Batrachomyomachia: Frogs 1, Mice 0

A new field of inquiry is often opened by a simple question. ‘Why does a trait disappear in one generation only to resurface in the next?’ wonders a monk, and in doing so becomes the founder of genetics. ‘Why do giant tortoises that live on islands identical both in climate and physical features differ from one another to such an extent that locals can tell at one glance where a particular individual has come from?’ inquires a budding naturalist and hits upon the theory of natural selection. ‘Why was the milkmaid so sure that she could not contract smallpox after having already had cowpox?’ marvels a country physician and . . . well, we all know what that simple question led to. Then, however, as the discipline grows, increases in complexity, and ages, the art of asking simple questions is somehow lost, to be replaced by the art of asking very complex and highly sophisticated ones. Indeed, sometimes the questions are so sophisticated that the questioner alone knows what is being asked, and sometimes even he does not. Often researchers forget to ask questions altogether. Fortunately, in most fields of study there are a few stubborn individuals who refuse to swim with the tide, who ignore the trends, keep going their own way 1 and keep asking simple questions. In immunology, one example is Hans G. Boman. At the time when others were chasing Ir gene phantoms and playing checkers withH2 charts and batteries of congenic H2 recombinant mouse strains, Boman and his coworkers were harking at what then seemed to be a hopelessly dull topic using a totally inglorious model organism [1]. Cecropia? Who, besides a few dry-as-dust lepidopterologists, has ever heard of it? And the topic? Who cares how a moth that does not even have a proper vernacular name clears a bacterial infection? Obviously by some form of antibodies, or not? But now that Cecropiaand cecropins have made their entry into immunology textbooks [2] and the whole issue of nonanticipatory (innate) immune response in insects and other invertebrates has become fashionable, Boman has left it largely to the travelling salesmen to spread the word, and is again engrossed in another simple question: what controls the normal flora? What, indeed? If textbooks are to be trusted, there are some 3×10 microorganisms living on the surfaces, both outer and inner, of the human body, three times as many as there are cells in the body [3]. Because they normally do not cause disease, they are considered to be commensals, or, where there is evidence that their presence is beneficial to the host, even symbionts. It would, however, be naı ̈ve to assume that the mass of ante portasaliens refrains from hostilities voluntarily. It would be akin to a 5th century Roman citizen believing that the hordes of Visigoths under Alaric camped out around the city’s ramparts had only come to trade goods. After all, we know very well how some of the commensals and symbionts behave when the body’s immune system is compromised! We also know that at least some, but probably all, pathogens were once commensal. The reverse might also be true (just like some heads-of-state are former terrorists). All available evidence indicates that it takes very little o change a commensal into a pathogen and vice versa; often just one mutation suffices [4]. So, what controls the normal flora? The short answer is: we do not know. In fact, we know so little about the normal flora that it is almost embarrassing. We are largely ignorant of its composition, origin, ecology, population dynamics, phylogenetics, evolution, relationship to pathogens, and its interaction with the host’s immune systems. Only a few dozen taxa have been isolated and identified to the generic level [3] and even fewer are known at the species or strain levels 1 undoubtedly only a small fraction of the genetic variability of the entire flora. We probably know more about the composition of the microflora in the hot springs of the Yellowstone National Park than about the makeup of the beasts that live in our colons, and it is not because the normal flora is less accessible or more difficult to study. The Scand. J. Immunol. 49, 11–13, 1999