SCIENCE & TECHNOLOGY
FIELDS OF GENES Strides in the new field of toxicogenomics, health effects of genetic taste sensitivity, and protective diets featured at AAAS meeting ELIZABETH K. WILSON, C&EN WEST COAST NEWS BUREAU
without spending millions," said Cheryl Lyn Walker, professor of carcinogenesis at the University of Texas' M. D. Anderson Cancer Center, Houston, and cochair of the symposium. Raymond WTennant, director of the National Center for Toxicogenomics, was the other cochair. With some proof-of-concept experiments, Paules and his colleagues have already shown that they can accurately deduce what toxic compounds rat liver cells were exposed to by looking at patterns of messenger RNA expression in microarrays.
HE ROLE OF GENES IN VARIOUS is to assemble enormous databases that aspects of human health—from contain information not only about getoxic chemicals to diet—was a netic responses, but about those of propervasive thread at the annual teins and metabolism as well. meeting of the American Asso"The Holy Grail is to predict whether IN A CELLp sequences of DNAsegments— ciation for the Advancement of Science or not a compound might be carcinogenic genes—are transcribed into lengths ofmessenger RNA (mRNA), which in turn (AAAS) last month in Denver, where scientists from many disciplines gath- EXPRESSIVE Patterns in microarrays reveal are translated into proteins that perform myriad functions, including ered to exchange information. gene responses to environment. DNA damage repair. The more acThe environment is full of subtively a gene is expressed, the greater stances that affect your well-being. the levels of mRNA. Exposure to From contaminants in a glass of water stresses such as chemicals or radiation to a sleeping pill, these compounds can affect gene expression and thus cause your genes to react. Some of mRNA levels. these effects may be far too subtle to To probe this, scientists take cells recognize before there's serious or lastfrom tissue (in Paules's case, livers) of ing damage. But a new discipline, treated and untreated animals (in this known as toxicogenomics, has arisen case, rats), extract their mRNA, and that will make it possible to identify label each with a different fluorescent and predict environmental effects. probe. On a substrate, they fabricate This nascentfieldis, as it sounds, a an array of dots, each ofwhich contains combination of genomics and toximany DNA segments from one gene. cology, a study of patterns in either They then wash the mRNA sample gene or protein expression that can across the chip, and mRNAhybridizes serve as biomarkers for exposure to with any complementary DNA. and effects of environmental stresses. Then the chip is exposed to laser 'We like to say that the state ofyour light, and the bound mRNA, with its health is a function of your environfluorescent tags, lights up. If there's a ment affecting your genes over time," lot of mRNA, the dot will fluoresce said Richard S. Paules, head of the mimore intensely signaling more gene excroarray group at the National Instipression. The fluorescence from the tute of Environmental Health Sciences' mixture ofa reference and the test samrecently created National Center for ple results in a spectrum of color. For Toxicogenomics. Paules spoke at a example, red may indicate the test gene AAAS symposium on toxicogenomics. is being highly expressed, or upreguIn just the past few years, DNAmilated; green may signal that it's being croarray technology and burgeoning suppressed, or downregulated. If both computational power have made toxtest and reference genes are expressed icogenomics possible. Scientists can equally the dot may be yellow A comnow take a comprehensive look at how puter analyzes the spectrum and calorganisms respond to different stressculates the levels of gene expression. es—primarily exposure to chemicals The patterns generated by genes at different concentrations over difexposed to different substances, in different durations. The goal, Paules said,
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Pathways you've been concentrating on for the past two or three decades turn out to be only one or two among manyp many important pathways/' HTTP://WWW.CEN-ONLINE.ORG
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SCIENCE & TECHNOLOGY ferent doses, for different amounts of time, mans into three groups of taste sensitiviWhen they first started the experiment, are then distinctive. Paules's group exposed ty. Some people, who Bartoshuk dubs "nonSamson said, they knew of but a few dozen rats to single doses of an enzyme inducer tasters," can't taste PROP at all. Those peogenes that were important in helping an (phenobarbital) and peroxisome proliferple who find PROP somewhat bitter are organism to recover from exposure to a ators such as clofibrate and gemfibrazil. known as medium tasters. And then there's DNA-damaging agent. But as they soon The toxicology of these compounds is well a group of people who find PROP so hordiscovered, those genes are only part of studied. The scientists tested the mRNA ribly bitter they just can't stand it. These the story from the rats' liver cells and found signifilast people are the "supertasters," those Oddly, they found little correlation becant differences in the expression of the who Bartoshuk said experience a "neon" tween whether a gene altered its expresgenes. They obtained another data set from world of taste. They are the ones who shy sion in response to a compound and rats exposed to the chemicals for 14 days. away from the bitterness in brussels whether a strain missing that gene was sensprouts or bell peppers. Then they tested blind samples of mRNA from animals But taste sensitivity has andosed with a variety of comother component: the density pounds for various times. By of taste bud structures on the 0 CH3 1^ comparing the gene expression 1 tongue. Known as fungiform II H3C—C—0—OH patterns to those they'd already H3C — 0 — S — C H 3 papillae, these structures are ex1 obtained from previous exper-^ tremely dense on the tongues II CH 3 1 0 intents, they were able to corof supertasters and sparse on 0" rectly determine 22 out of 23 the tongues of nontasters. Sutimes whether an animal had pertasters are more sensitive to EXPOSED Yeast strains show different sensitivities and been exposed to an enzyme inthe feel of fat and the heat of resistances to damaging agents such as ultraviolet light, ducer, peroxisome proliferator, chilies. methyl methanesulfonate (left), ferf-butyl hydroperoxide or neither of the two. (center), and 4-nitroquinoline-M-oxide. You need both the dense "With enough in formation, papillae and PROP sensitivity we can begin to evaluate exposure to an to be a supertaster, Bartoshuk said. "If sitive or resistant to the lethal effects of unknown substance," Paules said. you're a nontaster [with dense papillae}, the DNA-damaging compounds. you won't taste PROP, but you will taste They've also been able to identify gene "We were very surprised," Samson said. sugar and salt more intensely" Bartoshuk patterns that indicate the start of damage They began examining protein-protein said. before it shows up in the rest of the cell. interaction databases and developed proWomen are more likely to be supergrams to merge the interaction data with ANOTHER STUDY presented at the meettasters than men. Oddly, while women sutheir genomics database. The combinaing shows that the processes that help an pertasters tend to find fat less appealing tion uncovered whole networks of proteins organism recover from exposure to envithan their medium or nontaster counterinvolved in helping the cells recover. ronmental stressors are far more complex parts, male supertasters like fat more than DNA-damage-repair proteins are presthan previously thought. Leona Samson, other men. ent in the networks, but not as many as exprofessor of biological engineering and Now Bartoshuk has found that these pected, Samson said. Other proteins, such toxicology at Massachusetts Institute of taste-sensitivity differences are correlated as the product of RNA-processing genes, Technology, employs an approach known with profound health risks. are also very important in the DNA-damas genomic phenotyping to study how toxBartoshuk's colleague Marc D. Basson age-repair process. ic exposures affect the yeast Saccharomyces at Wayne State University Samson's group has now cerevisiae. School ofMedicine counttested 4,800 of the yeast Saccharomyces was the first organism to strains and has created an ed the number of polyps H7C3 have all its genes —some 6 , 0 0 0 —sein the colons of a group of "interactome" database, quenced. Researchers have now assembled men receiving colonoinvolving 5,000 proteins a library of knockout mutant yeasts, in scopies. Bartoshuk then and 20,000 interactions. which each strain has one gene deleted. tested the men for taste "Pathways you've been Researchers can use the mutants to help BITTER Some people sensitivity concentrating on for the deduce the importance of certain genes in find 6-n-propylthiouracil They found that the past two or three decades surviving environmental stress. unbearably bitter. Others more taste-sensitive the turn out to be only one or can't taste it at all. Samson's lab used a semirobotic system men, the more polyps they two among many many imin which they placed about 1,650 knockhad. The taste-sensitive portant pathways," Samout strains, along with a wild-type strain, men were also heavier and ate fewer vegson said. onto plates with arrays of agar dots. They etables. The implication is that the men's exposed each strain to several different taste sensitivity affected their diets, which GENES LOOMED large in another AAAS doses each of methyl methanesulfonate, symposium on human biodiversity Linda put them at risk for colon cancer. tert-butyl hydroperoxide, 4-nitroquinoBartoshuk, professor of surgery at Yale UniThe picture gets more complicated line-N-oxide, and ultraviolet light, all of versity, reported that a genetic predisposiwith evidence that a history of ear infecthem DNA-damaging agents. tion to like certain foods maybe related to tions may also affect your health. A comyour health. They then watched to see how the mon effect of the illness is to lose the The genetic ability to taste a bitter comstrains, with their different missing genes, sense of taste, as one of the important pound known as PROP (6-/z-propylthiofared. Surprisingly, a great number of nerves in tasting goes through the middle uracil) allows researchers to classify hustrains were sensitive to the compounds. ear.
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But taste inhibits oral pain and oral touch. If the taste sense is damaged, then that inhibition is released, and all of a sudden, a person is able to taste fat intensely. Backing that up is a correlative study that found that men who had a history of ear infections were heavier than those who didn't. An important reason that this research area has made great strides recently Bartoshuk said, has been the realization that different scales must be used for different
evidence that the plants used by these cultures contain protective chemicals. The evolution of the human diet can be traced back 2 million years, when early humans began eating more animals, Johns said at the meeting. They began consuming more fatty acids and cholesterol than previously, but early humans also ate antioxidant-rich plants that may have protected them from the free radicals generated during the processing of meat and fat.
bark of Acacia nilotica, which contains antioxidants, to their fat-based soups. The Maasai also chew gums from various plants. One gum comes from a plant related to myrrh and may lower cholesterol. Highlanders in Tibet consume numerous spices and medicinal plants that contain antioxidants. Cloves, for example, appear to protect human low-density lipoprotein from oxidation. Johns's group also studies the indige-
SAY AAH Supertasters have dense taste bud structures (right), while the structures of nontasters are sparse. tasters. "You can't make cross-group comparisons," she said. BUT THOUGH common nutritional lore deems high-fat diets killers, studies of the diets of various indigenous cultures paint a more nuanced picture. Human nutrition professor Timothy A. Johns at the Centre for Indigenous People's Nutrition & Environment at McGifl University Ste. Anne de Bellevue, Quebec, has gathered ample
Evidence for this protection can be found in indigenous cultures nowadays. Johns's group has been testing plant additives and medicines gathered from these cultures, finding they contain numerous powerful antioxidants. For example, Maasai pastoralists in East Africa don't eat many vegetables, and they have a diet high in meat and fat. Yet they don't have much heart disease. A possible protection comes from the addition of the
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nous peoples of the boreal forest in Canada, who use antioxidant-rich plants such as sumac, oak, and dogwood as treatments for diabetes symptoms. As a sobering finish, Johns pointed out that the diets of indigenous people are changing rapidly, and not for the better. The diets with barks, gums, and leaves that confer so much protection are increasingly being replaced by diets with cheap, refined carbohydrates. •
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