Journal of Histochemistry and Cytochemistry, Vol. 45, 1049-1050, Copyright © 1997 by The Histochemical Society, Inc.

Earl Philip Benditt

1916-1996


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DR. EARL PHILIP BENDITT, Professor Emeritus in the Department of Pathology at the University of Washington School of Medicine, died on May 27, 1996 at the age of 80.

Earl had long been acknowledged as a preeminent experimental pathologist of the twentieth century. His working career, spanning some 50 years, was characterized by two notable features: a chemical quantitative approach and a fantastic ability to recruit capable acolytes to advance his quest for answers to a wide range of pathological problems, most particularly inflammation, atherosclerosis, and amyloidosis.

Earl's career had deep roots in histochemistry. Indeed, it is a continuous thread that can be traced through Earl's opus. Early in his distinguished scientific career, Earl had three noteworthy publications in Volume 1 (1953) of the Journal of Histochemistry and Cytochemistry: a paper with George Gomori on the precipitation of calcium phosphate in the histochemical method for phosphatase localization (Gomori and Benditt 1953 ), and a seminal series of two papers with John French on the use of enzymes such as trypsin, pepsin, and malt extract as specific histochemical reagents in the identification of connective tissue components (French and Benditt 1953a , French and Benditt 1953b ). His affinity for things chemical was strengthened by his interactions with Frank Putnam, Al Dorfman, and George Gomori. He worked with Gomori on some details of the precipitates in the original histochemical method for alkaline phosphatase, and it was Gomori who showed him the selective staining of mast cells using the chloracetylester of naphthol AS. Gomori had synthesized the ester as a possible means of demonstrating acetylcholinesterase. Earl and Don Rowley had recently identified serotonin as a mast cell-derived mediator of inflammatory edema, and Earl took up the problem of defining the enzyme responsible for the histochemical reaction in mast cells. Using competitive inhibitors and a semiquantitative estimate of reaction rate, he showed that the ester substrate specificity of the mast cell enzyme closely resembled that of {alpha}-chymotrypsin. Later studies established that the mast cell enzyme was a protease, and the enzyme and a second mast cell protease were christened chymase and tryptase. In another seminal paper in 1970 (Benditt et al. 1970 ), he explained the underlying mechanism of the optical phenomenon of dichroism in polarized light that is characteristic of amyloid proteins stained with Congo Red. Most appropriately, Earl served as the fifteenth president of the Histochemistry Society in 1964.

Earl's career as an experimental pathologist began at the University of Chicago as a member of Paul Cannon's group, working on deficiencies of essential amino acids. Not all the connections in Earl's work are obvious, and by no means did all of his inventive hypotheses yield scientific gold. There was, however, a connection between his work on serotonin in mast cells and then in chromaffin cells and that on one of his highly productive scientific forays, amyloid. His work on serotonin interested him in the possibility that some pathological deposits might arise by a process akin to the tanning reaction responsible for the hardening of insect cuticle. George Martin worked for a while on possible oxidizing enzymes that might participate. The histochemical observation that amyloid was relatively rich in tryptophan fitted in a general way with the hypothesis. The death and autopsy of a patient with ulcerative colitis and enough amyloid in her organs for several years of work led to the isolation of amyloid A protein and all that followed. In the early experiments, Adams' method for staining tryptophan residues was used as the most convenient marker to follow the extraction process. Needless to say, amyloid turned out to have nothing whatsoever to do with tanning.

There may be other versions of the story of how Earl came to study atherosclerosis, but one creditable possibility is that it had its origins in the early stages of devising a grant renewal strategy. Earl had brought with him to the University of Washington an NIH grant entitled "Vascular Response To Injury"; it supported his extended laboratory throughout his 24-year term as Chairman of Pathology and beyond. Ed Smuckler working on liver cell injury, Russ Ross on wound healing, David Lagunoff on mast cells, and George Martin on serum oxidases all benefited from the largess of the grant. When it came time for a renewal application, Earl decided that a unifying theme justifying the grant title was in order. He fixed on the study of the proliferative response of endothelium to injury. Not much on this theme was done in the first years after the grant was funded. Then, following up on Stan Gartler and David Linder's brilliant demonstration of the monoclonality of uterine leiomyomas, Earl proposed to use the approach to test his hypothesis that the plaques of atherosclerosis were like benign tumors. He used vessels from African-American women who were heterozygous for glucose-6-phosphate dehydrogenase. It was not a simple study, either technically or interpretively, and Earl did much of the initial work by himself, spending hours dissecting out individual plaques in the cold room in an arctic parka. John, his eldest son, helped him and was a co-author of the seminal paper in the Proceedings of the National Academy of Science (Benditt and Benditt 1973 ). Later, Steve Schwartz took up the question of endothelial cell proliferation in situ, and Russ Ross discovered PDGF.

Writing in an editorial in 1971 (Benditt 1971 ), Earl speculated about the future of pathology and correctly predicted the revolution in our understanding of human disease that would result from the availability of new technologies, particularly the impact of computer technology. Furthermore, he predicted a "paradigm shift" that would be required for further progress. Inasmuch as the problems in biology and medicine that we are trying now to unravel were, in large part, defined by our scientific forebears more than a century ago, he noted that we may make the mistake of approaching them with a nineteenth century bias. This bias includes outmoded definitions of "normalcy" and the rigidity of classification systems. Earl was dismayed by scientific papers that were "replete with detail and barren of concepts that sensibly weld the details into the larger whole." He decried medical scientists whose training was involved only with the "bricks and mortar" of fact and technology and, as a consequence, who were missing "the feeling for the design, for purpose." Earl had an intellect that was as deep as it was wide; he was as comfortable (and as excited) discussing Brownoski and Kuhn as he was the latest published scientific findings.

Earl presided over the Department of Pathology at the University of Washington from 1957 until he relinquished the Chair in 1981. The department was by no means committed exclusively to his own research and that of his students. Buster Alvord, Rich Prehn, Bernie Wagner, Karle Mottet, Victor Gould, Ben Trump, Gary Striker and their programs prospered in the academic environment Earl created. The department spawned some seven chairs of pathology during Earl's tenure as chair, including Russell Ross, Earl's successor. The continuingly vital Department of Pathology at the University of Washington, which he created, developed, challenged, and inspired is a true legacy of Earl's. Over his scientific career, Earl received accolades that are too numerous to list, but the highlights certainly include membership in the National Academy of Sciences and the Rous-Whipple and Gold Headed Cane Awards from the American Association of Pathologists. Earl is survived by his wife, Marcella, and his four sons, John, Alan, Joshua, and Charles.

On a final personal note, both of us feel a deep sense of loss with Earl's death. Throughout our careers he never ceased to be both supportive and challenging. His memory and his standards for experimental science will stay with us, as it surely will with the many pathologists, histochemists, and other scientists who benefited from his work and from working with him.

David Lagunoff and Allen M. Gown

Literature Cited

Benditt EP (1971) Pathology and the future. Hum Pathol 2:337-339 [Medline]

Benditt EP, Benditt JM (1973) Evidence for a monoclonal origin of human atherosclerotic plaques. Proc Natl Acad Sci USA 70:1753-1756 [Medline]

Benditt EP, Eriksen N, Berglund C (1970) Congo red dichroism with dispersed amyloid fibrils, an extrinsic cotton effect. Proc Natl Acad Sci USA 66:1044-1051 [Medline]

French JE, Benditt EP (1953a) Histochemistry of connective tissue: I. The use of enzymes as specific histochemical reagents. J Histochem Cytochem 1:315-320

French JE, Benditt EP (1953b) The histochemistry of connective tissue: II. The effect of proteins on the selective staining of mucopolysaccharides by basic dyes. J Histochem Cytochem 1:321-325

Gomori G, Benditt EP (1953) Precipitation of calcium phosphate in the histochemical method for phosphatase. J Histochem Cytochem 1:114-122





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