Introduction to the "paradigm shifts in perspective" series.

The history of human knowledge has so uninterrupt-edly shown that to collateral, or incidental, or acci-dental events we are indebted for the most numerousand most valuable discoveries, that it has at lengthbecome necessary, in any prospective view ofimprovement, to make not only large, but the largestallowances for inventions that shall arise by chance,and quite out of the range of ordinary expectation.—Edgar Allan Poe, The Mystery of Marie Rogeˆt,1842These words, voiced by Auguste Dupin, a ﬁctional amateursleuth, contain an inalienable truth regarding the nature ofdiscovery. In science, the truly major advances, whichsubstantially change the way we think, termed ‘‘paradigmshifts’’ [1], often arise from the most unexpected quartersby individuals not considered to be in the mainstream ofinvestigators associated with a disease or observation. Withthis issue, Digestive Diseases and Sciences introduces anew series of articles entitled ‘‘Paradigm Shifts inPerspective’’ which is aimed at highlighting scientiﬁcﬁndings that have had a major impact on the ﬁeld ofgastroenterology. One of the motivations for creating thisseries is to increase the appreciation for ‘‘small’’ science,driven mostly by intellectual curiosity informed by a desireto understand disease pathogenesis, the principal well-spring for these advances. We plan to highlight advancesthat were initially under-appreciated, scorned, or evenforgotten, only to resurface or gain acceptance as the‘‘game changers’’ of gastroenterology. Since it can takedecades for the full import of a discovery to manifest, mostof the articles highlighted will be from the 1980s at thelatest.The ﬁrst of these articles is by Daniel Hollander, whowrites of his remarkable 1986 discovery in which hereports increased intestinal permeability in unaffected rel-atives of Crohn’s patients [2]. Although the familial natureof inﬂammatory bowel disease had been documented fordecades previous, few disease biomarkers that would pro-vide clues regarding its etiopathogenesis existed. Further-more, at that time the concept of intestinal permeability asa static, intrinsic property of epithelia was widely held.Lastly, the concept that increased intestinal permeabilitycould predispose to disease was virtually unknown.The publication of Dr. Hollander’s paper in 1986 markedan important year for the understanding of the nature ofintercellular junctions, with the publication of the cloning ofone of the ﬁrst junctional proteins, zonula occludens [ZO]-1.This ﬁnding, along with Dr. Hollander’s, marked the start ofthe current understanding of intercellular junctions as com-plex, dynamically regulated multiprotein structures, whichhave strong implications for disease pathogenesis. Althoughinterventions have not yet targeted permeability, the obser-vation that increased permeability could be a cause and notthe effect of mucosal inﬂammation and injury changed theway we thought about IBD speciﬁcally and about mucosalinjury in general. That junctional permeability could beunder genetic control, as Dr. Hollander ﬁrst reported, was arevolutionary ﬁnding, which helped ignite the current wideinterest in the structure and function of intercellular junc-tions. Indeed, 20 years after its publication, several groupsreportedthatincreasedintestinalpermeabilitywaspresentinrelatives of patients with familial Crohn’s disease who borespeciﬁcmutationsinthenucleotide-bindingoligomerizationdomain-containing protein [NOD]2/caspase recruitment