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Home , Bruce Ames, Jacques Monod

Copyright  2004 by the Society of America The 2004 GSA Honors and Awards The Genetics Society of America annually honors members who have made outstanding contributions to genetics. The Medal recognizes a lifetime contribution to the 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.

The 2004

Bruce Ames

Bruce Ames

URING a research career sparked by vision and for imidazole compounds accumulating in histidine- D enthusiasm and spanning more than 50 years, requiring Neurospora mutants, which allowed him to Bruce Ames has used microbes to solve basic genetic deduce much of the histidine biosynthetic pathway. problems that have direct implications for human well- During his postdoctoral research with B. L. Horeker being. In this research he has imaginatively combined at the National Institutes of Health, Ames initiated a genetics with to elucidate mechanisms un- long-term collaboration with bacterial geneticist Phil derlying expression, mutagenesis, and carcinogen- Hartman, who had an extensive collection of histidine- esis. Capitalizing on mutants from his early work on requiring (his) mutants of Salmonella typhimurium. These the genetics of histidine biosynthesis, he developed the mutants became the basis of Ames’ next 20 years of Salmonella “,” one of the simplest and most varied research, beginning with elucidation of the rest widely used assays for and potential carcino- of the histidine biosynthetic pathway. With Hartman he gens. A current Google search reveals Ͼ104 website ref- showed that a group of nine contiguous , now erences to the Salmonella Ames test, attesting to the known as the his , is coordinately regulated by extensive influence of Bruce’s work. In addition, he has a mechanism acting at the -proximal end of assessed the relative contributions to human carcino- the operon. Starvation for histidine derepresses the en- genesis of synthetic and natural chemicals in our envi- tire operon, the longest then known. These observations ronment and has recently investigated the roles of defi- had an important influence on the formulation of the ciency of vitamins and antioxidants in DNA damage and operon concept by Francois Jacob and Jacques Monod. aging. Analysis of constitutively derepressed his operon mu- Aside from his research projects at Bronx High School tants led Ames to the discovery that alterations in histi- of Science, Bruce began his research as a graduate stu- dine transfer RNA, such as reducing its level or eliminat- dent with Herschel Mitchell at Caltech in 1950. He ing some of its modified bases, derepress the operon. completed his Ph.D. degree in just three years with This observation was important to the subsequent eluci- research on histidine biosynthesis, one of the most com- dation by others of the mechanism of transcriptional plex pathways for synthesis of an amino acid. During attenuation that regulates expression of many genes in this time he developed a simple chromatographic assay bacteria.

Genetics 166: 645–651 ( February 2004) 646 Honors and Awards

In the mid-1960s, Ames began to think about a possi- mosomal breaks, apparently via reduced synthesis of ble connection between mutagenesis and carcinogensis, thymidylate, increased incorporation of uracil into a link that is widely accepted today but was controversial DNA, and its subsequent excision. Prompted by these at the time because many people thought viruses were results, he has investigated inadequate vitamin and min- the prime suspects for carcinogenesis. After moving to eral intake as a major source of DNA damage and multi- the University of California at Berkeley in 1967, Ames vitamin-mineral supplements for the prevention of DNA developed a test for mutagenesis based on reversion of damage. carefully selected Salmonella his mutants. A key feature Ames is currently focusing on understanding oxida- of this test was Bruce’s finding of a set of strains with tive damage to mitochondria and its contribution to mutations that are particularly sensitive to - aging. He has found that feeding normal mitochondrial induced reversion, which proved to be more informative metabolites such as lipoic acid and acetylcarnitine to than forward mutagenesis. An additional critical feature old rats can reverse some mitochondrial dysfunction. is the inclusion of liver extract, stemming from Bruce’s This research grew in part out of his earlier work on recognition that certain compounds become mutagenic the genetic control of the oxygen stress response in only after metabolism by an animal. During the develop- Salmonella, which established the key role of OxyR as ment of this test, undergraduates in a UC Berkeley lab a sensor of oxygen stress. Today, Ames continues his were asked to bring items from home to test for mutage- research on aging unabated, saying “aging has not dam- nicity—one brought a commonly used hair dye, which aged my enthusiasm genes.” proved remarkably potent. Subsequent tests by Ames Throughout his career Bruce has emphasized the im- and the students showed that 89% of hair dyes then portance of developing new, simple methods to analyze commercially available were mutagenic, a result that led complex problems, amply illustrated by the Ames test. to the reformulation of hair dyes. His chromatographic assay for imidazole compounds The Ames test is still in use today, more than 30 years was key to his early work on histidine biosynthesis. One after its development. In fact, it has become a workhorse of his articles in 1961 described a convenient method of high school labs, because it is simple, cheap, for determining the molecular mass of a by and so fast that results appear while you sleep. In many sucrose-gradient centrifugation. This article was one of cases it has saved much time and money by enabling the most frequently cited publications for many years, industry to weed out mutagenic chemicals early in the a record that has since been eclipsed by the Salmonella pipeline. Ames test, with more than 2500 PubMed citations in Ames’ determination of the mutagenicity of thou- the past 25 years. sands of compounds and complex mixtures, such as In his career at the NIH, UC Berkeley, and currently cigarette smoke, made it clear that there is a strong at the Children’s Hospital Oakland Research Institute, correlation between mutagenicity in the Ames test and Ames has trained approximately 150 undergraduate and carcinogenicity in rodents and humans. Animal cancer 50 graduate students and 100 postdoctoral fellows, many tests and the Ames test led to much public concern of whom are now scientific leaders training others in about the contribution to human cancer of synthetic the art and science of genetics and biochemistry. chemicals, including pesticides, in food and the environ- For most of this time Bruce’s wife Giovanna Ferro- ment. Ames, however, came to believe that naturally Luzzi Ames has been studying in a neighboring lab, the occurring chemicals, such as the pesticides that plants genetics and biochemistry of histidine permeation in produce in self-defense, probably account for most of Salmonella. Their combined labs have nurtured a pro- our exposure to exogenous carcinogens. For example, ductive environment, filled with humor. When chided he estimates that by weight, 99.99% of human dietary by her that he was not exercising enough, he retorted, pesticides are natural. These considerations led him to “What do you mean I don’t exercise enough? I exercise devise the human exposure dose/rodent potency dose every day. I run my experiments, skip controls, and jump (HERP) index, which relates the potency of a particular to conclusions.” compound and the daily exposure to it to other expo- Bruce Ames has received numerous other awards rec- sures such as the carcinogenic aflatoxins in peanut but- ognizing his achievements. Among these are the Eli ter. This test has injected the voice of reason into the Lilly Award (1964), election to the National Academy debate over the risks in our environment by putting of Sciences (1972), the Charles S. Mott Prize from the synthetic exposures in the context of the much greater General Motors Cancer Research Foundation (1983), exposure of natural chemicals. election to the Royal Swedish Academy of Sciences The realization that natural compounds can be car- (1989), the (1997), and the National Medal cinogenic led Bruce to turn his attention to the role of of Science (1998). diet in human health. In the early 1990s he and his Gerald R. Smith students showed that folic-acid deficiency leads to chro- Mark Johnston Honors and Awards 647

The 2004 Genetics Society of America Medal

Trudy F. C. Mackay

Trudy F. C. Mackay

HE 2004 GSA Medal is awarded to Trudy F. C. editor of that other Edinburgh beacon, Genetical Re- TMackay for her substantial contributions to quanti- search. After a postdoctoral period back in Dalhousie, tative genetics. Much of what we now know about the Trudy returned to Edinburgh in 1980 and began her genetic basis of variation in quantitative traits follows work with transposable elements. We were fortunate to from Trudy’s meticulous experiments on bristle num- be able to attract her to North Carolina State in 1987. ber in , and our future under- Quantitative, or measured, traits are of central impor- standing of the molecular mechanisms affecting tance for human health and agricultural production span and olfactory behavior will be shaped by Trudy’s and so our health and welfare will benefit from an un- current genetic dissection of these traits in Drosophila. derstanding of their genetic basis. Trudy has used the Trudy began her education in biology at Dalhousie number of sensory hairs of Drosophila melanogaster as University and in 1976 she went to the University of a model quantitative trait, and she used transposable Edinburgh on an 1851 Exhibition Scholarship. There elements to study the effects of mutation on such traits. she began a partnership with Douglas Falconer and Bill In a series of experiments she constructed lines that Hill that has ensured the continuation of excellence of differed in the numbers and locations of P elements and the Edinburgh school of . A very quantified their effects on bristle number and viability. visible symbol of this continuation was Trudy’s joining Trudy’s training in classical quantitative genetics al- with Falconer in 1996 as a coauthor of Principles of Quan- lowed her to provide statistically sound estimates of titative Genetics, the bible of quantitative genetics since pleiotropic and epistatic effects, and she demonstrated it first appeared in 1960. Trudy is also North American the asymmetric and highly leptokurtic nature of P-ele- 648 Honors and Awards ment effect on bristle number (e.g., Genetics 130: 315– colleagues reported on a genome-wide expression analy- 332, 1992). Most of the increase in mutational variation sis of smell-impaired and control lines of Drosophila mela- was due to a few lines with large effects, contradicting nogaster. They were able to identify new candidate genes conventional wisdom that quantitative variation is for regulating olfactory behavior. caused by many genes of small effect. This finding offers Trudy’s work on characterizing the genetic basis of hope for the ability to manipulate genes affecting quan- quantitative genetic variation follows a tradition of using titative traits of economic importance or those affecting Drosophila as a model organism that distinguished the human health. The P-element studies were accompa- work of her mentor Robertson and provided the first nied by an investigation, with long-term collaborator QTL interval mapping study of J. M. Thoday in 1961. Chuck Langley, of naturally occuring variation and a In her Nature Reviews Genetics article (2: 11–20, 2001), demonstration that this is correlated with variation at the Trudy made an eloquent case for the continued use of DNA sequence level (Science 266: 1697–1702, 1994). Drosophila as a model for human disease studies. This Although bristle number has proved to be a trait very nice review makes it abundantly clear that these with considerable genetic complexity, Trudy has more studies will owe much to her very careful experiments recently taken up the challenge of investigating longev- and interpretations. ity (e.g., Proc. Natl. Acad. Sci. USA 94: 9734–9739, 1997). Trudy’s research has made her an international figure She has mapped quantitative trait loci (QTL) with ef- and a worthy recipient of the GSA Medal, and her service fects on life span, survivorship, and mortality in Drosoph- to her profession demonstrates a generosity of spirit. ila melanogaster. Her finding of late age-of-onset QTL She has served on the GSA Board of Directors and was effects is consistent with the mutation accumulation hy- a member of the Genetics Editorial Board 1991–2002. pothesis of senescence, whereas her demonstration of Few volumes of Genetics in recent years have not carried sex-specific QTL effects suggests a novel mechanism for several of Trudy’s articles. Trudy has been a voice of maintaining genetic variation for life span, depending support for excellent research in population and quanti- on the existence of QTL genotype by sex interaction tative genetics at study sections and review panels. She for fitness. directs a training grant at North Carolina State and Together with husband Robert Anholt, Trudy has guides a large team of graduate and postdoctoral stu- been extending her genetic studies to behavioral traits, dents. I am fortunate to have her as a colleague—our with an emphasis on odor-guided behavior (e.g., Behav. Society and our profession are fortunate to have her Genet. 31: 17–27, 2001). In a recent Nature Genetics scientific leadership. article (35: 180–184, 2003) Robert, Trudy, and their Bruce S. Weir Honors and Awards 649

The 2004 George W. Beadle Medal

Norbert Perrimon

Norbert Perrimon

HE 2004 George W. Beadle Medal is awarded to acteristic of Norbert’s own research throughout the years. TNorbert Perrimon in recognition of his outstanding It was also in the Gans laboratory that Norbert first contributions to the Drosophila genetics community. started to use a dominant female sterile mutation as a His continuous development of new genetic and molec- tool for clonal analysis in the germline. After he moved ular tools have allowed Drosophila laboratories to make to the laboratory of Anthony Mahowald, then at Case rapid progress in many different fields of research. Nor- Western University for his postdoctoral work, he per- bert Perrimon has been a key figure in the genetic fected the dominant female sterile approach for the X analysis of many signaling pathways in Drosophila. He chromosome. This allowed him to test a large number not only has developed tools for these analyses, but also of mutations that are homozygous lethal, but yield inter- has made them readily available to the whole Drosophila esting when made homozygous in the germ- community. It is for these achievements that the GSA line after induction of mitotic recombination. Among honors Norbert Perrimon with this prize. the mutations that Norbert and his colleagues analyzed Norbert Perrimon began his scientific career in the in these first large-scale experiments were mutations in laboratory of Madeleine Gans at the University of . pole hole, the Drosophila Raf homolog, as well as muta- Madeleine Gans was one of the outstanding geneticists tions in hopscotch (the Drosophila JAK homolog) and of her time, and when Norbert joined her group, her disc large (which is involved in determining epithelial laboratory was involved in screens for female sterile and polarity). After establishing his own laboratory at mutations on the X chromosome of Harvard Medical School, Norbert Perrimon continued Drosophila. A deep appreciation for the power of genetic the study of several of the maternal genes involved in screens and the realization that unhindered sharing of embryonic patterning, in particular genes involved in tools and mutations allows rapid progress remained char- signaling pathways such as Raf and corkscrew, which led 650 Honors and Awards to further studies of the Torso and Egfr pathways; dishev- in combining the two systems into a useful tool that elled, zeste white 3 (sgg), and porcupine, which initiated allows Drosophila laboratories a relatively easy approach important work on Wingless signaling; and hopscotch and to studying the effects of their favorite mutations in marelle (Stat92E), which established the analysis of JAK/ germline clones. At the same time, Andrea Brand and STAT signaling in Drosophila. These experiments led Norbert undertook another risky experiment, trans- to many new insights in the signal transduction area forming the yeast GAL4 gene, a powerful transcriptional and influenced cell biological thinking about signal pro- regulator, into flies and inserting the GAL4 UAS target duction, transport, and reception in general. sites in front of test genes such as Raf and lacZ. The However, while pursuing these important scientific outcome of their efforts transformed the way Drosophila questions, Norbert Perrimon, in a unique manner, also laboratories have been designing mis- and overexpres- spent considerable time and effort making effective sion experiments, and countless screens and investiga- tools for developmental analyses in Drosophila. While tions into gene function have derived from this original the ovoD technique to induce homozygous germline set of experiments. clones by X-ray-induced mitotic recombination worked Very notably, Norbert Perrimon not only generated reasonably efficiently for the X chromosome, the avail- useful stocks and constructs that he used in his own able dominant female sterile mutations on other chro- research, but also very generously gave out those tools mosome arms were tedious and much less useful to to the scientific community as soon as they were avail- employ. Norbert decided that it would therefore be able. His inventiveness in developing the tools and im- worth transforming the dominant ovoD mutation on to mediate sharing of the stocks have impacted the way all the other chromosome arms, and he also realized that Drosophila laboratories perform experiments and have the newly introduced FLP-FRT system in flies would be led to numerous new insights that have affected the extremely useful for the induction of germline clones. Genetics community as a whole. In a heroic effort, Tze-Bin Chou and Norbert succeeded Trudi Schu¨pbach Honors and Awards 651 Previous Recipients of These Awards

Thomas Hunt Morgan Medal Genetics Society of America Medal George W. Beadle Medal

1981 Barbara McClintock and Marcus M. Rhoades Beatrice Mintz 1982 Gerald R. Fink 1983 Edward B. Lewis 1984 George W. Beadle and R. Alexander Brink David S. Hogness 1985 Herschel L. Roman 1986 Gerald M. Rubin 1987 James F. Crow 1988 Norman H. Giles David Botstein and Ira Herskowitz 1989 Dan L. Lindsley Allan C. Spradling 1990 Charles Yanofsky Nancy Kleckner 1991 Armin Dale Kaiser Bruce S. Baker 1992 Edward H. Coe, Jr. Maynard V. Olson 1993 Ray D. Owen Jonathan R. Beckwith 1994 David D. Perkins Leland H. Hartwell 1995 Matthew Meselson Eric Wieschaus 1996 Franklin W. Stahl Elliot Meyerowitz 1997 Oliver Evans Nelson, Jr. Christine Guthrie 1998 Norman H. Horowitz Ronald W. Davis 1999 Salome G. Waelsch Charles H. Langley 2000 Evelyn M. Witkin Jack W. Szostak and Robert Waterston 2001 Yasuji Oshima H. Robert Horvitz Gerald R. Fink 2002 Ira Herskowitz Robert Mortimer and Andre´ Goffeau 2003 David S. Hogness Jeffrey C. Hall Gerald M. Rubin and Allan C. Spradling