About the size and shape of a loosely coiled _ or rather,bunched _ length of garden hose, a human adult's smallintestine nestles in the abdomen, just south of the liverand stomach.

Between stomach and large intestine, this gut stretchessome 25 feet in length, by a bit over an inch in diameter.But if one were to open up a typical small intestine andspread out its total absorptive area, that convolutedsurface would neatly cover a standard football gridiron _5,300 square yards.

This multiplier effect depends on an internal intestinallining of innumerable tiny projections, called villi. Theirdensely packed expanse resembles a freshly mowed lawn,with each blade of grass a villus. Villi absorb nutrientsfrom digested food. An average villus is less than amillimeter high, and slender in proportion.

A single layer of epithelial cells paves the entire intricatetopography.

Connecting every two of these "blades" at their roots is asmall depression or dimple called a crypt. Here is howJeffrey Gordon, head of molecular biology andpharmacology at Washington University, St. Louis, setsthe stage for the intestine's crypts and villi:

"Crypts are the proliferative compartment of theintestine," Gordon told BioWorld Today. "Their job is asan engine, continuously producing new cells that migrateup along the length of the villus to its tip, and then sloughoff."

Gordon continued: "Every human re-lines his or herintestine with a new monolayer of cells approximatelyonce a week. Cells that acquire any genetic mutation orother damage from the harsh lumenal environment of thegut are simply discarded."

With its vast surface area thus exposed, the intestineneeds all the protection it can get. One of its commonest,yet least understood, nemeses is Crohn's disease, a formof inflammatory bowel disease (IBD).

Crohn's grim symptomatology sometimes strikes itsvictim with a sudden sharp belly pang, mimickingappendicitis. Then, its symptoms _ diarrhea, oftenbloody, plus fever, abdominal cramps, weight loss _persist and intensify, or wax and wane, as the years go by.

Ultimate Therapy: Snipping Away The Gut

Eventually, ulcers punch holes in the intestinal wall, andsometimes fuse two loops of gut into a blind-alley fistula.At such a point, the only remedy is surgery to remove theaffected length. Such excisions must often be repeateduntil only a stump of intestine remains, providing littleresidual digestive function.

Crohn's disease, and its equally dire colonic counterpart,ulcerative colitis, together constitute IBD, which afflictsone in 1,000 men and women in the U.S. alone.

Gastroenterologist Burrill Crohn of New York's Mt.Sinai Hospital, first described his eponymic disease in1932. From that day to this, Crohn's disease and IBDremain "of unknown etiology." Gordon aims to put atleast a dent in that wall of ignorance.

His paper in a recent issue of Science, dated Nov. 17,1995, introduces a pair of transgenic mouse strainsuniquely qualified to winkle out the molecular andcellular mechanisms of IBD, and the colon cancer thatusually follows. Its title: "Inflammatory bowel diseaseand adenomas in mice expressing a dominant negative N-cadherin."

Gordon explained: "We asked a very fundamentalquestion of the cadherin molecules, which function toglue intestinal epithelial cells together. We wanted todecipher their role in cell-to-cell contacts andinteractions."

He and his co-author, Michelle Hermiston, "insertedgenetically programmed embryonic stem cells intonormal mouse embryos," Gordon explained, "which werethus born chimeric. Their intestines contained apatchwork of normal and abnormal epithelium. The latterlacked functional cadherins only from their villusepithelial cells.

"The second type of chimeric mouse we created," Gordoncontinued, "had patches with cadherin defects in theircrypts as well as their villi."

He continued: "When we suppressed cadherin functiononly in the villus cells, the major and unexpected resultwas a disruption of cell-to-cell contacts. Cells migratedmore rapidly, didn't differentiate properly, and diedearlier than they normally would."

But the main surprise was that, "despite that quitesignificant disruption in contact between cells, there wasno inflammatory response; no disease effect."

However, when the team directed the mutant cadherins tocrypts as well as villi, "those animals developed thepathological changes of inflammatory bowel disease, withthe sort of alterations that you see in Crohn's disease."

Tracking Crohn's To Villus-Crypt Interaction

Thus, Gordon observed, "we uncovered a previouslyunappreciated difference in immuno-responsiveness incrypts as opposed to villi."

He interprets this to mean that when "perfectly normal _e.g., bacterial _ antigens penetrate through the cryptepithelium into the sacred space beneath _ in the senseof something that shouldn't be violated _ this generatesa very robust immune response." Gordon hypothesizesthat such illicit entry signals a burglar alarm to theimmune system. Ergo, inflammation; ergo, disease.

As for the chimeric animals' experience with intestinaltumors, "When we disrupted cadherin function in thevillus, there was no change in cell proliferation ordivision. Those cells remained in a non-dividing state,and those animals never went on to develop cancer."

But when disruption reached the gut's proliferativeengine, namely, the crypts, "some animals within threeweeks after birth, and most by 19 months, went on todevelop cancer."

Gastroenterologist Daniel Podolsky directs a NationalInstitutes of Health-funded center at MassachusettsGeneral Hospital, in Boston, for study of IBD's basicmechanisms. Asked whether he would have a use for anyof Gordon's transgenic mice, Podolsky told BioWorldToday, "If Jeff will send them here, I think we'd be quiteglad to pursue our interest in a lot of things with thosepowerful new models of his."

Podolsky finds those St. Louis mice "distinctive, in thatmany of their features parallel the kind of chronicintestinal inflammation we see in man, particularly inCrohn's disease. The question will be of course," heobserved, "whether his model would be powerful fordefining better therapeutic intervention, and _ at leastconceptually _ to test new putative therapeutic agents."n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.