Memorial Resolution of the Faculty of the University of Wisconsin-Madison on the Death of Professor Emeritus James A. Miller

Dr. James A. Miller, Professor Emeritus of Oncology, McArdle Laboratory for Cancer Research, died on Sunday, December 24, 2000.

Jim was born on May 27, 1915 in Dormont, Pennsylvania, a small town near Pittsburgh. He was the fifth of six sons whose parents had only an eighth-grade education but who greatly respected higher education. His interest in science was fostered and supported during his youth by his family, including his brothers, who imbued him with a strong work ethic. As a young man, he built a telescope from scratch, grinding the mirror to perfection with his own hands, a preview of the rigor and dedication he would bring to science in his later life.

He graduated from high school in 1933, after which he worked briefly in a welding shop at a steel mill. He used the steel mill income to take evening classes for the first year of college at the University of Pittsburgh. There he found a job, funded by the National Youth Administration, to assemble reagents for a freshman chemistry class. In 1935, with the help of his brothers, he enrolled in an honors course in chemistry at the University of Pittsburgh.

Jim's interests in chemistry and the use of animal models to study cancer biology were enhanced further during his college years through his job as an animal helper with Charles Glen King, professor of biochemistry. Dr. King was the first to isolate a vitamin (vitamin C) in a pure state. This job, plus assistance from his brothers, allowed Jim to continue in college. He graduated in chemistry with highest honors from the University of Pittsburgh in 1939.

Jim's experience in Dr. King's laboratory put him in contact with a Ph.D. research associate, Dr. Max O. Schultze, who had obtained his Ph.D. in the Department of Biochemistry at the University of Wisconsin-Madison. Dr. Schultze taught Jim about the rigors of biochemical research: how to ask important questions and how to perform the controls essential to the correct interpretation of experimental data. Encouraged by Dr. Schultze, Jim decided to come to Wisconsin for graduate training.

Jim was awarded a Wisconsin Alumni Research Foundation Scholarship in Biochemistry and began graduate work in the fall of 1939. He obtained his Ph.D. with Professor Carl Baumann, working on how 4-dimethylaminoazobenzene in the diet promoted liver tumors in rats. During this time, Jim and Dr. Baumann were collaborating with Professor Harold Rusch in the Medical School. Dr. Rusch became the director of the McArdle Laboratory for Cancer Research and, in 1940, hired Jim as a teaching assistant at the new cancer research center. Jim was conducting the graduate laboratory course in biochemistry, when he met Elizabeth (Betty) Cavert, who in 1942 became his wife and scientific collaborator. This immensely successful partnership lasted the next four and a half decades, until Betty's death from kidney cancer in 1987.

Jim obtained his Ph.D. in 1943 and became an instructor in McArdle. He was recruited to start a program on chemical carcinogenesis, and Betty soon joined him on the faculty. From that seemingly modest beginning, Jim Miller, along with Betty, became world-renowned scientists, recognized for major contributions in the areas of pharmacology, toxicology, and experimental oncology. His early work was on the aminoazo dyes, which were known to cause liver cancer in rats and to be metabolized in the animal. He began a research program to look for metabolites that were as active or more active than the original dyes in causing cancer. Within a few years, he made the major discovery that some of the dye metabolites were actually bound covalently to proteins in the liver. This result was the first observation of covalent binding of a xenobiotic carcinogen derivative to a cellular macromolecule. Other scientists later extended the observation to other carcinogens and showed that these carcinogens could bind also covalently to nucleic acids.

Jim knew that carcinogens were metabolized in vivo, so he decided to use techniques pioneered by one of his McArdle colleagues, Dr. Van R. Potter, to determine whether such metabolites would form in vitro. In collaboration with his graduate student (and future McArdle faculty member), Gerald C. Mueller, Jim incubated the carcinogen dimethylaminoazobenzene (DAB) with homogenates of liver and found that the DAB was metabolized in an oxygen-dependent manner by the loss of methyl groups and the addition of a hydroxy group to the molecule. This finding was the first report of cell-free metabolism of a carcinogen. In collaboration with another student, Allan H. Conney, Jim then showed in another first-of-its-kind experiment that pre-treating animals with certain chemicals such as 3-methylcholanthrene elevated the activity of the cell-free carcinogen-modifying enzymes (mixed-function oxidases). Jim, Betty, and their students identified novel compounds generated in vivo by metabolism of the parent carcinogen. These new compounds had N-hydroxy moieties and, when injected into animals, were more carcinogenic than the original compounds, acting as proximate carcinogenic metabolites. These and other studies led to the seminal concept that carcinogens are metabolized in one or more steps to highly reactive electrophiles, with the ability to react rapidly with cellular DNA and thereby to induce mutations, some of which lead to cancer.

These and other breakthroughs made Jim a world-famous scientist. His advice on chemical carcinogenesis was valued by many colleagues, and he served unselfishly on NIH study sections and advisory committees. He was honored in many ways for his contributions to science and medicine. He became WARF Professor of Oncology from 1980-1982, Van Rensselaer Potter Professor in 1982, and WARF Senior Distinguished Professor in 1984. The many awards and honors he received during his distinguished career included election to the National Academy of Sciences in 1978, the Bristol-Myers Award in Cancer Research in 1978, and the Mott Award from the General Motors Cancer Research Foundation in 1980.

In 1988 Jim wed Barbara (Butler), with whom he spent the remaining years of his life. He and Barbara enjoyed traveling and spending time with children and grandchildren. Jim loved life and continued to pursue his many interests, which varied from studying Darwin and astronomy to drinking good beer.

In spite of his fame, Jim remained throughout his career a kind, thoughtful, good-natured, and exceptionally modest colleague. He earned a reputation as a caring individual and a nurturing teacher and advisor. His former students and laboratory colleagues were precious to him, and they felt immense gratitude for his advice throughout their careers. The McArdle Laboratory for Cancer Research has established the "James A. Miller Fellowship Fund" to support graduate student education as a lasting tribute to Jim's life and work and to his dedication to student education. He will be missed by all of us who knew him and especially by the family he loved so much, his wife Barbara, his daughters Helen and Linda, and their families.

Memorial Committee

  • Norman Drinkwater
  • Paul Lambert
  • Henry C. Pitot
  • Jeffrey Ross, Chair

UW-Madison Fac Doc 1575 -1 October 2001