In part because genomic sequencing is “biased” and thus not a “good sampling of diversity in genomes,” the tree of life is “not happy,” says Jonathan Eisen of the University of California, Davis (UCD). “We need more experiments across the tree of life, not just in model organisms. . . And, eventually, we want a field guide to microbial behavior and ecology.”
Such grand ambitions for adding many, many more microbial twigs and branches to the tree of life seem a fitting tribute to the late Joshua Lederberg. While not one to shun the value in studying model microorganisms, it is easy to imagine him applauding current efforts to shake up, if not uproot, the tree of life by enormously expanding its genomic details. A generous sampling of those details-oriented efforts went on display last May during “Microbial Evolution and Co-Adaptation: a Workshop in Honor of Joshua Lederberg,” convened by the versatile Forum on Microbial Threats from the ?xml:namespace prefix = st1 ns = "urn:schemas-microsoft-com:office:smarttags" ?Institute of Medicine in Washington, D.C.
Phylogenomic analysis involves combing through genomic data, seeking clues as to how genetic changes lead to functional diversity and other novelties. In one approach, Eisen scrutinizes clusters of genes and their distribution patterns across microbial species—seeking, among other things, evidence for novel functions emerging as mutations accumulate within some of those clusters. For instance, Vibrio cholerae contains what seems to be a “massively expanded” set of MCP genes, which are part of the chemotaxis apparatus in Escherichia coli, he says. Assuming those genes would disappear if they were not being used, “they’re still being around suggests at least some function, possibly novel.”
Figuring out what those novel functions might be remains a “challenge,” Eisen says. Meanwhile, a similar review of sporulation-related gene clusters led him to realize that a particular anaerobic species, previously not thought to form spores, indeed does so. In the process, he uncovered what appears to be “eight new sporulation-related genes.”
Microbial communities, including those within biofilms that form in exotic environments, also provide a fruitful means for uncovering the richness of both genetic and metabolic diversity, according to Jill Banfield of the University of California, Berkeley. Even when members of these microbial communities prove indistinguishable on the basis of their genetics, it may be possible to tell strains apart by slight differences among their proteins, she says. Amid this ongoing interplay among bacterial species and strains within biofilms, she adds, viruses “have great potential to shape microbial communities.”
Moreover, despite many microorganisms carrying the genetically encoded Cas system that protects them against encroaching viruses and plasmids, apparently the “viral population is rapidly recombining to defeat this host-silencing system,” Banfield says. One upshot is that viral and microbial cellular populations are “very heterogeneous,” with “no two cells within a microbial community being
identical.” Thus, viruses and their microbial hosts share “incredible heterogeneity”—another sign that the microbial end of the tree of life is rich with detail.
The human microbiota is also rich in diversity, albeit not so much in terms of phyla but more so in terms of species and strains, according to workshop participant David Relman of Stanford University in Stanford, Calif. Not surprisingly, this richness is “perturbed” when individuals undergo treatments with antibiotics. For example, ciprofloxacin treatment “decreases the richness and evenness of microbial diversity,” he says. Bacteroides abundance then goes up in everyone tested so far, but in each individual a different species and strain changes more than others, he adds. “This microbial ecosystem may reflect who we are.”
However, describing the role of that ecosystem in health, disease, and recovery remains a major challenge. Moreover, the same can be said for many of the specific microbial species that we designate pathogens, according to Stanley Falkow, also of Stanford University. He suggests that some pathogens are merely commensals that carry virulence factors and “live in dangerous places”—that is, anatomic sites—where they may “avoid competition.” Thus, what are called “virulence” factors in one setting might pass as “colonizing” factors in another.
This blurring of terms is not restricted to the commensal-pathogen microbiota that associates with humans. Insects such as the cabbage white gypsy moth also provide habitats for commensal and pathogenic microorganisms, whose roles may become blurred under some circumstances, according to Jo Handelsman of the University of Wisconsin, Madison. For instance, when such moths are treated with antibiotics to knock out their gut microbiota, the “recovered community is more readily invaded than was the original,” she says, “and that is the opposite of what’s expected” based on ecological principles. Other experiments that involve additionally treating such moths with Bt toxin suggest that the gut bacteria themselves play a key role in making this toxin lethal to hosts, she points out. Bt toxin opens membrane pores, and the gut microbiota help to drive host-inflammatory responses that prove lethal—surely not a role that commensal microorganisms ordinarily play.
An important component to comprehending microbial diversity is “knowing what we don’t know,” says Eisen of UCD. Every indicator suggests there is plenty yet to learn. Moreover, judging from responses by other workshop participants to those remarks, he may well have been channeling Lederberg.
Jeffrey L. Fox
Jeffrey L. Fox is the Microbe Current Topics and Features Editor.