Microbes Rule

Courtesy of Gordon Vrdoljak, UC, Berkeley Pseudomonas syringae (left) and Pediococcus pentosaceus (right) Over the past year, major English-language newspapers worldwide have printed six stories about microbial genomes, as compared with 485 stories on the Human Genome Project.1 Yet, scientists have sequenced and published nearly 100 complete microbial genomes. Dozens more have been draft-sequenced, providing unpublished data that have gaps but are still usable. The public and press may be too enamored with the Human Genome Project (HGP) to pay much attention to the invisible world of microbes. But scientists, sequencing tools in hand, are finding microorganisms full of remarkable industrial potential. Microbial genomic data are paving the way for new and improved vaccines, better-tasting and safer fermented foods and beverages, stronger biodefense, and a cleaner environment. Courtesy of the Department of Energy Joint Genome Institute Lactobacillus gasseri "Most people ... don't appreciate that, to put it bluntly, microbes rule. They operate this planet, we don't. I think they should be getting vastly more attention," says Dan Drell, program director of the US Department of Energy's (DOE) Microbial Genome Program, a 1994 offshoot of HGP. The DOE is not the only player in microbial genomics, but it is a major one. It houses a draft sequencing facility in Walnut Creek, Calif., and funds complete sequencing projects nationwide, including many at The Institute for Genomic Research (TIGR) in Rockville, Md., where about 25 of the 100 complete microbial genomes have been sequenced. Other funding sources include the National Institutes of Health and the Defense Advanced Research Projects Agency. Outside the United States, the Wellcome Trust Sanger Institute, Cambridge, UK, is the microbial sequencing leader, having sequenced nine complete microbial genomes. Knowing a microbe's genome opens up a fascinating biological world. Scientists do it for utilitarian reasons, but most agree it is the basic science that really rivets them. BETTER HEALTH Streptococcus agalactiae (group B Strep) is a leading cause of life-threatening illness; about one-third of the cases involve the serotype V strain, which is particularly virulent. For unknown reasons, bacteria encapsulated by the serotype V polysaccharide are causing an increasing number of infections. "It is really emerging as a major human pathogen," says TIGR researcher Hervé Tettelin. "And we are trying to understand why. If you better understand how a species achieves virulence, you can better tackle them before they cause disease." Sequencing was the first step to reach that understanding.2 "Only when you have the whole genome sequence do you have all the pieces of the puzzle," says Tettelin. With classical approaches using mutants, "you only see the tip of the iceberg." The second step was comparing the sequence to other Streptococcus species.2 "That's where you really gain power," he says. "That helped us define the set of virulence genes that would be relevant to this organism." The next step, says Tettelin, will be to screen the relevant genes for potential vaccine candidates, much like what his colleagues did with Neisseria meningitis, using a new high-throughput approach made possible by complete genomic sequencing.3 Starting with some 600 potential vaccine candidates for N. meningitis, researchers have narrowed the playing field down to a handful.Tettelin, who finds the science behind the health goals most fascinating, says this is just one of many microbial sequencing projects with which he's been involved. "For any genome that you sequence," he says, "You have no clue as to what about 25% to 40% of the genes are doing." Drell agrees. "It's a little humbling to see that we don't know as much as we thought we did." It is not just the number of unknown genes, but also their arrangement that poses a mystery. Among streptococci there are islands of genes, Tettelin explains, sometimes as many as 25 genes in a row that some strains have and others do not. Drell describes these islands, or blocks, as "the footprints of lateral gene transfer." An investigator might notice, for example, a 20-30 kb stretch with a G-C content that looks different from the rest, as if it came from another type of bacteria altogether. This kind of lateral gene transfer, says Drell, means that "you don't have a clean tree of evolution that is rooted in a single primordial core genome. For millions, billions of years, bacteria have been sending genome segments back and forth, sort of like how we send E-mail, only natural selection caused some of it to be kept instead of trashed." Courtesy of the Department of Energy Joint Genome Institute Leuconostoc mesenteroides BETTER FOOD Like Tettelin, Bart Weimer of Utah State University sequences microbes for their commercial applications as well as their curious nature. Weimer and David Mills, University of California, Davis, formed the Lactic Acid Bacteria Genome Consortium, a group of about 24 US scientists who study the genomes of nine major food-related and evolutionarily related lactic acid bacteria. "The most exciting aspect of this is that we will understand how these organisms evolve," says Weimer. Mills agrees: "We're taking a small twig of the tree of life and sequencing a bunch of near neighbors and trying to understand their evolution." Lactic acid bacteria contribute to a $30 billion US industry of fermented products. From cheddar cheese to cabernet sauvignon, these bacteria are a part of everyday life, says Mills. Accessing their genomes will lead to better-tasting and safer products. These same bacteria also have potential probiotic applications.4 BETTER BIODEFENSE With the increase in biodefense funding that followed Sept. 11, 2001, many scientists, including TIGR's Ian Paulsen, are working on sequencing efforts for potential bioterrorist agents. Paulsen recently led the effort to sequence Brucella suis, the first agent the US military weaponized in the 1950s.5 Because the flu-like symptoms of brucellosis are not recognized until days after an outbreak, the ability to detect the bacteria's presence quickly would be crucial to controlling an outbreak. Genomic knowledge is key to developing these rapid detection techniques. But Paulsen and his colleagues are having fun, too. He and his collaborators compared B. suis' genome with those of a handful of other species. Surprisingly, not only is B. suis more closely related to its animal pathogen cousin Brucella melitensis than they had anticipated, but it is also more similar to plant pathogens than expected.5 This suggests, says Paulsen, that "there isn't that much of a fundamental difference between being a plant pathogen and an animal pathogen and a human pathogen." A BETTER ENVIRONMENT Scientists like DOE-funded Michael Daly, who helped sequence Deinococcus radiodurans,6 are using the data to learn how this extreme radiation-resistant organism can be used to clean groundwater and soil contaminated by US-generated radioactive waste during the Cold War. Conventional clean-up techniques cost hundreds of billions of dollars; the biological approach is a cost-effective alternative. "That's the kind of thinking that excites us," says Drell. Courtesy of the Department of Energy Joint Genome Institute Microbulbifer degradans Daly, of the Uniformed Services University of the Health Sciences, Bethesda, Md., says that he has demonstrated proof-of-principle that mercury and toluene degradation genes can be taken from other organisms--namely Escherichia coli and Pseudomonas--and functionally expressed in D. radiodurans.7,8 Now, Daly is taking the work one step further, because mercury and toluene aren't the only waste products out there. "These waste sites are extremely complex," he says. "Each one is essentially unique. We are systematically developing organisms that can treat a variety of compounds." All of Daly's research is conducted in simulated conditions in the laboratory. As he and Drell emphasize, a tremendous amount of experimental work needs to be done before the engineered organisms can be tested in contained natural settings--let alone actually released. "We have no idea what would happen if we did that," says Drell. Although the sequencing of D. radiodurans has made Daly's work easier, he admits that "no one needs all that sequence information to do that engineering." But, the complete genomic sequence also makes it easier to ask other kinds of questions. Daly wants to know what makes D. radiodurans the most radiation-resistant organism known. Could the answer lie in those unknown genes? With microbes, even basic science has utilitarian potential. After all, says Drell, "It's the most cost-effective way to get the most yield." Leslie Pray (lpray@nasw.org) is a freelance writer in Northampton, Mass. References 1. LexisNexis search, Academic Universe, Major world English language newspapers, Feb. 6, 2003. 2. H. Tettelin et al., "Complete genome sequence and comparative genomic analysis of an emerging human pathogen, serotype V Streptococcus agalactiae," Proc Natl Acad Sci, 99:12391-6, Sept. 7, 2002. 3. M. Pizza et al., "Identification of vaccine candidates against serogroup B meningococcus with whole genome sequencing," Science, 287:1816-20, 2000. 4. B. Beale, "Probiotics: their tiny worlds are under scrutiny," The Scientist, 16:20-2, July 22, 2002. 5 . I. Paulsen et al., "Brucella suis genome reveals fundamental similarities between animal and plant pathogens and symbionts," Proc Natl Acad Sci, 99:13148-53, Oct. 1, 2002. 6. O. White et al., "Genome sequencing of the radioresistant bacterium Deinococcus radiodurans R1," Science, 286:1571-7, 1999. 7. C.C. Lange et al., "Engineering a recombinant Deinococcus radiodurans for organopollutant degradation in radioactive mixed waste environments," Nat Biotech, 16:910-1, 1998. 8. H. Brim et al., "Engineering Deinococcus radiodurans for metal remediation in radioactive mixed waste environments," Nat Biotech, 18:85-90, 2000.

Microbes Rule

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Courtesy of the Department of Energy Joint Genome Institute
Lactobacillus gasseri