History

GUT HORMONE/REGPEP SYMPOSIA
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A symposium on Gastrointestinal Hormones was held at the University of Texas Medical Branch, Galveston, Texas, on 9-12 October 1974. 41 scientists from 10 countries presented papers.

Front row: Makhlouf, Tract, Larsson, Grossman, Gregory, Thompson, Bodansvky, Chey, McGuigan, Cohen, Andersson.

Second row: Gardner, Solcia, Rayford, Adelson, Kelly, Lambert, Johnson, Go, Hansky, Erspamer, Boden.

Third row: Said, Debas, Unger, Creutzfeldt, Konturek, Barrowman, Jacobson, Becker, Schofield, Dockray, Straus, Meyer, Galardy, Brown, Olbe, Bloom, Rehfeld. Not present: Yalow.

Viktor Mutt is probably the scientist who has single-handedly contributed the most to the development of gut endocrinology.

Viktor Mutt was born on December 29, 1923, in Tartu, the old Estonian university town. He spent ten years in New York between the world wars, where his father was consul-general for the Democratic Republic Estonia.

In 1943, after his return to Estonia, Viktor entered medical school. To avoid forced military service in the Soviet army, he fled, under dramatic circumstances, to Finland, worked illegally on a Finnish farm for nearly a year, and, eventually, at the end of World War II, he came to Stockholm where he obtained a job as technical assistant at the laboratory of Erik Jorpes, professor of medical biochemistry at the Karolinska Instituttet.

For the rest of his life, Viktor Mutt stayed at this laboratory. After passing the Swedish highschool exam, he joined the medical school at Karolinska, became bachelor of medicine, and in 1959 he defended his thesis on the purification of secretin. In 1960 he became docent, in 1962 research fellow, and in 1970 associate professor and head of the laboratory. Eventually, in 1979, he obtained a full professorship in biochemistry in Stockholm. After his retirement in 1989, Viktor continued his research until the very day of his death on September 9, 1998.

Viktor devoted his life to purification and identification of hormonal peptides from the gut, initially together with Jorpes, later with a number of younger scientists from Sweden (Birgitta Werner (his wife), Staffan Magnusson, Hans Jörnvall, Åke Rökaeus) and from the rest of the world (Joel Adelson, John Brown, Sami Said, Wolfgang Schmidt, Kezhio Tatemoto, Monique Vagne and others).

The peptide hormones and neuropeptides identified in Viktor’s laboratory illustrate the significance of his work:

  • secretins (of different lengths: 27, 28, 29 and 71 amino acids)
  • cholecystokinins (-33, -39 and -58)
  • vasoactive intestinal polypeptide (VIP)
  • peptide histidine-isoleucin and methionine (PHI and PHM)
  • gastric inhibitory polypeptide (GIP)
  • motilin; peptide tyrosine-tyrosine (PYY)
  • neuropeptide tyrosine (NPY)
  • galanin and several others.

A break-through was the method developed by Mutt and Tatemoto for identification of carboxyamidated peptides in tissue extracts. Carboxyamidation is a general characteristic of half the bioactive, regulatory peptides.

Viktor Mutt’s research has not only put gut endocrinology and the neuropeptide part of neurobiology on firm scientific footing. With his generous supply of bioactive peptides to laboratories all over the world, his work became a decisive prerequisite for a multitude of studies in gastroenterology, endocrinology and neurobiology, as well as for several diagnostic tests of, for instance, exocrine pancreatic function and gastrinomas.

In his later years Viktor received several major European awards, and in the USA he received the William Beaumont and Morton Grossman lecture awards. For several years, Viktor Mutt was also nominated for the Nobel Prize. In 1992, in view of Viktor Mutt’s unique contributions to science, the steering committee of the International Symposia on Regulatory Peptides in 1992 established a biannual lectureship to commemorate Viktor Mutt’s name in future research of regulatory peptides.

Jens F. Rehfeld

Rod Gregory made fundamental contributions to the study of gut hormones through his isolation of the gastric acid stimulating hormone gastrin, the characterisation of its spectrum of actions, the identification of structure-activity relationships and discovery that gastrin was produced in excess in the tumours of patients with Zollinger-Ellison syndrome.

In the mid-1950s the existence of gastrin was regarded by many as not yet proven. At the time, Gregory together with his long standing co-worker Hilda Tracy was attempting to characterise the gastric acid inhibitory factor in urine known as urogastrone (this was later shown by Harry Gregory, no relation, to be epidermal growth factor).

Gregory and Tracy required a stable background of acid secretion against which to test preparations of urogastrone, and for various reasons the available acid secretagogues were unsatisfactory. They set out, therefore, to make preparations of gastrin and in due course this became their main interest. By the late 1950s new methods of column chromatography were becoming available (notably ion exchange media suitable for small acidic peptides, and gel filtration media such as Sephadex). Using these, and working on a large scale with the antral part of pig stomachs obtained from local abattoirs they quickly produced gastrin preparations that were far superior to any generated hitherto from which it became possible to obtain essentially homogenous peptide in suitable quantities for sequencing.

The sequence of two gastrins was subsequently determined in collaboration with George Kenner who was a distinguished peptide chemist at the University of Liverpool, Chemistry Department at the time. The peptides were shown to be identical heptadecapeptides differing in the presence or absence of a sulphate group on a solitary tyrosine.

Kenner’s group then synthesised these peptides, and prepared many fragments and analogues which allowed the elucidation of structure-activity relationships including the crucial discovery that the C-terminal tetrapeptide amide was the minimal fragment with full biological activity. Shortly afterwards it became clear from the work of Viktor Mutt and Erik Jorpes on the intestinal hormone cholecystokinin, and that of Vittorio Erspamer on the amphibian skin peptide caerulein, that all three peptides shared an identical C-terminal pentapeptide amide and that this accounted for similarities in their biological properties.

Gregory and Tracy went on to show that the pure gastrins acted on a variety of different organs in addition to stimulation of acid secretion by the stomach, including stimulation of gastrointestinal motility, and weak stimulation of pancreatic secretion and gall bladder contraction. In due course they also identified other gastrins including peptides of 34-amino acid residues that are now known to be intermediates in the biosynthesis of the heptadecapeptides. Importantly, they also showed that gastrin could be isolated in large amounts from tumours of the Zollinger-Ellison syndrome and so providing a mechanistic link between these tumours and the acid hypersecretion that characterises the syndrome. They also made purified gastrin freely available to many researchers around the world which stimulated activity in the area including the subsequent development of radioimmunassays.

Rod Gregory was trained as a physiologist at the Department of Physiology at University College London in the early 1930s. He was introduced to gastrointestinal physiology in the laboratory of Andrew Ivy at Northwestern University, Illinois, where he obtained a PhD. His work on gastrin was carried out while he was Holt Professor of Physiology, and Head of Department, at the University of Liverpool (appointed in 1948) and while he had full teaching and administrative roles.

His qualities as a teacher influenced many generations of students including Professor Sir David Weatherall FRS, FMedSci (founder of the Institute of Molecular Medicine, University of Oxford) who recently noted that his own interests in medical research were stimulated by Rod Gregory “whose brilliant lectures were clearly from a man who was creating science as well as teaching it”.

Gregory’s work has proved enduring because he was one of the first to see, and to show, that progress in regulatory physiology depended on a rigorous understanding of molecular mechanisms and that work on the gut hormones required the widespread availability of pure peptides of defined sequence.

Graham J. Dockray

Morton Grossman, the father of modern gastrointestinal endocrine physiology, was born in Massilon, Ohio in 1919. He attended Ohio State University where he received an undergraduate degree in biochemistry. He entered medical school at Ohio State University but subsequently transferred to Northwestern University where he received both the MD and the PhD degrees in 1944.

In 1946 Dr. Grossman received an appointment at the University of Illinois, and he was promoted to Professor of Clinical Science in 1952 at the age of 32.

From 1951 to 1955 he served as Head of the Physiology Branch of the Medical Nutrition Laboratory, first in Chicago, then at Fitzsimmons Army Hospital Base in Denver.

In 1955 Dr. Grossman became Chief of Gastroenterology at the Wadsworth VA Medical Center in Los Angeles.

From 1955 until 1962 he ran the section and trained clinical gastroenterologists, all the while continuing his research and publishing 50 papers. He was one of the first scientists appointed to the newly created Senior Medical Investigator program at the VA, a position which provided him the time and support needed to continue his research until his death. He was also Professor of Medicine and Physiology at the UCLA School of Medicine.

In 1973 Dr. Grossman learned that the National Institutes of Health intended to fund a center for the study of peptic ulcer disease. Almost single-handedly he organized the Wadsworth-UCLA and Dallas GI groups to submit a proposal which was funded.

Thus, in 1974 Dr. Grossman became the first Director of the Center for Ulcer Research and Education (CURE).

Dr. Grossman became involved with the journal Gastroenterology in 1943, served on its Editorial Board from 1957 to 1959, was Associate Editor from 1959 to 1960, Editor from 1960 to 1965, and Chairman of the Editorial Board from 1973 to 1978.

In 1979 he was presented the Friedenwald Medal from the American Gastroenterological Association.

During his lifetim, Dr. Grossman authored 400 articles, along with a similar number of book chapters and abstracts. He trained fellows from all parts of the world and from diverse backgrounds. Many of them today hold positions of distinction as heads of departments of gastroenterology, surgery, and physiology. His friends and colleagues will most remember his curiosity, his encyclopedic memory, the breadth of his interests and his energy in pursuing them, his intelligence, his perfectionism, his fairness, his wisdom, his integrity, his devotion, and his kindness.

His most important contributions lay in defining the secretory mechanisms of the stomach and pancreas and the actions of regulatory gastrointestinal peptides. He organized the first International Symposium of Gastrointestinal Hormones meeting in 1976, and guided and nurtured the society’s biannual meetings as chair and member of the International Steering Committee. Beyond his own original contributions he synthesized much of the available knowledge in gastrointestinal physiology and endocrinology and set uncompromising standards for scientific validity and accuracy of reporting. He was truly one of the giants in gastrointestinal physiology of this century.

Vay Liang W. Go

The field of gastrointestinal Endocrinology has gained widespread attention over the last decades, as the importance of gut hormones in the regulation of glucose homeostasis, gastrointestinal functions and energy homeostasis has now become more and more evident. One of the fathers of this concept was Professor Werner Creutzfeldt, whose landmark research contributions pioneered this field for the past 50 years. His foresighted research activities have led to the detailed investigation of the incretin effect, i.e. the augmentation of insulin secretion by gut hormones, which has now been accepted as a key mechanism for postprandial glucose control. On August 30th, 2006, Werner Creutzfeldt passed away after a long and heroic struggle against a series of chronic illnesses. Perhaps as a small solace, he could see the emerging fruits of his long-standing and visionary research one year prior to his death, when the first member of the new drug class of incretin mimetics was launched for the treatment of type 2 diabetes, which for certain would not have been available at this time without the invaluable contributions made by him personally and the Goettingen research group.

Werner Creutzfeldt was born on May 11th, 1924 in Kiel,Germany, and attended Medical School at the Universities of Freiburg, Kiel, and Tübingen. In his early research projects – carried out at the University of Freiburg where he worked as a resident and later as a senior consultant – he provided a detailed description of the morphology and function of the islets of Langerhans and their abnormalities in various experimental models of diabetes. These studies still impress with their detailedness, accuracy and innovative methodology. In subsequent research projects, Werner Creutzfeldt examined the morphological and biochemical features of neuroendocrine tumours, the pharmacokinetics and pharmacodynamics of oral antidiabetic agents and the pathophysiology of “post-transfusion” hepatitis. These contributions soon became classic landmarks in the field. In 1964, Werner Creutzfeldt was appointed full professor and chairman of the Department of Medicine at the University of Göttingen, where he soon formed one of the most recognized groups in the fields of Gastroenterology and Endocrinology, from which numerous highly successful scientists emerged, many of which have subsequently taken over leading academic positions in Internal Medicine themselves.

Werner Creutzfeldt served in many national and international positions, including as President of the European Association for the Study of Diabetes (1971–1974), President of the European Pancreatic Club (1969), President of the German Diabetes Association (1967–1968), and President of the German Association for Gastroenterology (1976–1977). He was also Editor-in-Chief of the journals “Diabetologia” (1973–1976) and “Digestion” (1978–1992).

During his most impressive career, Werner Creutzfeldt has received many honours including the Claude-Bernard-Medal of the European Association for the Study of Diabetes, the Ludwig-Heilmeyer-Medal of the German Association for Internal Medicine, the Paul-Langerhans-Medal of the German Diabetes Association, the Ismar-Boas-Medal and the Thannhauser-Medal of the German Gastroenterological Society and the most prestigious Ernst-Jung-Medal for Medicine in Gold of the Hamburg Ernst-Jung-Foundation.

With more than 700 published original articles, reviews and book chapters, Werner Creutzfeldt’s scientific merits are too numerous to be described in detail. Perhaps the most important contributions made by the Göttingen research group directed and inspired by him include the characterisation of Gastric Inhibitory Polypeptide (GIP) in the physiology of postprandial glucose homeostasis, the uncovering of defects in the entero-insular axis in the pathophysiology of type 2 diabetes and the first description of the biological activity and antidiabetic effects of glucagon-like peptide-1 (GLP-1). In many ways, the development of dipeptidyl peptidase-4 (DPP-4) inhibitors and incretin mimetics as a novel concept in the pharmacotherapy of type 2 diabetes would be unthinkable without his fundamental contributions to the field.

Werner Creutzfeldt’s broad range of interests not only covered several aspects of Gastroenterology and Endocrinology, but also questions of ethics in Medicine, the brutal abuse and misconduct of medical research by the nazi-regime in Germany, as well as the history of diabetes and gastrointestinal research. Having experienced the crimes of the nazi-regime as a young man (his mother was imprisoned by the nazis during the war), he actively fought against antisemitism and the discrimination of minorities throughout his life. As chairman of the Ethics Committee of the Medical Faculty of the University of Göttingen, he was a thoughtful and critical defender of the boundaries for medical research in human subjects.

It was Werner Creutzfeldt’s vision that Gastroenterology, Endocrinology and Diabetology/Metabolism are one inseparable unit that should not be sub-divided into separate entities. He was one of the first scientists to realize the clinical importance of the gut as an endocrine organ and to uncover the close interaction between gastrointestinal motility, secretion and the regulation of energy balance. Today, his foresighted visions and ideas have become accepted doctrines in Internal Medicine, and his fundamental studies have paved the way towards new principles in our understanding of the pathophysiology and treatment of various diseases. Beside his research activities Werner Creutzfeldt was a brilliant physician who personally cared for his patients. His grand rounds on the ward were exceptional examples for his sophisticated clinical skills, his sharp intellect and his ability to dissect and analyse the clinical picture of a patient. One of this outstanding clinical lecture series was “Differential diagnosis in internal medicine” where he demonstrated that the physician should be able to deduce a diagnosis just from the patient’s history and examination. This demonstration of the “Art of Medicine” excited his medical students who regularly overcrowded his lecture halls.

Wolfgang E. Schmidt
Juris J. Meier
(Excerpt from Regulatory Peptides, 137, 2006, 105-106)

Throughout his scientific career, John Walsh worked at the interface between basic cellular and molecular aspects of gut hormones and their implications in human physiology and pathology.

John Walsh was born on August 22, 1938, in Jackson, Mississippi. He received his undergraduate and medical degrees from Vanderbilt University, and from 1963 to 1967, he completed his internal medicine residency at New York Hospital and Cornell Medical Center. In 1969, he spent a determinant year in the laboratories of Drs. Rosalyn Yalow and Solomon Berson (Nobel Laureates of Medicine in 1977), who had discovered the fundamentals to radioimmunoassay (RIA). During this short time, John Walsh was part of the “big” gastrin discovery and developed the first RIA for hepatitis B surface antigen.

In 1970, Dr. Morton Grossman recruited him to the Digestive Diseases Division of the UCLA School of Medicine where he launched his extraordinarily fruitful 30-year career as an independent gastrointestinal endocrinologist. Among Walsh’s early seminal findings, he established the importance of gastrin in the gastric phase of acid secretion in dogs and humans and demonstrated the paracrine action of somatostatin in the regulation of gastrin release. In collaboration with Helen Wang, a long time research associate, he landed his expertise in RIA to the development of a number of those for gastrointestinal peptide including somatostatin, pancreatic polypeptide, bombesin, neurotensin, motilitin, secretin, cholecystokinin, vasoactive intestinal peptide and substance P. These sensitive assays were state-of-the art, allowing the unraveling of the basic physiology of gastrointestinal hormones under both in vivo and in vitro conditions and are part of his legacy to share generously these valuable reagents.

John Walsh authored over 500 peer-reviewed articles and book chapters. Between 1973 and 1984, in the era of rapid discovery of peptide hormones, he was among the 250 scientists the most cited according to the Scientist. He earned many awards including the Distinguished Achievement Award from the American Gastroenterology Association (AGA), the AGA Kirsner Award for Clinical Research in Gastroenterology and the Abbott Distinguished Research Award from the Gastrointestinal Physiology Section of the American Physiological Society.

In addition, of his prolific scientific contributions, he was elected to serve in leadership positions as Director of the CURE: Digestive Disease Center from 1989 up to 2000, he was the AGA President from 1994 to 1995, and Editor-in-Chief of its journal, Gastroenterology. He also had maintained a true commitment to the Gut Hormone/RegPep symposia in organizing the 10th meeting in Santa Barbara and serving on the International Steering Committee since its inception in 1974.

Yvette Taché