Microbe Hunting

DOI: 10.1128/MMBR.00007-10

Article Figures & Data

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FIG. 1.
Growth of the viral sequence database mapped to seminal discoveries and improvements in sequencing technology. EM, electron microscopy. (Courtesy of Omar Jabado, reproduced with permission.)
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FIG. 2.
Staged strategy for pathogen discovery and proof of causation. In the molecular era of pathogen discovery, culture and molecular methods are pursued in parallel until an agent is detected, isolated, and characterized. +, positive result; −, negative result. ssRNA, single-stranded RNA; dsRNA, double-stranded RNA.

TABLE 1.

Criteria for proof of causation

Criterion reported by:
Koch (1890)	Rivers (1936)	Fredericks and Relman (1996)
A microbe must be present in every case of a disease	A virus must be associated with a disease with a degree of regularity	Candidate sequences should be present in most cases of disease and at sites of disease pathology
It must not be found in association with any other disease	The association cannot be incidental	Few or no sequences should be present in host or tissue without disease
After isolation and propagation in pure culture, the microbe must be capable of inducing the same disease	Rivers predicted that methods for proving causal relationships would evolve with improvements in technology; at the time of his writing, he invoked seroconversion and experimental inoculations but acknowledged the limitations of both	Sequences should diminish in frequency with resolution of disease and increase with relapse
		Sequences should be present prior to the onset of disease