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Martin and Ames 236 (5): 1372
J. Biol. Chem., Vol. 281, Issue 3, 3, January 20, 2006
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Classics
Sucrose Gradient Centrifugation for Low Molecular Weight Substances: the Work of Bruce N. Ames
A Method for Determining the Sedimentation Behavior of Enzymes: Application to Protein Mixtures
(Martin, R. G., and Ames, B. N. (1961) J. Biol. Chem. 236, 1372–1379)
Bruce Nathan Ames was born in 1928 in New York City. He attended the Bronx High School of Science where he did his first scientific experiments: growing tomato root tips in culture to determine the effects of plant hormones. After graduating from high school, Ames attended Cornell University, receiving his B.A. degree in chemistry/biochemistry in 1950. He then moved to the California Institute of Technology for graduate study with Herschel K. Mitchell in the biology department. There, Ames worked on the biosynthesis of histidine in Neurospora. After receiving his Ph.D. in 1953, Ames took a postdoctoral position in the National Institute of Arthritis and Metabolic Diseases at the National Institutes of Health (NIH). He worked with Bernard Horecker, who was featured in a previous Journal of Biological Chemistry (JBC) Classic (1).
At the NIH Ames isolated the enzymes involved in the histidine pathway using the intermediates he had isolated and synthesized at Cal Tech. As a result of a collaboration with Philip Hartman, Ames had switched from Neurospora to Salmonella, and in 1954, as an independent investigator at the NIH, he began work on gene regulation in histidine biosynthesis. He and Hartman showed that the histidine genes, which were in a cluster in Salmonella, could be overexpressed if histidine availability limited the growth rate. They also demonstrated that the cluster of genes was controlled by a regulatory sequence.
Ames became convinced that the histidine biosynthetic enzymes were in a complex in the cell. He encouraged Robert G. Martin, a medical student at Harvard who had come to his laboratory for a semester, to see if this was true using sucrose gradient centrifugation. At the time, sucrose gradient centrifugation had mostly been used for analyzing ribosomes and large molecules. Martin worked out a method to adapt the procedure to relatively low molecular weight substances and determined the molecular weights of several enzymes in the histidine biosynthesis pathway. This method is reported in the JBC Classic reprinted here. Although they did not find a complex of histidine biosynthetic enzymes, the Ames and Martin paper became one of the most cited papers in biochemistry.
A year after the Classic was published, Ames became a section head in the newly created Laboratory of Molecular Biology at the National Institute of Arthritis and Metabolic Diseases. Martin enjoyed his time at the NIH so much that he returned to Ames' laboratory as a postdoctoral fellow after finishing medical school. Martin later showed that the histidine biosynthetic genes were turned on and off as a unit and that a single mRNA was produced from the cluster of genes.
Sometime in 1964, Ames read the list of ingredients in a box of potato chips and began to wonder if preservatives and other chemicals caused genetic damage to humans. This led to his development of the "Ames test" for chemical mutagens. Using his mutants of Salmonella that required histidine for growth, he added just enough histidine to allow the bacteria to undergo a few cell divisions as well as the synthetic chemical being tested. If the added chemical was a mutagen, it would increase the mutation rate and hence the number of histidine-independent colonies. During the next several years Ames developed a set of sensitive tester strains using all of the known mutagens he could get his hands on. The Ames test has been used extensively to help evaluate the mutagenic and carcinogenic risks of a large number of chemicals.
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In 1968 Ames moved to the Department of Biochemistry and Molecular Biology at the University of California at Berkeley as a full professor. He served as Chairman of the department from 1983 to 1989. In addition, he formed the National Institute of Environmental Health Science Center at Berkeley in 1979 and served as its director until 2002. At Berkeley, Ames continued to work on the regulation of the histidine operon as well as mutagen testing. He developed a database of chemicals that cause cancer in animals, listing their degree of virulence. Later, Ames' research interest shifted to the question of aging, and he showed that the role of mitochondrial decay was a major contributor to aging and age-related degenerative diseases. Ames was also one of a team of Berkeley scientists who discovered how folic acid deficiency leads to DNA damage. In 1999 Ames moved to the Children's Hospital of Oakland Research Institute (CHORI) where he continues to work today. More can be read about Ames' research in his JBC Reflections (2).
Ames was elected to the National Academy of Sciences in 1972 and has received many awards including the Eli Lilly Award of the American Chemical Society (1964), the Mott Prize of the General Motors Cancer Research Foundation (1983), the Gold Medal of the American Institute of Chemists (1991), the Glenn Foundation Award of the Gerontological Society of America (1992), the Japan Prize (1997), and the National Medal of Science (1998).
REFERENCES
- JBC Classics: Horecker, B. L., Smyrniotis, P. Z., and Seegmiller, J. E. (1951) J. Biol. Chem. 193, 383–396 (http://www.jbc.org/cgi/content/full/280/29/e26)
- Ames, B. N. (2003) An enthusiasm for metabolism. J. Biol. Chem. 278, 4369–4380
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