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From illnesses borne by viruses to those sparked by defects in the body's own immune system, scientists in nine research programs at 300 Cedar St. will work to understand the causes of and to develop new treatments for devastating human diseases. Here, two postdoctoral researchers, Tim Huan (left) and Farida Bouzahzah, work in the rheumatology laboratory, part of the Vascular Diseases and Cardiology Program.

Scientists Join Forces To Delve Mysteries of Human Disease

Scientific advances during the last two decades have revealed many convergences among what were previously separate lines of inquiry into human diseases.

The configuration of space and the sharing of core resources at 300 Cedar St. will strengthen the collaborative nature of the enterprise.

Nine research programs are now based in the new building.Two programs, immunobiology and human genetics, are engaged in research that will provide the scientific underpinning for seven disease-oriented programs: arthritis and autoimmunity; asthma and lung diseases; diabetes and bone diseases; digestive diseases; hypertension and kidney failure; infectious diseases; and vascular disease and cardiology.


Yale's Section of Immunobiology, with five investigators of the Howard Hughes Medical Institute, ranks as one of the country's top academic programs in this critical field.

Richard Flavell chairs the section. His laboratory is working to understand how the immune system recognizes and responds to foreign infectious agents and why it sometimes attacks the body's own cells in autoimmune diabetes. Other investigators are studying the molecular mechanisms of antigen processing, a phenomenon in which fragments of proteins from viruses, bacteria and other disease-causing organisms bind to the MHC molecules on human cells during an infection; the cues that bring about an innate immune response to a specific antigen or pathogen; the genetic triggers of cancer; and the molecules and processes that allow organisms to respond to hundreds of millions of different antigens.

Human Genetics

With the complete sequencing of the human genome, molecular genetic strategies now play an increasingly central role in unraveling the pathogenesis of virtually every disease. The use of such strategies will cut across all disciplines of medicine.

To take advantage of the remarkable opportunities that lie ahead, Yale has established a new Center for Human Genetics that will foster work at the interface between basic molecular genetics and clinical medicine. The center is directed by Dr. Richard Lifton, an internationally known expert in the genetics of cardiovascular and renal disease. Lifton's own research has identified a set of human genes that control blood pressure, as well as mutations in those genes that result in clinically significant hypertension. His work has provided powerful new methods for patient screening, and over time, will revolutionize the design and development of anti-hypertension drugs.

The Center for Human Genetics is strategically located in the new building and includes six junior faculty members trained in the application of molecular genetic technologies to the study of human disease. Through close day-to-day contacts with other researchers in the building, Lifton and his colleagues will actively promote the use of genetic approaches throughout the other programs.

Arthritis and Autoimmunity

The Program in Arthritis and Autoimmunity, directed by Dr. Joseph Craft, seeks to understand the molecular and cellular basis for a medically important phenomenon known as autoimmunity, in which the body mistakenly produces antibodies against its own cells.

Much of the work in the Yale program focuses on systemic lupus erythematosus, an autoimmune disease that disproportionately affects young women and leads to arthritis, skin inflammation and internal organ damage.

Another focus of the arthritis and autoimmunity program is Lyme disease and Lyme arthritis. The basic mechanism of pathogenesis has been worked out at Yale, and a vaccine has been developed for people who live in areas where Lyme disease is prevalent. Second-generation vaccines are currently being tested, as well as vaccines against other tick-borne diseases. Related work is aimed at discovering why some patients have persistent infections that do not respond readily to antibiotics.

Asthma and Lung Diseases

Researchers in Yale's Program in Asthma and Lung Diseases, which is headed by Dr. Jack A. Elias, recently discovered the two genes, Interleuken-13 and Gamma-interferon, that cause pulmonary emphysema.

Using "transgenic" mice as a model system, investigators in the program demonstrated that this pair of genes, already known to cause inflammation, can produce emphysema similar to that seen in patients with chronic obstructive pulmonary disease.

The program also addresses a whole spectrum of common pulmonary disorders that, taken together, constitute a major public health problem. Since the early 1980s, the number of asthma cases in the United States and around the world has grown to epidemic proportions. Currently, 15 million to 18 million people in the U.S. are affected by asthma and an additional 30 million people have been diagnosed with emphysema and chronic bronchitis.

Based on recent research at the cellular and molecular levels, investigators in Yale's Program in Asthma and Lung Diseases have begun to suspect that asthma occurs when the immune system begins to attack normally benign substances with a vigor meant for pathogens. This idea raises the possibility of novel treatment strategies to prevent the inappropriate immune response.

Diabetes and Bone Diseases

Among the endocrine disorders that affect the American population, diabetes mellitus and osteoporosis are the most common.

Diabetes falls into two types: type 1, resulting from the autoimmune destruction of pancreatic islet cells, and type 2, otherwise known as insulin-resistant diabetes, which has been associated with obesity, hypertension and an extremely high incidence of coronary death. Postmenopausal osteoporosis is an estrogen-deficiency state in which the rate of bone loss results in a thin, fracture-prone skeleton. Taken together, these disorders command more attention and more National Institutes of Health (NIH)/industrial research support than all other endocrine diseases combined.

Three endocrine research groups, now scattered throughout the medical school, will be consolidated in the new building under the Program in Diabetes and Bone Diseases. These include an interdisciplinary group led by Dr. Robert Sherwin, which is working on the autoimmune pathogenesis of type 1 diabetes. The team is taking a multi-faceted approach to the problem of hypoglycemia and how it alters brain function in patients with diabetes, particularly during intensive insulin treatment.

A second group directed by Dr. Gerald Shulman seeks to understand the molecular mechanisms behind insulin resistance in patients with type 2 diabetes. Shulman's group is developing unique transgenic mouse models of insulin resistance and is at the forefront of investigators using nuclear magnetic resonance imaging and GC-mass spectroscopic techniques to study muscle, liver and fat metabolism in type 2 diabetes.

A third group led by Dr. Arthur Broadus has discovered a major new hormone that regulates bone development. This group is also exploring the role of parathyroid hormone related protein in the development of the mammary gland and in preventing neurodegeneration in the brain.

Digestive Diseases

Yale has long been a center for studies on the gastrointestinal tract and liver, with strengths across the entire spectrum of basic and clinical research.

In the Program of Digestive Diseases -- headed by interim chief Dr. Henry Binder -- molecular, cellular, physiologic and imaging methods are being used to explore fundamental questions of epithelial biology. In parallel, clinical studies on the pathophysiology of chronic liver diseases are under way, coordinated with an active program of drug trials.

Yale's excellence has been recognized by the award of a Digestive Diseases Research Core Grant from the NIH to support shared research facilities, pilot projects, and educational activities. In its most recent external review, this program, known as the Liver Center, was praised as a prestigious institution for education and research at the forefront of contemporary hepatology.

In the new building, the Program in Digestive Diseases will be located next to the Program in Nephrology, stimulating day-to-day interactions between scientists studying disorders in two morphologically related tissues, the intestine and the kidney.

Hypertension and Kidney Failure

Hypertension affects 50 million Americans and contributes to over 200,000 deaths annually from heart attack, stroke and end-stage renal disease (ESRD).

Despite enormous efforts, the pathogenesis of hypertension and the factors that lead to ESRD remain unknown in most patients. Research at the Yale School of Medicine now points to a large effect of inheritance. Genes have been found in which rare mutations lead to increased sodium reabsorption by the kidney, due directly to an increase in activity of sodium channels or indirectly to increased hormonal signaling.

The Program in Hypertension and Kidney Failure, led by Dr. Stefan Somlo and working in close collaboration with Dr. Richard Lifton, is building on this knowledge to learn more about the molecular mechanisms causing common forms of hypertension and ESRD. Genetic and physiologic studies are mutually reinforcing: physiologic dissection of renal sodium transport will continue to identify key candidate genes for genetic studies, which in turn will pinpoint specific mutations contributing to the development of hypertension and ESRD.

These findings will lead to studies of cellular physiology and, where necessary, genetically engineered animal models, with the goal of developing novel therapeutic agents. In parallel, clinical research is establishing the prevalence of mutations in the general population, and drugs are being developed to try to prevent progression of hypertension and ESRD.

Infectious Diseases

Over the past two decades, infectious diseases have re-emerged as a major health problem throughout the United States and around the world.

The SARS epidemic, outbreaks of E. coli infections from undercooked meat, cryptospordiosis from contaminated water, and tuberculosis as a result of AIDS are constant reminders that humans are surrounded by microbial pathogens which, given the right circumstances, can cause devastating illness. A second and even more worrisome issue is that of antibiotic resistance, which is now found in most species of pathogenic bacteria.

Drawing upon Yale's strengths in molecular biology, cell biology and immunobiology, researchers in the Program in Infectious Diseases aim to understand how infectious agents enter and survive in hosts. The program is led by Dr. Keith Joiner and focuses on intracellular pathogens such as Toxoplasma gondii (the organism that causes toxoplasmosis) and Plasmodium falciparum (the organism that causes malaria). These two parasites are closely related to one another, and while the diseases that they cause are quite different, many generalizations can be made from one to the other. Joiner and his colleagues are working to decipher the mechanisms by which the parasites receive nutrients from the host cell in which they reside. The long-range goal will be to develop drugs that interfere with nutrient acquisition, thus killing the parasites.

In the new building, investigators in the Program in Infectious Diseases will benefit greatly from proximity to colleagues in the Program in Immunobiology, who can be expected to contribute expert knowledge of the immune mechanisms that have evolved to ward off pathogens.

Vascular Disease and Cardiology

Cardiovascular disease and its complications -- myocardial infarction, congestive heart failure, stroke, cardiac arrhythmia, and peripheral vascular disease -- rank as the leading cause of death in the United States.

In recognition of this fact, the Yale School of Medicine moved in 1990 to create a strong basic research unit in endothelial biology. The new building will allow carefully planned expansion of this group to include investigators working on atherosclerosis, plaque instability and rupture, and cardiovascular gene therapy. Researchers in the Program in Vascular Disease and Cardiology will interact closely with Yale's noted clinicians in the area of cardiovascular medicine (interventional cardiology; cardiothoracic surgery; peripheral vascular surgery) and will take part in an interdepartmental program on organ transplantation.

Research on heart disease also includes investigations of the physiology of the organ itself, both before and after heart failure. Yale's research in this area has integrally linked basic and clinical investigations, focusing on such issues as diagnostic imaging, nuclear pharmacologic and electrophysiologic therapies, and transplantation. One of Yale's prominent investigators in this area is Dr. Jeffrey Bender, who is studying how inflammatory events in blood vessels cause atherosclerosis. This work could one day lead to new ways of preventing stroke, heart attack and the rejection of transplanted organs.


Facility Marks Major Step in Yale's $500 Million
Investment in the School of Medicine

Space Will Help Transform the Face of Medicine

Scientists Join Forces To Delve Mysteries of Human Disease

High-Tech Classrooms Promote State-of-the-Art Learning

Donors Helped Medical School Vision Become a Reality

Center Will Expand Breakthrough Research Using Magnetic Resonance

Building for the Future Continues

Yale Bulletin & Calendar