I started to take care of patients with inflammatory bowel diseases (IBD) in the late 1960s. At that time knowledge about the etiology of IBD and its therapy was quite limited. The commonly held belief at that time was that IBD is caused by an abnormal immunological reaction to luminal antigen(s). Most research funding went to attempts to investigate the possibility of immune dysfunction in Crohn’s disease. Many excellent immunologists concentrated on mucosal immune abnormalities but failed to recognize that such a tunnel vision might impede progress towards understanding the pathogenesis of IBD.

In 1984, I was approached by the parents of a son with Crohn’s disease who wanted to stimulate Crohn’s disease research. They had already spoken to several prominent leaders in IBD research and had asked for their ideas. They were disappointed by the paucity of new ideas regarding the causes and treatment of IBD; furthermore, they were uninterested in funding research along the accepted traditional lines but, rather, sought new ideas. I suspect that the family—knowing that I had no vested interest in the status quo and no dogmas that I would want to protect and perpetuate—decided that I might bring new ideas regarding both the etiology and the treatment of IBD. I explained to them that I did have clinical experience in the treatment of IBD but that my research up to that time was limited to the intestinal transport of lipids [1]. However, I indicated that I was willing to think about new directions in the research that would depart from the predominant theory of mucosal immunology and IBD. We decided to meet again after I had had a chance to consider the problem.

When I reviewed the literature back to the 1970s, I found two short studies reporting the possibility of increased intestinal permeability in patients with IBD [2, 3]. The reports were brief and not followed up on. At the time I was familiar with the work of Jared Diamond and Ernest Wright at the University of California, Los Angeles (UCLA) who had investigated the paracellular transport of water and electrolytes and its regulation by the intestinal tight junctions [4]. My area of work had been centered on lipid transport via cell membranes rather than tight junctions. Lipids, because of their solubility in the lipid cell membrane, are not absorbed to any appreciable extent through the tight junctions between enterocytes. On the other hand, water soluble compounds are absorbed to a significant extent through the aqueous environment of the tight junction between cells.

Basing my ideas on the two interesting and suggestive small studies from the early 1980s, I formulated a new research proposal that I presented to the family. I suggested that one area of research was the possibility that patients with Crohn’s disease might have a defect in the defensive barrier of the gut that would allow luminal antigens to penetrate the mucosa at an abnormal rate through the paracellular tight junctions and instigate an inflammatory process. I suggested to the family that the most direct and most conclusive way to investigate this possibility would be to study the hypothesis in patients and not in laboratory animals. If patients showed an increase in permeability to water-soluble markers the findings would indicate that the idea had merit. If not, then their funds and my efforts would be wasted. Since the parents were concerned about the possibility of an inherited mucosal permeability trait, I suggested that I would extend the initial studies to include both patients and their clinically healthy family members in order to examine whether the possible permeability defect was inherited. The donors agreed to my proposal.

I searched for a water-soluble marker that could be ingested orally, would not be metabolized, would be excreted, and could be measured in the urine of the patients in a relatively short period of time. I settled on the short-chain polyethylene glycol (PEG 400), which is nontoxic and not metabolized. Members of my laboratory team developed a high-pressure liquid chromatography system to measure PEG 400 in the urine, and we evaluated the system by ingesting the marker and measuring it in our own urine over different periods of time. Next, we partnered with Dr. Jerome Rotter and his human genetics research group at Cedars-Sinai Hospital who were studying the genetics of Crohn’s disease in families in the area. This allowed us to study the question in documented and evaluated patients with Crohn’s disease and their healthy relatives.

We applied to institutional study boards for approval, and, once approved, we spent many Saturdays with patients and their clinically healthy family members. We supervised the administration of the PEG 400 solutions, provided a standardized test meal, and supervised the timed urine collection.

To make a long story short, we were surprised to find a sizable group of patients and their clinically unaffected relatives with increased intestinal permeability to PEG 400. The findings were exciting because they showed a clear abnormality in the barrier property of the intestinal mucosa and, especially, because the same abnormality appeared in some of the clinically normal relatives [1].

Naively, we thought that this new finding of a barrier defect in patients and families with Crohn’s disease would be exciting and welcomed by journal reviewers and editors; however, the manuscript was rejected for publication by several leading gastroenterology journals. The study’s rejection was not because the reviewers had concerns about the design, methodology, or execution of the study but because they considered it of little relevance to the pathogenesis of IBD i.e., it was not in concert with the dominant dogma of the immunological causes of Crohn’s disease. One reviewer even suggested that we should develop an animal model in order to study the idea and validate it! Despite several rejections, we persisted in our efforts to publish the findings, which were finally published in a general internal medicine journal [1]. Since the original publication, many other investigators and clinicians have substantiated and amplified our findings and have delineated mechanistic changes that take place in the tight junctions of patients with IBD [5,6,7].

In the process of publishing the research, I learned that new findings and concepts that are not in concert with accepted dogma frequently meet resistance and rejection. One may think that valid methodologies and carefully documented trials that generate new data would be exciting to readers and could stimulate an examination of prevailing concepts. In fact, that is not the case. The medical scientific community is conservative, perhaps by necessity. It must guard against the premature introduction of new ideas and concepts. The management of patients requires caution, but such caution does inhibit medical advancements because, generally, we are more comfortable with time-honored beliefs and concepts. Openness to new ideas is a challenge that many of us are not willing to take. A paradigm shift requires openness to change. The acceptance of a new concept takes effort and a re-examination of one’s understanding and one’s ideas about any issue or belief. In medicine it requires multiple validations by other investigators before the medical community is finally willing to climb aboard. In the long run, however, the climb is worthwhile, rewarding, and beneficial to our patients and all of us.