APRIL 2001 VOLUME 14, NUMBER 4 © Copyright 2001 by the American Chemical Society
Editorial In Memoriam James A. Miller (1915-2000)1 Dr. James Alexander Miller, Professor of Oncology at the University of Wisconsin (Madison) McArdle Laboratory for Cancer Research, died December 24, 2000, from complications associated with diabetes. On January 14, 2001, a memorial service was held at the University to commemorate his life and his legacy of research that laid the foundations for much of the field we call chemical research in toxicology. He was preceded in death by his wife and research partner of 45 years, Elizabeth C. Miller, who died of metastatic renal cancer on October 14, 1987. James (Jim) Miller was born May 27, 1915, in Dormont, PA, near Pittsburgh to a middle-class family as the fifth of six brothers. He developed a keen interest in science at an early age after receiving gifts of chemistry and erector sets. Tragedy struck the Miller household during the 1920s when his oldest brother died of pneumonia, his youngest brother was killed by a car, and his mother, at age 49, died of a stroke. His father lost his job in 1930 and was unable to resume work because of illness. It was the three remaining brothers who supported Jim in his efforts to go on to college and keep the family together. Jim graduated from high school in 1933 and then took short-term jobs, including one assembling reagents for freshman chemistry classes at the University of Pittsburgh, which enabled him to attend evening classes. Finally, in 1935, with the help of his brothers, Jim enrolled at the University of Pittsburgh in a chemistry honors course. During his freshman year, he worked in the animal rooms for a Professor of Biochemistry, Charles Glen King, who had recently isolated the first 1
Please also refer to the excellent obituaries written by Miriam Poirier in Carcinogenesis and by Allan Conney in Cancer Research.
Elizabeth C. Miller (1920-1987) and James A. Miller (19152000). Photo by unknown photographer.
vitamin, ascorbic acid. There he met a postdoctorate from the Biochemistry Department at the University of Wisconsin, Max Schultze, who mentored him during his
10.1021/tx010499q CCC: $20.00 © 2001 American Chemical Society Published on Web 03/24/2001
336
Chem. Res. Toxicol., Vol. 14, No. 4, 2001
undergraduate days. Upon graduation in 1939 with highest honors, Max encouraged Jim to apply to the Biochemistry Department where he was awarded a Wisconsin Alumni Research Foundation (WARF) Scholarship in Biochemistry. There he joined the research group of Professor Carl Baumann who was interested in the effects of diet on liver tumors produced by a pure chemical, 4-(dimethylamino)azobenzene (DAB). Jim also was collaborating with Professor Harold Rusch at the McArdle Laboratory for Cancer Research on other chemical carcinogens. In fact, most of Jim’s Ph.D. thesis work was focused on the fluorescent properties of carcinogenic polycyclic aromatic hydrocarbons. While he was a senior graduate student, he became a teaching assistant for a first-semester biochemistry course. It was there he met and 8 months later married Elizabeth (Betty) Cavert in 1942. She became a graduate student in biochemistry, and her research was also carried out in Professor Baumann’s laboratory on the nutritional modulation of aminoazo dye carcinogenesis. Jim obtained his Ph.D. in 1943 and had started studies on DAB metabolism. In 1944, Harold Rusch offered him a position at the McArdle Laboratory and asked him to initiate a research program on these newly discovered chemical carcinogens. Betty soon obtained her Ph.D. in 1945 and was immediately recruited as a postdoctorate, and then as a faculty member in 1947. Together, Jim and Betty Miller formed a dynamic research collaboration that was to lay the foundations of chemical carcinogenesis, drug metabolism, and much of the mechanistic work for the field of chemical toxicology. During this time, they advanced through the academic ranks to become Professors of Oncology in 1969, Van Rensselaer Potter Professors of Oncology in 1982, and WARF Senior Distinguished Research Professors of Oncology in 1984. Their research accomplishments and scientific excellence were truly exemplary. To those of us who were fortunate to have worked in their laboratory, it was clear their individual talents, insights, and expertise were so complementary and synergistic that they truly represented the best that science can offer. Indeed, the Millers were the first spouses to be jointly elected to the U.S. National Academy of Sciences in 1978. Other awards included the Bertner, Papanicolaou, Rosenstiel, AACR Clowes, FASEB Life Sciences, Bristol-Myers, and General Motors Mott Awards. They also worked on numerous grant review and scientific advisory boards of the National Institutes of Health and American Cancer Society. As mentioned, the research interests of the Millers began with the class of chemicals known as the aminoazo dyes. Unlike the polycyclic aromatic hydrocarbons which induced tumors at sites of application, the aminoazo dyes induced tumors at a distant site, the liver, and their potency could be modulated by dietary alterations. This prompted the idea that metabolism played an important role. When a variety of ring- and N-substituted aminoazo dye derivatives were synthesized and tested for tumorigenic activity, structure-activity relationships began to emerge. Before the advent of radiolabeled carcinogens, Jim and Betty made use of the intense color of the aminoazo dyes and employed a variety of chemical and spectral techniques to discover that these dyes were bound covalently to liver proteins and that the structureactivity relationships for protein binding and carcinogenicity were nearly identical. This was a truly landmark
finding for it established macromolecular binding as an important initial event in chemical carcinogenesis. To understand how the aminoazo dyes became covalently bound, the Millers, like many other groups, were studying carcinogen metabolism. It was during their in vitro work in the 1950s that the Millers and their associates identified an NADPH-dependent liver microsomal oxidative enzyme system that was induced by 3-methylcholanthrene and benzo[a]pyrene and inhibited by CO. This work was directly responsible for the subsequent characterization by several laboratories of the carcinogen- and drug-metabolizing monooxygenases that would come to be known as the cytochromes P450. Carcinogens were still generally thought to be themselves the active principle up until the 1960s, and carcinogen metabolism was regarded as a detoxication mechanism. However, the Millers’ laboratory isolated an unusual glucuronide conjugate from the urine of rats given the hepatocarcinogenic insecticide 2-acetylaminofluorene (2-AAF). After a thorough chemical characterization, the aglycone was identified as a hydroxamic acid, N-hydroxy-2-AAF. Moreover, it was found to be a much more potent carcinogen than the parent compound, and it induced tumors at several sites, including the site of application. This work resulted in the concept of a proximate carcinogen, and they coined the term metabolic activation in chemical carcinogenesis and toxicology. Perhaps their greatest contribution and finest examples of scientific intuition came from an investigation in the late 1960s. When their effort to synthesize Nhydroxy aminoazo dyes was proving to be difficult, they decided to prepare an N-benzoyloxy ester derivative, with the idea that it would hydrolyze in vivo to give the N-hydroxy compound. However, when they studied this ester in vitro, they found it to be highly reactive and to readily bind covalently to proteins and to nucleic acids. It was also highly carcinogenic at sites of application and was a direct-acting mutagen. This work led to the term ultimate carcinogen. Similar work soon followed with N-acetoxy-2-AAF and with other N-hydroxyarylamines and amides. By 1969, the Millers were ready to postulate what they had earlier realized: that ultimate carcinogens were direct-acting mutagens because they were electrophilic and that carcinogen binding involved reaction with nucleophilic sites in cellular nucleic acids and proteins. And as important, metabolic activation was the process that involved the biotransformation of the carcinogen or proximate carcinogen into an ultimate carcinogen. During their lifetime, the Millers made major contributions to the elucidation of the metabolic activation and detoxification pathways not only for carcinogenic aminoazo dyes and arylamines/amides but also for polycyclic aromatic hydrocarbons, mycotoxins, allyarenes, ethionine, and urethane. They made important discoveries in the identification of carcinogen-DNA adducts, in the role of sulfuric acid ester metabolites as ultimate carcinogens in vivo, and in the nature of mutations in cellular oncogenes induced by chemical carcinogens. Throughout their career, they remained at the forefront of carcinogenesis and toxicological research. Their seminal findings, thoroughness of approach, motivation, and enthusiasm left an indelible mark on a generation of colleagues, students, and postdoctorates. Their impact on the field of cancer research and chemical toxicology continues in all of us who have been fortunate enough to have been affected by their integrity and by their example.
Chem. Res. Toxicol., Vol. 14, No. 4, 2001 337
Jim and Betty raised two daughters: Linda Forbess, M.S., a fiber artist and fabric expert in Schofield, WI, and Helen Alexander, Ph.D., an Associate Professor of Botany-Ecology at the University of Kansas (Lawrence, KS). Jim is survived by his second wife, Barbara Butler Miller, who had been Betty’s assistant for 9 years and who helped Jim rebuild his life after Betty’s death.
Fred F. Kadlubar Director, Division of Molecular Epidemiology, National Center for Toxicological Research, Jefferson, Arkansas 72079 TX010499Q
