The 2004 Thomas Hunt Morgan Medal Bruce Ames
Gerald R. Smith, Mark Johnston

The Genetics Society of America annually honors members who have made outstanding contributions to genetics. The Thomas Hunt Morgan Medal recognizes a lifetime contribution to the science of genetics. The Genetics Society of America Medal recognizes particularly outstanding contributions to the science of genetics within the past 15 years. The George W. Beadle Medal recognizes distinguished service to the field of genetics and the community of geneticists. We are pleased to announce the 2004 awards.

DURING a research career sparked by vision and enthusiasm and spanning more than 50 years, Bruce Ames has used microbes to solve basic genetic problems that have direct implications for human well-being. In this research he has imaginatively combined genetics with biochemistry to elucidate mechanisms underlying gene expression, mutagenesis, and carcinogenesis. Capitalizing on mutants from his early work on the genetics of histidine biosynthesis, he developed the Salmonella “Ames test,” one of the simplest and most widely used assays for mutagens and potential carcinogens. A current Google search reveals >104 website references to the Salmonella Ames test, attesting to the extensive influence of Bruce’s work. In addition, he has assessed the relative contributions to human carcinogenesis of synthetic and natural chemicals in our environment and has recently investigated the roles of deficiency of vitamins and antioxidants in DNA damage and aging.

Aside from his research projects at Bronx High School of Science, Bruce began his research as a graduate student with Herschel Mitchell at Caltech in 1950. He completed his Ph.D. degree in just three years with research on histidine biosynthesis, one of the most complex pathways for synthesis of an amino acid. During this time he developed a simple chromatographic assay for imidazole compounds accumulating in histidine-requiring Neurospora mutants, which allowed him to deduce much of the histidine biosynthetic pathway.

During his postdoctoral research with B. L. Horeker at the National Institutes of Health, Ames initiated a long-term collaboration with bacterial geneticist Phil Hartman, who had an extensive collection of histidine-requiring (his) mutants of Salmonella typhimurium. These mutants became the basis of Ames’ next 20 years of varied research, beginning with elucidation of the rest of the histidine biosynthetic pathway. With Hartman he showed that a group of nine contiguous genes, now known as the his operon, is coordinately regulated by a mechanism acting at the promoter-proximal end of the operon. Starvation for histidine derepresses the entire operon, the longest then known. These observations had an important influence on the formulation of the operon concept by Francois Jacob and Jacques Monod. Analysis of constitutively derepressed his operon mutants led Ames to the discovery that alterations in histidine transfer RNA, such as reducing its level or eliminating some of its modified bases, derepress the operon. This observation was important to the subsequent elucidation by others of the mechanism of transcriptional attenuation that regulates expression of many genes in bacteria.

In the mid-1960s, Ames began to think about a possible connection between mutagenesis and carcinogensis, a link that is widely accepted today but was controversial at the time because many people thought viruses were the prime suspects for carcinogenesis. After moving to the University of California at Berkeley in 1967, Ames developed a test for mutagenesis based on reversion of carefully selected Salmonella his mutants. A key feature of this test was Bruce’s finding of a set of strains with mutations that are particularly sensitive to mutagen-induced reversion, which proved to be more informative than forward mutagenesis. An additional critical feature is the inclusion of liver extract, stemming from Bruce’s recognition that certain compounds become mutagenic only after metabolism by an animal. During the development of this test, undergraduates in a UC Berkeley lab were asked to bring items from home to test for mutagenicity—one brought a commonly used hair dye, which proved remarkably potent. Subsequent tests by Ames and the students showed that 89% of hair dyes then commercially available were mutagenic, a result that led to the reformulation of hair dyes.

The Ames test is still in use today, more than 30 years after its development. In fact, it has become a workhorse of high school biology labs, because it is simple, cheap, and so fast that results appear while you sleep. In many cases it has saved much time and money by enabling industry to weed out mutagenic chemicals early in the pipeline.

Ames’ determination of the mutagenicity of thousands of compounds and complex mixtures, such as cigarette smoke, made it clear that there is a strong correlation between mutagenicity in the Ames test and carcinogenicity in rodents and humans. Animal cancer tests and the Ames test led to much public concern about the contribution to human cancer of synthetic chemicals, including pesticides, in food and the environment. Ames, however, came to believe that naturally occurring chemicals, such as the pesticides that plants produce in self-defense, probably account for most of our exposure to exogenous carcinogens. For example, he estimates that by weight, 99.99% of human dietary pesticides are natural. These considerations led him to devise the human exposure dose/rodent potency dose (HERP) index, which relates the potency of a particular compound and the daily exposure to it to other exposures such as the carcinogenic aflatoxins in peanut butter. This test has injected the voice of reason into the debate over the risks in our environment by putting synthetic exposures in the context of the much greater exposure of natural chemicals.

The realization that natural compounds can be carcinogenic led Bruce to turn his attention to the role of diet in human health. In the early 1990s he and his students showed that folic-acid deficiency leads to chromosomal breaks, apparently via reduced synthesis of thymidylate, increased incorporation of uracil into DNA, and its subsequent excision. Prompted by these results, he has investigated inadequate vitamin and mineral intake as a major source of DNA damage and multi-vitamin-mineral supplements for the prevention of DNA damage.

Ames is currently focusing on understanding oxidative damage to mitochondria and its contribution to aging. He has found that feeding normal mitochondrial metabolites such as lipoic acid and acetylcarnitine to old rats can reverse some mitochondrial dysfunction. This research grew in part out of his earlier work on the genetic control of the oxygen stress response in Salmonella, which established the key role of OxyR as a sensor of oxygen stress. Today, Ames continues his research on aging unabated, saying “aging has not damaged my enthusiasm genes.”

Throughout his career Bruce has emphasized the importance of developing new, simple methods to analyze complex problems, amply illustrated by the Ames test. His chromatographic assay for imidazole compounds was key to his early work on histidine biosynthesis. One of his articles in 1961 described a convenient method for determining the molecular mass of a protein by sucrose-gradient centrifugation. This article was one of the most frequently cited publications for many years, a record that has since been eclipsed by the Salmonella Ames test, with more than 2500 PubMed citations in the past 25 years.

In his career at the NIH, UC Berkeley, and currently at the Children’s Hospital Oakland Research Institute, Ames has trained approximately 150 undergraduate and 50 graduate students and 100 postdoctoral fellows, many of whom are now scientific leaders training others in the art and science of genetics and biochemistry.

For most of this time Bruce’s wife Giovanna Ferro-Luzzi Ames has been studying in a neighboring lab, the genetics and biochemistry of histidine permeation in Salmonella. Their combined labs have nurtured a productive environment, filled with humor. When chided by her that he was not exercising enough, he retorted, “What do you mean I don’t exercise enough? I exercise every day. I run my experiments, skip controls, and jump to conclusions.”

Bruce Ames has received numerous other awards recognizing his achievements. Among these are the Eli Lilly Award (1964), election to the National Academy of Sciences (1972), the Charles S. Mott Prize from the General Motors Cancer Research Foundation (1983), election to the Royal Swedish Academy of Sciences (1989), the Japan Prize (1997), and the National Medal of Science (1998).