiency the thymus surprisingly comes back to life and starts pumping out new T cells.
     Estrogen deficiency sets off a chain reaction, he explains, triggering increased production of IL-7, which causes production of new bone marrow stem cells and reactivates the thymus. “This thymic rebound results in a profusion of T cells, which in turn leads to increased generation of TNF.”
     While a thymic rebound may be helpful to people dealing with immunodeficiency diseases such as AIDS, the purpose in estrogen deficiency remains unclear. “There are times for the thymus to come back to life and make new T cells,” Pacifici says. “In estrogen deficiency, there is no clear helpful reason for that. It’s an unexpected phenomenon.”


More than happiness: the science behind satisfaction

Psychiatrist Gregory Berns is curious about how the human brain works. In his laboratory at Emory, he uses imaging techniques such as MRI to study how the brain functions during tasks that have a level of uncertainty, novelty, and even decision-making. His curiosity and research have led him to develop a theory about how people are motivated, which he explores in a new book, Satisfaction: The Science of Finding True Fulfillment.
     The book examines the drive that motivates people, from running a marathon to maintaining novelty in a relationship. “There were many activities that seemed mysterious to me, the culinary magic of great cooking, Aha! moments of intellectual stimulation, the fascination of self-inflicted pain, the challenge of a crossword puzzle,” Berns says. “The satisfaction of those pursuits appeared to derive from doing something novel and tapped directly into the motivation centers of the brain.
     “Everything I have encountered inside the research lab and out in the world suggests that satisfaction is not the same as either pleasure or happiness, and searching for happiness will not necessarily lead to satisfaction.”


Why response to therapy varies in rheumatoid arthritis

New findings by Emory researchers—that growth factors in the immune system have both pro- and anti-inflammatory roles in rheumatoid arthritis—help explain why some patients respond to current therapy for this disease and others don’t.
     Rheumatologists Cornelia Weyand and Jorg Goronzy have helped delineate three different subtypes of RA over the past 10 years (diffuse RA, germinal center synovitis, and aggregate synovitis) and say that rheumatologists need to develop diagnostic tools to discern differences among patients to help determine appropriate therapy. Current therapies targeting inflammatory growth factors are applied universally to all RA patients, without accounting for differences in disease, even though not all RA patients respond well to these therapies.
     In recent work, Weyand and Goronzy used a humanized mouse model to study growth factors known for helping B cells survive and differentiate. Two of these proteins, known as APRIL and BlyS, are targets of new experimental drugs currently in early-phase clinical trials.
     The researchers implanted human tissue from RA patients with the three types of disease into mice engineered to lack a natural immune response. They then treated the mice with a soluble receptor targeted to remove APRIL and BlyS from the affected tissue.
     They found that in the mice carrying tissue from patients with germinal center synovitis, the inflammatory process was halted. In mice carrying tissue from patients with the other two types of RA, however, the opposite happened, and the growth factors and inflammation increased.
     “This is a very surprising result,” says Weyand. “We found that these two factors do more than just support the growth and differentiation of B cells. They also can bind to T cells. In the tissues that had worsening of the disease, we found T cells binding APRIL and BLyS, telling us that these T cells had actually been suppressing the disease.”


  Mental health for the homeless

  Can intensive case management, education, and coordination of services for homeless people improve their mental health and keep them off the streets? That’s the question Emory psychiatrist Raymond Kotwicki is exploring with a $250,000 grant from United Way of Atlanta. His Education and Community Services Engagement Linkage (ECSEL) study will compare two similar groups of patients who are randomized to either a usual care group or an experimental group. Half of the participants will receive the same care they currently get at Grady Memorial Hospital, while the other half will receive enhanced levels of case management and services.
“Those receiving care through ECSEL are some of the leading users of expensive tertiary care such as psychiatric emergency services and hospitals,” says Kotwicki. “We hypothesize that the life support and case management services provided to homeless people will cost taxpayers less than safety net health services and jail.”


Trials against cancer

Emory’s Winship Cancer Institute is conducting some 115 clinicals trials, including a number initiated at Winship.
     Winship was the first cancer facility in the country, for example, to open a trial of a new combination of chemopreventive drugs for the oral cavity and larynx in former smokers. Researchers are using a combination of erlotinib and celecoxib to block epidermal growth factor receptor (EGFR) mediated signaling and to inhibit cyclooxygenase-2 mediated pathways.
     Erlotinib blocks EGFR tyrosine kinase protein messaging, which tells cancer cells to grow and divide, and celecoxib is an anti-inflammatory that reduces cell formation, blood vessel formation, and metastases. Individually, the drugs have been found to be effective chemopreventive agents. This study will evaluate the safety and effectiveness of the two drugs in combination.
     Winship is the only cancer facility in Georgia offering a phase 2 trial for transitional cell carcinoma, a common form of bladder cancer, testing the efficacy of the investigational drug Vinflunine. Previous studies have shown that the drug exhibits anti-tumor activity by inhibiting cell division. The purpose of the trial is to assess whether it will shrink tumors or slow their growth in patients with advanced bladder cancer that is worsening despite chemotherapy.
     Winship is one of only two cancer research facilities in the country to conduct a procedure to determine how much chemotherapy actually reaches certain kinds of brain tumors. In the procedure, a microdialysis catheter is inserted directly into the patient’s brain tumor. The patient then receives an intravenous infusion of methotrexate. Researchers use the catheter to remove fluid directly from the tumor. They hope to determine exactly how much of the drug reaches the tumor by removing fluid for 24 hours after the chemotherapy is delivered. Patients in the study have recurrent, malignant, high-grade gliomas, one of the most difficult types of brain tumors to treat.
     Finally, Winship researchers participating in a phase 3 multicenter, international study found that bortezomib, one of a new class of drugs known as proteosome inhibitors, showed promise against multiple myeloma, as reported in the New England Journal of Medicine last June. Proteosome inhibitors are designed to specifically inhibit the proteasome, an enzyme complex in the cell responsible for breaking down a variety of proteins, including many that regulate cell division. Unlike traditional chemotherapy drugs, this drug works at the molecular level to interrupt the mechanism that myeloma cells use to reproduce themselves. It also has less impact on normal cells, says Winship hematologist Sagar Lonial, one of the authors of the report.


  Time for a commerical break: incentive to invest in new technologies

  Emory has established a new Investor Challenge Fund that will provide a match for qualified investors who invest in promising technologies discovered by Emory scientists. The eligible technologies, including drug candidates, medical devices, and diagnostic tests, will have the potential for commercialization through licensing to start-up companies.
     Emory already provides proof-of-concept funding, in-house services for licensing new technologies to companies, assistance for new start-ups in the creation process, and some physical space for new start-ups. The University also participates as a limited partner in venture capital funds, such as the newly created $3.5 million Georgia Venture Partners Fund, established by Emory, Georgia Tech, and the University of Georgia.
     “Supporting private investment in our own research helps assure that the work of our scientists reaches patients, where it can do good,” says medical school dean Thomas Lawley.
     The University has made big strides in moving key discoveries from the laboratory to the marketplace over the past decade. For example, Emory has launched 35 start-up companies and currently has 24 licensed therapeutic products in various stages of drug discovery, clinical development, or regulatory approval.


Faculty Leadership

Richard Cummings, an internationally known expert in glycomics, is the new chair of the Department of Biochemistry. He comes to Emory from the University of Oklahoma, where he was chair of molecular biology.
     Glycomics is the study of the carbohydrate molecules produced by an organism, a major new research focus identified by the NIH. Cummings has played a key role in the Consortium for Functional Glycomics funded by the NIH. His research focuses on glycoconjugates, the carbohydrate molecules and their associated proteins that permit cells to communicate with and adhere to each other—transmitting and receiving chemical, electrical, and mechanical messages that underlie all cellular and bodily functions. His research focuses on the role of glycoconjugates in cardiovascular biology, autoimmune diseases, and parasitology.

David Stephens, Schwartzmann Professor, director of infectious diseases, and executive vice chair of medicine, has a new title and added responsibility as executive associate dean for research. An expert on meningitis, Stephens heads a lab that has led international efforts to define the molecular basis for virulence of bacteria causing this disease. He helped found what is now the Georgia Emerging Infections Program, a population-based laboratory surveillance and clinical research program focused on bacterial pathogens. He also led CDC’s clinical emergency response team in defining clinical issues in prophylaxis, diagnosis, and treatment of anthrax. He currently is principal investigator of the NIH-sponsored Southeastern Regional Center of Excellence for Emerging Infections and Biodefense.

Stephen Warren, chair and William Patterson Timmie Professor of Human Genetics at Emory, is the new president of the American Society of Human Genetics. He is renowned for groundbreaking genetic discoveries, including the identification of the cause of fragile X syndrome, the most frequently inherited form of mental retardation.


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