Medea and the Microtubule: Research Has Been Translational Ever Since Colchis
2009; Wiley; Volume: 23; Issue: 9 Linguagem: Inglês
10.1096/fj.09-0901ufm
ISSN1530-6860
Autores Tópico(s)Genomics and Rare Diseases
ResumoThe FASEB JournalVolume 23, Issue 9 p. 2791-2794 EditorialFree Access Medea and the Microtubule: Research Has Been Translational Ever Since Colchis First published: 01 September 2009 https://doi.org/10.1096/fj.09-0901ufmCitations: 1AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL To improve human health, scientific discoveries must be translated into practical applications. Such discoveries typically begin at “the bench” with basic research—in which scientists study disease at a molecular or cellular level—then progress to the clinical level, or the patient's “bedside.” [But] translational research is really a two-way street in which clinical researchers make novel observations about the nature and progression of disease that often stimulate basic investigations.NIH Roadmap for Medical Research, 2009 (2)[Medicine]: from the Indo-European root MAD or MED to reflect, to think, to meditate on ideas; In Greek µηδεα or medea meaning plans or counsels and subsequently schemes. This last meaning is seen in the Medea of Greek tragedy, Medea the Sorceress, the Schemer, the cunning.Thelma Charen, “The Etymology of Medicine,” 1951 (3)MEDEA: The best way is the most direct, to use the skills I have by nature and poison them, destroy them with my drugs. I know the drugs required for such things.CHORUS: Poor thing, the woman from Colchis, so unhappy…Euripides, Medea, 431BCE (4)Lord, do I have to listen to all this melodrama?Tyler Perry's Madea Goes to Jail (film), 2009 (5) Figure 1Open in figure viewer “Medea of Colchis borne to heaven after killing her children.” Attributed to the Policoro Painter (South Italy, active 420-380 BC). Lucanian Calyx-Krater, c. 400 BC. Red figure earthenware with added white, red, yellow, and brown Wash; H. 50.5 cm. The Cleveland Museum of Art, Leonard C. Hanna Jr., Fund 1991.1 Figure 2Open in figure viewer Metaphase arrest in experimental gastroenteritis induced by colchicine. Biaggio Pernice, 1889. Courtesy MBL/WHOI Library (1). TRANSLATING LITTLE SCIENCE INTO BIG SCIENCE These days, support for “translational research” is at its high water mark. Three years ago, the NIH Road Map for Medical Research modestly laid out a “bolder transforming vision for the 21st Century” as it launched its Clinical and Translational Science Awards (CTSA) Consortium (2). By the end of 2009, the national consortium will have funded 39 centers in 23 states, and by 2012, the NIH expects to establish 60 centers nationwide, with an annual funding commitment of $500 million. On the crest of this wave, Science will launch a new magazine in October of 2009 called Science Translational Medicine (6). The new journal will compete with such stalwarts as the American Journal of Translational Research [established January 2009 (7)] and the venerable Journal of Translational Medicine [established 2003 (8)]. A high tide lifts all boats: the long-running Journal of Clinical and Laboratory Medicine changed its moniker to Translational Medicine in 2006, the very year the NIH announced the CTSA (9). Sure enough, the flag officers are coming on board. The AAAS and Science,in conjunction with leaders of a score ofeminent societies and foundations, are launching the Clinical and Translational Science Network (CTSciNet) an on-line community that will combine a career-development Web portal for clinical and translational investigators with an “experimental evolving communications infrastructure (10).” What might account for this sudden burst of interest in translational research, a term traditionally applied to bringing science from the bench to the bedside? Many would argue that the last half century of individual discoveries in molecular and cell biology laid the groundwork: “little science.” Just a short decade ago, two legions of researchers, public and private, solved the double-crostic of the human genome: “big science” at its biggest. That achievement, and promises made at the time (e.g., “The Language in which God Created Life”) aroused high hopes among scientists and the public alike for a quick translation from divination into medical practice (11). As expected, our leaders have responded by forming the most worthy Clinical and Translational Science Awards Consortium: “big bucks.” However, we'd do well to wait a bit before expecting big news from the bedside. What the group assault on the human genome has already accomplished, and in record time, I'd argue, is to prompt the new “omic” revolution. ”Omics,” FISH and chips, and systems biology have produced armories of new tools that now include proteomics, lipidomics, metabonomics, nutrigenomics, and transcriptomics, und so weiter (big data) (12). With mastery acquired over these mountains of data by the revolution in information technology, the stage is set to plot abscissas of the bench against the ordinates of bedside with astounding results for both basic and clinical science (13). What about the other direction: bedside to bench? The flag officers who founded the Clinical and Translational Science Network correctly point out that [Translational research] is not one-way; the insights gained at the bedside, and from clinical and population-based studies, will spawn hypotheses, enabling scientists to probe the mechanisms of disease in new ways and ultimately enriching basic biology (10). Indeed, translations from the bedside to bench move more quickly than in the other direction. Many of us will remember that the first postmodern fashion in biomedical research was to label every possible discipline and every possible disease as “molecular.” Dozens of journals sprouted in the last half of the last century with titles ranging from Molecular Ecology to Clinical and Molecular Allergy. The molecular revolution in biomedicine traces directly to Linus Pauling's analysis of sickle cell anemia as a “molecular disease.” Herrick first described sickle cell anemia, with its characteristic deformity of red cells, in 1910; 39 years later Pauling looked at diffractions from those hemoglobin crystals in a Debye camera and molecular biology was on its way (14). A century after Herrick, Pauling's structural biology has moved from one laboratory feat to another, but we still have trouble treating sickle cell disease. Figure 3Open in figure viewer Colchicum autumnale. James Sowerby (1757–1822) for Woodville's Medical Botany (1792). Image courtesy Biodiversity Heritage Library, http://www.biodiversitylibrary.org. The pressure is on, therefore, to translate the new science of molecular structure, of gen- and other “omics,” into clinical discoveries, into treatment of disease. What our leaders want is translation, NOW, and more translation TOMORROW. Sadly, as Borges quipped “The original is always unfaithful to the translation (15).” MEDEA's PHARMAKON Translational research has been around longer than the NIH Road Map. Indeed, if “bench-to-bedside” means conjuring up a useful drug to bring to the clinic, the Greeks were there first. They passed it on in the myth of Medea who brought colchicine, her pharmakon (φαρµακοζ) from a workshop of potions to the bedside of kings. Then as now, a pharmakon had the power to poison or to cure. Medea was the daughter of Aeetes, ruler of Colchis, a kingdom on the Black Sea in western Georgia. She presided over an Asian cult of potions extracted from herbs at the foothills of the Caucusus. In his Medea, Seneca describes the practice: Her hand harvestswhatever earth creates in nesting springor when brittle frost balds trees beauty,forcing life inside itselfwith cold:grasses virulent with deadly flowersharmful juices squeezed from twisted roots (16) Among the most potent products squeezed from those twisted roots was the juice of Colchicum autumnale, the yellow crocus of Colchis. Both historians of medicine and of botany suggest that the legendary “golden fleece” sought by Jason and the Argonauts was nothing but a mass of golden crocus, an Asian pharmakon needed in Europe to treat podagra, the gout of kings. Podagra, the swollen great toe of the gouty, was well described by Hippocrates and extracts of the golden crocus were known as both poison and cure (17). On his quest to fetch the “golden fleece” from Colchis, Jason and the Argonauts set sail across the Aegean due east from Thessaly. They navigated the narrow straits of the Hellespont and Bosporos and braved the Black Sea in storm and tempest to land in Colchis. Once ashore, Jason was forced to perform a series of Herculean tasks set by King Aeetes as price for the fleece. But Medea and Jason had become lovers and the princess used her potions to overcome the warriors and dragons that stood guard over the fleece. Jason returned to Greece bearing gifts: not only the golden fleece but also Medea, the sorceress who knew its powers as pharmakon (18). But Medea's charms were lost in translation. To the Greeks, Medea remained a foreign “healer” from Colchis, an outsider, a schemer, a MADEA (forgive us, Tyler Perry). Soon, however, Medea has translated her basic pharmakon into regenerative miracles and marital havoc at royal bedsides from Iolcus to Corinth. Setting an example for our own decade, Jason deserted Medea to marry a younger princess, daughter of Creon, ruler of Corinth. In a fit of murderous revenge, Medea poisoned not only the princess and Creon, but also slew her own two children in cold blood (18). The sorceress went unpunished—she was saved by solar energy. Medea's grandfather, the sun god Helios, sent a chariot powered by winged dragons to transport Medea and the bodies of her two children away to distant Athens. New amatory and pharmaceutical adventures awaited her; eventually her progeny founded a new land, Media, home to the Medes and Persians. COLCHICLNE, TUBULIN, AND THE JAPANESE IRIS While the Greeks and Roman knew about the use of colchicine for gout and other disorders, the drug wasn't really available in pure form until the late nineteenth century, and problems with dosage, diagnoses, and toxicities abounded. Gout was the stuff of legend and history but colchicine remained a mystery: it stopped inflammation and the pain of acute gout, but had no effect on tophi, those ugly deposits around the joints. Moreover, it didn't seem to work until the patient developed terrible diarrhea (19). But thanks to the pioneering clinical discoveries of Alfred Garrod, Dyce Duckworth, and many others, a consensus was reached in the nineteenth century that colchicine was more or less specific for gout, that gout was caused by deposition of urate in joints and accumulation of these crystals resulted in tophi (20). By 1889, Duckwoth proposed that there was no more efficient agent than colchicines for acute gout, and instituted the dosage regimen that has remained intact until today: treat to the point of diarrhea, and then cut treatment to minimum (21). I might add that it was a century before a controlled clinical trial confirmed this method in 1987 (22)! It does make one wonder. The next contribution, also in 1889, came from an Italian pathologist, who was looking for an agent that might reliably produce gastroenteritis. Suitably enough, it was a Sicilian achievement. Pernice found that when therapeutic doses of colchicine were given to experimental animals, lesions were produced in the nuclei of gastric and intestinal cells that had a remarkable appearance under the microscope: the cells were arrested in metaphase (23). This translation to the pathologist's bench of a physician's observation (the first chap who wrote neatly of bedside colchicine was Alexander of Tralles in 580 CE) took over a millennium. More cause to wonder. Things moved faster then, but not too fast. An American botanist and a Belgian pathologist, independently and then jointly, rediscovered the effects of colchicine on mitosis in plant and animal cells almost half a century after Pernice (24, 25) The colchicine explosion was on—in botany, pathology, oncology, and finally, in cell biology. By 1945, it was clear that the drug had major effects on the mitotic spindle, that it could produce metaphase arrest and polyploidy, the latter a boon in horticulture (26). Indeed the Japanese irises in my garden, given to me by the late Currier McEwen, eminent rheumatologist and equally eminent iris fancier, owe their strength and deep color to tetraploidy. Twenty postwar years later the biological revolution took up colchicine in those citadels of pretranslational research, the University of Chicago and the Marine Biological Laboratory at Woods Hole. In 1967, Ed Taylor and Gary Borisy used tritiated colchicine to identify the target of colchicine action in dividing and nondividing cells. (27, 28) The protein they identified was the dimeric building block of microtubules, subsequently given the name “tubulin” by Mori (29). The role of tubulins in excitable and nonexcitable tissue is now documented in over 18,500 publications in PubMed. We know now that the traffic of intracellular cargo in every cell in our body is carried on the tracks of microtubules. It's a two-way process, like translational research (30). When colchicine binds to tubulin, it stops the assembly of microtubules and then their integrity. But what about colchicine's major clinical use in gout, and its major toxic effects on the gut? Both are dependent on the interference by colchicine on a vital, microtubule-dependent process. The nature of that process? As someone who has tussled with the problem with respect to gouty inflammation, I must admit that although every possible sort of mediator from lysosomal hydrolases, to eicosanoids, to Toll-like receptor signals and “inflammasomes” have been implicated, we have suggestive clues but no real culprit. (31, 32) And as for the gut? It seems that microtubules are needed to keep our intestinal cells pointed in the right direction, a function disrupted when some bacteria pretend they are colchicine (33). But for a real explanation, we're still at sea and in dire need of new translations, or better yet, wisdom. One hopes that someone in one of those 60 translational research centers will find the real answer; whether by “omics” or luck, the way everything else in the story of colchicine and microtubules popped up. Perhaps Helios will come along with that chariot! Gerald Weissmann Editor-in-Chief 1 The opinions expressed in editorials, essays, letters to the editor, and other articles comprising the Up Front section are those of the authors and do not necessarily reflect the opinions of FASEB or its constituent societies. The FASEB Journal welcomes all points of view and many voices. We look forward to hearing these in the form of op-ed pieces and/or letters from its readers addressed to [email protected]. REFERENCES 1Pernice, B. (1889) Sulla cariocinesi delle cellule epiteliale e dell endotelio dei vasi della mucosa dello stomato e dell' intestino, nello studio gastroenterite sperimentale (nell avvelenamento per colcico) Sicilia Med. 1, 265– 279 2 Re-engineering the Clinical Research Enterise (2009) NIH Roadmap for Research. http://nihroadmap.nih.gov/clinicalre-search/overview-translational.asp. Accessed July 2009 3Charen, T. (1951) The Etymology of Medicine Bull. Med. Libr. Assoc. 39, 216– 221. 4 Euripides (431BCE) Medea (D. A. Svarlien, trans., (2008) Hackett, Indianapolis. p. 18 5Scott, A. O. (February 21, (2009) Review of “Tyler Perry's Madea Goes to Jail” The New York Times. p. C1 6 Science Translational Medicine: Integrating Medicine and Science (2009) http://www.sciencemag.org/marketing/stm/. Accessed July 2009 7Lee, W.-H., Languino, L. R., Hung, M.-C., Dubinett, S. M., Iczkowski, K. A., and Wang, D. (2009) Editorial: The launch of the American Journal of Translational Research. Am. J. Transl. Res. 1, 1 8Marincola, M. J. (2003) Editorial: Translational Medicine: A two-way road J. Transl. Med. 1, 1 9Laurence, J. (2006) Editorial: Translating translational research. Translational Research 148, 1 10Andrews, N., Burris, J. E., Cech, T. R., Coller, B. S., Crowley, W. F.Jr., Gallin, E. K., Kelner, K. L., Kirch, D. G., Leshner, A. I., Morris, C. D., Nguyen, F. T., Oates, J., and Sung, N. S. (2009) Translational careers. Science 324, 85 11 Anon. (June 27, (2000) Genetic secret unlocked; Breakthrough could change health care. Daily Gleaner. Fredericton, NB, Canada. p. 1 12Dennis E. A. (2009) Lipidomics joins the omics evolution. Proc. Natl. Acad Sci. USA 106, 2089– 2090 13 FANTOM Consortium, Suzuki, H., Forrest, A. R., vanNimwegen, E., Daub, C. O., Balwierz, P. J., Irvine, K. M., Lassmann, T., Ravasi, T., Hasegawa, Y., deHoon, M. J., et al. (2009) The transcriptional network that controls growth arrest and differentiation in a human myeloid leukemia cell line. Nat. Genet. 41, 553– 562 14Pauling, L., Itano, H. A., Singer, S. J. and Wells, I. C. (1949) Sickle cell anemia, a molecular disease. Science 110, 543– 58 15Borges, J. L. (1943) quoted in Waisman, S. Borges and Translation: The Irreverence of the Periphery. Bucknell University Press, Lewisburg Pennsylvania. p. 113 16 Seneca (1st century BCE) Medea (F. Ahl, trans., (1986) Cornell University Press, Ithaca New York. p. 84 17Eigsti, O. J. and Dustin, P. (1955) Colchicine. Iowa State College Press, Ames, Iowa. p. 3, ff. 18Gayley, C. M., and Bulfinch, T. (1893) The Classic Myths in English Literature. Ginn and Company, Boston and New York. p. 244, ff. 19Porter, R. and Rousseau, G. S. (1998) Gout: The Patrician Malady. Yale University Press, New Haven 20Weissmann, G. (2007) Galileo's Gout. Bellevue Literary Press, New York. pp. 13, ff. 21Duckworth, D. (1889) A Treatise on Gout. Blakiston, Philadelphia. p. 348 22Ahern, M. J., Reid, C., Gordon, T. P., McCredie, M., Brooks, P. M., and Jones, M. (1987) Does colchicine work? The results of the first controlled study in acute gout. Aust. NZ. J. Med. 17, 301– 304 23Pernice, B. (1889) Sulla cariocinesi delle cellule epiteliale e dell endotelio dei vasi della mucosa dello stomato e dell' intestino, nello studio gastroenterite sperimentale (nell avvelenamento per colcico) Sicilia Med. 1, 265– 279 24Dustin, A. (1934) Contributions a l'etude des poisons caryoclastiques sur les tumeurs animals Bull.. Acad. Roy. Med. Belg. 11, 187– 502 25Eigsti, O. J. (1938) A Cytological Study of Colchicine Effects in the Induction of Polyploidy in Plants. Proc Natl Acad Sci USA. 24, 56– 63 26Levine, M. (1945) Colchicine and X-Rays in the Treatment of Plant and Animal Overgrowths. Botanical Review 11, 145– 180 27Borisy, G. G., Taylor, E. W. (1967) The mechanism of action of colchicine. Binding of colchicine-3H to cellular protein. J. Cell Biol. 34, 525– 533 28Borisy, G. G., and Taylor, E. W. (1967) The mechanism of action of colchicine. Colchicine binding to sea urchin eggs and the mitotic apparatus. J. Cell Biol. 34, 535– 548 29Mohri, H. (1968) Amino-acid composition of “Tubulin” constituting microtubules of sperm flagella. Nature 217, 1053– 1054 30Kulic, I. M., Brown, A. E., Kim, H., Kural, C., Blehm, B., Selvin, P. R., Nelson, P. C., and Gelfand, V. I. (2008) The role of microtubule movement in bidirectional organelle transport. Proc. Natl. Acad. Sci. USA 105, 10011– 10016 31Zurier, R. B., Hoffstein, S., and Weissmann, G. (1973) Mechanisms of lysosomal enzyme release from leucocytes. I. Effect of cyclic nucleotides and colchicine. J. Cell Biol. 58, 27– 41 32McCarty, D.J. (2008) Urate crystals, inflammation, and colchicine. Arthritis Rheum. 58, S20– 24 33Gill, R. K., Borthakur, A., Hodges, K., Turner, J. R., Clayburgh, D. R., Saksena, S., Zaheer, A., Ramaswamy, K., Hecht, G., Dudeja, P. K. (2007) Mechanism underlying inhibition of intestinal apical Cl/OH exchange following infection with enteropathogenic E. coli. J. Clin. Invest. 117, 428– 437 Citing Literature Volume23, Issue9September 2009Pages 2791-2794 FiguresReferencesRelatedInformation
Referência(s)