Scientific Report 2007

Molecular and Experimental Medicine

Chairman’s Overview

It has been a dynamic year for the Department of Molecular and Experimental Medicine. Two of our senior faculty members, both of whom had been in the department continually since their postdoctoral training, collectively 38 years, assumed senior responsibilities in other institutions. Roberta Gottlieb became director of the Bioscience Center at San Diego State University and Gregory Del Zoppo accepted an appointment as professor of medicine at the University of Washington in Seattle. This seeding of other institutions with outstanding investigators is part of our mission. At the same time, it has given us an opportunity to provide much-needed additional space for our departmental core facilities and for investigators whose programs have expanded.

This year we have also been able to accommodate an important new initiative spearheaded by our clinical colleagues at Scripps Health, namely, the application of advanced genomic techniques to the understanding and, ultimately, the treatment of human disease. The internationally known cardiologist Eric Topol has been appointed chief of genomic medicine and translational science for Scripps Health and will perform some of the basic studies in this department. The implementation of this program has made possible the recruitment of a number of other leading investigators in genomics. Nicholas Schork and Kelly Frazer, along with the junior staff that they have recruited, bring expertise in biomedical informatics and in the rapidly evolving technology of high-throughput DNA analysis. These programs fit well with the widespread activities in genetics already extant in the Department of Molecular and Experimental Medicine and provide us with much needed expertise in these important new areas.

Details of the accomplishments of our faculty can be found in the pages following this overview, and as has been my usual practice, I do not try to summarize the diverse work of my colleagues here. Instead I focus on one important approach to the study of human health, an approach that is widely used in our department. Alexander Pope (1688–1744) in his Epistle II: Of the Nature and State of Man With Respect to Himself, as an Individual wisely observed, "The proper study of mankind is man." This statement is as true today as it was then. But the study of complex diseases of mankind in humans is difficult, both because of ethical constraints and because of the heterogeneity of mankind. Thus, even though our ultimate aim is to understand the diseases of humans, animal models have been a valuable resource in our investigations of human disease.

Historically, animal models of infectious disease have been a cornerstone of understanding the pathogenesis of these diseases. Indeed, 1 of Koch's 4 postulates, the classical criteria for the demonstration that a microorganism plays a causative role in a disease, is the reproduction of the disease in a "healthy organism." Although this "organism" has occasionally been a human, as in the fatal self-inoculation of the infectious organism by Chagas to reproduce Arroya fever, experimental animals are almost universally used for this purpose. But in recent years, the use of animal models has been expanded to include the growth of tumors in mice and other hosts and the study of genetic diseases that either occur spontaneously or are induced by targeted disruption of genes or the development of transgenic animals.

The faculty members of the Department of Molecular and Experimental Medicine strive to better understand human disease and consequently make extensive use of animal models, always, of course, in strict conformity with the guidelines of the American Association for Accreditation of Laboratory Animal Care.

Francis Chisari and his colleagues focus on the pathogenesis of the hepatitis viruses. In some of these studies, the classical approach is used, and experimental animals are infected with the virus. In other studies, an innovative method pioneered by Dr. Chisari is used; transgenic animals in which a part of the virus replicates have been created, so that the pathogenesis of the disease can be studied under carefully controlled conditions.

Brunehilde Felding-Habermann is using a mouse model to study treatment of breast cancer. In her studies, human tumors are allowed to grow in a genetically immunocompromised mouse. This method makes it possible to study treatment strategies; Dr. Felding-Habermann is investigating an antibody that she and her colleagues have developed. Ultimately, the antibody may prove to be useful in the treatment of human tumors.

Thomas Deuel and his colleagues are studying the growth of mammary tumors in mice. Their aim is to define the factors that may stimulate tumor growth, particularly the role of pleiotrophin, a cytokine that Dr. Deuel discovered.

A number of research groups in the department are using mouse models to study genetically determined human disease. Joel Buxbaum and his group are studying a common polymorphism of the gene encoding transthyretin that causes heart disease in African Americans. He has created a transgenic mouse model in which this human mutant transthyretin is overproduced. These studies could lead to better understanding of this disease. Extending these studies, the Buxbaum group has created mice that carry both a human Alzheimer's disease gene and the overexpressed transthyretin gene. Interestingly, overexpression of the transthyretin gene appears to suppress the effect of the Alzheimer's gene, a surprising effect that is well worth exploring.

A number of genes are known to be involved in iron homeostasis in humans. In work in my laboratory, we make extensive use of mice in which some of these genes have been disrupted or mutagenized. Included are the genes encoding HFE, transferrin receptor 2, β₂-microglobulin, and hemojuvelin. These studies have given us valuable information on the roles of each of these components in the iron signaling pathway. In collaboration with Bruce Beutler's group in the newly formed Department of Genetics, we have been investigating a mutation induced by N-ethyl-N-nitrosourea in a gene encoding transmembrane serine protease 6 (Tmprss6). The lack of this gene, previously of unknown function, causes iron deficiency. We are trying to determine whether mutations of this gene also exist in humans and whether such mutations contribute to the high incidence of iron deficiency.

Tom Kunicki and his colleagues observed that mice that lack an important collagen receptor have a bimodal bleeding response. A positional cloning effort in collaboration with scientists at the Genomics Institute of the Novartis Research Foundation led to the discovery of a gene, klf4, that modifies the hemostatic response of these mice. The role of this newly discovered polymorphism in human disease remains to be elucidated.

Animal models have played a critical role in our understanding of human disease. An animal model, the pancreatectomized dog, led directly to appreciation of the fact that the pancreas was involved in diabetes, and this finding was soon translated into the discovery of insulin and the saving of hundred of thousands of lives. Animal models made possible the whole field of tissue transplantation. They have been critical in the development of vaccines to protect us against infectious diseases. The illusion that a computer could substitute for an animal is just that—an illusion. Biology is simply too complex to make using a computer rather than an animal a reality. The study of human diseases and the use of animal models continue to be essential efforts to improve human health, and such models help scientists at Scripps Research better understand disease.