News and Publications

Chairman's Overview

Ernest Beutler, M.D.

The scope of research in our department is so broad that our research programs overlap with those of every department in TSRI. Even finding a name to distinguish the department has been difficult. When I assumed the chairmanship in 1978, we were the Department of Clinical Research. When we merged with the Departments of Biochemistry and Cellular Biology, we became the Department of Basic and Clinical Research, and now in the present decade, we are the Department of Molecular and Experimental Medicine. Throughout this time, the term clinical research or experimental medicine has been included in the name. This inclusion signifies an unvarying focus of the department: its interaction with clinical medicine.

The following pages describe some of the clinical and clinically related research under way in the department. Most of the divisions of the department are engaged in clinical trials that directly involve patients, usually in the General Clinical Research Center, which is supported by the National Institutes of Health. The Division of Biomathematics is involved in virtually every clinical study that is under way. Analysis of clinical trials can become quite complex, because not every patient entering a study completes the study, and because so many variables may conceivably play a role in the outcome.

Scientists in the Division of Arthritis Research are studying cartilage from patients with different kinds of arthritis to better understand how the death of cartilage cells leads to joint disease.

Because the formation of abnormal blood clots is fundamental to the pathogenesis of the most important causes of death and disability--strokes and heart attacks--much of the work being done in the Division of Experimental Hemostasis and Thrombosis involves patients. Included are understanding and interdicting the interaction of blood platelets with the lining of blood vessels, studying the vascular endothelium, and investigating the treatment of strokes. Also under investigation are genetic polymorphisms of blood proteins and platelet receptors that may help identify persons who are at high risk for heart attacks and strokes.

Researchers in the Division of Research Rheumatology study the pathogenesis of a variety of autoimmune diseases. The antibodies that appear in the blood of patients with these diseases provide clues for both understanding and diagnosing abnormalities such as systemic lupus erythematosus, scleroderma, and Sjörgen's syndrome. Investigations are under way in patients with allergic rhinitis, asthma, and hereditary angioneurotic edema to gain understanding of the factors that cause and modulate these disorders.

Members of the department in the Division of Hematology have started a clinical trial to study the effect of a common gene mutation on health. Working with staff at Kaiser-Permanente, they will study 60,000 patients to determine the effect of mutations of the gene that causes hereditary hemochromatosis (iron storage disease). This clinical trial is arguably the largest of its type that has ever been undertaken. Cladribine (2-chlorodeoxyadenosine), a drug developed in this department, has been used successfully, in collaboration with the Division of Neurology, Scripps Clinic, as a treatment for multiple sclerosis. A multicenter trial confirmed the effectiveness of this drug, and the Food and Drug Administration is considering licensing cladribine for the treatment of multiple sclerosis, in addition to treatment of hairy cell leukemia, a disease for which it is already licensed.

Transfusing blood granulocytes is difficult, partly because storage of granulocytes has been almost impossible. Now, in the Division of Biochemistry, a simple storage method has been devised that will allow storage not only of blood granulocytes but also of stem cells in bone marrow.

Viral hepatitis is one of the world's major killers. The various types of hepatitis have been under intensive study in the Division of Experimental Pathology. Currently, the T-lymphocyte response to hepatitis B and C viral proteins in the blood and liver biopsy specimens of infected patients is under investigation. Phases 1 and 2 of a clinical trial of a new type of hepatitis vaccine have been successfully completed.

Those divisions whose work does not deal directly with patients are nonetheless engaged in research projects that are bound to have an important impact on patients in the future. The emergence of antibiotic-resistant bacteria has been an increasing problem, and the Division of Cellular Biology is working with industry to develop a new and more effective class of antibiotics. Oncogenes, mutated regulatory genes, are probably the basis of most or all forms of cancer. The Division of Oncovirology has been systematically isolating such genes from animal tumors. The genes that are identified can then be sought in human tumors, and the genes that play an important role in tumorigenesis can be used both for diagnosis and as targets for treatment. The gene for PAX3-FKHR, for example, is generated by a chromosomal translocation that occurs consistently in alveolar rhabdomyosarcoma in children and may play a central role in the development of that tumor.

Only 12 of our 46 full-time faculty members and 26 of the 83 research associates hold M.D. degrees, and only 9 are licensed to practice medicine. Thus, our focus on clinical research has always depended on interaction with practicing physicians, particularly those at Scripps Clinic. Indeed, 25 of these physicians hold adjunct faculty positions in the Department of Molecular and Experimental Medicine. It has always been a challenge to foster these relationships between clinical medicine and bench research. In addition, in the 1990s, doing meaningful studies in patients has become particularly difficult for several reasons.

First, the demand on clinicians to generate revenue has escalated to a point where taking time to think about or do research is a luxury that health care administrators do not encourage. The number of patients has increased, but the number of clinicians has not. The workload has increased, but the compensation has decreased. The focus in health care delivery has become an economic one, and intellectual activities such as pondering the cause and treatment of disease have taken a back seat. For example, recently, every clinician at Scripps was required to attend a meeting that lasted more than 2 hours to learn how to write notes in patients' charts to maximize the billing returns and to avoid criminal penalties imposed under government programs.

Second, in an attempt to protect the legitimate rights of patients who are participating in clinical trials, professional medical ethicists have played an increasing role. Unfortunately, they have been unable to agree on requirements for studies, and even the most straightforward investigations become mired in endless debate about fine legal points. The result is long delays and often scuttling of worthwhile projects. An interesting case in point is the collection of DNA from patients' blood samples, the mainstay of many cutting-edge clinical studies. Extensive rules and long consent forms have been constructed, and patients must be warned of the possible risk to their insurance status if somehow the samples or the results of the assays fell into the wrong hands. Detailed attention has been given to "anonymizing" samples, a procedure that makes it impossible to either obtain vital additional information or use data obtained for the participant's benefit. Yet, there is no documented case of any patient ever having had insurance denied or rates raised because of DNA testing. Twenty years ago, when investigators doing cutting-edge research used serum or blood cell samples, no such prohibitions existed, and I am unaware that patients were harmed by the lack of constraints. By insisting on such constraints now, the public is shooting itself in the foot; much important research simply does not get done.

Third, a polarization in the clinical research community between laboratory- and clinic-based scientists has occurred. The often cited rationale is that each form of endeavor is so complicated and demanding that no one person can do both laboratory- and clinic-based research. Specifically, laboratory-based scientists are concerned that less than full-time devotion to laboratory research will place them in a noncompetitive position with respect to research grants. Although this view has some merit, enough examples exist of capable physicians who have hands-on laboratory programs to prove that to do both laboratory- and clinic-based research is possible. Such physician/scientists have a distinct advantage in translating what is found in the laboratory to the clinic, because they have intimate involvement with both places. Yet, the pool of such scientific hybrids is almost vanishing.

These problems are not, of course, unique to TSRI; they occur nationwide. However, we are attempting to overcome the obstacles that stand in the way of first-rate clinical research. Our General Clinical Research Center is one of our greatest assets. It allows investigators to carry out meritorious clinical research projects without requiring outside funding. The development of cladribine was financed almost entirely in this way. The Skaggs Clinical Scholars Program recently initiated by Dr. Lerner is a innovative way to bring the physicians who are most strongly motivated to perform outstanding clinical research together with TSRI faculty. The funding that will be provided by this program will make time for research available, even under fiscal stringencies that exist in the world of medicine today. Finally, we are fortunate to count among our faculty a few of the vanishing breed of physician/scientists who are able to carry out first-rate laboratory work but also continue to take care of patients.