The Nobel Pancreas: A Historical Perspective
2013; Elsevier BV; Volume: 144; Issue: 6 Linguagem: Inglês
10.1053/j.gastro.2012.10.056
ISSN1528-0012
Autores Tópico(s)Pancreatitis Pathology and Treatment
ResumoFor everyone interested in the pancreas, it is truly a noble organ. Known to the ancient Greeks, its name in Greek “pan kreas” translates as “all flesh.” Aristotle believed its function was to protect the great vessels and 4 centuries later Galen claimed it to be a cushion for the stomach.1Modlin I.M. Champaneria M.C. Chan A.C.K. et al.The history of the pancreas.in: Berger H.G. Warshaw A.L. Büchler M.W. The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery. 2nd ed. Blackwell Publishing Limited, Hoboken, NJ2008: 9-41Google Scholar The Renaissance anatomists, beginning with Vesalius, defined its structure with its ducts, first shown by Johann Wirsung in 1642, to empty into the intestine. Regnier de Graaf, of the Graafian follicle, was the first to study pancreatic secretion in 1664, using a goose quill inserted into the duct. In the 19th century, Claude Bernard in Paris, and others, showed the digestive capabilities of pancreatic juice for fat, carbohydrate, and protein.1Modlin I.M. Champaneria M.C. Chan A.C.K. et al.The history of the pancreas.in: Berger H.G. Warshaw A.L. Büchler M.W. The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery. 2nd ed. Blackwell Publishing Limited, Hoboken, NJ2008: 9-41Google Scholar, 2Howard J.M. Hess W. History of the Pancreas: Mysteries of a Hidden Organ. Kluwer Academic, New York2002Crossref Google Scholar Paul Langerhans, a medical student in Berlin, described the eponymous islets in 1869 and in 1889, Miring and Minkowski described experimental diabetes in the dog after pancreatectomy.3Bliss M. The Discovery of Insulin.25th Anniversary Edition. University of Chicago Press, Chicago2007Google Scholar In addition to understanding the anatomy and physiology of the exocrine pancreas, Hans Chiari had described the autodigestion of the pancreas that accompanies pancreatitis in 1896. By 1900, the histology and general understanding of the function of the pancreas was in place. The 20th century was to be occupied first with understanding the control of pancreatic secretion and then the understanding of specific cell types of the pancreas as molecular machines evolved to carry out specific functions. A timeline for this increase in understanding of the pancreas and its diseases is shown in Figure 1. More detailed coverage of the last 160 years is shown in Figure 2.Figure 1Depth of knowledge of the pancreas and pancreatic disease has accelerated during the last 150 years. Above the curved line are placed major discoveries and awarding of Nobel Prizes for work on or using the pancreas. Below the line are indicated the founding of organizations and journals associated with study of the pancreas: AGA, American Gastroenterological Association; APS, American Physiological Society; IAP, International Association of Pancreatology; NPS, National Pancreatic Societies (American, European, Japanese, etc). The Philosophical Transactions of the Royal Society, the first forerunner of today's scientific journals, was initiated in 1662 shortly after the founding of The Royal Society in London. Pancreas, the first journal devoted to the pancreas started in 1986; Pancreatology, published by the IAP began in 2001 (not shown). For lack of space, American organizations and journals are indicated.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 2Recent timeline of major events in understanding of pancreatic function (black) and pancreatic disease (red).View Large Image Figure ViewerDownload Hi-res image Download (PPT) In 1896, the Swedish inventor Alfred Nobel died, and in his will he left much of his fortune—earned in the manufacture of explosives, including dynamite, which he invented—to establish prizes that bear his name in different areas of knowledge to be chosen by different academies in Stockholm or Norway. One of these prizes in Physiology and Medicine and another in Chemistry will be discussed here. The first Nobel Prizes were awarded in 1901 and they have been awarded annually since then to one to three individuals in a specific area. In this Commentary, I will review the advances in scientific knowledge in which the pancreas led the way to the extent that it was recognized by the awarding of 5 Nobel Prizes for work that either related directly to products of the pancreas or used the pancreas as a cellular source to understand fundamental physiological and cell biological processes. I will also note some omissions and controversies. The early years of the 20th century were marked by understanding of the neural and hormonal control of the pancreas. One of the early giants of modern physiology was Ivan Petrovich Pavlov who, before studying the conditioned reflexes for which he is best known, studied the neural control of gastric and pancreatic secretion. Pavlov, working in St Petersburg, Russia, developed the first modern physiology laboratory with multiple staff who worked together as a team. They showed that psychic stimulation or putting food in the stomach led to secretion from the pancreas, which was collected via a pancreatic fistula.4Todes D.P. Pavlov's Physiology Factory: Experiment, Interpretation, Laboratory Enterprise. The Johns Hopkins University Press, Baltimore, MD2002Google Scholar Acid and fat were especially good stimulants and carbohydrate was not. His laboratory also identified enterokinase, the intestinal activator of trypsin, and described the cephalic phase of pancreatic secretion. Pavlov's work was first summarized in a series of lectures and then in a book published first in Russian and then in English in 1902 entitled, The Work of the Digestive Glands.5Pavlov I.P. The Work of the Digestive Glands A facsimile of the first English edition published in 1902. (First published in Russian in 1887). Oxford Historical Books, Abingdon, UK1994Google Scholar Pavlov's contribution was recognized when he received the Nobel Prize in 1904 “in recognition of his work on the physiology of digestion.” Meanwhile, another famous experiment was carried out by William Bayliss and Ernest Starling at University College in London, in which they showed that an extract of the intestinal mucosa, when injected into a dog with its pancreas completely denervated, led to copious secretion of pancreatic juice.6Bayliss W.M. Starling E.H. The mechanism of pancreatic secretion.J Physiol. 1902; 28: 325-353PubMed Scopus (710) Google Scholar This was, in fact, the first demonstration of a chemical messenger or “hormone,” a term coined by Starling in his Croonian Lecture of 1905 to the Royal College of Physicians. Thus was born the field of Endocrinology. Starling, probably the most famous physiologist not to win the Nobel Prize, also discovered “Starling's Law of the Heart” and described the physical forces regulating capillary fluid exchange. However, in his youth, he had fallen in love with German culture and was a vocal German supporter in the period just before WWI, which might have affected his chances at the prize.7Henderson J. A Life of Ernest Starling. Oxford University Press, Oxford2005Google Scholar The second Nobel Prize awarded for the study of the pancreas went to Frederic Banting and John Macleod in 1923 for the isolation of insulin.3Bliss M. The Discovery of Insulin.25th Anniversary Edition. University of Chicago Press, Chicago2007Google Scholar By the early 1900s, it was widely believed that the islets of Langerhans produced an internal secretion into the blood that regulated carbohydrate metabolism. A number of investigators around the world tried to make extracts of the pancreas to treat diabetes, but failed. Banting, a young physician in Toronto without research training, was aware of work showing that ligation of the pancreatic duct caused the acinar cells to atrophy, and he realized that removing their proteolytic enzymes would help to isolate intact insulin. In 1921, Banting discussed his approach with Macleod who, as Professor and Chair of Physiology and a noted scientist with knowledge of the area of research, provided him with facilities and the assistance of a medical student, Charles Best. Banting and Best first showed that pancreatic extract would cure the diabetes of a pancreatectomized dog. They then found that they could extract insulin from normal beef pancreas and, with the assistance of Bertram Collip, a biochemist on sabbatical leave in Toronto, they purified insulin. In January 1922, insulin was given to a 14-year-old boy with diabetes, resulting in stabilization of blood glucose, an event that reverberated worldwide. In 1923, the Nobel Prize was awarded to Banting and Macleod, leading to a violent controversy over who should have been awarded the prize, with Banting angry that Macleod shared the prize and Best was not recognized, while Macleod felt that Collip should have been included.3Bliss M. The Discovery of Insulin.25th Anniversary Edition. University of Chicago Press, Chicago2007Google Scholar Meanwhile, Eli Lilly began large-scale production of porcine insulin (Iletin), which was widely available in North America by the middle of 1923, surely one of the fastest tracks from bench to bedside. By the end of 1923, insulin was also being produced in England and Denmark. Other later Nobel Prizes were awarded to Frederick Sanger (1958), who determined the molecular structure of the insulin molecule, and Rosalyn Yalow, for the radioimmunoassay of insulin (1977), the first radioimmunoassay. The next time the exocrine pancreas visited Stockholm was in 1946, when John H. Northrup shared the Nobel Prize in Chemistry for the discovery that enzymes were proteins and could be crystallized.8Northrop J.H. The preparation of pure enzymes and virus proteins Nobel lecture, December 12, 1946.in: Nobel Lectures, Chemistry 1942−1962. Elsevier Publishing Company, Amsterdam1964Google Scholar Northrup, working at the Rockefeller Institute, initially crystallized pepsin from gastric juice. As part of a long and productive collaboration with Moses Kunitz, they crystallized trypsin and trypsinogen, discovered and crystallized chymotrypsinogen as a contaminant in trypsin, and Kunitz went on to crystallize ribonuclease, deoxyribonuclease, and the trypsin inhibitor from pancreas and soy beans. They recognized that trypsin inhibitor prevents premature activation of trypsin, and mutations in the pancreatic trypsin inhibitor are now known as causes of hereditary pancreatitis.9Whitcomb D.C. Genetic aspects of pancreatitis.Annu Rev Med. 2010; 61: 413-424Crossref PubMed Scopus (140) Google Scholar As the head of the Rockefeller Laboratory, Northrop received the Nobel Prize, but Kunitz was later elected to the National Academy of Science and is much better known to pancreatologists of today for being associated primarily with trypsin inhibitor.10Herriot R.M. Moses Kunitz 1887−1978 A Biographical Memoir. National Academy of Sciences, Washington, DC1989Google Scholar In addition, deoxyribonuclease and ribonuclease A enzymes are referred to as Kunitz units. Beginning in the 1940s, the pancreas was overtaken by, and helped shape the emerging discipline of, cell biology. The new techniques of ultracentrifugation and electron microscopy allowed detailed understanding of cell function. Because the pancreas is primarily made up of one cell type, the acinar cell (which makes up >90% of the pancreas), it and the liver were favorite organs to study before the advent of cell culture. George E. Palade, a Romanian immigrant working at the Rockefeller Institute in New York City with Keith Porter, provided the first ultrastructural descriptions of mitochondria, endoplasmic reticulum (ER), and ribosomes. In 1955, Palade published a definitive paper on the guinea pig pancreas ER.11Palade G.E. The endoplasmic reticulum.J Biophys Biochem Cytol. 1956; 2: 85-98Crossref PubMed Scopus (121) Google Scholar At this time, he began a fruitful collaboration with Phillip Siekewitz to carry out combined cell fractionation and ultrastructural evaluation to define the secretory process. This led to the characterization of zymogen granules, and the discovery that newly synthesized secretory protein was within the lumen of the rough endoplasmic reticulum (RER). With Lucien Caro in vivo, and then in more detail in vitro with Jim Jamieson, electron microscopic autoradiography of guinea pig pancreas was used to define the secretory pathway from RER to Golgi to zymogen granules followed by exocytosis.12Caro L.G. Palade G.E. Protein synthesis, storage and discharge in the pancreatic exocrine cell An autoradiographic study.J. Cell Biol. 1964; 20: 473-495Crossref PubMed Scopus (369) Google Scholar, 13Jamieson J.D. Palade G.E. Intracellular transport of secretory proteins in the pancreatic acinar cell I. Role of the peripheral elements of the Golgi complex.J Cell Biol. 1967; 34: 577-596Crossref PubMed Scopus (520) Google Scholar George Palade was awarded the Nobel Prize in 1974,14Palade G. Intracellular aspects of protein synthesis.Science. 1975; 189: 347-358Crossref PubMed Scopus (2346) Google Scholar along with Albert Claude and Christian De Duve, “for their discoveries concerning the structural and functional organization of the cell.” In 1973, Palade and Jamieson moved to Yale to establish a Department of Cell Biology, where the two trained and influenced a number of today's pancreatologists. At this point, the overall secretory pathway was known but its molecular machinery was not. The last Nobel Prize concerning the pancreas is somewhat tangential, but the experiments could not have been performed without it. Günter Blobel born in Eastern Germany, now Poland, joined the Palade group at Rockefeller as a postdoctoral fellow in 1967 after receiving his PhD at Wisconsin. Blobel investigated the question of how messenger RNA species coding for secretory proteins associate with the RER and how the nascent proteins end up in the ER lumen. In 1971, he and his collaborator, David Sabbatini, put forward the signal hypothesis that all nascent secretory proteins possess an amino terminal sequence element that binds the ribosome to the ER membrane.15Blobel G. Sabatini D.D. Ribosome-membrane interaction in eukaryotic cells.Biomembranes. 1971; 2: 193-195Crossref Google Scholar To test the hypothesis, they took the RER system apart to obtain individual components, with the goal of reconstituting translation. The recombination failed until they tried using ER membrane from canine pancreas, which worked because of its low amount of ribonuclease. Blobel and Bernard Dobberstein showed that a secretory protein, immunoglobulin light chain, was processed to a smaller form as it entered the ER lumen. Later, Blobel's laboratory defined the signal recognition particle, the signal recognition particle receptor, the signal peptidase, and the translocon, a water-filled pore through which the nascent protein is extruded. Many of these were multiple protein complexes. In 1999, Günter Blobel was awarded the Nobel prize for defining how proteins are targeted within the cell.16Blobel G. Protein targeting (Nobel lecture).Chembiochemistry. 2000; 1: 86-102Crossref PubMed Scopus (110) Google Scholar As the pancreas is one of the most active protein-synthesizing organs in the body, Blobel's findings started our understanding of the acinar cell as a molecular machine. The final recent-past area that is arguably worthy of a Nobel Prize, and where the pancreas led the way, is the understanding of phosphoinositide turnover and the mobilization of intracellular Ca2+. In 1953, Hokin and Hokin17Hokin M.R. Hokin L.E. Enzyme secretion and the incorporation of P32 into phospholipides of pancreas slices.J Biol Chem. 1953; 203: 967-977Abstract Full Text PDF PubMed Google Scholar showed that secretagogues stimulated the incorporation of 32P into phospholipids using slices of pigeon pancreas. They later showed that the phospholipid involved was phosphoinositol. In 1975, Robert Michel published a seminal review relating phosphoinositol turnover to cell activation and Ca2+ signaling.18Michell R.H. Inositol phospholipids and cell surface receptor function.Biochim Biophys Acta. 1975; 415: 81-147Crossref PubMed Scopus (1662) Google Scholar Several groups in the early 1980s, including those of James Putney and Michael Berridge, showed that the primary event seemed to be the breakdown of the polyphosphoinositide, phosphatidyl-4,5-bisphosphate, and in 1983, Streb et al19Streb H. Irvine R.F. Berridge M.J. et al.Release of Ca2+ from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol-1,4,5-trisphosphate.Nature. 1983; 306: 67-69Crossref PubMed Scopus (1796) Google Scholar reported in Nature that one of the breakdown products, inositol trisphosphate, would release stored intracellular Ca2+ from permeabilized pancreatic acini. Later, this was shown to involve Ca2+ release from the ER through an inositol trisphosphate receptor, which acts as a gated Ca2+channel. This cellular control system, largely worked out with pancreatic acinar cells, is now known to apply to almost all cells in the body. Are there other areas of pancreatology that could move from noble to Nobel? The cloning of the cystic fibrosis gene and the characterization of its protein, cystic fibrosis transmembrane conductance regulator, as a gated anion channel could be one.20Riordan J.R. Rommens J.M. Kerem B. et al.Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.Science. 1989; 8: 1066-1073Crossref Scopus (5963) Google Scholar How about the understanding of, or better yet the cure for, pancreatic cancer?21Hingorani S.R. Petricoin E.F. Maitra A. et al.Preinvasive and invasive ductal pancreatic cancer and its early detection in mouse.Cancer Cell. 2003; 4: 437-450Abstract Full Text Full Text PDF PubMed Scopus (1818) Google Scholar Only time will tell. But I for one will be listening to my morning radio in October for each year's announcements. In addition, some of these recent subjects are discussed in this issue of gastroenterology.
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