Immunology and Microbial Science

Chairman’s Overview

Progress in biomedical research demands innovation and depends on our ability to identify the leading edges of science. The approach to science that looks backward instead of forward stifles originality and perpetuates conventional thinking. I am always impressed by the ability of our department members to develop new paradigms to advance scientific knowledge. The environment at Scripps Research encourages our scientists to apply the very latest approaches to solving core problems of immunology. This often involves taking risks, especially in today’s world of peer-reviewed funding where out-of-the-box thinking is not always rewarded. However, I am pleased to report that our investigators are continuing to take appropriate risks with their science and, as a result, are being widely recognized for their accomplishments. This is evidenced by the numerous scientific papers published by our department members and by the prestigious awards and other forms of recognition bestowed upon them. Some of these are highlighted below.

But first I would like to acknowledge some key transitions within our faculty. During the past year, Norman Klinman retired after an incredibly productive career of more than 30 years in the field of immunology research. In 2006, he received the Excellence in Mentoring Award from the American Association of Immunologists for “exemplary career contributions to a future generation of scientists.” Many of Dr. Klinman’s more than 50 former trainees attended the award ceremony, which was held in Boston in May. We wish Dr. Klinman all the best in his future activities. We will always welcome his presence at Scripps Research.

The end of 2005 also marked the departure of Jonathan Sprent, who returned to his native Australia after 30 years in the United States—first at the University of Pennsylvania and then at Scripps Research. Dr. Sprent is currently professor at the Garvan Institute of Medical Research in Sydney, where he will continue his seminal work on T-cell function combining his unique knowledge of the immune response in whole animals with molecular models using cell-based systems. We look forward to reading about Dr. Sprent’s new findings as they impact immunologic memory and tolerance, transplantation immunity, and cancer immunotherapy. His longstanding collaborations with Charlie Surh at Scripps Research will undoubtedly continue, and we will welcome his visits to our campus.

Coinciding with these departures is the recent recruitment of Karsten Sauer, who joined us after a number of years at the Genomics Institute of the Novartis Research Foundation. Dr. Sauer specializes in studies of lymphocyte signal transduction and will bring additional strength to our department in this important field. Defects in lymphocyte development or function underlie various immune disorders, including immunodeficiencies, inflammatory and autoimmune diseases, and allergy. Dr. Sauer’s studies promise to significantly expand our understanding of these key processes in health and disease. Specifically, his laboratory will combine state-of-the-art genomic and proteomic profiling techniques, functional genomics, high-throughput screening, and imaging technologies as well as classical biochemistry, molecular biology, and cell biology to explore the functions of novel signaling modules. This effort will result in a new understanding of how antigen-receptor signaling directs diverse cellular responses and how its malfunction leads to immunologic disease. We look forward to Dr. Sauer’s contributions as an active faculty member in our department.

Highlights of scientific publications provide clear evidence of the important place our department holds within the national and international community of scientists interested in immunology. Bruce Beutler has provided Scripps Research with a unique resource in the form of a program of random germline mutagenesis. During the past year, he and his colleagues have provided remarkable new insights into mechanisms of innate and adaptive immunity. Key findings include those of Koichi Tabeta and his colleagues, published in Nature Immunology, in which an unanticipated function has been assigned to the Unc93b1 gene product. These investigators showed that a mutation in Unc93b1, known as the 3d mutation, disrupts signaling via Toll-like receptors 3,7, and 9, and also alters antigen presentation. Building on these data are findings from Kasper Hoebe and colleagues, published this year in Immunity, have identified a novel pathway of T-cell activation that appears to be independent of Toll-like receptor signaling. Taken together, these two publications promise to shape our thinking about mechanisms involved in promoting adaptive immunity through the innate immune networks.

In addition to uncovering new biology, the germline mutagenesis approach provides new insights into protein structure as revealed in Proceedings of the National Academy of Sciences by Zhengfan Jiang and his colleagues, who describe molecular details of interactions between MyD88 and Toll-like receptors. We also look forward to continued productivity and seminal advances from Bruce Beutler and his group during the coming year.

Adding to the department’s strengths in innate immunity is the work done in the laboratory of Jiahuai Han. DaSilva Correia and his group provided an unexpected insight into a mechanism whereby Nod1 regulates the function of the estrogen receptor. Nod1 provides a brake on the estrogen receptor, and the absence of Nod1 results in enhanced sensitivity to estrogen and promotes tumor growth in a xenograft model. This work was published in Proceedings of the National Academy of Sciences.

Members of Luc Teyton’s laboratory combine structure-function studies with both cell-based and animal models to probe the function of the natural killer T-cell receptor and its ligand. This work, which was published in Nature and Nature Immunology, includes a longstanding collaboration with Albert Bendelac at the University of Chicago. Following on studies of immune regulatory pathways is work done by Charlie Surh and his colleagues, which was published in Science. This report documents an unexpected finding showing how an immune complex of anti-IL2 and IL2 act to stimulate T-cell subsets. These data not only provide new insights into uses of therapeutic antibodies but also alert us to concerns about unanticipated side effects. Another advance in understanding adaptive immunity comes from Michael McHeyzer-Williams and members of his laboratory, whose work on B-cell function was recently described in an article published in Immunity.

In both the United States and worldwide, HIV and hepatitis C infection remain significant problems for which there are still no appropriate therapies. Dennis Burton and his group continue their important research in these two areas. This past year, they published articles in Science, Nature Immunology, and Proceedings of the National Academy of Sciences that provided insights into key issues for advancement of new treatments. These recent publications represent the important collaborations established by Dennis Burton and his colleagues both inside and outside of Scripps Research.

Work from the laboratory of Hugh Rosen combines chemical and genetic approaches to proof-of-concept studies that will allow a better understanding of human disease mechanisms. This work paves the way for the development of new small-molecule therapeutics for use in immunologic and inflammatory diseases in humans. Specifically, publications in Nature Immunology, Nature Chemical Biology, and other top journals illustrate the importance of the approaches implemented by Hugh Rosen and his group. Further illustration of the power of genetics is found in work published in Nature Medicine by members of the J-D Lee’s laboratory. Here they used conditional knock-out of the HSP40 gene to prove a role for this protein in a serious human syndrome, cardiomyopathy. This work may well lead to the development of drugs that can be used to selectively intervene in this serious medical problem.

These examples illustrate the productivity of the members of our department. More details and a complete list of accomplishments can found in the individual reports. I apologize in advance for not including comments about each publication from the 2005-2006 period and urge readers to examine the reports for more details. As always, it is a great pleasure for me to read the material from each of our faculty members and to reflect on the progress of the past year.