Tuesday, January 26, 2016


Whipple disease, previously a disease of unknown etiology, is characterized by organ inflitratons by foamy macrophages (i.e., scavenger cells that "eat" bacteria and debris). The organ most often compromised is the small intestine, where infiltration of infected macrophages in the lamina propria (i.e., a strip of connective tissue subjacent to the epithelial lining of the small intestine) causes malabsorption. Whipple disease is rare. It occurs most often in farmers and gardeners who work with soil.

Whipple disease was first described in 1907, but its cause was unknown until 1992, when researchers isolated and amplified, from Whipple disease tissues, a 16s ribosomal RNA sequence that could only have a bacterial origin (Relman, 1992). Based on molecular features of the ribosomal RNA molecule, the researchers assigned it to Class Cellulomonadacea, and named the species Tropheryma whipplei, after the man who first described the disease, George Hoyt Whipple.

Particularly noteworthy, in the case of Whipple disease, is that Koch's postulates were not satisfied.

Koch's postulates are a set of observations and experimental requirements proposed by Heinrich Hermann Robert Koch in the late 1800s, intended to prove that a particular organism causes a particular infectious disease. For the experimentalist, the most important of the Koch's postulates require the extraction of the organism from a lesion (i.e., from diseased, infected tissue), the isolation and culture of the organism in the laboratory, and the consistent reproduction of the lesion in an animal injected with the organism. In the case of Whipple disease, the bacterial cause was determined without benefit of isolation or culture. The consistent extraction from Whipple disease tissue of a particular molecule, characteristic of a particular species of bacteria, was deemed sufficient to establish the infectious origin of the disease.

If it were possible to isolate and culture T. whipplei, it is highly unlikely that the disease could be experimentally transmitted to animals or humans; hence, another opportunity to satisfy Koch's postulates would fail. How so? As a general rule, bacteria in the human body are eaten by macrophages, wherein they are degraded. In the case of Tropheryma whipplei, only a small population of susceptible individuals lack the ability to destroy T. whipplei organisms. In rare, susceptible individuals, the organisms multiply within macrophages. When organisms are released from dying macrophages, additional macrophages arrive to feed, but this only results in the local accumulation of macrophages bloated by bacteria. Whipple disease is a good example of a disease caused by an organism but dependent on a genetic predisposition, expressed as a defect in innate immunity, specifically a reduction of macrophages expressing CD11b (also known as macrophage-1 antigen)

Aside from our inability to culture and extract the T. whipplei organism, Whipple disease cannot be consistently reproduced in humans because the T. whipplei organism can only infect and grow in a small portion of the human population. In short, T. Whipplei fails to satisfy Koch's postulates. As we learn more and more about the complexity of disease causation, formerly useful paradigms, such as Koch's postulates, seem inadequate. When we encounter rare diseases of infectious cause, we might expect to find that the pathogenesis of disease (i.e., the biological steps that lead to a clinical phenotype) may require several independent causal events to occur in sequence. In the case of Whipple disease, the infected individual must be exposed to a soil organism, limiting the disease to farmers and gardeners. The organism, residing in the soil, must be ingested, perhaps by the inhalation of dust. The organism must evade degradation by gut macrophages, limiting disease to individuals with a specific type of defect in cell-mediated immunity, and the individual must have disease that is sufficiently active to produce clinical symptoms.

It has been proposed that Koch's postulates be updated to accommodate modern molecular techniques, and to adjust for the complex ways that organisms interact with humans. The very meaning of biological causation has changed as we learn more and more about disease. We now know that there are many instances wherein the infectious agent cannot account for all of the cellular processes that culminate in disease (Inglis, 2007).

Relman DA, Schmidt TM, MacDermott RP, Falkow S. Identification of the uncultured bacillus of Whipple's disease. N Engl J Med 327:293-301, 1992.
Inglis TJ. Principia aetiologica: taking causality beyond Koch's postulates. J Med Microbiol 56:1419-1422, 2007.

- Jules Berman (copyrighted material)

key words: precision medicine, rare disease, whipple's disease, infectious disease, pathogens, jules j berman