Elizabeth C. Miller and James A. Miller Biography

Elizabeth C. Miller and James A. Miller are known for their ground-breaking research into the mechanism of chemical carcinogenesis. The Millers' discoveries laid the foundations for understanding the metabolic interactions with carcinogen ic chemicals that produce cancer in experimental animals. Their work sparked intensive research into carcinogenesis and public interest in carcinogens.

James A. Miller was born in 1915 in Dormont, Pennsylvania, a small town just south of Pittsburgh. His father, John, was the manager of circulation for the Pittsburgh Press, and his mother, Emma Stenger, was a homemaker. Two brothers died in their youth. In 1929, his mother died and his father became seriously ill. "All the children had been taught to earn their keep," Miller told Laura Newman in an interview. "It fell to the four boys to stick together, absent mother and father." Despite the economic pressures, Miller completed high school in 1933, gaining high grades in science.

Miller credits the National Youth Administration, a New Deal youth employment program, with giving him his first job in chemistry--filling reagent bottles at the chemistry department at the University of Pittsburgh. Within two years, Miller beg an the day program and an honors chemistry course. At the University of Pittsburgh, Miller got a job in an animal room lab with Charles Glen King , a well-known biochemist who had crystallized the first vitamin, vitamin C, and Max Schultze , who had train ed at the University of Wisconsin. "I finally found myself," Miller told Newman. He graduated with a B.S. in chemistry in 1939. Schultze urged Miller to apply for a Wisconsin Alumni Research Foundation (WARF) scholarship in biochemistry at the University of Wisconsin, which he was awarded in 1939. He began laboratory research on the metabolism of recently identified chemicals that could induce cancer in animals. Miller received an M.S. and Ph.D. degrees in biochemistry from the University of Wisconsin in 1941 and 1943 respectively. Miller met Elizabeth Cavert in his second year at Wisconsin when he became her teaching assistant in a biochemistry lab. Miller soon found her to be an outstanding student and the two shared research interests. In August of 194 2, the couple married.

Elizabeth Cavert Miller was born on May 2, 1920 in Minneapolis, the second daughter of Mary Elizabeth Mead and William Lane Cavert. Her father was the Director of Research in Agricultural Economics at the Federal Land Bank in Minneapolis, Minnesota. Her mother was a graduate of Vassar College. In 1941, Elizabeth Cavert received a bachelor's degree in biochemistry from the University of Minnesota and was elected to Phi Beta Kappa. She also received a Wisconsin Alumni Research Foundation (WARF) schola rship and began graduate work in a joint biochemistry and home economics program. Initially, she was denied entry to the biochemistry program, which Miller attributed to a sex bias and the lack of jobs for graduating male Ph.D.'s.

Before Cavert met James A. Miller, her goal of pursuing biochemistry research seemed unattainable. Miller became an important advocate, however, and succeeded in convincing Dr. Carl Baumann to take her on as a biochemistry graduate student. Cavert o btained an M.S. degree in biochemistry in 1943 and a Ph.D. in 1945. She began to study the metabolism of the vitamin pyridoxine in mice in Baumann's lab.

In 1944, Miller joined the new McArdle Laboratory for Cancer Research at the University of Wisconsin and continued to study experimental chemical carcinogenesis. Elizabeth A. Miller joined McArdle as a postdoctoral fellow in 1945. There, the Millers began their productive partnership in research into the mechanisms of chemical carcinogenesis. "When we started our work, little was known about chemical carcinogenesis ," said Miller.

In 1947, the Millers became the first researchers to demonstrate that a foreign chemical, an aminoazo dye caused cancer in rats, by binding with proteins in the liver in a process referred to as covalent binding. In tissues that were not sensitive t o the carcinogenic effect of the azo dye, there was no binding. The Millers' subsequent research described the molecular events leading to metabolic activation of a large number of carcinogens. In 1949, Miller further demonstrated that one chemical may al ter the carcinogenicity of a second chemical by influencing its enzymatic metabolism. Allan Conney , chairman of cancer research, Rutgers University said in a commemorative interview published in the Journal of NIH Research in 1 992: "This study set the stage for many aspects of modern toxicology and led to an enhanced understanding of mechanisms of toxicity of drugs, environmental toxins, and carcinogens."

After the structure of DNA was discovered in 1953, the Millers realized that DNA played a major role in the binding of chemical carcinogens. The Millers and their associates were the first to recognize that initiation of carcinogenesis is dependent on metabolic reactions of carcinogenic chemicals with DNA. They also demonstrated that mutagenicity depends upon alteration of genetic material. The Millers' work stimulated intensive research on the binding of carcinogens to DNA, the mechanisms of mutage nesis, the activation of proto-oncogenes, and the inactivation of tumor suppressor genes.

In 1960, the Millers reported that a metabolite proved to be much more carcinogenic than its parent compound and produced tumors in tissues including the site of administration. This research demonstrated that the initiation of carcinogenesis depend ed on metabolic activation to electrophiles, a major unifying concept of their research. These findings not only were significant for cancer research, they also opened up a new field of study of drug interactions in metabolic studies in toxicology and pha rmacology.

Between 1968 and 1971, the Millers and their associates were the first to demonstrate that chemical carcinogens are potential mutagens, with mutagenicity dependent on metabolic conversion and access to the genetic material. This work set the stage f or more rapid testing of potential mutagens and risk assessments of chemicals in humans. Subsequently, the Millers evaluated the carcinogenecity of food additives, contaminants, drugs, environmental pollutants and industrial chemicals, stimulating a growi ng public awareness and concern about potential carcinogens.

The Millers' commitment to cancer research and public health policy spanned more than forty-five years. Elizabeth C. Miller was editor of Cancer Research, the journal of the American Association for Cancer Research (AACR ), between 1954-64; James A. Miller was associate editor between 1978-81. Elizabeth served as president of the American Association for Cancer Research between 1976 and 1978 and was twice elected to its board of directors. She was appointed to President Carter's Cancer Panel of the National Cancer Institute from 1978 to 1980. The Millers were concurrently admitted to the National Academy of Sciences in 1978. They participated in grant review and policy committees for numerous groups including the National Cancer Institute, the American Cancer Society, and the National Academy of Science. In 1973, Elizabeth became associate director of the McArdle Laboratory and served in this capacity until her retirement in 1987. Both were appointed WARF Seni or Distinguished Research Professor of Oncology and Emeritus Professor of Oncology. By the time they retired in the 1980s, the Millers had written more than 300 papers on chemical carcinogenesis and mentored 42 McArdle researchers.

The Millers' preeminent contributions to the study of carcinogenesis have been recognized with over 25 awards, including the Papanicolaou, 1975, First Founder's Award from Chemical Industry Institute of Toxicology, 1978, and Mott Award from General Motors Cancer Research Foundation, 1980.

The Millers had two children, Linda Ann, a fiber artist, and Helen Louise, an associate professor of botany. When her children were young, Elizabeth held a half-time appointment, but worked full-time in research and administration. The family enjoye d hiking, camping and travel. Elizabeth died on October 14, 1987, of kidney cancer. In 1988, Miller remarried Barbara Butler, a teacher of religious studies. In 1992, the Journal of NIH Research commemorated the Millers' 45-ye ar contributions to cancer research by reprinting the 1947 landmark study and interviewing Miller.