Curtis C. Harris, Chief of the Laboratory of Human Carcinogenesis at the National Cancer Institute (NCI) in Bethesda, Maryland, has made major contributions to the understanding of this and related topics. He pioneered the development of in vitro models using human tissues and cells to compare metabolic pathways for the activation of chemical carcinogens and detoxification in humans and laboratory animals. He and Andres Klein-Szanto were the first to show that chemical carcinogens in tobacco smoke induce neoplastic transformation of human bronchial epithelial cells in the laboratory. He has gained international recognition for his cellular and molecular studies of asbestos-induced human pleural mesothelioma and lung cancer. More recently, Harris has made significant contributions to the discovery that mutation of the p53 tumor suppressor gene is one of the most common genetic lesions in human cancers. Understanding of the p53 gene in human tumors has revealed critical molecular links between environmental carcinogens and specific human cancers. In all, Harris's published papers have had a large impact on his scientific peers: last year in these pages, Harris was featured among the 50 most-cited biomedical scientists of the 1990s (see Science Watch, 9[3]:1-2, May/June 1998).

   Harris is a child of the space age. Aged 14 when the Soviet Union orbited Sputnik, the Earth's first artificial satellite, he benefited from the U.S. reaction to that event, which took the form of financial and philosophical encouragement of science education. Harris started doing research for high school science fairs. As an undergraduate majoring in zoology at the University of Kansas (B.A., 1965), he received a research participation award from the National Science Foundation to work on radiobiological immunology. Those studies led to his first paper, which he published while still an undergraduate. During his last undergraduate year he boosted his CV by working as an instructor and helping to teach an honors biology course and a graduate course in quantitative immunochemistry.

   Harris then earned his M.D. in 1969 at the University of Kansas School of Medicine. During medical school, his interest quickly turned to carcinogenesis. In collaboration with Donald Svoboda and Jan Reddy (now chair of the pathology department at Northwestern University), he published eight reports on nuclear structure and function and on chemical carcinogenesis.

   In his junior year of medical school, he accepted what was essentially a post-doctorate at NCI. He earned a certificate in internal medicine at the University of California Los Angeles Hospital, and then, in 1971, moved to NCI, where he finished his clinical training and continued his research. He has remained there since, moving up the institute's research ladder. Harris talked to Science Watch correspondent Peter Gwynne about his research and its implications.

What persuaded you to go into laboratory, rather than clinical, research?

   Harris: I always wanted to go into academic medicine. For a number of years I kept the balance between clinical and laboratory research until 1981, when I became chief of the Laboratory of Human Carcinogenesis. Because of the wave of molecular biology coming into cancer research, I thought that the greatest opportunities were in the laboratory. I believed that if I was going to get serious about that area, I would have to spend essentially full time in the lab. Now, I consider myself primarily a laboratory researcher–a physician-scientist.

How did you decide on subject matter for your research?

   Harris: When I joined NCI in the Laboratory of Experimental Pathology, my strategy–which I still have–was to use clinical and epidemiological observations to generate hypotheses, and test them in the clinic or in the laboratory using animal models and in vitro systems. Early in my career, long before it became fashionable, I developed in vitro models using human tissues and cells, including tissue implant and cell cultures from human donors. The idea was to use these in vitro models to study the effects of negative and positive growth factors, to introduce genes, and to expose the cells to chemical carcinogens.
   Human studies have gone largely in three directions: molecular carcinogenesis, improving molecular diagnosis, and molecular epidemiology. The two major facets of molecular epidemiology are the dosimetry of carcinogen exposure, and the inherited predisposition. These studies focus on the gene-environment interactions in determining an individual’s cancer risk. I spend about a third of my time now in molecular epidemiology, and two thirds in the areas of molecular diagnosis and carcinogenesis.

How did the p53 gene become part of your research?

   Harris: Two groups in Europe and two in the U.S. discovered p53 in 1979. It is a cellular protein frequently overexpressed in mouse and human tumor cell lines. It was cloned a few years later by Ed Harlow, Moshe Oren, and Arnold Levine. They and others found that the mouse and human p53 genes which they were investigating were nuclear oncogenes. In retrospect, they were studying missense mutants of p53 and not the normal gene.
   In the late 1980s, we were searching for candidate tumor-suppressor genes. One site frequently deleted in lung cancer was on chromosome 17p13; the location of the p53 tumor-suppressor gene. Bert Vogelstein's lab at Johns Hopkins and my lab got together to ask two simple questions: Is p53 frequently mutated in human cancer, and is it mutated in several types of human cancer? In both cases, the answer was yes. That led to a paper in Nature in 1989 (See table on next page, paper #3). These results further stimulated our interest in p53, because of its high mutation frequency in human cancer.

How did you proceed then?