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Molecular and Experimental Medicine

Ernest Beutler, M.D., Chairman

ne of the great challenges of modern medicine is to understand how and why diseases manifest differently in different patients. Why do some people with a genetic predisposition for a disease develop that disease while others don't? Why does a virus attack one patient aggressively while the same strain behaves in a relatively benign fashion in another? How does a genetic disease that comes from a single mutation in a single gene differ from person to person? And what are the mechanisms of diseases caused by multiple genes?

And the larger question is, of course, what can we do about these diseases?

With a staff of 50 scientists, the Department of Molecular and Experimental Medicine (MEM) encompasses a wide range of specialties and interests. The department was formed in the early 1980s and since that time has occupied a position at the interface of clinical and basic research. The mission that unites the department is the quest to understand the mechanisms of diseases and to devise strategies to improve health.

Though a number of its members have significant clinical experience, MEM is not a clinical department per se. Even so, MEM faculty are particularly interested in the clinical applications of their work.

One example is a program that tackles hepatitis B, a serious disease caused by a virus that attacks the liver. More than 350 million people worldwide, including 1.25 million Americans, suffer from the disease. Hepatitis B is the leading cause of liver damage and claims over a million lives a year worldwide.

But why are some patients able to rid themselves of the virus, while others continue to carry it and develop serious liver damage? Why do 15 to 25 percent of chronic sufferers die? Answers to these questions may lead to improved treatments.

Under the leadership of Frank Chisari, M.D., the department has become a world leader in the study of hepatitis, especially of the body's immune response to the disease. Chisari and his team of researchers study the immunobiology and pathogenesis of hepatitis B and related viruses in transgenic models and in infected patients.

Other researchers in the department are attempting to understand blood clots such as those that cause cardiovascular disease, particularly heart attacks and stroke.

STUDYING BLOOD CLOTTING AND ARTHRITIS

Zaverio M. Ruggeri, M.D., is conducting basic research to address the main disease-causing mechanisms responsible for arterial and venous thrombosis, the clotting of veins and arteries, and is laying the foundation for novel and more efficient therapeutic approaches. Ruggeri and his team study the interaction between vessels and blood platelets, the cell fragments that carry the chemicals the body uses in hemostasis, in which blood clots at a site of injury. Members of the Ruggeri lab are particularly interested in the structures of the adhesion proteins that mediate the formation of blood clots and the receptors on the platelets. Lab members have been solving the structures of these interacting molecules and piecing together how they work.

Such detailed knowledge of the three-dimensional structure of these adhesive proteins is indispensable for understanding the differences between normal hemostasis, where bleeding is stopped after a cut, and pathological thrombosis, in which a clot of platelets occludes blood flow and causes cardiovascular disease.

Another serious disease, arthritis, is the topic of research in a laboratory headed by Martin Lotz, Ph.D. Osteoarthritis is the most common form of the disease and arises from the degeneration of cartilage in joints. Lotz, who heads the MEM's division of arthritis research, studies cartilage and investigates how one can influence its growth.

Joint trauma, for instance, is a known risk factor for osteoarthritis, but there are no pharmaceuticals to limit this tissue damage. Using models of cartilage injury, Lotz and his team have found that apoptosis, or programmed cell death, can be induced by mechanical stress in joints, and they are testing inhibitors to see whether they can decrease progress to osteoarthritis. Lab members are also looking at the stimulation of cartilage damage by chemical signals released by immune system cells and investigating whether blocking these signals represents a viable approach to preventing osteoarthritis.

In another line of research with clinical implications, Ernest Beutler, M.D., and other members of the department have collaborated with Kaiser Permanente on the largest DNA study in history. Recently completed, this epidemiological study examined the DNA and clinical data of some 41,000 patients for genetic susceptibility to a disorder known as hereditary hemochromatosis. Hemochromatosis is a metabolic disorder in which excess deposits of iron occur in the liver, pancreas, and other organs. Among other manifestations, cirrhosis of the liver, diabetes, and cardiovascular diseases may result.

Although it was originally thought that most people with the mutation that causes hemochromatosis were symptomatic and suffered a high mortality rate if untreated, the results of the study show clearly that very few manifest the disease. Most who are homozygous for this genetic mutation seem to enjoy a normal life span. This study may lead to a rethinking of the cost-benefit of screening normal populations for this disease and of the importance of its early treatment.

Investigators in the department are also participants in the Scripps Cancer Center with physicians from Scripps Clinic and the ScrippsHealth system, institutions which together treat 25 to 30 percent of all the cancer patients in the San Diego area. The cancer center's goal is to facilitate the development of new cancer drugs from their beginnings in the laboratory to their final approval for use by cancer patients. This program will enable researchers to contribute more directly to the solutions they seek by moving potentially useful laboratory findings quickly and seamlessly into the clinic through their close collaboration with clinical staff.