illustration of our strong bias toward bacteria that are amenable to cultivation (Hugenholtz, 2002).

Given these facts, it is concerning but perhaps not surprising that clinical microbiology continues to rely heavily upon cultivation-based methods. In fact, cultivation methods have improved considerably over the past several decades with advances in the scope and diversity of media components, control of environmental conditions, use of heterologous host cells, and use of growth-promoting factors (Mukamolova et al., 1998) A number of recently recognized and newly described microbial pathogens have been cultivated successfully in the laboratory, including spirochetes, rickettsia, actinomycetes, and a variety of viruses. Because the internal environmental conditions of the human body are viewed as more hospitable to life and are more easily replicated in the laboratory than are many external environmental conditions, we often assume that microbial cultivation efforts have been relatively successful. To be sure, there is no dearth of known, cultivated microbial pathogens.

On the other hand, we should not be so complacent about the completeness of our inventory of microbial pathogens, or about the sensitivity of detection methods for cultivation-amenable microorganisms. When traditional diagnostic methods are rigorously applied to syndromes of suspected infectious etiology, such as pneumonia, encephalitis, lymphocyte-predominant meningitis, pericarditis, acute diarrhea, and sepsis, only a minority of cases can be explained microbiologically. The majority of emerging infectious disease agents are zoonotic organisms, and as such are better adapted to nonhuman environmental conditions. In addition, a long list of chronic inflammatory diseases with features of infection remain poorly understood and inadequately explained from a microbiological perspective. Thus, it seems fair to speculate that the identification of pathogens in only seven bacterial divisions and the absence of any known pathogens within the domain Archaea may represent an imperfect understanding of the true diversity of microbes capable of causing human disease. Furthermore, it seems reasonable to conclude that current methods are lacking in sensitivity.

Molecular Approaches for Microbial Pathogen Detection and Identification: Seeking Signatures

In an effort to avoid reliance on cultivation and to establish alternative and complementary approaches, one might view the goal of microbial detection and pathogen discovery as identifying molecular signatures of infection. These signatures must be reliable in identifying a microorganism and in establishing the relationships between a previously uncharacterized organism and those that have previously been characterized. Molecular signa-



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