interview with Science Watch® - July/August 1999 Vol. 10, No. 4, a
publication of the Institute of
What happens at the molecular level to convert a normal cell into a cancer cell? That fundamental question lies at the root of an entire subdiscipline of medical researchmolecular carcinogenesis. Increasingly, cancer researchers are focusing their efforts on the genetic alterations that have led to specific cancers. Understanding the molecular signatures of cancers, they reason, will lead to the development of better therapies.
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, 9:1-2, 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.
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 researchera physician-scientist.
Harris: When I joined NCI in the Laboratory of
Experimental Pathology, my strategywhich I still havewas 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.
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.
Harris: The work went in two different directions. The
first was to extend the observations to many different kinds of cancers and to determine
the timing of p53 mutations in cancer development. This led to the finding that the
mutational spectrum in the p53 gene is quite different from that in other tumor-suppressor
genes, in that the majority are missense mutations. That can lead to a loss of
tumor-suppressor function but, in certain mutants, a gain in oncogene function.
Harris: The other major area
is p53 function, particularly in apoptosis. p53 has multiple functions. It upregulates
certain genes and suppresses others, including those involved in apoptosis. It's clearly
involved in one or more of the apoptotic pathways. p53 is also involved in cell-cycle
checkpoints, DNA repair, and chromosomal segregation. In fact, we have a long laundry list
of p53 functions. Different domains of the protein have different functional activities.
The research community has shown a great interest in this: in defining what portions of
the protein are important for its activity; in investigating interaction with other
proteins that might modify their function; and seeing what portion of p53 is involved with
modification of apoptotic function. Because most cancers are clonally derived, these
mutations have affected p53 functions in such a way as to give clues regarding how the
mutations are involved in carcinogenesis.
Harris: Is it possible that NO and its oxyradical
derivatives might cause damage in cells and might in fact be an endogenous carcinogen?
That's been an interesting question. It's important to know that NO is produced by three
different isoforms of nitric oxide synthase. Two produce very small bursts and
concentrations of NO. The third form, which is inducible, is found mainly in macrophages
and epithelial cells. When activated, this produces much more NO over a more prolonged
time and is thought to be a defense against pathogenic organisms, such as bacteria. This
could have some pathological consequences for the host, including chronic inflammation
leading to cell damage. There is accumulating evidence that chronic inflammation is a
Harris: Molecular epidemiology is an emerging field in
cancer research. Interesting leads have been generated from studies of a few hundred
subjects. We want to take this back to the clinic to see if one can extend this
information to much larger population-based studies and contribute to improved cancer risk
assessment, particularly at the level of the individual. One of the challenging goals of
molecular epidemiology is to identify individuals at high cancer risk.
Harris: p53 keeps surprising all of us, because of its involvement in multiple pathways and its multiple functions. p53 is clearly at the crossroads of the pathways responding to cellular stress, including DNA damage, hypoxia, and oncogene activation. Understanding these pathways should pay dividends in the prevention and treatment of cancer. I'm still prepared to be surprised by p53.
From an interview with Science
Watch® - July/August 1999 Vol. 10, No. 4, a publication of the Institute of Scienctific Information®.