Elizabeth Ziegler MD 1942—2006

Abstract

to the endotoxin community the death of our colleague, Elizabeth Ziegler, Professor of Medicine Emeritus at the University of California, San Diego School of Medicine. Elizabeth died on January 2, 2006 of complications from diabetes, a disease that posed a continuing challenge to her for many of her adult years. This did not, of course, keep her from being a dedicated teacher, scholar and friend, and the many of us who have had the extraordinary opportunity to interact with this remarkable woman will sorely miss her. Elizabeth was the ultimate optimist, not only in her perspectives of her own life, but also in the goodness of others and in mankind overall. Elizabeth received her Bachelor of Arts degree from Mount Holyoke College and her Doctor of Medicine degree from the John’s Hopkins University School of Medicine where she also served as a resident in internal medicine. She was then recruited to the University of California, San Diego School of Medicine as a research fellow in infectious disease where, under the tutelage of Dr Abraham Braude, she developed her life-long interest in the mechanisms of pathogenesis of septic shock. More particularly, she joined Dr Braude in developing one of the very first therapeutic intervention strategies for the treatment of patients with septic shock. By immunizing volunteer firemen with a Gram-negative vaccine from the galactose-epimerase deficient strain of Escherichia coli (the so-called J-5 mutant), she, Dr Braude and their colleagues developed a heterologous human immune serum that, when administered to patients with septic shock, provided significant protection in comparison to control pre-immune serum. The results of these studies, reported in the New England Journal of Medicine, stimulated great interest in the potential promise of rough, Oantigen-deficient Gram-negative organisms as potential in the antigens in the preparation of vaccines to improve therapeutic outcomes in septic shock. The advent of monoclonal antibodies in the early 1980s further stimulated interest in this field and Drs Ziegler and Braude and their colleagues were among the first to capitalize upon this technology to create monoclonal antibodies against common LPS antigens, and more specifically lipid A and core polysaccharide determinants. Considerable efforts by these investigators and others were directed towards establishing the therapeutic efficacy of one such monoclonal antibody in both experimental animal models of LPS toxicity and experimental infection, and ultimately in a comprehensive placebo-controlled, double-blinded clinical study of patients with sepsis. Although the results of this study appeared, at least in some aspects, to duplicate the results of the earlier polyclonal antibody studies, sufficient methodological questions were raised concerning both the antigenic specificity of the therapeutic monoclonal antibody and its therapeutic efficacy that its acceptance by the overall medical and scientific community was continuously challenged. While later in vitro studies, some of which were carried out by the writer of this memoriam, unequivocally established the ability of that antibody investigated by Elizabeth and her colleagues to bind to lipid A, the ultimate evidence of therapeutic efficacy was never unequivocally confirmed in septic patients. Parenthetically, similar states befell other experimental strategies to generate protective immunity with anti-lipid A antibodies, as well as related strategies involving the specific targeting of inflammatory mediators generated by immune mediators cells in response to endotoxin LPS. While these multiple defeats placed a collective damper upon many investigators, including Elizabeth Ziegler, in further pursuing the concept of immunological intervention in the treatment of sepsis, they nevertheless established forever, to both the medical community and the general public, the critical importance of sepsis and shock as human diseases that should not be overlooked in efforts of medical researchers to improve human health.