A Scientific Koan
2003; Elsevier BV; Volume: 123; Issue: 6 Linguagem: Inglês
10.1378/chest.123.6.1792
ISSN1931-3543
Autores Tópico(s)Cystic Fibrosis Research Advances
ResumoIn the Zen Buddhist tradition, a koan is a “Zen presentation in the form of a Zen challenge.”1DeMartino R. On Zen communication. Communication 8(1). Cited in: App, U. 1994. Master Yunmen: from the record of the Chan master “gate of the clouds.” 1983, 53Google ScholarCleary2Cleary T Instant Zen: waking up in the present. North Atlantic Books, Berkeley, CA1994Google Scholarhas described the koan as follows: “These stories and sayings contain patterns, like blueprints, for various inner exercises in attention, mental posture, and higher perception, summarized in extremely brief vignettes.” Among the most famous of the koans is the teaching to reflect on the sound of a single hand clapping. In commenting on this koan, Yamamba is quoted as saying: the echo of the completely empty valley bears tidings heard from the soundless sound. This is something that can by no means be heard with the ear. If conceptions and discriminations are not mixed within it … [and] you proceed straightforwardly without interruption in the study of this koan, you will suddenly pluck out the karmic root of birth and death and break down the cave of ignorance3Yabukoji..in: Yampolsky PB The Zen master Hakuin: selected writings. Columbia University Press, New York, NY1971: 164Google Scholar. I define the scientific koan as a question that may superficially appear to be quite simple but deeper reflection on the question leads to greater insight. One such scientific koan that has engaged my research laboratory for many years is, “What causes cystic fibrosis (CF)?” To the medical student or others who have not reached enlightenment, the answer is simple. Defects in the CF transmembrane ion regulator (CFTR) protein lead to abnormal chloride transport, and the resulting epithelial dysfunction produces the many manifestations of this disease. It may be apparent how a defect in ion transport can lead to abnormally salty sweat, one of the principal manifestations of CF. However, in the 13 years since CFTR was first described,4Kerem B Rommens JM Buchanan JA et al.Identification of the cystic fibrosis gene: genetic analysis.Science. 1989; 245: 1073-1080Crossref PubMed Scopus (3140) Google Scholar5Riordan JR Rommens JM Kerem B et al.Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.Science. 1989; 245: 1066-1073Crossref PubMed Scopus (5811) Google Scholarit remains mysterious how an ion-channel defect can produce chronic Pseudomonas aeruginosa infection leading to tracheobronchitis and relentless bronchiectasis, exocrine pancreatic insufficiency and fat malabsorption, or even agenesis of the vas deferens resulting in male infertility.6Wine JJ Cystic fibrosis: how do CFTR mutations cause cystic fibrosis?.Curr Biol. 1995; 5: 1357-1359Abstract Full Text Full Text PDF PubMed Scopus (17) Google ScholarConcentrating on this challenge, investigators have learned that the CFTR is more than just a chloride channel and can directly regulate other cellular processes such as the epithelial sodium channel,7Reddy MM Light MJ Quinton PM Activation of the epithelial Na+ channel (ENaC) requires CFTR Cl-channel function.Nature. 1999; 402: 301-304Crossref PubMed Scopus (199) Google Scholarand may indirectly affect a variety of intracellular processes as well.8Barasch J Kiss B Prince A et al.Defective acidification of intracellular organelles in cystic fibrosis.Nature. 1991; 352: 70-73Crossref PubMed Scopus (418) Google ScholarCFTR is a large and complex channel, so it is not surprising that it would have diverse functions. The link between these functions of CFTR and CF disease remains a matter of speculation and debate. In this issue of CHEST (see page 2130) Dr. Joanne Tobacman presents the hypothesis that CFTR may regulate the metabolism of sulfatase enzymes, specifically arylsulfatase B (N-acetylgalactosamine 4-sulfate). Diminished activity of arylsulfatase B has been documented in lymphoid cell lines from patients with CF compared with normal control subjects, and increased concentrations of sulfated glycosaminoglycans have been demonstrated in CF airway secretions. Dr. Tobacman suggests that this may be responsible for persistent infection with Pseudomonas, a sulfatase-producing organism. She also notes that the lysosomal storage disease, Maroteaux-Lamy syndrome, (MLS) which is due to severe deficiency of arylsulfatase B, has been associated with growth failure and lung disease. Dr. Tobacman further hypothesizes that patients with CF have infrequent infection by tuberculosis because this organism lacks sulfatase activity. As interesting as this hypothesis is, before we are deafened by the thunderous applause of a sea of solitary hands, there are some important points to consider. Persons with CF have almost none of the manifestations of MLS, and patients with MLS show none of the clinical manifestations of CF. Although patients with MLS have restrictive airways disease due to extensive deposition of unmetabolized substrate, they do not acquire bronchiectasis, nor do they have chronic Pseudomonas infection. Although MLS patients have growth failure, it is due to poor energy intake and use rather than pancreatic insufficiency, which is the main cause of growth failure in patients with CF. Patients with MLS do not have abnormal sweat test results, and patients with CF do not have the extensive bone abnormalities of MLS. Although it is plausible to assume that the CF heterozygote advantage is resistance to an infection such as tuberculosis that may kill you before the age of reproduction, data suggest that the CF heterozygote advantage is probably resistance to secretory diarrhea, especially that due to cholera.9Gabriel SE Brigman KN Koller BH et al.Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model.Science. 1994; 266: 107-109Crossref PubMed Scopus (367) Google ScholarTuberculosis resistance has not been documented in patients with CF or in CF carriers, although resistance to tuberculosis has been postulated as being a heterozygote advantage in Tay-Sachs disease.10Spyropoulos B Tay-Sachs carriers and tuberculosis resistance.Nature. 1988; 331: 666Crossref PubMed Scopus (14) Google Scholar Readers of CHEST are accustomed to seeing well-written articles describing the results of hypotheses-driven research. Often these results have a direct impact on patient care. Less commonly, we publish articles such as this that can better be described as a “research-driven hypotheses.” Medical hypothesis, when well presented, challenge existing dogma and force us to examine what we know and what we think we know. In speaking of the Korean Zen tradition, Batchelor11Batchelor S Introduction to the Korean Zen tradition.in: Sunim K Way of Korean Zen. Weatherhill, New York, NY1985: 3-56Google Scholarwrites that “the Korean term hwadu usually refers to the particular question itself as well as the state of mind to be cultivated through concentrating on the question … the term kwadu is also used as a virtual synonym for the Japanese term koan.” Most of us would agree that the contemplation of a scientific koan can challenge what we think and what we believe. This can be of great value to us all every now and Zen.
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