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Summer 2007 Vol. V, No. 4

Faculty of Medicine and Medical Center: Deep Roots, Endless Skies

A New Era of Medical Research at AUB

Throughout its history, the men and women associated with AUB’s School (and later Faculty) of Medicine have been engaged in research that has contributed to an understanding of some of the most important health care issues in the region and enhanced the quality of medical care that patients receive at AUH.

When the Lebanese civil war broke out, however, it had a significant impact on the quality and quantity of research taking place not just at the Faculty of Medicine, but at AUB generally. There were many reasons for this: difficulty replacing aging equipment and purchasing supplies, faculty attrition, and the paramount need for the remaining faculty to care for patients and educate students during a war. Since the mid-1990s, however, there has been a concerted effort at all AUB faculties to invest in laboratories and equipment and to stress the pivotal role that research plays in AUB’s mission.

At the Faculty of Medicine, Dr. Nadim Cortas, vice president for Medical Affairs and Raja N. Khuri Dean of the Faculty of Medicine, and his colleagues are in the midst of a multi-year effort to build and strengthen the Faculty’s research capacity. They have already established the Core Facility Laboratories, and the regulatory infrastructure that is required for medical research such as the Institutional Review Board (IRB) and the Institutional Animal Care and Utilization Committee (IACUC). The Faculty of Medicine is also investing heavily in people. Working with a team of academic reviewers from leading universities in the United States, it was determined that AUBMC needed to establish a core group of 15 investigators to start a PhD/MD-PhD program and grow to an optimal steady state number of 20. The ten investigators who are already on board are featured in the research profiles that follow.

Initial support for these men and women (trained assistants, laboratories, equipment, supplies, travel funds, etc.) was provided by both internal and external funds. Dr. Ali Bazarbachi, assistant dean for research, notes that there has been a 50 percent increase in intramural funding in the last three years that has resulted in a 300 percent increase in the amount of extramural grants at the Faculty of Medicine. More than two-thirds of total research funding at the Faculty of Medicine now comes from external sources.

During the last ten years, research output has also increased significantly in both quality and quantity. The number of publications by researchers at the Faculty of Medicine has increased from 63 in 1996 to 258 in 2006. There has also been a significant increase in the number of articles related to original research (from 25 percent in 1996 to 48 percent in 2006), and in the “impact factor” of the journals in which faculty members are being published. (A journal’s “impact factor” is a frequently cited number that is used to measure the importance of a particular journal in its field.) The number of articles in journals with impact factors greater than two has increased from 15 in 1996 to 84 in 2005.

Establishing a National Neonatal Network

Khalid A. Yunis (AUB BS ’75, MD ’80), FAAP; Associate Professor of Pediatrics; Director, Newborn Services; Director, National Collaborative Perinatal Neonatal Network

Because much of Lebanon’s statistical information base eroded during the Lebanese civil war, there is a desperate need for national health statistics. The National Collaborative Perinatal Neonatal Network (NCPNN) was established in 1998 to meet the need for national health statistics related to maternal and neonatal health. With the 19 hospitals throughout the country that are participating in the network, we are currently capturing information on more than 20 percent of all deliveries in Lebanon. We are actively recruiting additional hospitals. When the network includes data on at least half of all deliveries in Lebanon, the NCPNN will be representative of the entire population of pregnant women and their newborns in Lebanon.

We plan to expand the NCPNN to neighboring countries with the ultimate goal of establishing a regional research network. We believe that identifying common problems, pooling resources, and proposing solutions collectively will increase our effectiveness and is critical to ensure the long-term sustainability of this initiative.

The NCPNN includes routine statistics on important health indicators such as neonatal mortality, fetal death rate, birth defects, and cesarean section rates. We use this data to conduct in-depth multi-center research projects investigating trends, associations, and risk factors of neonatal outcomes. Our specific research interests include birth defects, particularly consanguinity and its associated health risks, which are especially prevalent in this region.

D is for Bones

Ghada El-Hajj Fuleihan (AUB BS ’79, MD ’83), MPH 1997 (Harvard School of Public Health); Professor of Medicine; Department of Internal Medicine; Director, Calcium Metabolism and Osteoporosis Program

Our research group is investigating the epidemiology of osteoporosis in Lebanon, which we have shown is as common a chronic disease in this country as it is in the western world. In fact, 20 percent of elderly women (above 65 years of age) and 11 percent of elderly men in Lebanon have osteoporosis as defined by vertebral compression fractures. Our team has established normative databases for bone mass in adolescents, the young, and the elderly in Lebanon, and evaluated lifestyle predictors of bone mass such as dietary calcium, vitamin D, and exercise. The team also demonstrated that these variables are at levels below international guidelines in many Lebanese and therefore suboptimal to maximize bone health. We have investigated the efficacy of bisphosphonates in preventing bone loss that is usually experienced by premenopausal women who are undergoing chemotherapy for breast cancer and in preventing bone loss that takes place after bone marrow transplantation.
Another main area of investigation is elucidating the effect of vitamin D, a vitamin produced in the skin in response to sunshine, on health in general and bone health in particular. Hypovitaminosis D (vitamin D deficiency) is common in Lebanon, across all age groups. This finding can be partially explained by low sun exposure, use of sun blocks, clothing style, and low consumption of foods rich in vitamin D such as fortified milk, fish oils, etc. We have conducted randomized trials that have established the efficacy of vitamin D replacement in promoting musculoskeletal health in normal growing children and in adults with epilepsy.
The overall goal of our investigations is to identify affordable and effective interventions, amenable to modifications through public health policies, to optimize bone health in the Lebanese.

Fighting a Worldwide Epidemic

Fuad Ziyadeh (AUB BS ’76, MD ’80), Associate Dean for Academic Affairs, Faculty of Medicine; Professor of Medicine and Biochemistry

The focus of my research is the early development and subsequent progression of diabetic kidney disease, the most common cause of chronic kidney failure worldwide. When I started working on the problem more than 15 years ago, very little was known about the cellular and molecular mechanisms of kidney injury in diabetes. With my laboratory research team at the University of Pennsylvania in Philadelphia, where I was until October 2005 when I came to AUB, we first developed the appropriate tools and models. Then we moved on to connect the known features of diabetes (such as high blood sugar, high blood pressure, etc.) to the pathology and the characteristic manifestations of kidney disease in diabetes.

We were able to discover that the missing link was a signaling protein known as transforming growth factor-beta (TGF-beta). This messenger hormone-like substance, which we found to be produced in excessive amounts by kidney cells in the diabetic state, tells the kidney cells to produce excess scar tissue, setting in motion a cascade of events that eventually destroys the kidney architecture and compromises kidney function. A successful trial with diabetic mice opened the door for the rational development of new drugs that can be tested in humans to effectively treat diabetic kidney disease.

Although I have always been fascinated with the kidney, my interest in diabetic kidney disease is the result of the advice of a good friend and mentor who urged me to focus my research on pressing research questions that had immediate relevance to human disease. Unfortunately, diabetic kidney disease, a major complication of the worldwide epidemic of diabetes, is one of those pressing research questions. It is already increasing in developing countries and is projected to increase even more dramatically in the future with obesity on the rise.

A New Matrix forStem Cell Research

Marwan El-Sabban, PhD; Professor, Department of Human Morphology; Director, Biological Imaging Facility

Regenerative medicine is an exciting and emerging branch of medicine in which cell and tissue-based therapies are used to treat disease. It encompasses the fields of tissue engineering, biomaterials, stem cell therapy, and the study of associated human diseases. Stem cell therapy and regenerative medicine offer promising treatments for some human diseases, which have proven to be difficult to treat.

I have long been fascinated by the concept of organ-specificity of cancer metastasis. This led ultimately to my research on the role of cell-cell and cell-matrix interaction in cellular function with a special focus on the role of hetero-cellular communication in cancer metastasis and regenerative medicine.

I am currently involved in several research projects. I am working with Dr. Samir Alam, a cardiologist at AUBMC, on an animal model of myocardial infarction and in vitro stem cell cultures to monitor the homing of stem cells to injured heart tissue. I am also collaborating with Dr. Ali Bazarbachi on the use of organ-derived matrix extracts to induce organ-specific differentiation of human bone marrow-derived stem cells in vitro. The initial project to differentiate stem cells into bone cells has been successfully completed and has since been expanded to include other diseases including repair of cartilage, engraftment of bone marrow cells, and pancreas and liver regeneration.

In addition to the significant and important work that we are doing at AUB, we are also collaborating with a research laboratory in Denmark to grow stem cells in bioreactors under microgravity. This will allow us to differentiate cells fully in three-dimensional cultures, which mimic the cell environment inside an organism. This is important because recent research has shown that cells behave very differently when they are grown in three dimensions. We will also benefit from our collaborators’ extensive proteomics (study of proteins) experience in the identification of specific differentiation markers.

Surviving Leukemiaand Lymphoma

Ali Bazarbachi, MD, PhD; Professor of Medicine; Director, Bone Marrow Transplantation Program

My area of research activity focuses on developing oncogene-targeted therapies for human leukemia, a malignant disease (cancer) of the bone marrow that affects men and women of all ages throughout the world, by agents other than DNA-damaging chemotherapeutic agents. My laboratory is also looking at the role that the formation of new blood vessels (angiogenesis) plays in the way that leukemic cells impact organs.

We are using the chemotherapy-resistant adult T-cell leukemia/lymphoma (ATL) as a model. Since ATL results from infection by the HTLV-I virus and is resistant to conventional chemotherapy, I focused on developing strategies to cure ATL by targeting the virus. My research efforts were rewarded with the discovery of a very effective treatment for ATL using a combination of the antiviral agents zidovudine and interferon alpha. This is now a protocol that is widely used for the treatment of ATL throughout the world.

Although the zidovudine/interferon treatment achieved a high response rate and improved chances for survival, most of the patients eventually relapsed.It was clear that a more effective treatment was needed. Through my research I have demonstrated that the combination of Arsenic trioxide and interferon alpha is an extremely potent and specific inhibitor of the proliferation of ATL cells and has little effect on normal cells. This combination has proven to be effective in treating relapsed ATL patients. I have also shown that proteasome inhibitors, natural or synthetic retinoids, could also be interesting targeted therapies for ATL.

Working together, Dr. Marwan El-Sabban and I are exploring a new area of ATL research with his discovery of the role of angiogenesis and gap junction mediated communication in ATL. We have also recently identified a potentially interesting new mechanism for targeting tumor cells in which leukemic cells move through the endothelial barrier using an angiogenic-like mechanism.

Battling BattenDisorders in Children

Rose-Mary Boustany (AUB BS ’75, MD ’79), Chairperson, Abu-Haidar Neuroscience Institute; Acting Chair, Psychiatry; Professor of Biochemistry and Pediatrics

While doing a fellowship in neurogenetics and neurochemistry at Massachusetts General Hospital, I codirected a diagnostic laboratory for rare inherited disorders affecting the brains of children. Batten disorders, also called the neuronal ceroid lipofuscinoses (NCLs), while clinically well described, were not identifiable by a specific test. They cause night blindness, epilepsy, progressive motor and mental decline, and rapid shrinking of the brain, and early death. It was the plight of families in search of a diagnosis and a cure, and the challenge of understanding these diseases, that were the impetus for my work.

It quickly became clear to me that the rapid loss of brain tissue must be due to an accelerated form of neuronal cell death or suicide called “apoptosis.” In 1995, we discovered the first of the genes that caused the juvenile variant: CLN3. Although the intact CLN3 gene promoted cell survival, its defects unleashed premature cell death. This principle of accelerated neuronal death has held true for most of the 10 NCL types known, and caused by genes termed CLN1-CLN10.

Along the way, we stumbled upon a known non-addictive painkiller that could protect NCL cells from inevitable cell death. This drug is now used all over the world and seems to slow the degenerative process. Unfortunately, it is not curative.

This work is important, not just because it opens avenues for treatment of a rare disorder like juvenile NCL, but also because it deepens our understanding of other neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease, and may shed light on basic cellular processes at the root of common proliferative disorders, such as cancer and inflammation.

Genetic Causes for a Broken Heart

Georges Nemer (AUB BS ’92), PhD; Assistant Professor, Department of Biochemistry

Cardiac abnormalities are one of the leading causes of death in most countries. Although there has been a great deal of progress in recent years in providing relief for many patients as a result of the development of new surgical techniques, there has been less attention paid to the causes of cardiac abnormalities. That is my interest.

To discover the causes, we need a better understanding of our genome: the DNA molecules that are the functional structural units that make up our cells. It is these molecules where most errors responsible for any changes at the level of the organs, including the heart, occur. These molecules are susceptible to external damage created by a variety of agents including UV light, chemicals, and stress. Although we have a defense mechanism even during embryogenesis that responds to external challenges by repairing most errors, some still do occur and cause permanent damage, which is referred to as DNA mutation and/or chromosomal aberration.

By screening for mutations, we have enhanced our understanding of how these mutations occur and the consequences for patients when they occur. We have been able to use the blood samples that we have collected from patients and their families to do DNA extraction and try to identify the part of the three billion bases that compose our genome that is mutated. This screening for mutations will allow us to offer affected patients genetic counseling and will lead to an earlier pre-diagnosis of abnormal heart development.

Understanding Chronic Pain and Addiction

Nayef E Saadé, DSc; Professor and Chairman, Department of Human Morphology

A group of us (Drs. H. Al-Amine, S.F. Atweh (AUB MD ’74, MS ’71, BS ’69), J.J. Chediac, S.J. Jabbur, B. Safieh-Garabedian, and myself) are working together to better understand chronic pain and other chronic inflammatory diseases affecting the organism in general and the gastrointestinal tract, in particular. We are researching the plasticity of the functions of the nervous system and the existence of discrete cross-talk pathways between the nervous and the immune systems. We are also trying to clarify the relationship between the behavioral manifestations of addiction and the recognized roles of dopamine, glutamate, and opioids such as morphine. To do this, we are testing various drugs to determine their effect on interleukins and neurotrophic factors that have been shown to modulate the sensorimotor abnormalities observed in patients with drug dependence.

This work will further the understanding of the neural mechanisms involved in the action of drugs and stimulants and the possible neurobiological changes that can lead to addiction. Our hope is that this research will lead to the design of new strategies for the treatment of drug addiction, chronic pain, and chronic inflammatory diseases affecting various systems in the body.

Investigating Cell Suicide

Ghassan Dbaibo (AUB BS ’82, MD ’86), Professor, Department of Pediatrics; Associate, Department of Biochemistry

My research focuses on the mechanisms of cell death or apoptosis: a process of organized cell death in which the cell is triggered to commit suicide. The cell recognizes certain external or internal signals as stressful and so proceeds with self-elimination. This can be thought of as a form of altruism where the cell commits suicide to protect the rest of the organism. Examples of apoptosis are the elimination of a virus-infected cell to prevent spread of the virus or the elimination of a cell that is transforming into a cancer to prevent its propagation.

Interestingly, viruses have developed ways to delay this process and increase their chances of multiplying so that the dying cell will be full of virus particles when it dies. We are interested in genes from adenovirus that regulate cellular apoptosis. When we understand how these genes work, we can then consider how we might use them as tools in the treatment of a variety of diseases. Genes that promote apoptosis could be used to treat cancer by inducing the suicide of cancer cells or to limit the damage caused by heart attacks and strokes by saving cells that are normally lost in the days following the acute loss of blood supply to the heart or brain.

Normalizing Life with Epilepsy

Mohamad Mikati (AUB BS ’76, MD ’80), Director, Adult and Pediatric Epilepsy Program; Professor and Chairman, Department of Pediatrics

Although epilepsy is a very common brain disorder, it is not well understood. This leads to unnecessary suffering for many patients with epilepsy. Through my research I am working to alleviate this suffering by finding new medications to treat epilepsy and defining better ways to care for patients undergoing epilepsy surgery. This approach has enabled us to achieve the best results for surgical therapy of epilepsy anywhere in the world. We recently published in the prestigious journal Epilepsia the first and only study to document normalization, rather than just improvement, of quality of life after epilepsy surgery.

I am also working in the laboratory to understand why seizure activity injures brain cells and how to prevent that from happening. We have identified several molecules that may be helpful in the development of medications that will be more effective in controlling epileptic seizures. We have also discovered many agents that can protect the brain from the effects of seizures and that may eventually lead to the development of totally new therapies. We are also working to identify genes that may be causing epilepsy, specifically in the Lebanese and Arab populations.

The Saab Medical Library: the Oldest Medical Library in the Region

The Saab Medical Library (SML) is also celebrating its 140th anniversary this year. Although the library was established at the same time as the medical school in 1867, it moved to its present location across from the hospital and became the Saab Medical Library only in 1975, when it was dedicated to the memory of Dr. Nicholas Saab, an AUB alumnus (MD ’59) and a physician at the hospital. The library moved from Van Dyck Hall, where it had been since 1925, to its current location.

Because SML is one of the most advanced medical libraries in the region, Medical Librarian Hilda Nassar and her colleagues are often asked for their advice. “Whenever we purchase a particular e-resource, for example, many libraries in the region follow,” Nassar explains. “In fact, people seek our advice for all aspects of managing health libraries.”

The library is constantly updating its collection and expanding its services. It has published an e-newsletter since 1996 and established a Lebanese Corner in 1984 where it is gathering all publications about Lebanon and/or by Lebanese authors in the fields of medicine and related health sciences.

The SML collection includes at least one gem: a 1593 edition of Avicenna’s Canon of Medicine. Avicenna (also known as Ibn Sina), who lived between 980 and 1037AD, was a Persian physician, philosopher, and scientist, who wrote more than 400 books. His Canon of Medicine was a standard medical text at many European universities for hundreds of years. Nassar tells how during a visit to the National Library of Medicine in Bethesda in 1993, the librarian there proudly showed her one of their prized possessions: a 1597 edition of Avicenna’s Canon. “When I told them that we at AUB had a 1593 edition, they did not believe me. I promised that when I returned to Beirut, I would photocopy the title page and send it to them so they could see the date, which I did!”

Thanks to a gift from an anonymous physician (a graduate of AUB), SML will soon include a History of Medicine section where it will display some of the more interesting and rare items in its collection. In addition to Avicenna’s Canon, the display will feature Dr. John Wortabet’s Fundamentals of Autopsy, 1871 (in Arabic) and Van Dyck’s Principles of Pathology, 1878 (in Arabic). These volumes are all part of SML’s E-Historical Collection, which may be found on-line by clicking on “Resources” at http://smlweb.aub.edu.lb/.