Jan Gösta Waldenström and His World : The Life and Work of a Giant in Science, Medicine and Humanity 9783031367380, 9783031367397

Table of contents :
Foreword by Robert A. Kyle
Foreword by Giampaolo Merlini
Preface
References
Acknowledgements
Contents
1 A Family of Pioneers
References
2 Childhood in Stockholm and Student Years in Uppsala
References
3 The Red Urine Story
3.1 A Diagnostic Triumph
3.2 The First Publication
3.3 Hans Fischer in Munich
3.4 In Munich with a Rockefeller Stipend
3.5 Back in Sweden
3.6 The Doctoral Thesis
References
4 Letters to a Special Friend
Reference
5 Assistant Professor in Uppsala
5.1 Early Hematology Research
5.2 The Growing Family
References
6 Two New Diseases
6.1 Uppsala, A Mecca of Physical Chemistry
6.2 The Svedberg and the Ultracentrifuge
6.3 Electrophoresis and Arne Tiselius
6.4 Purpura Hyperglobilinemia
6.5 Macroglobulinemia
References
7 Exploring Medical Science in Wartime America
7.1 Through Mined Waters to New York City
7.2 Exploring Science in New York City
7.3 Boston, “The Medical Capital of America”
7.4 Washington University in St. Louis
7.5 The University of Minnesota in Minneapolis
7.6 The Mayo Clinic in Rochester
7.7 Final Comments
References
8 Turbulent Final Years in Uppsala
8.1 Selecting a New Professor and Chairman
8.2 The Winner in Uppsala
8.3 The “Looser”
References
9 “The Great Faculty” in Lund
9.1 Introduction
9.2 Pathology and Bacteriology
9.3 Anatomy and Histology
9.4 Physiology, Medical Chemistry, and Pharmacology
9.5 The Department of Medicine
References
10 Malmö General Hospital—MAS
10.1 The Early Years
10.2 The Next Generation
10.3 Medicine
References
11 Arrival in Malmö
11.1 The Department of Medicine
11.2 Department of Surgery
11.3 Obstetrics and Gynecology
11.4 Orthopedic Surgery
11.5 Pathology and Bacteriology
References
12 Autoimmune Hepatitis
12.1 The German Society for Digestive and Metabolic Diseases—DGVS
12.2 The 15th Congress of the DGVS
12.3 A New Liver Disease
References
13 A Charismatic Leader
13.1 The Commander-in-Chief
13.2 The Early Team
13.3 New Routines
13.4 Exciting the Medical Students
References
14 The Carcinoid Syndrome
14.1 The Discovery
14.2 Intestinal Carcinoid
14.3 A Meeting in Malmö
14.4 Clinical Features
14.5 From Bedside to the Bench
14.6 Recent Contributions in the Carcinoid Syndrome
References
15 Beginning of a Golden Age
15.1 The New Wing
15.2 Radiology
15.3 Pathology
15.4 The First Ph.D. Students
15.5 Private Life
References
16 Gammopathies—Jewel in the Crown
16.1 A New Family
16.2 The Harvey Lecture “Gammopathies”
16.3 Monoclonal and Polyclonal Gammopathy
16.4 Epidemiology of Gammopathies
16.5 The Värmland Study
16.6 Genetics of Monoclonal IgM
16.7 MGUS, SMM, and MM
16.8 Familial Autoimmunity
References
17 Porphyria Research from Malmö
17.1 Introduction
17.2 The Porphyrin Diseases as Inborn Errors of Metabolism
17.3 Enter Birgitta Haeger-Aronsen
17.4 Neuropsychiatry and Genetics of Porphyria
17.5 Diabetes Insipidus
17.6 Pathogenesis of Porphyria and Its Rational Therapy
References
18 Inga Marie Nilsson—“The Queen of Coagulation”
18.1 A Rising Star Getting Help from Stockholm
18.2 Erik Jorpes
18.3 The Doctoral Thesis of Inga Marie Nilsson
18.4 Anti-hemophilic Globulin
18.5 Early Use of Cohn Fraction I-0 (AHF) in Von Willebrand’s Disease
18.6 Hemophilia in Sweden
18.7 Professor of Coagulation Research
18.8 Factor VIII Bypass with Activated Factor VII
18.9 A Royal Bleeding Condition
18.10 The Legacy
References
19 Carl-Bertil Laurell and His Outstanding Laboratory of Clinical Chemistry
19.1 Introduction
19.2 Carl-Bertil Laurell in Uppsala
19.3 Carl-Bertil Laurell in Lund
19.4 Carl-Bertil Laurell Arrives in Malmö
19.5 Alpha-1 Antitrypsin Deficiency
References
20 The Division of Cardiology
20.1 The Period 1950–8
20.2 Bengt W. Johansson as Leader
20.3 Concluding Comment
References
21 Bengt Skanse and Endocrinology in Malmö
21.1 Bengt Skanse
21.2 Thyroid Diseases
21.3 Other Contributions
21.4 Aldosterone
21.5 Continued Growth of Endocrinology
21.6 The Tragedy
21.7 Endocrinology After Bengt Skanse
References
22 Hematology
22.1 The International Society of Hematology
22.2 Hematology Research in Malmö
22.3 Concluding Remarks
References
23 A Friendship with Bertel von Bonsdorff
23.1 Bertel von Bonsdorff
23.2 All Light Comes From the East
23.3 The Friendship and the Letters
23.4 The Bertel von Bonsdorff Festschrift in 1964
23.5 The Jan Waldenström Festschrift in 1966
23.6 ISA, The International Society of Amyloidosis
References
24 Visitors and Visits
24.1 Introduction
24.2 VIIth International Congress of Internal Medicine 1962
24.3 Partners in Progress
24.4 Visitors to Malmö
24.5 Two Very Special Visitors
References
25 The Nobel Symposium on Gamma Globulins
25.1 Nobel Symposia
25.2 The First Day: Structure of Gamma Globulins
25.3 Day 2. Structure and Heterogeneity of Gamma Globulins
25.4 Day 3. A Visit to Uppsala
25.5 Day 4. Control of Biosynthesis
25.6 Days 4–5. Clinical Aspects on Control of Gamma Globulin Synthesis
25.7 The Take Home Message
References
26 Emeritus Professor of Medicine
26.1 The Farewell Lecture
26.2 JW’s Private Practice
26.3 Editor of Acta Medica Scandinavica
References
27 New Activities in Stockholm
27.1 Skandia International Symposia
27.2 Radiumhemmet, Jerzy Einhorn, and Oncology in Sweden
27.3 The THX Doctor
References
28 Jan Waldenström. An Esteemed Globetrotter
28.1 A Popular Visitor
28.2 The Jahre Prize
28.3 Other Honors
28.4 Fogarty Scholar at NIH in 1978
28.5 At Home
28.6 Concluding Remark
References
29 Macroglobulinemia—An Update
29.1 1984—The 40th Anniversary
29.2 Significant News from the Bing Center for Waldenström’s Macroglobulinemia
29.3 10th International Workshop on Waldenström’s Macroglobulinemia
29.4 Macroglobulinemia Then and Now, a Success Story
References
30 Happy Years
30.1 A Man with Temperament
30.2 JW More Private
30.3 The 80th Birthday at Torup Castle
References
31 The Final Years
31.1 The Last Decade
31.2 The Legacy
References
Author Index

Citation preview

Springer Biographies

Jan Gösta Waldenström and His World The Life and Work of a Giant in Science, Medicine and Humanity

FRANK WOLLHEIM

Springer Biographies

The books published in the Springer Biographies tell of the life and work of scholars, innovators, and pioneers in all fields of learning and throughout the ages. Prominent scientists and philosophers will feature, but so too will lesser known personalities whose significant contributions deserve greater recognition and whose remarkable life stories will stir and motivate readers. Authored by historians and other academic writers, the volumes describe and analyse the main achievements of their subjects in manner accessible to nonspecialists, interweaving these with salient aspects of the protagonists’ personal lives. Autobiographies and memoirs also fall into the scope of the series.

Frank Wollheim

Jan Gösta Waldenström and His World The Life and Work of a Giant in Science, Medicine and Humanity

Frank Wollheim Department of Rheumatology Faculty of Medicine Lund University Lund, Sweden

ISSN 2365-0613 ISSN 2365-0621 (electronic) Springer Biographies ISBN 978-3-031-36738-0 ISBN 978-3-031-36739-7 (eBook) https://doi.org/10.1007/978-3-031-36739-7 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

To Hedda, Ernst, Claes, and Magnhild

Foreword by Robert A. Kyle

Jan Waldenström always said that he had learned from individual patients or a small number of them. I have had the same experience and always said that “my patients have taught me everything that I have learned”. I became interested in the field when I was on Hematology Rounds at St. Marys Hospital, Mayo Clinic, and saw a serum protein electrophoretic pattern (SPEP) in early 1959. I asked the consultant, Ned Bayrd, “What is this?” He simply replied that spikes were seen in multiple myeloma and Waldenström’s Macroglobulinemia and that we don’t know much about it so, “Look into it”. This led to my review of all the SPEPs from January 1956 through May 1959. I found that patients with a spike (height:width ratio) of 4:1 or greater or a ratio of 3:1 and an electrophoretic mobility faster than gamma globulin in 71% of multiple myeloma patients. Only 5% had a normal pattern. This was published in 1960 (JAMA 174:107–113, 1960). On that same Hospital Service, a patient was admitted with a diagnosis of multiple myeloma, but she actually had primary systemic amyloidosis (now designated as AL amyloidosis). My experiences on that Hematology Service led me into the field of multiple myeloma and the dysproteinemias. During my later review of Mayo Clinic patients with a diagnosis of multiple myeloma, I found an interesting patient. When seeing a new patient, it is my habit to look at their past history. To my surprise, I found that the patient had been to the Mayo Clinic in 1945 because of weakness and fatigue. A very high sedimentation rate of 118 mm/hr led to the performance of the albumin/globulin ratio which indicated an increased serum protein level. At that time, serum protein electrophoresis was only a research tool because it took one technician one day to perform electrophoresis on one patient. Her bone marrow contained only 3.6% plasma cells and roentgenograms showed no lytic lesions or fractures. The patient was reassured, and no treatment was given.

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She returned in 1958, and an SPEP revealed a gamma spike of 2.9 g/dL. The elevated sedimentation rate and laboratory tests were unchanged. She was again advised that no treatment was indicated and sent home. Then, five years later, she developed severe back pain and her physician made a diagnosis of multiple myeloma. She was treated with cyclophosphamide and then returned to the Mayo Clinic for a second opinion. She was told to continue the cyclophosphamide but died several months later. We published her case entitled “Benign” Monoclonal Gammopathy: A Potentially Malignant Condition? in 1966 (Am J Med 40:426–430, 1966). I soon noted several such patients in my hematology practice. In 1978, I published 241 patients and introduced the term “Monoclonal Gammopathy of Undetermined Significance” (MGUS). The current term used for these patients was Benign Monoclonal Gammopathy which had been introduced by Jan Waldenström in the 1950s. In 1961, Jan in his Harvey Lecture introduced the monumental concept of Monoclonal and Polyclonal Gammopathy. Monoclonal gammopathies consisted of multiple myeloma, Waldenström’s Macroglobulinemia or “Benign Monoclonal Gammopathy” while the polyclonal gammopathies showed a broad-based pattern and had a reactive or inflammatory process such as chronic liver disease, rheumatoid arthritis and related disorders, or other inflammatory diseases. In 1978, I reported 241 cases of MGUS consisting of (1) patients without a significant increase in monoclonal protein (57%), (2) patients with more than 50% increase in monoclonal serum protein or development of a monoclonal urine protein but no evidence of symptomatic multiple myeloma (9%), (3) patients who died without five-year serum studies (23%), and (4) patients in whom multiple myeloma, Waldenström’s Macroglobulinemia, or amyloidosis developed (11%). Thus, only a tenth (11%) of the patients with Monoclonal Gammopathy of Undetermined Significance (MGUS) actually developed multiple myeloma or a related disorder over a 5+ year follow-up (Am J Med 64:814–826, 1978). My experiences with the Monoclonal Gammopathies have led to a 6+ decade career in the field of the monoclonal gammopathies. I have been stimulated by Jan over the years and became a close, personal friend for the remainder of his life.

Foreword by Robert A. Kyle

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Jan Waldenström and Robert Kyle in 1995? © Private archive Robert Kyle

Rochester, MN, USA

Prof. Robert A. Kyle, MD

Foreword by Giampaolo Merlini

I first met Prof. Waldenström on the steps of the Malmö General Hospital “Medicinska Kliniken” in a dark late September afternoon in 1977, on my arrival after a long train journey across Europe. I vividly remember his warm welcome and my joy for the fortunate encounter. A book written by Prof. Waldenström attracted me to Malmö. It was entitled Monoclonal and Polyclonal Hypergammaglobulinemia: Clinical and Biological Significance, and I read it right after my graduation, in 1976. In this book, a group of remarkably interesting patients with myeloma and other related conditions were discussed, in search of the molecular basis of their clinical manifestations. This fascinated me, and I applied for a fellowship from the Swedish Institute Svenska Institutet, whose support allowed my training with Prof. Waldenström. I had the great privilege to spend hours with him discussing patient records, and that was the basis for the formulation of a new staging system for multiple myeloma that we published together in Blood, overcoming with some difficulties his skepticism for statistics. The encounter with Prof. Waldenström left a profound imprint on my scientific and human formation. I was deeply impressed by his quest for the molecular mechanisms of diseases, which was at the basis of his discovery of Waldenström’s macroglobulinemia and of his studies on porphyria and paraneoplastic syndromes. This is the most important teaching I received from him and has modeled all my research. The concept of “sick” molecules that he put forward in a later paper in 1989 is extraordinarily up to date if we think of the vast realm of diseases caused by “sick” misfolded proteins. During my time in Malmö, we established a strong relationship that continued until his death with regular, periodic encounters in Sweden and Italy. I remember several journeys we took together visiting botanical gardens or museums, and each occasion was a source of teaching and inspiration. He cared about my scientific education, and he was convinced that at that time “big science” was in the States. He introduced me to his close friend Elliott Osserman at Columbia University, where I developed my interest for systemic amyloidoses, that represents the field of my research since then. Professor Waldenström visited me in New York several times, and I remember unforgettable visits to the Metropolitan Museum, the Guggenheim Museum, the Frick Collection, and to the National Gallery in Washington. He had a very sharp eye for masterpieces, and his comments on Rembrandt’s xi

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paintings and on Leonardo’s Ginevra de’ Benci (1474/1478) still resound vividly in my mind. But the most important discussions were about science where he deployed his original, frequently counterintuitive, views on biological phenomena and clinical practices. He was a giant in Medicine! We had also the opportunity to discuss personal life. He taught me the value of cultivating friendships, he was a real master in this, and he had friends all over the world. He introduced me to several leading Swedish scientists with whom I established scientific and personal links that are still lively. He confided to me about his years in Uppsala, first as student and then as Professor, depicting the extraordinary, unique scientific milieu and his acquaintance with the Nobel Laureates The Svedberg and Arne Tiselius and other bright personalities, including Dag Hammarskjöld, who became his closest friend. They had long discussions at the fireplace, animated by good wine, about science and social events. He amused me with one of the first applications of Svedberg ultracentrifuge technology, to determine that an unclassified flower actually belonged to the Rosa genus; the great Linnaeus tradition was intensely cultivated in the academic circle. He also told me how the availability of serum electrophoresis, by using Tiselius apparatus, further stimulated his interest in monoclonal immunoglobulins. By the way, he was a strong opponent of the term “paraprotein” because monoclonal immunoglobulins are normal proteins and the knowledge we have about immunoglobulin structure derives from them. In one of his last letters to me, he recalled the happy years he had in Uppsala and the tremendous blow he suffered when he had to leave that splendid environment. This incredibly rich scientific and cultural milieu was the fertile soil of Waldenström’s genius. Frank Wollheim has accomplished an outstanding endeavor with his accurate, vivid, and entertaining description of the unique atmosphere that permeated the medical research in Sweden at the time of Waldenström’s life. He makes clear that the outstanding achievements by Waldenström were nurtured by many excellent colleagues in a unique epopee that modeled the international medical science.

Foreword by Giampaolo Merlini

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Leonardo de Vincy https://www.nga.gov/collection/art-object-page.50724.html 6 February 2022 February 2022

Prof. Giampaolo Merlini Policlinico San Matteo Pavia, Italy

Preface

“On DECEMBER 1, 1966 the world lost one of this century’s giants in hematology”. The first sentence of a tribute to Jan Waldenström by another legendary physician, Robert A Kyle [1], remains valid but covers but one side of this man’s legacy. I was attracted by Waldenström’s charisma in medical school and influenced to become an internist by a most inspiring undergraduate teacher. Waldenström realized the importance of undivided internal medicine for patient care, teaching, and research. His diverse field of interest has been compared to those of Sir William Osler, and they encompassed hepatology, endocrinology, oncology, and not least autoimmunity and rheumatology, and he impacted all of them significantly. It is an exciting but daunting task to cover his life. He was a dedicated and beloved physician and undergraduate teacher and always stressed the fact that humanity was an essential part of a complete doctor. At the same time he was an expert botanist in the tradition of Carl Linnaeus, interested in tracing rare orchids and visiting botanical gardens in cities around the world. This interest sharpened the eye to spot minute details in nature and at the encounter with patients. Writing this book coincided with the pandemic but fortunately allowed me to interview several of Waldenström’s scholars and friends who could provide some first-hand information. It has been essential to have contact with the sons Anders, Dag, and Erik. I am very grateful that two of Waldenström’s close friends and collaborators in science, Robert A. Kyle and Giampaolo Merlini, have contributed forewords which enrich the book. The dedicated help of Eric Matteson with editorial and linguistic censorship has been essential throughout the work. Eric turned down my invitation to be a co-author. It has been an immensely enjoyable learning experience to penetrate Waldenström’s development from student years and early achievement to maturity as innovative investigator. It is indeed striking to follow his pigeon whole sense for abnormalities in individual patients, his adventures around the world and penetrate his phenomenal network among several leading scientists of the 20th century. The shaping of a creative environment as professor and chairman of a new department where I was privileged to work in formative years is a center core of the book. Waldenström was not a friend of autobiographies by physicians. However, his friends in Pavia persuaded him in the 1990s to compile Reflections and Recollections xv

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from a Long. Life with Medicine [2]. They contain much of his personal philosophy and inform on several memorable experiences in his life. With special satisfaction Jan Waldenström points out that several of his most important contributions were derived from the observation of an individual or only very few patients. My first idea for subtitle to this book was and Editorial in the Journal of Internal Medicine titled “In Defense of the Anecdotal” addressing this subject [3]. But although Jan Waldenström passed more than 25 years ago, no Waldenström biography has been published previously. It was my aim to fill this void. Documents, letters, and photos have been obtained from colleagues, family, and traced in archives and libraries. They are supplemented with material from my own files. As mentioned it has been possible to interview children of Jan Waldenström as well as colleagues and their descendants who have contributed valuable information. Soon all who had a first-hand contact with the great man will be gone. The work has been a very rewarding learning experience regarding medical history and developments in science in the 20th century as they relate to the work of Waldenström. His ability to observe clinical details and reveal their biologic background form an enduring model of translational medicine for clinical investigators. The reader will become familiar with impressive discoveries of new diseases, with achievements of a great teacher and mentor, and a dedicated bedside physician. Lasting warm relations with scholars and friends in Sweden [4] and around the world and realization that humanity contributes to the professional quality of physicians are other characteristics for which Jan Gösta Waldenström is remembered. Lund, Sweden December 2022

Frank Wollheim

References 1. Kyle RA, Anderson KC. A tribute to Jan Gösta Waldenström. Blood 1997;42:45–47 2. Waldenström JG. Reflections and recollections from a long life with medicine. Haematologica series, Ferrara Storti Foundation. Il pensiero scientifico, Rome 1994. pp 1–136 3. Waldenström JG. In defense of the anecdotal. J Intern Med 1989;226(1):1–4 4. Wollheim F. Jan Waldenström and Dag Hammarskjöld: a friendship between two Swedish humanists. Hektoen International 2017. https://hekint.org/2017/01/29/jan-waldenstrom-anddag-hammaskjold-a-friendship-between-two-swedish-humanists/

Acknowledgements

The list of individuals who have helped during writing this book is extensive. I would like to start by thanking the sons of Jan Waldenström Anders, Dag, and Erik, who have provided essential support in form of documents, photos, critical reading, advise, and encouragement throughout the work. Eric Matteson has been a dedicated helper with linguistic editing of each chapter. Bengt W Johansson and Jörgen Malmquist have been providing important information and careful proofreading and correction. I am grateful to Prof. Berndt Ehinger at Sydsvenska Medicnhisoriska Sällskapet i Lund who created a large archive of photos, 40 of which appeared in the book. I would also like to thank Chester Alper, Boston, Haralampos Moutsopoulos, Athens, Tom Pettersson, Eva Stockman and Martin von Bonsdorff, Helsingfors, C. Peter Mauri, Helsingfors, Francesco Dammaco, Bari, John Kelly Smith, Johnson City, TN, Matthew Liang, Boston, Gunnar Husby, Oslo, Harro Jenss, Worpswede, Germany, Jochen Kalden, Erlangen †, Josef Smolen, Vienna and Ferdinand Breedveld, Leiden, Rolf Rau, Düsseldorf, Sir Gordon Duff, Oxford, Auli Toivanen, Turku, Eng Tan, La Jolla, CA, Peter Schur, Boson, Stanley Pillemer, Washington, David Pisetsky, Chapel Hill, Marc Hochberg, Baltimore, Wilfried von Studnitz, Feldafing, Germany, and Maximillian Broglie, Wiesbaden, Germany. Swedish colleagues and friends include Nils Olof Abdon, Göran Adielsson, LarsOlof Almér, Ingvar Anderson, Karl-Erik Andersson Sture Andersson, Kristofer Andréasson, Betty Bauer, Anders Bentsso, Hans Bennich, Stig and Gunilla Berglund, Erik Berntorp, Lena and Per Björkman, Margareta Blombäck, Johan Cullberg †, Björn. Dahlbäck, Torsten Denneberg, Olof Edhag, Lars Edvinsson, Berndt Ehinger, Inger Enkvist, Ulla Evaldsson †, Raili Eyrich †, Ulf de Faire, Gösta Gahrton, Anders Grubb, Gunnar Gunnarsson, Folke Gyland, Göran Hansson, KVA, Ulla Hedner, Jan Hällen †, Nils Johan Höglund, S. Gunnar Johansson, Meliha Kapetanovic, Dick Killander, Göran Kronwall, Erik Larhammar, Martin Laurell, Ido Leden, Åle Lernmark, Folke Lindgärde †, Otto Ljungberg, Felix Mitelman, Ulrrich Moritz, Erna. Möller, Jan Niléhn, Peter M. Nilsson, Elisabeth and Claes Nordborg, Erling Norrby, Urban Ringborg, Mårten Rosenqvist, Magnhild Sandberg, Tore Saxne, Jan Sievers, Beata Skanse, Pål Stenberg, Henry Svensson, Fredrik Tersmeden, Per Tiselius, Nils

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Gunnar Toremalm †, Erik Trell, Ingemar Turesson, Karin Wetrell, Claes Wollheim, and Kjell Öberg. Last but certainly not least, I am grateful to Ms. Angela Lahee at Springer/Nature in Heidelberg, who conveyed my proposal’s acceptance by the publisher.

Contents

1

A Family of Pioneers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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2

Childhood in Stockholm and Student Years in Uppsala . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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3

The Red Urine Story . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 A Diagnostic Triumph . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 The First Publication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Hans Fischer in Munich . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 In Munich with a Rockefeller Stipend . . . . . . . . . . . . . . . . . . . . . . 3.5 Back in Sweden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6 The Doctoral Thesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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4

Letters to a Special Friend . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Assistant Professor in Uppsala . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Early Hematology Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 The Growing Family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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6

Two New Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1 Uppsala, A Mecca of Physical Chemistry . . . . . . . . . . . . . . . . . . . 6.2 The Svedberg and the Ultracentrifuge . . . . . . . . . . . . . . . . . . . . . . 6.3 Electrophoresis and Arne Tiselius . . . . . . . . . . . . . . . . . . . . . . . . . 6.4 Purpura Hyperglobilinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5 Macroglobulinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Exploring Medical Science in Wartime America . . . . . . . . . . . . . . . . . . 7.1 Through Mined Waters to New York City . . . . . . . . . . . . . . . . . . . 7.2 Exploring Science in New York City . . . . . . . . . . . . . . . . . . . . . . . 7.3 Boston, “The Medical Capital of America” . . . . . . . . . . . . . . . . . 7.4 Washington University in St. Louis . . . . . . . . . . . . . . . . . . . . . . . . 7.5 The University of Minnesota in Minneapolis . . . . . . . . . . . . . . . . 7.6 The Mayo Clinic in Rochester . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.7 Final Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

55 55 57 63 71 72 74 77 77

8

Turbulent Final Years in Uppsala . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1 Selecting a New Professor and Chairman . . . . . . . . . . . . . . . . . . . 8.2 The Winner in Uppsala . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3 The “Looser” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

79 79 84 86 89

9

“The Great Faculty” in Lund . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 9.2 Pathology and Bacteriology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 9.3 Anatomy and Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 9.4 Physiology, Medical Chemistry, and Pharmacology . . . . . . . . . . 97 9.5 The Department of Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

10 Malmö General Hospital—MAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.1 The Early Years . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2 The Next Generation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.3 Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

111 111 114 114 117

11 Arrival in Malmö . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.1 The Department of Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.2 Department of Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.3 Obstetrics and Gynecology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.4 Orthopedic Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.5 Pathology and Bacteriology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

119 119 123 124 124 126 127

12 Autoimmune Hepatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.1 The German Society for Digestive and Metabolic Diseases—DGVS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.2 The 15th Congress of the DGVS . . . . . . . . . . . . . . . . . . . . . . . . . . 12.3 A New Liver Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

129 129 134 134 137

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13 A Charismatic Leader . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.1 The Commander-in-Chief . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.2 The Early Team . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.3 New Routines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.4 Exciting the Medical Students . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

139 139 140 142 145 147

14 The Carcinoid Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.1 The Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.2 Intestinal Carcinoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.3 A Meeting in Malmö . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.4 Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.5 From Bedside to the Bench . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.6 Recent Contributions in the Carcinoid Syndrome . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

149 149 150 150 151 153 156 158

15 Beginning of a Golden Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.1 The New Wing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.2 Radiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.3 Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.4 The First Ph.D. Students . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.5 Private Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

161 163 164 165 167 167 169

16 Gammopathies—Jewel in the Crown . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.1 A New Family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.2 The Harvey Lecture “Gammopathies” . . . . . . . . . . . . . . . . . . . . . . 16.3 Monoclonal and Polyclonal Gammopathy . . . . . . . . . . . . . . . . . . 16.4 Epidemiology of Gammopathies . . . . . . . . . . . . . . . . . . . . . . . . . . 16.5 The Värmland Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.6 Genetics of Monoclonal IgM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.7 MGUS, SMM, and MM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.8 Familial Autoimmunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

171 171 172 172 178 179 182 183 183 187

17 Porphyria Research from Malmö . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.2 The Porphyrin Diseases as Inborn Errors of Metabolism . . . . . . 17.3 Enter Birgitta Haeger-Aronsen . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.4 Neuropsychiatry and Genetics of Porphyria . . . . . . . . . . . . . . . . . 17.5 Diabetes Insipidus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.6 Pathogenesis of Porphyria and Its Rational Therapy . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

189 189 190 192 194 196 197 199

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18 Inga Marie Nilsson—“The Queen of Coagulation” . . . . . . . . . . . . . . . 18.1 A Rising Star Getting Help from Stockholm . . . . . . . . . . . . . . . . 18.2 Erik Jorpes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18.3 The Doctoral Thesis of Inga Marie Nilsson . . . . . . . . . . . . . . . . . 18.4 Anti-hemophilic Globulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18.5 Early Use of Cohn Fraction I-0 (AHF) in Von Willebrand’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18.6 Hemophilia in Sweden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18.7 Professor of Coagulation Research . . . . . . . . . . . . . . . . . . . . . . . . . 18.8 Factor VIII Bypass with Activated Factor VII . . . . . . . . . . . . . . . 18.9 A Royal Bleeding Condition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18.10 The Legacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

201 201 202 205 205 206 209 212 217 217 218 220

19 Carl-Bertil Laurell and His Outstanding Laboratory of Clinical Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19.2 Carl-Bertil Laurell in Uppsala . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19.3 Carl-Bertil Laurell in Lund . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19.4 Carl-Bertil Laurell Arrives in Malmö . . . . . . . . . . . . . . . . . . . . . . . 19.5 Alpha-1 Antitrypsin Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

223 223 224 225 228 236 238

20 The Division of Cardiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20.1 The Period 1950–8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20.2 Bengt W. Johansson as Leader . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20.3 Concluding Comment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

241 241 243 250 252

21 Bengt Skanse and Endocrinology in Malmö . . . . . . . . . . . . . . . . . . . . . . 21.1 Bengt Skanse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.2 Thyroid Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.3 Other Contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.4 Aldosterone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.5 Continued Growth of Endocrinology . . . . . . . . . . . . . . . . . . . . . . . 21.6 The Tragedy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.7 Endocrinology After Bengt Skanse . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

255 255 257 258 259 260 262 263 265

22 Hematology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22.1 The International Society of Hematology . . . . . . . . . . . . . . . . . . . 22.2 Hematology Research in Malmö . . . . . . . . . . . . . . . . . . . . . . . . . . . 22.3 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

269 269 273 283 284

Contents

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23 A Friendship with Bertel von Bonsdorff . . . . . . . . . . . . . . . . . . . . . . . . . 23.1 Bertel von Bonsdorff . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.2 All Light Comes From the East . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.3 The Friendship and the Letters . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.4 The Bertel von Bonsdorff Festschrift in 1964 . . . . . . . . . . . . . . . . 23.5 The Jan Waldenström Festschrift in 1966 . . . . . . . . . . . . . . . . . . . 23.6 ISA, The International Society of Amyloidosis . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

287 287 287 289 294 295 296 298

24 Visitors and Visits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24.2 VIIth International Congress of Internal Medicine 1962 . . . . . . . 24.3 Partners in Progress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24.4 Visitors to Malmö . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24.5 Two Very Special Visitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

301 301 301 304 305 310 313

25 The Nobel Symposium on Gamma Globulins . . . . . . . . . . . . . . . . . . . . 25.1 Nobel Symposia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25.2 The First Day: Structure of Gamma Globulins . . . . . . . . . . . . . . . 25.3 Day 2. Structure and Heterogeneity of Gamma Globulins . . . . . 25.4 Day 3. A Visit to Uppsala . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25.5 Day 4. Control of Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25.6 Days 4–5. Clinical Aspects on Control of Gamma Globulin Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25.7 The Take Home Message . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

315 315 317 319 321 324

26 Emeritus Professor of Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.1 The Farewell Lecture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.2 JW’s Private Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.3 Editor of Acta Medica Scandinavica . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

333 333 335 336 342

27 New Activities in Stockholm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27.1 Skandia International Symposia . . . . . . . . . . . . . . . . . . . . . . . . . . . 27.2 Radiumhemmet, Jerzy Einhorn, and Oncology in Sweden . . . . . 27.3 The THX Doctor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

343 343 349 354 355

28 Jan Waldenström. An Esteemed Globetrotter . . . . . . . . . . . . . . . . . . . . 28.1 A Popular Visitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28.2 The Jahre Prize . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28.3 Other Honors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28.4 Fogarty Scholar at NIH in 1978 . . . . . . . . . . . . . . . . . . . . . . . . . . .

357 357 358 359 360

326 329 330

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28.5 At Home . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362 28.6 Concluding Remark . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365 29 Macroglobulinemia—An Update . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29.1 1984—The 40th Anniversary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29.2 Significant News from the Bing Center for Waldenström’s Macroglobulinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29.3 10th International Workshop on Waldenström’s Macroglobulinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29.4 Macroglobulinemia Then and Now, a Success Story . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

367 367

30 Happy Years . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30.1 A Man with Temperament . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30.2 JW More Private . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30.3 The 80th Birthday at Torup Castle . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

377 377 378 382 388

31 The Final Years . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31.1 The Last Decade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31.2 The Legacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

389 389 395 396

369 370 373 374

Author Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397

Chapter 1

A Family of Pioneers

Abstract This chapter presents the Waldenström family tree starting with his greatgrandfather who was the first of five generations of physicians. He was also the first district medical officer in the district of Luleå encompassing 25% of Sweden’s total area. Appointed in 1919 he fathered 5 children and managed to support all his 10 sons through high school and university studies. One son born in 1835, the grandfather of Jan, was an outstanding surgeon. He died from appendicitis 1879 only 44 years old on the day he was supposed to be installed as professor of medicine in Uppsala. His oldest son Henning became a prominent investigating orthopedic surgeon and professor at Karolinska Hospital. Jan was his only son. Three of Jan’s 7 children became significant MD PhD physicians, specializing into clinical chemistry, cardiology, and endocrinology. One can speculate on whether this accumulation of talent was nurture or nature.

Jan Gösta Waldenström, JW, the subject of this book, was very proud of his family. “Five generations of physicians”, was the title of a speech given by JW late in life. His pride was not unfounded, as will be shown in this first chapter. Emperor Napoleon’s competitor and his first field marshal Jean Baptiste Bernadotte (1766– 1844) was elected crown prince of Sweden in 1810 and became King under the new name Karl XIV Johan in 1818. Under his capable leadership Sweden, although still a poor country, experienced a peaceful modernization and recovery from wars and mismanagement. Our story begins in 1810 in the southern University Lund. Erik Magnus Waldenström (1795–1870), JW’s remarkable great-grandfather, was the first of the five generations. His father Anders Waldenström (1762– 1825) was an educated priest, teacher, and farmer in Dalsland in central Sweden, burdened by financial liabilities after acquisition of Kärnrud, a small farm in Frändefors where Erik Magnus was born. He studied medicine in Lund from 1810 until 1817. It is said that he could hardly afford to buy shoes, and had to borrow the needed textbooks from classmates, copy them and learn from his handwritten notes during night hours [1]. Despite economic hardship he obtained his doctor of medicine degree in 1917 and passed the examination for his doctor of philosophy (Ph.D.) degree with a thesis written in Latin in 1919 titled

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Wollheim, Jan Gösta Waldenström and His World, Springer Biographies, https://doi.org/10.1007/978-3-031-36739-7_1

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Fig. 1.1 Erik Magnus Waldenström 1850s. Uploaded by Per Erik Sundström. https://www.wik itree.com/photo.php/3/3b/ Waldenstrom-11.jpg

“De haemorrhagiis parturientium” (On bleedings in connection with childbirth) (Fig. 1.1). In the same year, Erik Magnus was appointed as district medical officer in the northernmost episcopate of Sweden and settled in Luleå, now one hour north of Stockholm by jet. In 1819, the journey from Stockholm required some three weeks. Luleå was more akin to a village with only 1000 in habitants, but the province occupied one quarter of Sweden’s total area. He was the only physician, and often had to undertake extensive travel by horse and boat to make sick calls. His contract stipulated wide-ranging responsibilities but came with a modest salary. One Saturday each month he had to serve at Gammelstad’s church village where a large number of families from remote parts of the district gathered for market and church. Dr. Waldenström soon became a much trusted physician, known to spend considerable time with his patients. When he made house calls, the patients felt better as soon as his steps were heard at the door. The remedies consisted of Peruvian bark, opium, and other plant extracts. Dr. Waldenström became known for accomplishing successful cataract surgery. In 1827 he restored the vision of six blind patients. In 1836 there was an outbreak of smallpox during which he was an efficient vaccinator. By the time he retired in 1862 the population of Luleå had doubled. The town had a hospital, and the district had five district medical officers. In 1820, Erik Magnus married Frederika Sofia Boedeker (1800–1835). They had eight children born between 1821 and 1834. In 1837, he was remarried to Margareta Magdalena Govenius (1816–1888) and fathered another seven children. Some farmland with cattle and poultry helped to support the growing family. The children participated in the care of the animals. Milk and milk products were never in short supply for the large household. Erik Magnus was a strict but loving father. He had a sharp temperament and made a frequent use of slaps, but then soon changed to warm friendliness. Thanks to thrifty habits probably recalling his own hardships as a student, he was able to support all ten sons during their academic studies. None was forced to take on debt. He was a forceful member of the municipal executive board of the city for many years and remained a friend of the poor and working class people. Also a passionate botanist, Erik Magnus was elected member of “Linnésamfundet” in 1832. This was a forerunner of the twentieth century Linnaeus Society. In 1850

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Fig. 1.2 Gammelstad’s (Old town) church village where Erik Magnus had to provide medical service once a month. Gammelstad is now listed as a World Heritage Site. Courtesy Gammelstad Visitor Center. https://trippa.se/tripp/varldsarvet-gammelstads-kyrkstad

Fig. 1.3 Ceremony in Arjeplog 9. September 2022. The white box about to be buried contains the scull of an unknown Lapp. It was donated by Erik Magnus to the Department of Zoology of the Lund University in 1852, and now given back to the Lappish congregation of Arjeplog. Courtesy Per Karsten, Historic Museum, Lund University. https://www.arjeplognytt.se/2022/09/09/dulutj-dalatjsamiska-kvarlevor-begravda-efter-130-ar/

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Fig. 1.4 Side-wheeler S/S Berzelius. Drawing by Per Wilhelm Cedergren. National Maritime Museum, Stockholm. https://digitaltmuseum.se/011024830995/teckning/media?slide=0, https:// digitaltmuseum.se/01©SMM/Anneli Karlsson

he donated a scull of a diseased Lapp to his Alma Mater in Lund (Figs. 1.2, 1.3 and 1.4). Two of Erik’s sons, Paul Peter (1838–1917) and Johan Anton (1839–1879), left Luleå on the side-wheeler S/S Berzelius in August of 1855. They arrived in Uppsala via Stockholm and entered their first two years at the private Lyceum school. Paul Peter was mainly interested in theology and classical languages. He won a threeyear scholarship for writing Latin poetry and later became a priest in the Lutheran state church. But after disagreeing with its rules regarding free communion, the significance of the creed, and the management of mission, he came into conflict with the state church and handed in his resignation. He became a senior religious lecturer in Gävle and rose to fame as “PP Waldenström” when he co-founded the independent Mission Covenant Church of Sweden, Missionsförbundet, in 1878. Ideally, “PP” envisioned a church composed of independent congregations, open for all who had been baptized at birth or as adults, or in exceptional instances were not baptized at all. Soon the number of congregations mushroomed was united into the Svenska Missionsförbundet. At its height, it had over 100,000 members. A sister organization in the USA is the Evangelical Covenant Church. In Sweden the members were called Waldenströmare (Waldenströmians). PP Waldenström was also an active politician and became a member of the Swedish Parliament. Today a student residence in Uppsala bears his name (Fig. 1.5). Paul Peter’s younger brother Johan Anton was also a brilliant student most interested in natural sciences and botany. He graduated as a medical doctor in Uppsala. His

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Fig. 1.5 Paul Peter Waldenström. https://www. alvin-portal.org/alvin/attach ment/download/alvin-record: 157764/ATTACHMENT0001.tiff Public Domain Mark

great-grandson Anders Waldenström has given an initiated account of Johan Anton’s pioneering academic career [3]. His exceptional performance as physician and scientist impressed his peers. The faculty provided him with a one-year bursary to study abroad. He visited the universities of Dresden, Prague, Vienna, and Würzburg. He spent ample time with Theodor Billroth in Vienna and Friedrich Daniel von Recklinghausen in Würzburg. On returning to Uppsala, he was made assistant professor and awarded the position of assistant surgeon at the Academic Hospital. He completed a dissertation on optimizing the time to operate a cataract, but was also the first surgeon to perform a successful laparotomy on a case of severe volvulus in Sweden. He was appointed “Doctor for the Town and its Poor” in Uppsala. In Uppsala, Johan Magnus also opened his “Waldenström Polyclinic,” which he developed into a busy medical center for surgery attracting patients from other parts of the country as well. There he trained enthusiastic fellows. He pioneered cataract surgery, management of gynecologic diseases, and abdominal surgery. In addition, he often was called on as locum professor of medicine. In October of 1879, Johan Magnus was appointed to the vacant chair of Practical Medicine at the university in Uppsala. While composing his inaugural speech, he fell ill with abdominal pain and self-diagnosed appendicitis. He was unable to persuade any of his colleagues to perform the needed surgical intervention which could have saved his life. He died on the 15th of November 1879, the day of the scheduled inauguration as professor. At the funeral a week later, the cathedral of Uppsala was filled with mourners and the grave was covered by 150 wreaths [3]. In his unfinished 15-page inauguration speech he was critical of the title of professor: “This very word professor is seen by

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Fig. 1.6 Johan Anton Waldenstöm. https://www. alvin-portal.org/alvin/attach ment/download/alvin-record: 90463/ATTACHMENT0001.tiff. Photographer Heinrich Osti, Uppsala Public Domain Mark

many as a vast dividing wall, which makes the distance between the teacher and the taught far too great. Away with it! It should rather be the opposite—let the scholar approach the teacher: for to whom can a disciple turn more safely for advice and information?”. On the 5th of January 1880, his widow gave birth to their second child, a son who was christened Johan Anton like his father. Johan Anton Jr. grew into a prominent surgeon and became head of surgery in Falun in 1914. In 1927, he was awarded an honorary doctorate by Uppsala University (Fig. 1.6). Johan Anton Jr’s older brother, Johan Henning (1877–1972) rose to prominence as one of the first academic orthopedic surgeons in Sweden. In 1906, he became in charge of a pediatric ward at St. Göran’s Hospital in Stockholm. A significant proportion of the children had skeletal tuberculosis. His diagnostic acuity helped him to discover a new disease. The first patient was an eight-year old boy with a limp that was considered to be functional. But radiographic examination showed a flattening necrotic lesion of one hip. Henning found nine similar cases and wrote a doctoral thesis on this condition which he interpreted as a benign form of tuberculosis and suggested the name coxa plana. The following year the same condition was independently described by three investigators and characterized as developmental rather than infectious. It is now known as Legg-Calvé-Perthes-Waldenström’s disease.

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Fig. 1.7 Henning Waldenström. Uploaded from Portrattarkiv.se picture of Henning Waldenström. https://portrattarkiv.se/det ails/sj9PGLAlnmUAAAA AABJvvw PDM

Henning became assistant professor in 1910 and left St. Göran’s Hospital in 1936 when he was promoted to professor and chairman of pediatric orthopedics at the Karolinska Hospital. Like his father, he was an inspiring teacher and his scholars ended up in leading positions in Sweden. As a vibrant 85-year-old emeritus professor, he attended a dissertation in Malmö in 1962 asking relevant questions ex auditorio. The defendant was a radiologist, Lars Andrén and the dissertation dealt with the early diagnosis and prevention of sequelae of congenital hip luxation [4] (Figs. 1.7 and 1.8). The life and career of Henning Waldenström’s only child, JW, is the theme of this book. JW had seven children. Three of the five sons constitute the 5th generation of physicians. Johan (1935–2013) became a respected M.D., Ph.D. in clinical chemistry at the University of Gothenburg. He was promoted to Head of the Department of Clinical Chemistry in Uddevalla. Anders, born in 1943, also started his academic career in Gothenburg where he graduated with a M.D. Ph.D in cardiology. He was promoted to the chair of cardiology at Umeå University. While still in Gothenburg, Anders described the enhanced catecholamine excretion from injured myocardium [6]. Following up this observation, his group showed that treatment of patients suffering from acute myocardial infarction with a beta blocking agent reduced myocardial damage and diminish mortality [7]. This seminal finding set off a furious international debate in the 1980s and 1990s, but the Swedish team was correct and the treatment became accepted practice. Anders and his group still perform cutting-edge molecular research related to exosomes released from heart tissue.

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Fig. 1.8 A children’s ward at Lovisa Hospital attended by Henning Waldenström. From: Ehrenpreis [5] © Springer Verlag

Another son, Dag, was born in 1960 earned a Masters of Engineering degree and had a successful career in the aircraft division of SAAB. The third son to become a physician, Erik, was born in 1962. He received his M.D. in Malmö, spent 17 years in Uppsala where he specialized in endocrinology, and became assistant professor. He returned to Malmö as a respected associated professor in the Department of Endocrinology there. Clearly Jan had reason be proud of the generations of physicians preceding and following him. One may ponder whether the familial accumulation of outstanding academic achievers was a consequence of “nature or nurture”. Probably it can be viewed as a happy result of a combination of both. Interestingly, genome-wide DNA studies of identical twins which had been separated and raised in different families suggest that genetics has a stronger influence on academic achievement than the early environment [8].

References 1. Provinsialläkare JG. 1819–1862. Erik Magnus Waldenström. Luleåbygdens Forskarförening; . p. 1–4. http://lulebygden.se/tidning/Tidning-LF-93-Artikel-Erik-Magnus-Waldenstrom.pdf 2. Waldenström PP. Minnesanteckningar 1838–1875. Samlade och ordnade av Bernhard Nyrén. Svenska Missionsförbundets Foreleg, Stockholm; 1928. http://runeberg.org/waldminn/ 3. Waldenström A. Johan Anton Waldenström, a versatile doctor and pioneer: professor of medicine and practicing surgeon. Ups J Med Sci. 2015;120(2):90–4. 4. Andrén L. Pelvic instability in newborns with special reference to congenital dislocation of the hip and hormonal factors. A roentgenologic study. Acta Radiol Suppl. 1962;212:1–66.

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5. Ehrenpreis T. 100 years of pediatric surgery in Stockholm, with personal memories from the last 50 years. Prog Pediatr Surg. 1986;20:17–33. 6. Waldenström AP, Hjalmarson AC, Thornell L. A possible role of noradrenaline in the development of myocardial infarction: an experimental study in the isolated rat heart. Am Heart J. 1978;95(1):43–51. 7. Hjalmarson A, Elmfeldt D, Herlitz J, Holmberg S, Málek I, Nyberg G, Rydén L, Swedberg K, Vedin A, Waagstein F, Waldenström A, Waldenström J, Wedel H, Wilhelmsen L, Wilhelmsson C. Effect on mortality of metoprolol in acute myocardial infarction. A double-blind randomised trial. Lancet. 1981;2(8251):823–7. 8. Smith-Woolley E, Ayorech Z, Dale PS, von Stumm S, Plomin R. The genetics of university success. Sci Rep. 2018;8(1):14579. https://doi.org/10.1038/s41598-018-32621-w.

Chapter 2

Childhood in Stockholm and Student Years in Uppsala

Abstract Raised as an only child in Stockholm Jan received a first-class education including classic and modern languages. His father infused an interest in nature and science. In 1924 he moved to Uppsala and started medical school. Dag Hammaskjöld became his closest friend. They traveled together and spent a term in Cambridge where Jan attended a course of biochemistry in Sir Frederik Gowland Hopkin’s institution

In 1905, the young doctor Henning Waldenström married Elsa Maria Laurin (1870– 1939). Her father was the master printer Gustav Leonard Laurin (1836–1879), working for the publishing house Norstedt, the oldest in Sweden. Elsa had a very lively intellect and tended to become nervous, and “she was not easy to live with” due to this anxiety [1]. Jan was born on the 17th of April 1906 in Stockholm and raised as an only child by a devoted, loving mother. Jan’s father worked long hours, so that the most time he could spend with his son was on Sundays. Elsa had more time and could spoil her only child seven days a week and introduce him to the world of books and the arts. Nevertheless, Jan was also strongly influenced by his father during their regular extended Sunday walks in the abundant parks and green spaces in Stockholm. These walks nurtured Jan’s lifelong interest in nature, in particular botany. Familiarity with common and rare plants sharpened his observational ability and was rewarded by the happy pleasure of recognizing an unusual flower—or patient. It trained the eye to pay attention to discrete details and was useful training for a future physician [1] (Figs. 2.1 and 2.2). The Waldenström family lived in an apartment house on Kommendörsgatan 3, adjacent to the green “Humlegården” in central Stockholm. Jan loved skiing there and other places in the winter. When there was no snow the Sunday walks with his father were compulsory even if the weather was not inviting. Although Jan rather would have preferred to stay indoors on such days, it was during these walks that he was introduced to his father’s work. Henning infused Jan with an early interest in the pursuit of science. Henning had predicted that understanding metabolism would become the way to better understanding of disease mechanisms. Jan came to admire Henning’s work and later considered him his most important teacher [1] (Fig. 2.3).

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Wollheim, Jan Gösta Waldenström and His World, Springer Biographies, https://doi.org/10.1007/978-3-031-36739-7_2

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Fig. 2.1 Elsa Waldenström maiden name Laurin. Courtesy Anders Waldenström

Fig. 2.2 Jan Waldenström aged 4. Courtesy Anders Waldenström

Henning worked mostly with children, many suffering from scoliosis. He employed a Russian method of putting the child in a plaster cradle which was slowly adjusted to support a straighter position. The treatment could require the child to spend many months in a hospital bed and demanded a good deal of patience,

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Fig. 2.3 Humlegården (The hops farm) with a statue of Carl Linnaeus. https://www.visitstockholm. se/o/humlegarden/. Assessed 2 February 2022

encouragement, diplomacy, and empathy of the physician in order to be successful. Another common diagnosis was tuberculosis and other causes of osteomyelitis. Chronic suppurating inflammation frequently caused deposition of amyloid in the liver and spleen. By examining liver biopsies Henning could show regression of the deposits when the bone lesions healed, contradicting the dogma of irreversibility which prevailed at the time. This research was published in Klinische Wochenschrift and Acta Chirurgica, leading medical journals of the time [2]. Jan remembered his time in school as “on the whole quite happy”. Subjects included Greek and Latin. He became fluent in German, French, and English at an early age. However, the teachers who had the most influence on him were biologists. One was Gunnar Täckholm, who had a doctorate in botany. He was particularly interested in the chromosomes of members of the rose family which made him a proponent of molecular biology, but he was not always able to get his pupils to share his enthusiasm. He would soon become a successful professor in Kairo and move to Egypt with his wife Vivi Täckholm. Jan graduated from high school with top grades and started medical studies in Uppsala in 1924. Uppsala was a city of culture, dominated by the oldest university of the country. Jan remembers with pleasure the tradition that a group of 8–12 students from any faculty would subscribe to living in a “matlag” (food team), where a landlady provided housing and basic meals. Jan was the only medical student in his matlag. Three of the members studied history, one studied history of art, one law, and one political science. Dinner was at 4 pm. The house had no central heating, but after dinner the students gathered at the fireplace where they indulged in “endless discussions” while consuming roasted chestnuts and drinking cheap red wine. Humanity and the arts were essential ingredients of student education in those years [1].

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In 1926, Jan’s parents divorced, and his mother Elsa moved to Uppsala for a year where her best friend Agnes Hammarskjöld lived. Agnes was the wife of the county governor Hjalmar Hammarskjöld (1862–1953). Their home was situated in the Renaissance period Uppsala Castle. Hjalmar was a distinguished judge and had served at the international court in The Hague. He was prime minister of Sweden in the difficult period from 1914 to 1917. Agnes’ maiden name was Almquist. One of her ancestors was Jonas Love Almquist (1793–1866), a leading liberal and therefore controversial author, poet, and composer. The Hammarskjölds had 4 sons. The youngest, Dag Hammarskjöld (1905–1961), was frequently invited to Jan’s matlag, although he did not take all meals there, since his home was in the Castle of Uppsala. Dag was a welcome participant in the discussions at the matlag. Dag and Jan had quite different personalities but had common interests in literature, philosophy, the arts, religion, and nature. Both were also fluent in French, German, and English. Jan, Dag, and another member of the matlag, Rutger Moll (1902–1987), developed a lasting friendship and three were to correspond for many years. Several of the letters from Jan to Dag from 1925 and onward survive at the Royal Library in Stockholm and those from Dag to Jan with Jan’s son Anders. The letters reveal what the friends had on their minds. History professor Karl E. Birnbaum has written a book focusing on Dag Hammarskjöld’s spiritual nature in part based on this unpublished material [3]. Looking back, Jan concludes that the discussions were a crucial part of his education, a training in “finding arguments and in logical thinking” [1]. Radio was nascent and television did not exist, and the comradery of the matlag avoided the frustrating experience of reading of a book in isolation about penguins and other things of little interest, “learning a lot that I really did not care for” [1]. Soon the friendship between Dag and Jan would include excursions to the nearby forests, and hiking in Swedish and Swiss mountains. Birding and botany were then and later common hobbies. Jan and Dag would also spend time with their mothers at the fireside in the Castle and at cultural events in Uppsala. Years later Jan had kept a concert with Beethoven’s 9th symphony in fond memory [1]. French poetry was one of Dag’s special interests. With time Dag would become personally acquainted with several poets. One was Felix Leger, a former diplomat. His nome de guerre as a poet was Saint-John Perse. Dag successfully nominated him for the Nobel Prize in literature in 1960. A most influential preclinical teacher in Uppsala at that time was the professor of anatomy, J. August Hammar (1861–1946). Jan was not a fan of morphology, but this “typical professor, rather absent minded, factual and dry” in his lectures presented relevant biological and medical problems. His main interest was endocrinology and the production of hormones, in particular from the thymus. He published a comprehensive monograph of 700 pages in 1926–9 and was acclaimed as a pioneer in the field of thymus research at the first international thymus congress in 1962. Among clinicians, Jan was greatly influenced by the professor of surgery Gunnar Nyström (1877–1964). He was a fine surgeon and organizer with a keen interest in the care of patients. The “most brilliant professor” was Robin Fåhraeus (1888–1968), well known for having rediscovered the erythrocyte sedimentation rate, ESR, in 1921 [4]. Fåhraeus was unaware of the publication 75 years earlier where the sedimentation of erythrocytes was described by Herman Nasse (1807–1892) in Bonn in 1836

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[3]. This discovery was overshadowed by Rudolf Virchow’s (1821–1902) fame and discovery of the cellular basis of pathology. Nasse also noted the difference in blood in the normal and pregnant state, and the importance of fibrin in plasma for the sedimentation rate. Fåhraeus’ mother had been a great actress and Jan noted that “the professor had inherited much from her”. Although his interest was in general pathology, he was professor of pathologic anatomy, a field in which he was not an expert. Fåhræus’ shortcomings as a teacher shaped Jan’s “deep rooted criticism of morphologic pathology”, which would not be reversed until much later. Jan’s main interest soon focused on internal medicine. The professor of medicine in Uppsala was Gustaf Bergmark (1881–1951), who had studied in Paris with Georges-Fernand Widal (1862–1929) and in Breslau with the pediatrician Adalbert Czerny (1863–1941). Bergmark was appointed professor of applied medicine and pediatrics in 1916 and of applied medicine from 1921 until his compulsive retirement in 1946. At that time, internal medicine was still a unified specialty including neurology and current subspecialities. Professor Bergmark was an excellent teacher of “the fundamentals” [1]. The medical students spent six months full-time in his department and also four additional months as “medical assistants” at the end of medical school while also preparing for the important final oral examination in internal medicine. In medical school the more experienced senior students also served as informal tutors for the younger ones. The professor would test the students’ knowledge and abilities in physical examination, using hands, eyes, and ears on ward rounds. These were attended not only by the students but also by members of the staff. The students feared these teaching rounds and labeled them “slaughter-rounds”. The professor was merciless when students performed poorly. Although stressful, this system produced well trained doctors, and later as professor, Jan would perform similar although more benign teaching rounds in Malmö. Jan was particularly impressed by one member of the department’s staff, Elsa Segerdahl (1894–1975). She pioneered the diagnostic use of bone marrow examination in Sweden, and triggered Jan’s interest in hematology. She defended her doctoral thesis in 1935. When widowed in 1937, she left the university and became chief of medicine in the minor city hospital of Bollnäs to the north of Uppsala. Jan and others strongly felt that she should have been promoted to a more important post. Later as professor, Jan enjoyed visiting her several times in Bollnäs. In the fall of 1927 Jan and his friend Dag paused their studies in Uppsala and spent a term in Cambridge, England. While Dag studied political sciences, Jan attended an advanced biochemistry course in the laboratory of Sir Fredrick Gowland Hopkins (1861–1947) who in 1914 became the first professor of biochemistry in Cambridge. Sir Frederick had performed feeding experiments in animals which led to the discovery of vitamins, for which he was awarded the Nobel Prize in physiology or medicine in 1929 “for his discovery of the growth-stimulating vitamins” shared with Christiaan Eijkman (1858–1930) (Fig. 2.4). Among the personages he met in “Hopi’s” lab, Jan mentions J. B. S. Haldane (1892–1964), called Jack. Haldane came from an aristocratic family but like several others in the lab he was a socialist. Hopi was a brilliant scientist, mathematician,

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Fig. 2.4 Department of Biochemistry in Tennis Court Street, now called The Hopkins Building built in1924. With permission http://www.cambridge2000.com/cambridge2000/html/0005/P5160957. html. Assessed 23 May 2022

founder of developmental genetics, contributor to enzyme kinetics, and inventor of the term “cloning”, just to mention some examples of his many contributions. He left England after the Suez crisis of 1956 and moved to India, where his credo was that the first duty of a citizen was to be a nuisance to the government. Jan’s special mentor in Cambridge was Joseph Needham (1900–1995). Needham’s father was a physician, and although Joseph was initially inclined to study medicine, he was influenced by Hopkins to switch to biochemistry. He specialized in chemical embryology and would later publish an impressive monograph on the biochemistry of the fetus. Needham was also interested in politics. Despite an aristocratic background he leaned to the left and was fascinated by the communist leader Zhou Enlai (1898–1978). He learnt Chinese from the daughter of a visiting Chinese scientist in the department and became an expert sinologist. He spent much time traveling in China and was to write a multivolume treatise on the history of Chinese science wherein he emphasized that essential tools for the advancement of western science and culture including the horse saddle stirrup, gunpowder, printing, the magnetic compass, and clockwork were all invented in China. Jan mentions that he had the pleasure of meeting this impressive man again in 1982 and that he was “as mentally alert as ever” [1]. The time in Cambridge among these and other legends in science must have been thrilling for the young medical student from Sweden. It shows his lively ability to establish close relations with distinguished scientist which followed him throughout the years. Back in Uppsala Jan was fascinated by a book by the experimental zoologist John Runnström (1888–1971). The author on developmental embryology was a truly

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pioneering investigator, who was strongly influenced toward dynamic biochemical rather than traditional morphological investigation morphological by spending time at the Rockefeller Institute from 1931 to 3 with Leos Michaelis. Runnström’s favorite experimental model was the sea urchin egg. It bears witness to Jan’s curiosity and instinct for quality in research that he recognized the contributions of Runnström, who was to become a personal friend. Most clinicians in later generations may have learnt about Runnström only through Jan’s pen [1, 5, 6]. Jan was also fascinated by Hans Spemann’s discovery of chemical organizer and inducer signals in embryology [7]. Reflecting on his own education, Jan much regretted in later years that he had not devoted more time to basics of biochemistry and developmental biology before starting medical studies. But Jan was an outstanding medical student. While still a senior medical assistant in internal medicine, he encountered an individual patient. Penetrating her disease “from bed to benchside” led to his first major contribution to science. This will be the subject of the next chapter.

References 1. Waldenström JG. Reflections and recollections from a long life with medicine. Haematologica series, Ferrara Storti Foundation. Rome: Il pensiero scientifico; 1994. p. 1–136. 2. Waldenström H. Über das Enstehen und Verschwinden des Amylois beim Menschen. Klin Wchshr. 1927;6:2235–7. 3. Karl E. Birnbaum. Den unge Dag Hammarskjölds inre värld. Dualis, Ludvika; 1998. 4. Jorpes E. Robin Fåhreus and the discovery of the erythrocyte sedimentation test. Acta Med Scand. 1969 Jan–Feb;185(1–2):23–6. 5. Gustafson T. John Runnström. In memoriam 1888–1971. Exp Cell Res. 1972 May;72(1):1–14. 6. Runnström J, Monné L. Cytoplasmic structure of the sea urchin and starfish egg. In: The Svedberg. 1884 30/8 1944. Uppsala: Almqvist &Wiksell; 1944. p. 500–7. 7. Hamburger V. Hans Spemann and the organizer concept. Experientia. 1969;25:1121–5.

Chapter 3

The Red Urine Story

Abstract In 1932 still a medical assistant and not yet MD, Jan diagnosed a case of the rare and little known condition of porphyria. He embarked on fundamental investigations and discovered a chromogen in the urine of this and other patients with the condition. He went to Nobel Laureate Hans Fischer in 1934–5 as recipient of a Rockefeller stipend performing fundamental research and establishing a diagnostic assay based on the chromogen. Back in Sweden he examined the endemic porphyria cases in northern Sweden and completed a milestone thesis based on 100 cases of the disease in 1937. In Munich he experienced the disastrous political development in Germany and back home predicted the coming catastrophes, but nobody believed him.

3.1 A Diagnostic Triumph In the summer of 1932 Jan was serving as senior medical assistant on one of the internal medicine wards when the responsible attending physician suffered a minor traffic accident and needed to be replaced. Professor Bergmark then assigned the medical assistant Jan Waldenström, JW, to fill in for him. This turned out to be the start of JW’s first professional triumph. One of the patients on the ward, a 49-yearold woman, had been admitted with severe cramping colic, marked constipation, vomiting, hypertension, headache, and confusion. She was restless in bed and hallucinated. The diagnosis was unclear, but Jan got a clue when he learnt from a nurse that the patient passed dark red urine. Microscopy did not show hematuria. From his time in Cambridge (Chap. 2) Jan was familiar with a book by the successor of Sir William Osler as Regius professor of medicine in Oxford, Sir Archibald E. Garrod (1857–1936), titled “Inborn Errors of Metabolism”, first published in 1909. The third edition was published in 1926, the year before JW’s sojourn in the laboratory of Sir Frederick Gowland Hopkins. In Cambridge, the book was dedicated to Sir Frederick, a friend and scientific co-worker of Sir Archibald. One of the 10 chapters in this classic textbook dealt with “hematoporphyria congenita,” presenting the characteristic symptoms of porphyria which were very similar to those

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Wollheim, Jan Gösta Waldenström and His World, Springer Biographies, https://doi.org/10.1007/978-3-031-36739-7_3

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of the patient on the ward in Uppsala. Such patients cold pass red urine. The name porphyria is derived from the Greek word for purple, πoρϕ ´ ρα. The condition, then also named porphyrinuria, was considered to be extremely rare. A review from 1931 could only find 41 published cases [1]. JW promptly performed a true “bedside-to-bench” action. He walked to the laboratory of the eminent emeritus professor Carl Mörner (1864–1940) in the Department of Physical Chemistry in an adjacent building carrying a test tube filled with the patient’s red urine. JW told the professor that he was bringing urine from a patient with suspected porphyria and would like to use his Gitter spectroscope. The professor became interested and consented. JW could demonstrate that the urine contained large amounts of a substance with the absorption spectrum of porphyrins. This confirmed the diagnosis; the medical student had accomplished a remarkable independent exploit. Unfortunately, the correct diagnosis did not prevent a tragic outcome. In a paper of JW published in 1934 her history is presented in detail as case number I where it states “No signs of porphyria in the family”. The information that the family was from the north of Sweden passed unrecognized [2]. The patient had not reported earlier attacks of abdominal cramping and had not been exposed to hypnotics, known to trigger attacks of porphyria, but she did have a two-year history of alcohol abuse, another trigger. The intestinal symptoms had continued, she developed weakness of the arms and the mental condition deteriorated. She became paranoid, felt that someone was chasing her, and finally committed suicide by jumping out of the third floor window.

3.2 The First Publication Jan passed his medical qualifying examinations with distinction in 1933 and was soon employed as a junior house officer in the department of medicine. Curiosity regarding porphyria stimulated him to start a search for additional cases in hospital records and he also advertised for more cases among colleagues. Within a year he had identified 10 additional cases and could perform detailed spectroscopic and chemical studies on urines from six of them. A full paper was published in 1934 [2]. A review of the literature revealed that the majority of the 19 publications were case reports of only one or a couple of patients. It was known that some conditions, e.g., pernicious anemia, then still a deadly disease, lead poisoning as well as some hypnotics could cause increased urine excretion of porphyrin. Jan states: “Therefore the assumption of a toxic factor as causative also in idiopathic acute porphyria is very near at hand”. In support of an environmental influence, he cites a paper from 1890 describing two unrelated women with the disease who lived in the same household [3] and another report of two women who had succeeded each other working in the same restaurant [4]. Surprisingly he argues against the importance of “endogenous disposition” proposed in Germany by Günther [5]. JW cited a paper from 1931 reporting three siblings with the diseas [6] and one from 1912 of a mother and daughter with typical features of acute porphyria

3.3 Hans Fischer in Munich

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[7]. However, rather than accepting these reports as supporting Günter’s argument for a genetic etiology, JW comments that exogenous factors could not be ruled out even in these cases, and that excessive excretion of porphyrin actually had not been well documented in all the familial cases. He therefore concluded that “the question of heredity has to be left to the future”. Mislead by incorrect statement in routine case records JW later never trusted such documents. A bon mot by JW in future years would be “you cannot trust anybody, least of all yourself.”

3.3 Hans Fischer in Munich See (Fig. 3.1). In the 1934 paper JW also refers to the fundamental work on the biochemistry of red color in blood and bile pigments by Hans Fischer (1881–1945) in Munich who had started as a student of medicine in Munich and Marburg. In 1902 he become a fellow at the Department of Medicine of “the king among clinicians,” Friedrich von Müller (1858–1941) in Munich. He became the professor in 1902 and was distinguished as Geheimrat in 1913. Hans Fischer qualified as double PhD in both medicine and chemistry. He left medicine and became a full-time biochemist at the Technical University in Munich. There he was appointed professor in 1921. Friedrich von Müller’s interest in liver diseases triggered Fischer’s groundbreaking basic work on bile and blood pigments. A janitor in his busy laboratory happened to suffer from a benign form of congenital porphyria and excreted large amounts of porphyrin. His urine became a superb source of study material for the work on porphyrins for many years. Hans Fischer showed that the red blood pigment hemin was a tetrapyrrole where four pyrrole molecules formed a ring linked by metin bridges (–C=CH–). Bilirubin was shown to be an open chain of four pyrrols. In 1928 Hans Fischer accomplished the complete synthesis of hemin, the red pigment in blood. He also Fig. 3.1 Hans Fischer. Swedish photo, Nobel Prize.org. Photographer unknown, Nobel Prize Outreach AB 2022. Mon. 23 May 2022. https://www.nob elprize.org/prizes/chemistry/ 1930/summary

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Fig. 3.2 Formula of hemin. From Hans Fischer’s Nobel Lecture https://www.nobelprize.org/upl oads/2018/06/fischer-lecture-3.pdf [8]

showed it to have the oxygen-biding iron atom in the middle of the ring. In addition he showed that chlorophyll had an identical structure as hemin but magnesium as the inside metal atom. Hans Fischer was awarded the 1930 Nobel Prize in chemistry for truly remarkable accomplishments [8]. Henning G Söderbaum, chairman of the Nobel Committé for Chemistry, formulated the work as follows: “This synthesis was the pinnacle of his [Hans Fischer’s]research endeavors—which, in view of both their scale and the incredible complexities associated with them, deserve to be called an epic achievement” (Fig. 3.2). In Uppsala one of JW’s patients had frequent episodes of cramps and could be studied in detail. She passed colorless urine which became pink and then purple when exposed to light. JW could show that this pigment was not urobilin, the pigment derived from liver bilirubin, which is a normal metabolic product and gives urine its yellow color. He was unable to crystallize the abnormal compound but realized its significance because he identified it in urines from all his other patients with porphyria. Its presence was being demonstrated when colorless urines immediately developed a pink color upon addition of Ehrlich’s aldehyde reagent, p-dimethyl amino benzaldehyde in acid solution. Urines from control patients with pernicious anemia or lead poisoning did not contain this chromogen [2]. JW had made the fundamental discovery of a substance that much later was named porphobilinogen. He was now firmly committed to the task of uncovering the nature of the new chromogen. He published his findings in Acta medica Scandinavica, in a paper that could have been accepted by any leading biomedical journal of the time [2]. In order to explore porphyrins and the newly discovered chromogen in depth, JW realized that he should join Hans Fischer’s laboratory in Munich. He applied successfully for a Rockefeller stipend to spend a year with the world’s leading investigator of

3.4 In Munich with a Rockefeller Stipend

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hemoglobin at the time. The Rockefeller foundation was a most important supporter of global biomedical research after World War I, and Alan Gregg, a Harvard M.D., was its erudite director from 1930. JW was to meet him a decade later in New York and start a lasting friendship. The farsighted Gregg had no problem to dedicate foundation support to a young Swedish physician to pursue a promising research project in Germany. The decision was perhaps helped by Greggs reading of the Acta Medica Scandinavica paper [2]. The young doctor, his wife, and their first child, Magnus, moved into a flat near the English Garden in Munich in the fall off 1934. On the 30th January in 1933 the aging President Paul von Hindenburg named Adolf Hitler chancellor of Germany. This constitutional and legal act was the end of a 13-year history of the fragile democratic Weimar republic. It was the tragic start of 12 disastrous years in German history. The Nazi takeover transformed the constitutional country into a brutal dictatorship in less than three months. When German university students organized the infamous “cleansing” of the libraries of their universities from unwanted “degenerate” books and wanted the secretary of propaganda, Dr. Josef Göbbels to be a speaker at the public burning of the books on the 10th of May, the cabinet minister was at first reluctant, but agreed when he witnessed the unexpected general enthusiasm for the initiative at all German universities. Göbbels delivered one of his infamous speeches at the book burning on the Opernplatz in Berlin, just opposite the main campus of the Wilhelm von Humboldt University. Resistance was weak and silenced by widespread organized terror and fear of being murdered by Nazi gangs or being imprisoned in one of the mushrooming prisons and concentration camps. Many “Aryan” intellectuals supported or tolerated the anti-Semitic terror which facilitated their own careers or enriched them.

3.4 In Munich with a Rockefeller Stipend When JW arrived in Munich most “non-Aryan” employees had already been denounced and thrown out of German universities. Hans Fischer was “Aryan” and could retain his position. One less fortunate star among Friedrich von Müller’s many exceptional students was Siegfried Thannhauser (1885–1962). In 1931 Thannhauser was appointed professor and chairman of medicine at the prestigious university in Freiburg. But since he was “non-Aryan” he was denounced and humiliated and in 1934 dismissed by the vice chancellor of the university, a famous professor of philosophy, Martin Heidegger. Heidegger was the first Nazi vice chancellor of a German university and transformed his position into that of a local “Führer”. Fortunately, Thannhauser was able to resume his outstanding research at Tufts University in Boston, invited by Joseph Pratt in 1935. Working there for the rest of his life, he could not forget the degrading treatment he suffered in Freiburg and resisted several post-war invitations to visit Germany. A street in Freiburg now carries his name. Tannhauser was an only child, born in a wealthy art loving family. A relative, Justin Tannauser donated a large number of significant twentieth century art to the

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Fig. 3.3 Franziska and Siegfried Tannhauser sailing to USA in 1935. https:// www.dgim-history.de/filead min/_processed_/9/8/csm_ ThannhauserOpaOmaAboa rdShip_3_e2359b9a53.jpg 24 May 2022. Photographer unknown. © Kitty Munson Cooper San Diego, with permission

Guggenheim museum in New York, the Tannhauser collection. Siegfried Tannhauser collected medieval art and donated to the Boston Fine Arts Museum (Fig. 3.3). In Munich Hans Fischer gave JW a bench space in his private laboratory where he supervised the work almost daily. The nature of the urinary pigments was investigated utilizing their different solubility in water and organic solvents combined with their behavior in the new technique of chromatography and other chemical purification procedures. Urine and blood from patients with porphyria and from lead-poisoned rabbits were explored. Lead exposure was known to induce porphyrinuria in human lead poisoning. JW refined the method for measuring excretion of porphyrins and also described a specific assay for quantifying the colorless chromogen later named porphobilinogen [9, 10]. He failed to crystalize the chromogen, despite working in the laboratory of the world’s most successful crystallizer. Fischer was known as the man who only had to spit into his hand to obtain crystals: “Der spuckt in die Hand, und schon krisallisiert es aus”. Successful crystallization of porphobilinogen was only achieved almost two decades (Chap. 17) [11]. Glimpses of life in Munich appear in letters to Dag Hammarskjöld as well as in Jan’s memoir [12]. A letter sent from Munich on the 9th December in 1934 describes the wonderful paintings in the Pinakothek, the museum with “old masters”, but also tells of a lecture given by the visiting Nazi ideologist Alfred Rosenberg which everyone was obliged to attend. The letter is carefully phrased in order not to offend the German sensors. Another letter sent from Cortina d’Ampezzo in the Italian Alps shortly later is more outspoken. In this he writes that after the talk everyone in the audience applauded the non-sensical pseudoscientific racist nationalistic message except Hans Fischer. In his memoir, Jan relates the experience on returning to Uppsala in 1935. He was not believed when claiming that Germany was now ruled by a band of criminals and that this would have disastrous consequences not only for Germany. Friends in disbelief responded by pointing out that Germany after all was the country

3.5 Back in Sweden

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of Goethe and Schiller. JW also recalls that he attended the Munich Oktoberfest in company of a scientist in the laboratory who was a devoted member of the Nazi SS organization. On their way home when both had consumed a number of pints of strong Munich bier, Jan said “I do not understand why nobody has the guts to shoot Hitler”. To his surprise the Nazi scientist answered “I ask myself exactly the same”. Toward the end of JW’s stay in Munich, Fischer confided his sadness to JW when they were alone and nobody could be overheard: “Sie zerstören alles”, they ruin everything. In 1945, Munich and his institute were in ruins. Fischer in despair committed suicide. It is little comfort that Rosenberg, who later oversaw the Nazi terror in Poland, was executed in Nürnberg in 1946.

3.5 Back in Sweden The young family returned to Uppsala in the summer of 1935. On the way back time was spent with JWs ailing mother at the sanatorium where she was hospitalized. In Uppsala JWs father Henning had purchased a comfortable home for the couple located in the nice Kåbo section of town. Elisabet was expecting their second son Johan. JW expanded the use of his porphobilinogen assay and encouraged colleagues in the country to send him urine to analyze from suspected patients. A respected friend of JW, Arthur Engel (1900–1996), was the chief of medicine in the northern city of Boden. He was an excellent physician trained at the Karolinska. Engel sent him several positive urine samples of patients from the area which had been submitted to the Boden hospital, and often died. They had been referred by Dr. Einar Wallquist (1896–1985), a remarkable district medical officer in the small market town of Arjeplog who was curious regarding their diagnosis. Wallquist had graduated from the Karolinska in 1922 and moved to the post in Arjeplog that same year. He was charmed both by the scenery and by the inhabitants, their open friendliness and adherence to traditional Lapp culture and values, and he remained there all his life. He was to write some 20 books based on his life in the north and was nicknamed Lappmarksdoktorn, “Doctor of the Lapp country” [13] (Fig. 3.4). Einar Wallquist had for some years observed patients with the mysterious and often fatal illness known by the locals as “the red illness”. Wallquist could not figure out the diagnosis but was struck by the fact that multiple cases occurred in certain families. He had begun to explore church registers and archives of ancestors and discovered that many of the families descended from a young man born in 1701 who moved to the area and fathered a large number of children. The patients had attacks of abdominal cramps, developed neurologic deficits, and often died at young age. Wallquist referred some of the patients to the Department of Medicine in the city of Boden and finally learned the correct diagnosis. Engel and Wallquist could publish a brief paper in 1935 detailing a large family pedigree [14]. Decades later Wallquist would devote a chapter in one of his books about Arjeplog. to porphyria [15]. After returning to Sweden JW travelled to Boden and examined a large number of the patients guided by Einar Wallquist and Arthur Engel. At a meeting in Uppsala

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Fig. 3.4 Scenic charm of Arjeplog © Johan Fjellström, Arjeplog. https://www.arjeplog.se/images/ 18.2608810515b2f230e513e28d/1491212204631/VK_-DSC07367%20-%20kopia.jpg Fig. 3.5 Einar Wallquist with a young patient, 1930s [17]. https://sv.wikipedia. org/wiki/Einar_Wallquist#/ media/Fil:Einar_Wallquist. jpg 4 February 2022

in 1936 JW could present 40 Swedish patients at a meeting in Uppsala [16]. In one pedigree it was shown that three separate families had common ancestry eight generations back in the 17th century. Thus there was ample proof of autosomal dominant inheritance (Fig. 3.5).

3.6 The Doctoral Thesis

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3.6 The Doctoral Thesis JW’s material of patients kept growing through influx of cases from all over Sweden. In 1937 the number of porphyria cases had passed 100 and he finalized his doctoral thesis “Studien über Porphyrie” dedicated to “My wife” [18]. The defense took place on 8th May in the main auditorium of the department of pathology. The faculty opponent was the professor of physiology Gunnar Blix and the defendant’s selected opponent was Elsa Segerdahl. They were both impressed by the work of JW. The mocking third opponent was the pediatrician Bo Wahlquist, a friend and scientific collaborator. The monograph was Published as a 254-page supplement of Acta medica Scandinavica. It was written in German, then still considered to be a main language for medical literature and frontline science (Fig. 3.6). The thesis is divided into a biochemical and a clinical section. The biochemical section presents the four-pyrrole ring structure of coproporphyrin, which Hans Fischer had been able to crystalize and synthesize. It is the normal precursor molecule of heme and hemoglobin. In contrast, the liver pigment is a chain formed by four pyrroles. The normal porphyrin end product is called uroporphyrin. Using chromatography and different solubility in organic solutes reveals details of the blood and bile pigments in the urine and feces. With JWs new assay the unique chromogen could be identified in all patients, but also in some asymptomatic first degree relatives. The clinical part contains detailed case reports of 100 Swedish patients from 19 multi-case families. The patients were mainly young adults and children. Of the 100 patients, 60 were female. The age of onset was always after puberty and peaked between 20 and 35 years of age. The mortality was staggering; 48 of the Fig. 3.6 Title page from JW’s thesis [18]. Photo Frank Wollheim

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patients had died, often at a young age. It describes characteristic intestinal and neuropsychiatric symptoms which dominate the clinical picture. Hypersensitivity to sun and skin manifestations found in porphyria in other countries was uniformly absent. In particular, this distinguished the condition from a similar form of acute porphyria, found in South Africa which caused sensitivity to sunlight and extensive skin lesions but also shared the abdominal symptoms of the Swedish cases. The discovery of asymptomatic relatives who excreted abnormal amounts of the chromogen was an important new result from systematic family investigations. These were presented in a chapter under the heading “Latent porphyria”. The condition, now named acute intermittent porphyria, AIP, became known as “The Swedish form of AIP”. The designation as “acute” was as JW pointed out a misnomer since the condition is based on a genetic defect present at birth which becomes manifest after an environmental trigger. JW therefore proposed the alternative designation “pyrrolia” but this did not meet with success. As mentioned, the book ends with the details of the one hundred case histories, a phenomenal number assembled by searching all over Sweden. Study of the 19 multicase families indicated as mentioned dominant autosomal heredity with variable penetrance. The term “idiopathic porphyria was now obsolete. According to JW it was only used to conceal ignorance of the real mechanism. The identification of healthy carriers related to diseased individuals indicated that patients usually were heterozygous. JW alludes to his first case and states that his repeated questions regarding other cases of the disease in the proband’s family were consistently denied. It later became known that her mother had died at a young age with symptoms indicative of AIP (Chap. 17). Jan passed the examination with honors. On 13th May, the faculty decided to reward it with the rare highest grade of “Berömlig”, laudable, which is only awarded for an exceptionally outstanding Ph.D. thesis. After delivering required undergraduate lectures he was awarded the title “docent”, corresponding to assistant professor, and could continue his academic career as a staff member of the department of medicine in Uppsala. Two years later an important paper was published in collaboration with Bo Vahlquist, a future professor of pediatrics in Uppsala [19]. Here it was shown that the molecular weight of porphobilinogen is around 226 g per mol, and that the red porphobilin is about twice as large. Fresh urine from patients with porphyria usually has normal color, but becomes red in room air or at acid pH, as shown in the following figure. They also showed that boiling pure porphobilinogen in acid solution results in formation of a porphyrin. The authors acknowledge the support of the Nobel Laureate The Svedberg and his student, the future Nobel Laureate Arne Tiselius. These investigators are discussed further in a following chapter. This was the beginning of the red urine story. In Chap. 17 more recent porphyria developments will be discussed (Fig. 3.7).

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Fig. 3.7 The six left tubes show acid urine from porphyria patients. The next two tubes show disappearance of the color when the urines were made alkaline. The last two tubes show a colorless urine at pH 7.2 and the same urine made acid and boiled for 10 min. Figure from ref. [20] with permission

References 1. Mason VR, Farnham RM. Acute hematoporphyria: report of two cases. Arch Intern Med (Chic). 1931;47:467–83. 2. Waldenström J. Observations in acute porphyria. Acta Med Scand. 1934;31683:281. 3. Rankin JE, Pardington GL. Two cases of haematoporphyrin in the urine. Lancet. 1890;136:607– 9. 4. Zur WH, der Porphyrinkrankheit K. Deutsch Archiv klin Med. 1925;149:255. 5. Günther H. Die haematoporphyrie Deutsch Archiv klin Med. 1912;105:89. 6. Micheli D. Zwei Fälle familiärer Porphyrie. Deutsch Archiv klin Med. 1931;171:154. 7. Barker LF, Estes WL Jr. Family haematoporphyria and its association with chronic gastroduodenal dilatation, peculiar fits and acute polyneuritis. JAMA. 1912;59:718–9. 8. Fischer H. On haemin and the relationships between haemin and chlorophyll. Nobel lecture; 1930 Dec 11. https://www.nobelprize.org/uploads/2018/06/fischer-lecture-3.pdf 9. Waldenström J. Untersuchungen über Harnfarbstoffe, hauptsächlich Porphyrine, mittels der chromatographischen analyse. Dtsch Archiv klin Med. 1935;178:38–49. 10. Waldenström J, Fink H, Hoerburger W. Über ein neues Porphyrin bei acuter Porphyrie. HoppeSeylers Archiv phyiol Chemie. 1935;233:1. 11. Westall RG. Isolation of porphobilinogen from the urine of a patient with acute porphyria. Nature. 1952;170:614–6. 12. Waldenström, JG. Reflections and recollections from a long life with medicine. Haematologica series, Ferrara Storti Foundation. Rome: Il pensiero scientifico; 1994. p. 1–136. 13. Wallquist E. Få mans land (A scarcely populated neighborhood). Bonnier, Stockholm;1939:75– 92.

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14. A, Engel Wallquist E. Hereditär porfyrinsjukdom (Hereditary porphyria). Nord Med Tidskr. 1935;10:1521. 15. Wallquist E. Släktsjukan. In “De kranka och de uslingar”, A. Bonniers Stocholm; 1968. p. 204– 11. 16. Waldenström J. Familjär porfyri. Nord Med Tidskr. 1936;11:527–9. 17. Wallquist E. Kan doktorn komma. Bonniers Stockholm; 1935. 18. Waldenström J. Studien über Porphyrie. Acta med Scand. 1937;92(Suppl 82):1–254. 19. Waldenström J, Vahlquist B. Studies on the excretion of porphobilinogen with so called acute porphyria. Acta Med Scand. 1944;117:1–14. 20. Waldenström J, Vahlquist B. Studien über die Entstehung der roten Harnpigmente (Uroporphyrin und Porphobilin) bei der acuten Porphyrie aus ihrer farblosen Vorstufe (Porphobilinogen). Hoppe-Seylers Zschr physiol Chemie. 1939;260:189–209.

Chapter 4

Letters to a Special Friend

Abstract This chapter is based on original unpublished letters from Jan Waldenström to Dag Hammarskjöld mostly archived in the Hammarskjöld collection at the National Library of Sweden.

The close friendship between JW and Dag Hammarskjöld has been mentioned (Chap. 2). Saved documents bear witness of a relation of utmost importance to both. Letters and postcards from JW to Dag date from student years in 1925 to mature life in 1955 and are available at the Swedish National Library in Stockholm. They convey insight into the intimate development of JW in transforming years. JW’s characteristic handwriting was easy to read in the early documents. Later it became increasingly hard to decipher. An example of an early document is a postcard mailed by JW from Brügge in Belgium in January of 1926. It communicates that JW was not impressed by preceding tourist experience in Holland. It reached its destination although the address was frugal: “Dag Hammarskjöld, Ronneby, Sweden”. Ronneby had some 4000 inhabitants at the time, and in 1926 Dag was not yet world famous (Figs. 4.1 and 4.2). Later in 1926 Jan’s parents were divorced. On April 22nd, Jan wrote a letter to Dag dealing with this. A translation of the beginning reads: “Thank you for your letter that made me both glad and sorrowful. Glad for the deep sympathy and friendship it discloses which I also felt so strongly when we talked in the evening. And sad since I obviously was unable to show you how immensely grateful I am for all that you have done and also that you misunderstood my account of the event as just a formal message. It must really be true, what Rutger in a letter once critically characterized as my immensely tight and impervious shell causing you to misunderstand me”. Rutger Moll was another member of the “matlag” (Chap. 2), and a lifelong friend and admirer of Dag Hammarskjöld. This shell was to remain intact through the years. But in the letter Jan is aware of this quality and ascribes it to a combination of shyness and inability to express himself. The rest of the letter expresses Jan’s gratitude for Dag’s understanding and also for the fact that Jan’s mother suffered more from the divorce than his father who soon remarried. But as shown by letters from him to Elsa they maintained friendly contact [1]. A further reflection was that the new situation

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Fig. 4.1 Postcard from JW to Dag Hammarskjöld dated 7-1-26. In Hammarsljöld papers, National Library Sweden © Erik Hammarskjöld family

Fig. 4.2 Front side of 4.1 © Erik Hammarskjöld

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Fig. 4.3 Fjällnäs, Dag Hammaskjöld’s favorite refuge in the Swedish mountains. © Photo Johan Bjelke. Retrieved 4 February 2022. https://www.funasfjallen.se/sommar/fjallnas/

offered opportunities to be of help and return some of the love bestowed on him over the years from his mother. Religion and philosophy were much on the minds of the students. An example is a letter from July 12th of that year where Jan made the following statements: “To realize that a person’s past is so similar to that of oneself at present, must be a rare thing, but to know that the different goals we aim for are the same, that must be the strongest force for lasting unification. Now we not only face responsibility to ourselves and to the purpose of our lives, but also need to adapt values of a friend, and therefore I believe that our friendship will bring me closer to a religious concept of existence than anything else in life… In its highest form our friendship leads to a belief in immortality related to that referred to by Ernst in ‘Schiller’s death’, we do not (only) survive as individuals but (also) in other people by having influenced them”. The author has been unable to trace the reference to Ernst in Schiller’s death, but it is known that Schiller was a favorite author of JW (Fig. 4.3). Five years later Jan was traveling in Italy. On a postcard dated January 2, 1931 we read: “How was your stay in Fjällnäs? …How immensely nice it would be to meet and talk about all [the] curious things we have experienced. Do you remember that we used to refer to an angel in the Uffizi Gallery? Here it is with its wonderful expression: ‘Angelo Annuntiante’ by Melozzo da Forlì”. Fjällnäs was Dag’s favorite place in the mountains of Lapland (Fig. 4.4). During Jan’s and Dag’s months in Cambridge in the fall of 1926 Dag attended the political science lectures of John Maynard Keynes (1883–1946), an experience which became very useful when he finalized his master’s degree the next year in Uppsala. Dag’s tutor in Uppsala was a conservative authoritarian professor named Fritz Brock (1877–1956). Brock was reluctant to accept Dag’s liberal views in his master’s thesis, calling it “a slipshod piece of work”. However, he was persuaded to accept the work but did not give it the high rating Dag had hoped for. Consequently, Dag transferred to Stockholm for his Ph.D. dissertation. On June 11, 1927, Jan wrote:

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Fig. 4.4 Angelo Annuntiante’ by Melozzo da Forlì © Postcard. The Hammarskjöld papers, National Library of Sweden. © Erik Hammarskjöld family. The original paining is in the Uffizi Gallery in Florence

“I was so glad to receive your letter that I have to write at once and congratulate, before going to the library and read silly books…, I am proud of you and glad that our stay in England not only was a mutual pleasure for us but also had a fruitful consequence. You deserve all success…and no one can be more happy about this than your friend Jan”. Meanwhile Dag had been accepted as a respected member of a political science club in Stockholm where Gunnar Myrdal (1898–1987) was active. Myrdal was a leading economist and social democratic politician. Dag permanently moved to the more liberal environment in Stockholm. In 1933, he defended his doctoral thesis in Uppsala with good but not highest grades. He was now no longer motivated to pursue an academic career. Instead he was soon to rise rapidly as a government official. Dag was undersecretary in the Department of Finance for 10 years. Looking back, the powerful finance secretary Ernst Wigforss (1881–1977) acknowledged that “my financial agendas were those conferred by Dag Hammarskjöld”. Wigforss was one of the architects of the Swedish welfare system in the 1930s and 1940s. In a letter from Dalecarlia dated August 12, 1929, Jan tells of his growing interest in spending time in the company of women. Jan is in Dalecarlia and tells about a bicycle excursion to a scenic hill called Tällberg. Whereas female company previously had been mostly “bothersome”, it now could be both pleasant and interesting to meet some young ladies, provided they were both pretty and intelligent, and could listen and respond. “However there is only one with whom meetings are both immensely

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Fig. 4.5 View from Tällberg in Dalecarlia https://tallbergsby.se/tallbergs-by/. © Photo Tällberg

enjoyable and distressingly difficult. But she is the only one I like more every time we meet” (Fig. 4.5). A follow-up on this theme is a letter from Helsingborg on September 10, 1930, in which Jan discusses two women, Astrid, a nurse and Elisabet, a cousin of his once removed. Elisabeth was a granddaughter of P.P. Waldenström. He describes Astrid and Elisabet as poles apart. In favor of Astrid is that life with her would be easier, and also that it would bring fresh genes into the family. On the other hand, living with Elisabet could make life “rich, beautiful, and filled with variation, provided she could love me”. Elisabet was an independent woman with serious artistic ambitions. She was a talented amateur painter and would later study with André Lhote 1885– 1962(1885–1962) in Paris. It was Elisabet that Jan would marry in 1932. The first of their 5 children, Magnus, was born in 1933. Letters to Dag bear witness of a rich and passionate relationship. The year 1932 was also a seminal in Jan’s scientific life, as will be dealt with in the next chapter.

Reference 1. Erik Waldenström. Private archive.

Chapter 5

Assistant Professor in Uppsala

Abstract The new fully fledged “docent” did not rest after the successful dissertation. He completed a paper on uveoparotitis in which he questioned the prevailing view that it was a form of tuberculosis. He learnt to master the new technique of sternal marrow examination from Elsa Segerdahl. He published papers on aspects of “chlorosis”, iron deficiency. And he lived comfortably in a nice home with a growing family in a city of culture.

5.1 Early Hematology Research (See Fig. 5.1). Uppsala University is the oldest university in Sweden, founded in 1477 at the request of Pope Sixtus VI (1414–1484) as an institution of learning for priests. Uppsala is also the site of the Lutheran Archdiocese in Sweden. Nathan Söderblom (1866–1931) was the charismatic incumbent until his death in 1931. His first employment was at the hospital in Uppsala. He had studied at the Sorbonne and probably had been advisor to Alfred Nobel (1833–1896) when he planned his prizes. Söderblom was professor of theology in Uppsala from 1908 and in Leipzig 1912–14, and Archbishop from 1914. He was a friend of the Hammarskjöld family and one of the trustees of the university. He fully recognized the student Dag Hammarskjöld as an exceptional humanitarian individual. Ecumenicalism and peace work was his special concern, and he was awarded the Nobel Peace Prize in 1930. He helped Uppsala to become a city with windows wide open to the world. This atmosphere suited the future globetrotter Jan well (Fig. 5.2). As mentioned in a foregoing chapter, Elsa Segerdahl (1894–1975) was an accomplished member of the department of medicine headed by professor Gustaf Bergmark. Hematology was her prime interest. She pioneered the use of sternal puncture, a method that had only recently been described. In a paper published in 1934 she points out the importance of the bone marrow and that its total weight is around 2, 5 kg, making it heavier than the liver She presented her experience with bone marrow examination based on her some 90 procedures [1]. Pernicious anemia was one of the

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Wollheim, Jan Gösta Waldenström and His World, Springer Biographies, https://doi.org/10.1007/978-3-031-36739-7_5

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5 Assistant Professor in Uppsala

Fig. 5.1 Uppsala Castle and Cathedral, Uppsala University Library. Creator Erik Daglberg. Artist Willem Swiddle. urn:nbn:se:alvin:portal:record-83120 (nbn)

Fig. 5.2 Nathan Söderblom. Archbishop of the Swedish Lutheran Church. Commemorative stamp from The Federal Republic of Germany 1968

conditions with a pathognomonic appearance on bone marrow smears she was able to describe. She defended her Ph.D. thesis in 1935. Segerdahl’s husband, Axel W. Persson, (1888–1951) was a world-famous professor of archeology and classics history. Every year he would spend time performing archeologic field work in Greece. In 1926, he discovered an intact royal tomb with rich treasures in gold and silver in Dendrà on Peloponnese. The team could celebrate with wine tasting out of a golden vessel which had been found next to the queen. During WWII he and his wife performed humanitarian work in Greece for the Red Cross. He suffered a fatal stroke while on an archeological dig in Greece [2]. The Waldenström family was close to this couple. Jan would to visit Elsa frequently after her move to Bollnäs in 1952.

5.1 Early Hematology Research

39

Jan did not rest his oars for long after his successful thesis defense. A condition called febris uveoparotidea, considered mainly a concern of ophthalmologists, had been subject of numerous reports in ophthalmological journals and was usually regarded as a manifestation of tuberculosis. Jan was attracted by the variability and multi-organ manifestations of the condition and highlighted these in a paper with five “typical cases” of Heerfordt’s uveoparotitis. The common microscopic features were granulomas without caseation, nevertheless interpreted by the pathologist as typical tuberculosis. In one case, parotid histology only showed monocyte infiltration and fibrosis. Various neurological symptoms were also noted. These included facial paresis, “encephalitis lethargica, fatigue, and positive Babinski sign” [3]. Jan’s conclusion regarding the mixed characteristics was that three features, namely tubercular structures without caseation, a large percentage of tuberculin negative cases and very few positive findings of tuberculous bacilli “immediately associate the malady with…the so called Morbus Besnier-Boeck”, a disease now known as sarcoidosis. Eighty years later the triad of anterior uveitis, parotitis and neural lesions still is considered as a rare and atypical form of sarcoidosis and quoted as the Heerfordt-Waldenström syndrome [4]. The true nature of sarcoidosis remains unknown (Fig. 5.3). Elsa Segerdahl’s work in hematology greatly impressed Jan, and hematology became a primary interest of his as well. One pursuit was the study of the common form of hypochromic anemia. This condition was also known as “achyloric” anemia, but Jan could document this to be a misnomer since achylia was often absent in the patients seen in the department. Another popular name in the nineteenth and early twentieth century was “chlorosis”, also a misnomer, describing young woman with Fig. 5.3 Bilateral parotid swelling. From [3] with permission

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5 Assistant Professor in Uppsala

pale rather than green complexion. Jan reviewed the history of “chlorosis” and his own contributions to the field in a Swedish language paper published in 1941 [5]. He cites the Swedish work of Frans Warfvinge (1834–1908) from 1907, showing the curative effect of iron treatment. It is however surprising that Warfvinge believed that chlorosis had an infectious etiology. Encouraged by his chief, Jan started to investigate manifestations of iron deficiency, for which he introduced the term sideropenia. Reliable methods for determination of serum iron had only recently been introduced into the clinic. He reported on epithelial changes related to iron deficiency and their healing in the esophagus [6]. New observations on the Plummer-Vinson lesions in the esophagus, named after two Mayo Clinic physicians, Henry Stanley Plummer (1874–1936) and Porter Paisley Vinson (1890–1959), were presented in two publications showing their reversibility after oral administration of iron in high doses [7]. He observed that the patient’s dysphagia could resolve despite persistent radiographic evidence of strictures. He emphasized the well-known presence of brittle nails or koilonychias. He documents their presence in patients with low serum iron, even when their hemoglobin was normal. The changes always improved upon treatment with adequate administration of iron. The same applied to rhagades (fissures) at the corner of the mouth, and to the sideropenic atrophy of tongue papillae [7]. Jan exceled in precise clinical observations and connecting them with laboratory findings. As Jan had shown, sideropenia could cause other symptoms besides anemia, and he was also aware of the fact that low serum iron levels could be caused by infections and also occurred after initiation of remission inducing therapy in patients with pernicious anemia. He hypothesized that serum iron was regulated by metabolic processes similar those regulating serum glucose. While the prevalence of common conditions like diabetes and pernicious anemia was well established, that of sideropenia was not, and only a few hospital-based reports existed. Jan fully realized that determination of serum iron was a prerequisite for a meaningful epidemiologic study of sideropenia [8]. In 1920, Karl Otto Bonnier (1856–1941), Sweden’s leading publisher, started a series of excellent books presenting current medical topics to the general population. Academic authorities, mostly full professors, were selected to present their field of interest. One was Jan’s teacher Gustaf Bregmark, another Jan’s uncle Johan Waldenström. Jan was chosen to write the volume on hematology “Blodsjukdomarna och deras behandling” (Hematologic disorders and their treatment), published in 1944 (9). This 200-page volume included chapters on all branches of hematology. It shows that Jan was an enthusiastic teacher not only of medical students but also the public. Complex data were presented in simple terms yet avoiding oversimplification. An example is his presentation of the presence of high numbers of white myeloid cells in the blood of patients with leukemia. He points out that inspection of the blood specimen in the sedimentation tube reveals an opaque white layer (of white blood cells) above the red erythrocytes. Jan emphasizes how much one can learn just from observing the sedimentation tube: a fuzzy border between plasma and erythrocytes indicates the presence of increased number of young reticulocytes. They are not as dense as the older erythrocytes and therefore fall at a lower speed.

5.2 The Growing Family

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5.2 The Growing Family See (Fig. 5.4). The family of Jan and Elisabet was growing. Their second son, Johan, was born in 1935, Agnes in 1938, and Anders in 1943. The family lived in a home at Sveavägen 21 in the quiet neighborhood of Kåbo, nicknamed “city of professors”. Arne Tiselius and his family lived close by. The parents and their children developed warm friendships. A following chapter will show that Jan and Arne were also closely linked professionally. Arne’s son, the later rheumatologist Per Tiselius, was particularly close to Jan’s second son Johan, and Per has fond memories of “common skating, hunting, and shared traditions at Christmas time” (See Fig. 5.5).

Fig. 5.4 The Waldenström home, Sveavägen 21, Kåbo, Uppsala ©Anders Waldenström

Fig. 5.5 JW and Elisabet with son Johan in 1935. © Anders Waldenström

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References 1. Segerdahl E. Über Knochenmarkspunktionen (On sternal punctures). Acta Med Scand. 1934;(suppl59):173–181. 2. Axel W. Persson, urn:sbl:7106, Svenskt biografiskt lexikon (art av Paul Åström). 3. Waldenström J. Some observations on uveoparotitis and allied conditions with special reference to the symptoms from the nervous system. Acta Med Scand. 1937;91:53–68. 4. Fraga RC, Kakizaki P, Valente NYS, Portocarrero LKL, Teixeira MFS, Senise PF. Do you know this syndrome? Heerfordt-Waldenström syndrome. Ann Bras Dermatol. 2017 Jul–Aug;92(4):571–72. 5. Waldenström J. Är chlorosen verkligen utdöd? (Has chlorosis really disappeared?) Svenska Läkartidningen. 1941;38:1613–27. 6. Waldenström J. Iron and epithelium. Some clinical observations. Part I. Regeneration of the epithelium. Acta Med Scand. 1938;95:380–97. 7. Frantzell A, Törnquist R, Waldenström J. Examination of the tongue: a clinical and photographic study. Acta Med Scand. 1945;122:209–37. 8. Waldenström J. Blodsjukdomarna och deras behandling. (Hematologic disorders and their treatment) (9). Stockholm: Albert Bonniers förlag; 1944. p. 3–20.

Chapter 6

Two New Diseases

Abstract The unique tradition from Nobel Laureates Svante Arrhenius and current excellency of The Svedberg and his department where both the ultracentrifuge and electrophoresis techniques were created combined with JW’s outstanding bedside skill were instrumental in his breakthrough descriptions of purpura hyperglobulinemia and macroglobulinemia in 1943–4. JW was indeed the right person at the right time at the right location.

6.1 Uppsala, A Mecca of Physical Chemistry JW was a master of sharp clinical observation and “pigeon-holed memory and intrepidity” [1]. In addition, he was lucky to work in the environment of the world leading center of physical chemistry in Uppsala and he was to make the very best use of it by performing what is now termed translational research. This resulted in the discovery of two (!) new diseases in 1943, one of which would make him world famous. The discoveries were based on his observations of just a few patients with distinguishing clinical features. The tradition of outstanding physical chemistry in Uppsala would become instrumental for JW’s discovery of the new diseases. The tradition started with a Ph.D. student in Uppsala, Svante Arrhenius (1859–1927). He was the descendant of farmers. His father was a surveyor employed as manager of some of the Uppsala University’s estate. The son had inherited a strong interest in biology and wanted to explore its secrets using methods of both physics and chemistry. His physics professor in Uppsala did not understand the potential of this approach, which is why Arrhenius moved to Stockholm. Here the professor of physics Erik Edlund (1818–1888) offered him a position at the Swedish Academy of Sciences and later at the new Stockholm University. He studied the influence of electrical bursts on salts for instance sodium chloride in solutions and discovered the migration of their respective components to the negative and positive electrode. Other compounds, for instance arsenic did not migrate. Arrhenius had discovered the behavior of ions. Arrhenius presented this groundbreaking finding in his doctoral thesis in Uppsala in 1884. He passed the examination but due to the critique of the local professor © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Wollheim, Jan Gösta Waldenström and His World, Springer Biographies, https://doi.org/10.1007/978-3-031-36739-7_6

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the work did only earn a mediocre mark which barred him from becoming “docent” needed for continuing in academic advancement at the universities. In disappointment Arrhenius sent his thesis to two leading experts in physical chemistry, Jacobus van’t Hoff (1852–1911) in Amsterdam and Wilhelm Ostwald (1853–1932) in Riga. Ostwald was so impressed that he promptly traveled to Uppsala and offered him a position in his department. Arrhenius however stayed in Sweden and was now accepted as docent in Uppsala and also given a three- year travel award. This allowed him to visit centers of excellence in Europe. Back in Sweden he became full professor of physics at the young University College of Stockholm. In 1903 he the became first Swedish Nobel Prize Laureate: “The Nobel Prize in Chemistry 1903 was awarded to Svante August Arrhenius in recognition of the extraordinary services he has rendered to the advancement of chemistry by his electrolytic theory of dissociation.” In 1909 Arrhenius declined an offer to become professor at Germany’s leading university in Berlin. Ostwald, van’t Hoff, Arrhenius, and Walther Nernst (1864– 1941) are considered as founding fathers of physical chemistry. They all were Nobel Laureates (Fig. 6.1).

Fig. 6.1 Svante August Arrhenius. Photogravure Meisenbach Riffarth & Co. Leipzig—Zeitschrift für Physikalische Chemie, Band 69, von 1909.—Scanned, image processed and uploaded by Kuebi = Armin Kübelbeck Publik domain. https://sv.wikipedia.org/wiki/Svante_Arrhenius#/media/Fil: Svante

6.2 The Svedberg and the Ultracentrifuge

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6.2 The Svedberg and the Ultracentrifuge Uppsala University was fortunate to attract a brilliant young investigator who would follow along the path of Ostwald and Arrhenius. Theodor “The” Svedberg’s (1884- 1971) interest in electricity started while he still was a high school boy in Örebro and built a Marconi transmitter and a Tesla converter [2]. In Uppsala he impressed the teachers by his experimental proficiency and finished his B.A. in record time in 1905. That year he embarked on the study of metal sols using an improved ultra-microscope developed by the Austrian physicist Richard Zsigmondy (1865–1929) [3]. This required a high-intensity light source. Electricity was not yet installed at the university so Svedberg had to build his own generator. With the microscope he was able to study Brownian motion in colloidal solutions and could confirm a theory of Albert Einstein and von Smoluchowsky regarding the composition of materiel. Svedberg received his degree as doctor of philosophy in 1908 with a thesis soon regarded as a classic [4]. He was professor and chairman of physical chemistry in Uppsala from 1912 until the compulsory retirement in 1949, mentoring generations of Swedish and foreign fellows. Svedberg had noticed that sedimentation of the components in colloidal solutions was related to their size and wanted to use this feature to study them in detail. Spontaneous sedimentation was very slow, and in order for it to become practical as an analytic method it needed to be accelerated. Svedberg was probably inspired by Gustaf de Laval (1845–1913) who patented his “Separator” for the separation of milk in 1878. This revolutionized the production of cream. A company called Separator was founded, and the Separator became widely used in Sweden and abroad (Fig. 6.2). Svedberg needed a centrifuge with augmented performance, a so-called ultracentrifuge. The work was impeded by lack of funding in Uppsala, which is why some important early developments were achieved while Svedberg worked as visiting professor at the University of Wisconsin. The completed ultracentrifuge generated a centrifugal force of 106 gravities. The separated macromolecules were visualized

Fig. 6.2 Swedish Commemorative stamp from 1963 honoring Gustaf de Laval

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by the Schlieren optical method. The instrument also allowed collection of separate fractions. An early observation was that proteins were macromolecules of distinct size and not a continuum of different sizes as previously believed. Many proteins were 17,500 kD, and this size was later designated one Svedberg unit, abbreviated as “S”. His favorite molecule was hemocyanin with a molecular weight of 1 million. With the improved ultracentrifuge Svedberg was able to show that hemoglobin was a homogenous protein with a molecular weight of 68,000, four times greater than expected. This was the greatest surprise of his lifetime in science. Robin Fåhræus (Chaps. 2 and 8), the later professor of pathology and introducer of the erythrocyte sedimentation rate, was a coworker of Svedberg and had stayed at the laboratory during the first run. When Fåhraeus noticed signs of the surprising result he called Svedberg at 3 AM, who wasted no time and immediately joined him in the laboratory [5]. The ultracentrifuge revolutionized the study of chemical and biochemical matter. Swedberg was awarded the Nobel Prize in 1926 for his observation of the molecular composition of “disperse systems”, motivated by his earlier work related to his thesis. But he devoted his Nobel lecture to the recent work on the Ultracentrifuge which made him a legend [6]. The instrument remains an important research tool to this day. In 1930, the Department of Physical Chemistry, the first in Sweden, moved to a new building (Table 6.1). The Department of Physical Chemistry attracted scientists from overseas. Table 6.1 Molecular weights of some proteins calculated by ultracentrifugation with permission from[5] C 1926 American Chemical Society Substance

method

observer

Ovalbumin (electrolyte-free)

Molecular weight 34,500

equilibrium

Nicholas and author 1926

Haemoglobin (electrolyte-free)

67,700

equilibrium

Fåhraues and author

Haemoglobin (electrolyte-free)

68,000

speed

Author 1926

Haemoglobin (buffer pH 6.2–7.7)

68,100

speed

Nicholas 1927

Phycocyanin (buffer pH 7.0–7.9)

105,900

equilibrium

Lewis and author 1927

Phycocyanin (buffer pH 7.0)

105,000

speed

Lewis and author 1927

Phycocyanin (buffer pH 5.0–6.8)

207,700

equilibrium

Lewis and author 1927

Phycocyanin (buffer pH 5.0–6.8)

226,800a

speed

Lewis and author 1927

a Owing to the difficulty of measuring the speed of diffusion of the phycoerythrin exactly, this value

is less accurate than the preceding value

6.2 The Svedberg and the Ultracentrifuge

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Frank Horsfall came from Columbia University in New York. Michael Heidelberger visited from the Rockefeller Institute. Kai Oluf Pedersen (1901–1991) joined the department in 1930. This young chemist left Copenhagen much against the advice of his superiors. He wanted to work with The Svedberg in Uppsala, a decision he never regretted. He stayed in Uppsala for the rest of his life and contributed significantly to the development of ultracentrifugation and its application in clinical science. He coauthored the book “The Ultracentrifuge” in 1940 [7]. With Heidelberger he published a paper on the size of antibodies [8] (Fig. 6.3). In 1949 the university received donation from Gustaf Werner which was used to construct and accommodate a large accelerator, a synchrocyclotron in a new Gustaf Werner Institute with The Svedberg as director. In 1977 it was re-named The Svedberg Laboratory. In addition to his contributions to science The Svedberg was an ardent botanist. His herbarium contained 11,000 species and was donated to Uppsala University. He was also an accomplished artist of landscapes and textiles.

Fig. 6.3 The Svedberg, painting by Isaac Grünewald as a gift from friends to celebrate his 50th birthday in 1934. He is depicted with an ultracentrifuge rotor. The painting by a prominent modern Swedish artist has been donated to Uppsala University Photo Michael Wallerstedt. https://kemisa mfundet.se/utlysning-the-svedbergpriset-2019/ 14.June 2022

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6.3 Electrophoresis and Arne Tiselius Arne Tiselius (1902–1971) joined the laboratory of The Svedberg as research assistant in 1925. By then, Svedberg had realized that in addition to size, electrical charge was a distinguishing feature of macromolecules with a possible analytic potential. He entrusted Tiselius with the task of developing an instrument for the electrophoresis of macromolecules. After five years the outstanding young investigator defended his Ph.D. thesis entitled “The moving boundary method of studying the electrophoresis of proteins” [5]. Although the work was well received Tiselius switched to studies of the ion diffusion in zeolites. He collected them on the Faroe Islands and then moved to Princeton as recipient of a Rockefeller grant. In 1935 he returned to Uppsala and resumed work to improve the technique of electrophoresis. Convection still hampered protein separation and caused blurring. With the help of the institute’s instrument workshop Arne Tiselius modified the electrophoresis apparatus. The new instrument consisted of a U-shaped tube built of flat cells with a rectangular cross-section enclosed in a cooling envelope, allowing performing the analytic run at 4 °C. With this tool he showed that serum consisted of well-defined protein fractions of albumin and three different globulins which he named α, β, and γ. He was unable to publish this fundamental discovery in chemical or biochemical journals. It was considered it “too little chemical”, but in 1937 the work was finally accepted by Transactions of the Faraday Society [9]. It did not take long for the scientific community to realize the importance of this paper. Tiselius was flooded with requests for reprints. Later in the year he was able to publish a paper showing that immune sera contained increased amounts of γ globulin [10] Fig. 6.4. As mentioned, Arne Tiselius was a personal friend of Jan who could follow his experimental work from “rink side” and become acquainted with visitors to the laboratory. In Uppsala, the new instrument allowed isolation of the distinct fractions. A

Fig. 6.4 Arne Tiselius at work in the 1950s. © Courtesy Per Tiselius

6.4 Purpura Hyperglobilinemia

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guest from the Rockefeller Institute, Elvin Kabat (1914–2000), (Chap. 25), came to Uppsala, bringing his immune sera for analysis following up on Michael Heidelberger’s (1888–1991) previous studies in Uppsala [11]. In order to further strengthen the collaboration between the investigators in New York and Uppsala Arne Tiselius was invited to work at “the Institute” for a year. His sojourn in New York in 1939 was interrupted after two months due to the start of WWII. In Uppsala he was appointed to a newly established chair as Sweden’s first professor of biochemistry. His department, adjacent to that of Svedberg, soon flourished with activity thanks to the new analytic instrument. After the war both Swedish and foreign scientists crowded the laboratory of Tiselius. In 1948, Arne Tiselius was awarded the Nobel Prize in chemistry “for his electrophoretic and analytic adsorption work, in particular his discovery of the complex nature of serum proteins”. In 1952, Arne Tiselius could move into a new more spacious building. Among his visiting scientists was Henry Kunkel (1916–1983) from the Rockefeller Institute, who will be addressed in a following chapter. Tiselius collaborated with the drug company Pharmacia in Uppsala in the development of the carbohydrate dextran for blood substitution. The PhD student Jerker Porath worked on chromatographic techniques and invented a method for the separation of material in columns filled with dextran of homogenous bead size. He discovered that molecules could conveniently be separated by “gel filtration”. The largest molecules would pass faster through the columns, whereas smaller were slowed by diffusing into the beads. The diffusion was regulated by their size and shape. The method patented as Sephadex in 1954 would soon be used in research laboratories and industry worldwide and the product greatly contributed to the growth of Pharmacia [12].

6.4 Purpura Hyperglobilinemia Thanks to Robin Fåhreus (1888–1968) and the work on its standardization by Erik Westergren, the sedimentation rate, ESR, was in general use early in Sweden. Jan realized the potential of applying ultracentrifugation and electrophoresis to investigate conditions with elevated ESR. In 1943, he published a full-length paper in Swedish with the subtitle “A study of essential high ESR” [13]. A total of 37 patients with persistent ESR above 120 mm/hour were observed between July 1940 and April 1943. Their diagnoses included myeloma, liver cirrhosis, polyarthritis, systemic lupus erythematosus (SLE), and others. A common finding was greatly increased levels of “globulin”. Diminished amounts of albumin were found among the six cases of myeloma, but the other patients usually had normal levels of albumin and often elevated levels of total protein. Jan concluded in his paper that the new methods of ultracentrifugation and electrophoresis were useful research tools but were too complicated for routine clinical use. He elaborates on alternative methods such as Takata-Ara precipitation, formol-gel testing, altered viscosity and the euglobulin test. He could not foresee the introduction of paper electrophoresis a few years later [14].

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The lasting importance of the Swedish paper is its description of three patients followed over eleven, nine, and “only two” years’ time respectively, with a previously unknown disease. One man and two women suffered from recurrent purpura, mainly of the lower extremities. The numerous disease flares could be precipitated either by local pressure or occur spontaneously. Each purpuric lesion was only a few mm wide but after healing it left a characteristic brown pigmentation (Fig. 6.5). The long-term prognosis was benign. Jan realized the novelty of these cases and named the condition “purpura hyperglobulinemia” [15]. His observations were soon confirmed by several other investigators. The condition is still known as “Purpura hyperglobulinemica Waldenström”. In 1952 Jan published three new cases with more clinical details and also a color illustration. In later years he mused over the fact that his first paper in Swedish language, containing but six lines on the new syndrome in the English summary was always cited by other authors, but almost never the more extensive second English language paper. This form of hyperglobulinemia is now established as an autoimmune disease manifestation. Patients have positive rheumatoid factor, and as already recognized by Jan, this finding can be associated with diseases such as Sjögren’s syndrome, SLE, uveo-parotitis and others [16].

Fig. 6.5 Purpura hyperglobulinemia. From Waldenstr¨om [15] with permission

6.5 Macroglobulinemia

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6.5 Macroglobulinemia Myeloma was a severe disease which caught JW’s interest early. His first paper on myeloma was published in 1942 and addressed its early diagnose [17]. Patients with myeloma usually had an extremely elevated ESR due to “hyperglobulinemia”. Skeletal lesions visualized by radiography were useful diagnostic signs and caused severe pain. Examination of the bone marrow revealed increased presence of plasma cells, and patients suffered from secondary anemia. The nature of this severe disease was unclear. It was debated whether myeloma was a malignancy or a metabolic disease akin to the lipoidoses, and might result in the deposition of aberrant protein. This was before Astrid Fagraeus’ milestone demonstration in Stockholm that plasma cells produce antibodies which are gamma globulins [18, 19]. The diagnosis of myeloma itself was usually straight-forward, but therapy was only symptomatic and the prognosis poor. JW’s pigeonhole memory for patients and his curiosity for the unusual, allowed him to recognize two patients with suspected myeloma and their atypical features. One was a farm worker born in 1881 admitted with pain in shoulders and ankles. He had a history of frequent nose bleeds and had developed a modest anemia. The ESR was 135 mm/h. The patient was dismissed with a prescription for oral iron. He returned after some uneventful years in March of 1942 with fever and a lobar pneumonia. His ESR was now 145. The radiograph of the cranium and pelvis did not show any abnormality. The patient’s acute symptoms soon improved. It turned out that the nose bleeds had recurred in recent months and bleeding from the gingiva was also observed. “The patient was treated several times at the Medical Clinic with venesections, retransfusion of his own erythrocytes and transfusion”. A year later some enlarged lymph nodes were detectable. One of these was excised, and the surgery resulted in bleeding from the wound for two weeks. A bone marrow examination showed “Some increase of plasma cells. No signs of tumor. Decidedly no myeloma /Gellerstedt” [20]. On two later occasions the sternal puncture showed 70 and 64% lymphocytes, respectively. In the following months the patient had repeated episodes of nose bleeds, a hemarthrosis in one knee, and multiple bleeds in the ocular fundi. He required further blood transfusions. The second patient was a farmer born in 1878. In 1941, he had a thrombosis of one retinal artery and gingival and nasal bleeds. The patient suffered further bleeds in 1942 and 1943 and was treated with blood transfusions on several admissions. His ESR was always between 140 and 150 mm/h. A sternal puncture showed 93 percent lymphocytes. There were no lesions indicative of myeloma on radiographs of the skeleton. This patient also had some enlarged lymph nodes. In both patients it was difficult to draw blood due to high viscosity. Jan studied the blood with a modified Ostwald’s viscometer and showed it to be 10 or more times higher than normal. Another observation was that blood smears prepared from both patients were of “poor quality”. JW had made the discovery of symptomatic hyperviscosity. And now, just like in 1937 when JW encountered his first patient with acute intermittent porphyria (Chap. 3), he went from bedside to the bench and carried

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the blood samples to the Department of Physical Chemistry. Here his friend Kai Pedersen found the presence of high amounts of homogeneous protein peaks in both sera with a sedimentation coefficients of 19 and 20 Svedberg units, respectively. This corresponds to a molecular weight of approximately one million. For comparison, gammaglobulins sediment with 7 S and had molecular weights around 170,000. The 19 and 20 S proteins migrated faster on electrophoresis than the gammaglobulins but were extremely homogeneous like myeloma protein peaks. It was clear to Jan that he had made an important discovery and he submitted a paper with the findings to Acta Medica Scandinavica on the 2nd of September 1943. This was the birth of macroglobulinemia and would soon make him world famous. Two weeks after the submission his third son, Anders, was born. While the world was involved in almost universal warfare JW had discovered two new diseases in a country spared from the war (Fig. 6.6). The following year soon after publication of the Acta Medica paper [19], he would leave his wife and three sons and a daughter in Uppsala for new adventures overseas. This is the subject of Chap. 7. JW’s wife Elisabet got instructions to consult their friend docent Erik Wassén (1901–1981) for minor medical problems, and the more senior colleague Hilding Berglund (1887–1962) for more serious problems during his long mission abroad. Erik Wassén became later professor of medicine in Gothenburg. Hilding Berglund was the chairman of the Department of Medicine at St. Erik Hospital in Stockholm.

References

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Fig. 6.6 Proofs of the first page of the paper reporting the discovery of macroglobulinemia with remarks by the author [20]. © Courtesy Anders Waldenström

References 1. Björkman SE. Jan Waldenström. Acta Med Scand. 1966;suppl179:5–8. 2. Wågberg L. Theodor Svedberg—Världsledande fysikalisk kemist, entreperenör, botaniker och konstnär. Svenska nationalkommittén för kemi, augusti; 2016. 3. Zsigmondy R. Zur Erkenntnis der Kolloide. Jena, G Fischer; 1905. 4. Svedberg T. Studien zur Lehre von den kolloiden Lösungen, Uppsala; 1908. 5. Svedberg T, Fåhraeus R. A new method for the determination of the molecular weight of the proteins. J Am Chem Soc. 1926;48:430–8. 6. Svedberg T. The ultracentrifuge. Svedberg. The Nobel lecture; 1927 May 19. Stockholm https:// www.nobelprize.org/uploads/2018/06/sveerg-lecture.pdf 7. Svedberg T, Pedersen KO. The Ultracentrifuge. Oxford: The Clarendon Press; 1940.

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8. Heidelberger M, Pedersen KO. The molecular weight of antibodies. J Exp Med. 1937;65:393– 414. 9. Tiselius A. A new apparatus for electrophoretic analysis of colloidal mixtures. Trans Faraday Soc. 1937;33:524–31. 10. Tiselius A. Electrophoresis of serum globulin II. Electrophoretic analysis of normal and immune sera. Biochem J. 1937;31:1464–77. 11. Tiselius A, Kabat E. An electrophoretic study of immune sera and purified antibody preparations. J Exp Med. 1951;69:119–31. 12. Porath J. Fractionation of polypeptides and proteins on dextran gels. Clin Chim Acta. 1959;4:776–8. 13. Kunkel HG, Tiselius A. Electrophoresis of proteins on filter paper. J Gen Physiol. 1951;35:89– 118. 14. Waldenström J. Kliniska metoder för påvisande av hyperproteinämi och deras praktiska värde för diagnostiken. Nord Med. 1943;20:288–95. 15. Waldenström J. Three new cases of purpura hyperglobulinemica. A study in long-lasting benign increase in serum globulin. Acta Med Scand Suppl. 1952;266:931–46. 16. Finder KA, McCollough ML, Dixon SL, Majka AJ, Jaremko W. Hypergammaglobulinemic purpura of Waldenström. J Am Acad Dermatol. 1990;23(4 Pt 1):669–76. 17. Waldenström J. Die Frühdiagnose der Myelomatose. ActaChir Scand. 1941;87:1942. 18. Fagraeus A. Plasma cellular reaction and its relation to the formation of antibodies in vitro. Nature. 1947;159(4041):499. 19. Fagraeus A. The plasma cellular reaction and its relation to the formation of antibodies in vitro. J Immunol. 1948;58(1):1–13. 20. Waldenström J. Incipient myelomatosis or “essential” hyperglobulinemia with fibrinognenopenia—a new syndrome? Acta Med Scand. 1944;117:216–47.

Chapter 7

Exploring Medical Science in Wartime America

Abstract Wartime isolation prompted the Swedish Government and Health Board to commission JW to undertake an extended fact-finding trip to leading centers of medical research in USA in 1944–5. This 7-month activity established JW’s early important network of contacts. The receptive traveler visited institutions in New York, Boston, St Louis, Minneapolis Rochester, MN, and other places. The chapter is based on JW’s own account from 1993.

7.1 Through Mined Waters to New York City We have seen that already as a medical school student, Jan showed an appetite for learning experiences abroad, when he spent months in Cambridge in 1927, and later his year with a Rockefeller stipend in 1934–5 in Munich. In 1939 he spent time in the UK and established new contacts there. Now, in November of 1944, the young assistant professor would leave Sweden for an extended stay in the United States which turned out to be significant for himself, for those around him, and for later medical practice and research in Sweden. Although Sweden was fortunate to remain neutral during World War II one consequence was isolation and a dearth of information from the outside world regarding ongoing developments in science, not least from the United States. Travel was severely restricted and few visitors came to the country. Journals did not arrive regularly. The internet had not been invented. Sweden’s Surgeon General Axel Höjer (1890–1974) and Undersecretary Tage Erlander (1901–1985) in the Health Department realized the need for the country to remedy the void of information. In the fall of 1944, they invited JW to undertake an extended seven fact-finding month visit to the United States to explore important developments in medical research. One could ask why a relatively young individual was selected for this task. Was it his brilliant academic achievements? It is possible that Axel Höjer became acquainted with Jan through the 1939 letter in support of the Jewish doctors (Chap. 5). Perhaps it was difficult to find competent candidates who had the courage to travel overseas at the time. In any case, it appears likely that Höjer was aware of JW’s performance in science and his already established international network. In retrospect, JW turned out to be a perfect choice for © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Wollheim, Jan Gösta Waldenström and His World, Springer Biographies, https://doi.org/10.1007/978-3-031-36739-7_7

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Fig. 7.1 The Johnson Line’s M/S Argentina 2 built in 1943 l Kommandobryggan. See courtesy © Webmaster Mats https://kommandobryggan.se/johnson/argentina43.htm

the task. Unfortunately, it has not been possible to find official or private documents relating to the important event. JW’s own account is an important source, although scanty and recorded at age 87, half a century later [1]. Copies of a few letters from Jan to colleagues in Sweden are found in the private archive of Anders Waldenström (Figs. 7.1 and 7.2). The trip started in on 27 November of 1944 when the commissioned delegates left Gothenburg onboard a Swedish merchant ship “with a very big Swedish flag painted on the vessel”. It was most likely the M/S Argentina of the Johnson Line. The first stop was Kristiansand in occupied Norway for clearance by the German command. The ship continued to Torshavn on the Faroe Islands to obtain the British command’s permit of passage. It then navigated through mined waters protected only by a “paravane serving like a snow-plough” and the hope that no German submarine would violate the passage permission and attack the ship. Three weeks later, the vessel arrived in La Guairá, Venezuela, the first neutral port-of-call. The delegates then flew from Caracas to Miami where they met with ice-cold northern winds and continued by train to New York, which was just experiencing a blizzard. There was a long line for cabs at Grand Central Station. When he was finally “safely installed” in one, it drove for half a minute to the Biltmore around the corner. As he got out of the cab another vehicle ran over JW’s bag. After this inauspicious start, the Biltmore Hotel on Vanderbilt Avenue, one of the city’s three classical palace hotels, fortunately turned out to be an agreeable accommodation. It had a Swedish manager who was delighted to host a countryman. It did not often happen during the war. The friendly Mr. Lindholm helped JW in subsequent months when he encountered difficulties to find accommodation. There was a shortage of hotel beds in wartime New York City due to the needs of army personnel in transit, and civilians often had to move between hotels even during short stays. Nevertheless, JW soon came to love and enjoy New York City. A number of

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Fig. 7.2 Postcard sent by JW at departure from Gothenburg to his children 23. November 1944. “On this kind of a boat your father will leave for America. Imagine, when we one time will travel to curious countries and animals. Be kind to mother and to yourselves and think often of you dad who thinks of you and is longing”. Courtesy Anders Waldenström

close friends helped to make it one of his favorite destinations in coming years (Fig. 7.3).

7.2 Exploring Science in New York City On one of his first nights in New York City, JW was invited to dinner by Alan Gregg of the Rockefeller Foundation and was delighted that Otto Loewi, a good friend from before the war, and his wife Gilde Goldschmidt, were other guests. Otto Loewi (1873–1961) was born in Frankfurt and studied medicine in Strasburg. In 1902, he proved that dogs were able to produce proteins by feeding them only with amino acids, although it took some effort to make the protein-free diet palatable. In Graz in the 1920s, he performed experiments on Hungarian frog hearts which demonstrated the mechanism of chemical nerve stimulation by acetylcholine for which he shared the 1936 Nobel Prize with Sir Henry Dale (1875–1968) who had discovered chemo transmitters in vertebrates. In 1938, Otto Loewy was imprisoned by the Nazis in Vienna and only released after he had transferred the Nobel Prize money from Stockholm to a German bank. His wife owned property in Italy and was detained until 1940 when she was dispossessed of all belongings. Otto Loewi was employed at New York University. JW reflected “He had a most admirable mind and wide

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Fig. 7.3 The Biltmore hotel, built in 1912, demolished in 1981. From a 1917 postcard. https://upload.wikimedia. org/wikipedia/commons/5/ 55/Biltmore-NewYorkCity. jpg 15 June 2022

interests in the sciences and humanities and a great sense of humor” [1]. When JW later visited Loewi at his office at New York University, Loewi was compiling a letter to the Nobel committee. Loewi asked Jan “Guess whom I am nominating?” Jan gave the right answer, Oswald Avery. Avery (1877–1955) was investigating the chemical nature of the genetic material responsible for the pathogenicity of pneumococci. He was inspired by work of Frederick Griffith (1879–1941) in England who had found that the pathogenic feature was present in rough (R) strains and transmitted by heat killed smooth (S) strains [2]. Working at the Rockefeller Institute, Avery had just produced evidence that the genetic information was not located in proteins but in DNA [3]. The Nobel Committee unfortunately never awarded Avery or Griffith for their fundamental contributions (Fig. 7.4). Alan Gregg (1890–1957) had graduated from Harvard Medical School in 1916. He joined the Rockefeller Foundation in 1919, served in Brazil, became associate director of education in 1922, associate director of science in 1929 and director of science 1930–1951. As a former Rockefeller fellowship recipient JW was pleased to meet with his benefactor in person in New York and start a lasting personal friendship (Fig. 7.5).

7.2 Exploring Science in New York City Fig. 7.4 Sir Henry Hallett Dale (left) and Otto Loewi were close friends since 1902. Photo in Stockholm from 1936 when they became Nobel Laureates. Photographer unknown https://commons.wikimedia. org/wiki/File:Henry_Hallett_ Dale_and_Otto_Loewi_1 936.jpg 6. February 2022

Fig. 7.5 Alan Gregg. https://www.alliancemaga zine.org/analysis/learningfrom-the-past-to-create-thepresent/22-24-alan-gregg. © Rockefeller Archive Center with permission

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The Rockefeller Institute was funded in 1901 by John Rockefeller (1839–1937), who had wisely made his friend Simon Flexner (1863–1946) its first director. In 1910, Flexner recruited Jacques Loeb (1859–1924), then professor of physiology at the University of California at Berkeley. Loeb, an immigrant from Germany, was a legendary scientist, portrayed by Sinclair Lewis (1885–1951) in the novel “Arrowsmith”. He worked at the Institute the rest of his life. It was his habit to buy a red rose for his wife each night at the flower stand on York Avenue outside the Institute. The price was five cents in 1910, and Loeb always gave the florist a nickel coin. This habit continued for 14 years. The florist never had the courage to tell him that the price had gone up. It was on Simon Flexner’s initiative that the Institute included both a hospital allowing bedside medical research and science departments. He also favored medical doctors as basic science investigators. Cross-fertilization between the different specialists was fostered by Flexner’s initiative of common lunch meals. JW remembered “The fare was frugal but the scientific atmosphere was rich” [1]. Similar traditions prevailed in many comparable institutions well into the second half of the twentieth Century but then gradually disappeared, even at the Rockefeller Institute. Thomas M. Rivers (1888–1962) came to the Institute in 1922 and was appointed director of the hospital in 1937. His observation that viruses needed living cells for replication can be considered as the birth of modern virology [4]. Before Rivers, viruses were merely characterized by their small size and ability to pass through filters which retained bacteria. Frank Horsfall (1906–1971) was recruited to the Rockefeller Institute by Rivers. Horsfall had graduated from McGill University in Canada in 1932, receiving the Holmes Gold Medal. He wanted to pursue a career in surgery like his father, a prominent surgeon in Boston, and spent a year at the Peter Bent Brigham (1807–1877) in pathology as a promising trainee. Due to severe sensitivity to formaldehyde he had to change plans. Having no regrets, he selected medicine. After internship at the Royal Victoria Hospital in Montreal, Horsfall joined the Rockefeller Institute in 1934. “The Institute” was still small but had an extraordinary staff of physicians combining clinical and basic science work. It was a prime location for young medical doctors as a platform that could soon lead to good academic positions around the country. Horsfall remained at Rockefeller for 25 years. He became a member of Rivers’ pneumonia team and studied pneumococcal immune sera raised in rabbits with great enthusiasm, turning out a large number of papers. In 1937, Rivers was appointed director of the Institute and selected Horsfall as his successor to lead the pneumonia team. In 1959, Horsfall moved across York Avenue as director of the Sloan Kettering Institute for Cancer Research (Fig. 7.6). Jan was acquainted with Horsfall from the time Frank spent with Arne Tiselius in Uppsala [6]. JW was impressed by the breath of his knowledge about current medical research, and JW’s mission benefitted greatly from his advice on places of current excellence. Horsfall arranged meetings at the Institute for JW with experts in various fields and suggested other worthwhile places to visit in the U.S. The friendship with Frank Horsfall was enduring and later included Jan’s son Anders and other Swedes. Columbia University and its affiliated Presbyterian Hospital of Manhattan was another place where JW would meet with outstanding clinicians and scientists. Robert

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Fig. 7.6 Frank Horsfall [5] http://www.nasonline.org/ publications/biographicalmemoirs/memoir-pdfs/hor sfall-frank.pdf. © American Association of Immunologists 1961. Photographer unknown. With permission. https:// www.aai.org/About/History/ Past-Presidents-and-Off icers/FrankLHorsfall

F. Loeb (1895–1973) was the chief of medicine there, and a legend like his father Jaque Loeb. JW characterized him as “one of the most cultured men I have met” [1]. A reading of Loeb’s biography in a masterful essay by Alexander Bearn (1923– 2009) confirms that this was not an overstatement [7]. One of Robert Loeb’s early contributions to science was the discovery of the life-saving salt replacement for patients with Addison’s disease [8]. During Jan’s wartime visit, Loeb was involved in the search for new anti-malarial compounds, badly needed for the war effort. This endeavor resulted in the synthesis of chloroquine [9]. Loeb was a legendary bedside physician, but did not like giving lectures. He started the day at 8 AM, gathering staff and students in his office for voluntary informal discussions of current events and problems. The room was always crowded. Loeb’s farsighted competence made him an influential force in American medicine. JW would meet Loeb only once on this trip but several times in later years. Loeb’s devotion to the patients and memory of their case history equaled that of JW. As a teacher he could be sarcastic and was not only respected but often also feared (Fig. 7.7). At Columbia Jan also met with David Rittenberg (1906–1970), David Shemin (1911–1991), and Irving London (1918–2018), all once collaborators of the German refugee Rudolf Schoenheimer (1898–1941). He had been professor of pathology in Freiburg. Sadly, Schoenheimer committed suicide in 1941. In 1933, Schoenheimer had met with Rittenberg in the Department of Biochemistry, which was to be a truly propitious encounter. It led to the introduction of tagging tracer isotopes for the invivo study of metabolic processes. While Schoenheimer could formulate metabolic questions, Rittenberg was able to apply the use of the stable isotope deuterium incorporated in water. The new technology allowed fascinating insights into rapid intermediary steps in the synthesis and metabolism of biologic products. Jan once owned Schoenheimer’s classic book on the new methods [10] . To his regret this long outof-print treasure was stolen from him. Schoenheimer’s group was about to elucidate

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Fig. 7.7 Robert Frederick Loeb. © Archives and Special Collections, Columbia University Health Sciences Library. With permission

intermediary compounds and steps in the biosynthesis and breakdown of heme and the proper place of JW’s molecule porphobilinogen (Chaps. 3 and 17) in vivo [11, 12] (Fig. 7.8). Michael Heidelberger (1888–1991) was recruited to Columbia University from the Rockefeller Institute as the department’s chief chemist by Loeb’s predecessor Walter W. Palmer (1882–1950) when Palmer moved to Columbia in 1922. Both had worked in Dexter van Slyke’s (1883–1971) laboratory at Rockefeller. At the Rockefeller Institute Heidelberger had worked with Avery on the pathogenicity of the R forms of pneumococci. This eventually led to the previously mentioned recognition that the genetic material of cells consisted of DNA and not of proteins. Heidelberger had worked in Uppsala (Chap. 6) and was now professor of immunochemistry. JW knew him from his stay in Uppsala when he had worked with Kai Pedersen and Arne Tiselius [13]. Heidelberger had become involved in developing an anti-pneumococcal vaccine urgently needed by the military forces. A most productive student of Heidelberger, Elvin Kabat, (1914–2000) was another acquaintance from Uppsala where he also had worked with Kai Pedersen (Chap. 6). He was now involved in the immunochemical characterization of blood group antigens, one of his many contributions to medical science. Another erudite scientist JW may have encountered at Columbia was the eminent professor of biochemistry Erwin Chargaff (1905–2002), a refugee from Austria.

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Fig. 7.8 David Rittenberg visiting the Weizmann Institute in Israel for a corner stone ceremony in 1946. The institute was still named after U.K. donor Israel Sleff. Zoltan Kruger. Public Domain https://en.wikipedia. org/wiki/David_Ritten berg#/med

Chargaff’s careful investigations of purified DNA established that the number of guanine units always equaled those of cytosine and that the same applied to adenine and thymine, and also that the relative amounts varied between species. Chargaff’s careful observations over several years were important for the later discovery of the double helix by James Watson (born 1928) and Francis Crick (1916–2004), although the Nobel Laureates never cited his work or mentioned the help and information he provided when he visited them in Cambridge UK.

7.3 Boston, “The Medical Capital of America” After his rather rough introduction to the city, Jan came to love New York, its abundance of exciting basic and clinical investigators, its cultural pulse, its museums, and the growing number of lifetime friends. To continue his mission, JW was obliged to move further northeast (Fig. 7.9). In Boston Jan visited a number of hospitals, many of which were affiliated with Harvard. “The investigative spirit was truly alive” [1]. Like in New York the Swedish visitor was impressed by the close contact between bedside and basic science medicine. At Massachusetts General Hospital (MGH), one of the most prominent physicians was the chief of medicine, James Howard Means (1885–1967). Means was the son of a businessman with a scientist’s mind who was able to retire at the

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Fig. 7.9 James Howard Means. Paining by Piertro Pezzati. Harvard University Portrait Collection, Gift of Mrs. George May to Harvard Medical School,1998

age of 40 years from business and devote the rest of his life to aeronautics. Means had spent time at Massachusetts Institute of Technology (MIT), where he realized the importance of exploiting metabolism and biochemistry to make advances in medicine. Thyroid diseases were a main field of interest. At MIT, Means learnt about radioactivity from the physicist Robley D. Evans (1907–1995), the father of nuclear medicine. Artificial radioactivity was discovered by the couple Frédéric Joliot (1900–1958) and Irène Curie (1897–1956) in 1934. Already in 1935 they shared the Nobel Prize in Chemistry. Production of new radioactive elements could be accomplished by cyclotrons. The University of California at Berkley had a cyclotron by 1934. At MIT the first cyclotron was in use from 1940. When it was needed for the atomic bomb project in 1943, it was sold to the U.S. government for one dollar and moved to Los Alamos, New Mexico. The use of radioactive isotopes in basic and clinical research continued despite the war. On a visit of JW to the department of physics, Evans told him that his interest in radioactive isotopes was triggered by a wealthy patient who believed in the health benefit of ingesting radioactive material. This patient had made frequent visits to the Austrian Spa Bad Gastein where he indulged in taking the radioactive waters. After he died as a consequence of this habit, Evans obtained access to autopsy material. He detected radioactivity in various organs including the thyroid gland. The affinity of iodine for this gland was well known. When I-138 became available in the late 1930s, collaborative research between the clinicians Saul Hertz (1905–1950) and his chief Means at MGH and the physicists Evans and Arthur Roberts (1931–2004) at MIT began. It was well underway at the time of Jan’s visit, although by then Hertz had left MGH and joined the Navy as a medical officer [14].

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Means’ department ranked as one of the leading units in the country. One of Means’ special interests concerned thyroid disease [15]. In 1921, his enthusiasm attracted the brilliant young Fuller Albright (1900–1969), whom Jan characterized as a physician who “saw clinical medicine in its unsurpassed quality” [1]. Albright was raised in a large tightly knit affluent aristocratic New England family where humor was always present. Fuller was in JW’s words “cherubic, ebullient, and gregarious”. He finished Harvard Medical School as best in his class and remained at MGH for his entire professional life, with the exception of one year at Johns Hopkins and one year in pathology in Vienna with the prominent pathologist Jacob Erdheim (1874–1937). Albright specialized in endocrine diseases and can be considered one of the founders of modern endocrinology [16]. Early papers published in the 1930s with Joseph Aub (1890–1973) and Walter Bauer (1898–1963) described hyperparathyroidism [14]. Many seminal papers were published in the following 15 years. He had an unconventional and sometimes provocative attitude toward science. As a respected Harvard man he once was invited to give a talk at Yale University. After putting forward a rather fancy hypothesis to explain a perplexing finding he stopped and asked “How many think I am right?” Nobody dared to respond. He then asked “How many think I am wrong?” Again complete silence in the polite audience. Then came the final question: “How many of you think at all?” [1]. Albright was afflicted with Parkinson’s disease starting in 1937, possibly a consequence of the Spanish flu he had suffered from in1918. When JW met him, Albright’s speech was markedly affected and he walked with strong propulsion. He remained mentally sharp until suffering an intracerebral bleed which left him helpless in his hospital bed for his remaining years. One of his co-authors Walter Bauer emerged as a father of modern rheumatology. Bauer would succeed Means as chairman of medicine in 1950. He contributed fundamental clinical studies on rheumatoid arthritis and established it as a truly systemic disease. After one of Bauer’s presentations, Albright reflected “We now know everything on the disease except its cause and cure”. JW concludes “I have never met an investigator who enjoyed his scientific work more intensely than Fuller Albright. He always maintained that scientific work must be fun in order to be productive and I strongly agree” [1]. Another outstanding investigator JW met at MGH was Steven Krane (1927–2013) [17]. Krane would emerge as a pioneer in the investigation of connective tissue biology and mentor for many later leaders in rheumatology (Fig. 7.10). At the Peter Brent Brigham Hospital, JW visited with George Widmer Thorn (1906–2004), chief of medicine since 1942. Thorn’s youthful looks led visitors to take him for a house officer. JW was impressed by the prodigious output of outstanding scientific work despite substandard crowded premises, limited resources, and a small staff. Over time, Thorn mentored a large number of American and foreign fellows onto their path to leading positions. He was a strong promoter of interaction with basic science at MIT. His main field of interest was endocrinology. He was one of the first to use mineralocorticoids to treat patients with adrenal insufficiency. The cardiologist of his department was Lewis Dexter (1910–1995), a pioneer of heart catheterization and accidental discoverer of the wedge pressure. When on one occasion the catheter unintentionally appeared in the lung he panicked, wondering

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Fig. 7.10 Fuller Albright. Public domain Photographer unknown. https://collections. countway.harvard.edu/onv iew/items/show/5897

whether he had perforated the heart. The patient however remained unaffected; the catheter had just passed into the pulmonary artery. Dexter became a legendary teacher. Thorn pleased JW by telling him that he had tried to recruit Albright for the position as chief of cardiology because he thought that a biochemical approach would be useful in cardiology. JW would never forget the wisdom of Thorn’s philosophy. The medical science achievements under Thorn at the Peter Bent Brigham have been depicted as “splendor in squalor” (Fig. 7.11). Boston City Hospital, one of the oldest communal hospitals for the poor in the U.S., had over 1000 beds when JW visited. Its Harvard branch contained the famous Thorndike Memorial Laboratory. Its first director was Francis Weld Peabody (1874– 1927), who had the vision to create a building with spacious laboratories and an attached patient ward. The hospital governance board agreed with the plan, and the Thorndike laboratory was opened on November 15, 1923 [19]. Here Peabody contributed to the understanding of pernicious anemia and developed the laboratory into a leading center of research in hematology [20]. JW met its second director there, George Richards Minot (1885–1950). Minot had been diagnosed with severe diabetes in 1921 by Elliott P. Joslyn (1969–1962) at MGH and treated with the only known therapy at the time, serious diet restriction. Minot survived for one year on 530 cal daily. Then he was rescued by the arrival of insulin. Minot shared the Nobel Prize in 1934 with William Murphy (1892–1987) and George Whipple (1885–1950) for the discovery of the life-saving liver therapy for pernicious anemia. Minot told JW of his first patient, “An elderly Bostonian who had been given different types of treatment without result. Minot had read reports on the experiments performed by Whipple and Frieda Robscheit-Robbins (1888–1973)who

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Fig. 7.11 George Widmer Thorn. Briigham and Woman’s Hospital https:// www.thelancet.com/journals/ lancet/article/PIIS01406736%2804%2916794-9/ful ltext [18]. © The Lancet With permission

had a great part in this program. They bled dogs and followed the speed of regeneration of red cells (after administration of raw liver)”[1]. With his younger associate William Murphy, Minot presented 40 patients with pernicious anemia successfully treated with 150 g daily of lightly cooked liver at the Young Turks meeting in 1926 [21]. Minot introduced counting of reticulocytes as a sensitive method for early detection of response or failure of treatment. After this success Minot began collaboration with the professor of physical chemistry Eddin J. Cohn (1892–1953) at MIT and would establish that the active component of the liver extract was water soluble and could be concentrated to a powder. This process was commercialized by Ely Lilly, much to the relief of patients who did not fancy the taste of almost raw liver. The identity of the active factor as vitamin B12 was only established in 1948 with help of the new chromatography method. Minot and Cohn had also done work on hemophilia, trying to isolate the protective factor in normal serum. At Thorndike JW also met with William Castle (1891–1990), a dedicated member of the laboratory since 1925. Almost all patients with pernicious anemia suffered from atrophic gastritis. Castle could show that this caused the absence of a factor which he named intrinsic factor, present in normal gastric mucosa that was needed for the absorption of the essential food component vitamin B12 [22].Years later, the factor was identified as a glycoprotein produced by gastric parietal cells which binds to B12 and facilitates its absorption in the gut. Autoantibodies against parietal cells are present in most patients with pernicious anemia and block the function of intrinsic factor. Pernicious anemia has subsequently been identified as a true autoimmune disease. With these discoveries, a deadly disease had become curable and its nature

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clarified. Great discoveries were achieved based on clear thinking but with very limited resources and inexpensive equipment, much to the taste of JW. The Joseph H. Pratt Diagnostic Hospital was opened in 1938. Joseph H. Pratt (1872–1956), an internist and forerunner of cognitive behavioral therapy, named the cardiologist Sam Proger (1906–1984) as its director. Proger assembled a small number of specialists in different fields and this group practice soon reached great prominence. The hematology service was strengthened in 1943 when William Dameshek (1900–1969) joined Pratt. He had arrived in the U.S. at age 3, obtained a medical doctorate at Harvard Medical School in 1923, and worked at Boston City Hospital and Beth Israel Hospital before joining Pratt’s group. JW describes him as “a tall man lodged in a very small office”. Their friendship became very warm after a harsh start “because the host was not very friendly (at first)” [1]. Dameshek was an outstanding investigator but also a competent organizer of a large medical practice. In 1934, Proger convinced Siegfried Thannhauser (1885–1962) that it was time for him to leave Germany and join the Pratt group. Thannhauser was perhaps the most brilliant of Friedrich von Müller’s (1858–1941) fellows in Munich as mentioned in Chap. 3. As a young investigator, like JW he was fascinated by Sir Archibald Garrod’s (1857–1936) concept of inborn errors of metabolism. He completed a Ph.D. in 1924 dealing with the pathogenesis of gout, stressing the importance of renal function in the etiology. In the same year he was promoted to assistant professor, Dr. med. Habil., and moved to Heidelberg. In 1927, he was promoted to professor of medicine in Düsseldorf and in 1930 elected to the prestigious chair of medicine in Freiburg. Hans Adolf Krebs (1900–1981), the discoverer of the Krebs cycle and Nobel Laureate in 1953, had difficulties to find a research position, but he was hired by Thannhauser as chief of the department’s research laboratory. In a letter from the 1970s Krebs remembered Thannhauser as a friendly professor who inspired and encouraged his staff to engage in independent scientific work. In April of 1934, Thannhauser was sacked as chairman, degraded to “doctor’s assistant” and forced to move to Heidelberg. This was how the Nazi regime humiliated outstanding non-Aryan physicians. In Boston in 1935 at age 50 Tannheuser had to start a new carrier from scratch. He soon became popular both as clinician and as productive investigator of lipid metabolism and lipoidoses. He attracted students from all parts of the U.S., and after WWII also from his country of birth. JW recalls a lengthy discussion of an intricate endocrinology problem between George Minot, himself, and Siegfried Thannhauser. At the end of their conversation JW noted the remarkable number of outstanding investigators that had a Jewish background. Thannhauser then said that the obligatory study of the Talmud was a likely contributing factor providing training in analytic thinking. Thannhauser was also an accomplished pianist. His favorite composers were Haydn and Mozart. The Tannhauser family collected Gothic art which they donated to Boston’s Fine Art Museum. After the war Thannhauser received several invitations to visit Germany which he turned down, but a street in Freiburg now is named Thannhauser Strasse [23]. A first cousin, Justin Thannhauser (1892–1976), an art dealer first in Munich and later in New York City, donated a substantial number of

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Fig. 7.12 Siegfried Thannhauser in his Boston laboratory in 1941. From [23]. © Falk Foundation e.V. Freiburg, Germany

late nineteenth and early twentieth century master pieces to the Guggenheim Gallery in New York (Fig. 7.12). Thannhauser had many friends in New York. One was Henry Maurice Stratton (1901–1984) who came to the U.S. as frustrated “non-Aryan” émigré from Austria in 1938. He had been a medical student but became a publisher and was now in charge of Grune & Stratton. Coinciding with one of JW’s visits in Boston he had the idea to start a hematology journal and asked Thannhauser if he could suggest an editor. The immediate answer was “The obvious choice is my colleague William Dameshek working one floor below me”. Stratton organized a meeting of hematologists in Boston where the naming of the journal was discussed. At the meeting JW supported the suggestion by George Minot to name it “Blood”. The first edition appeared in January of 1946. Dameshek was to be its chief editor from inception until his death in 1969. Although some hematologists initially were skeptical, Blood soon became the leading hematology journal. Stratton continued to be a strong supporter of the discipline of hematology. In 1956, he started an annual hematology club meeting and in the same year he helped to organize the American Society of Hematology. JW would decades later publish “Diagnosis and treatment of multiple myeloma” with Grune and Stratton. JW’s rewarding friendships with a number of immigrants from Central Europe was based not only on common interests in science but also by his effortless mastery of German. Henry Stratton in particular enjoyed communicating with Jan in his mother tongue (Figs. 7.13 and 7.14).

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Fig. 7.13 William Dameshek. © Blood 1970;35:1–3 with permission

Fig. 7.14 Cover page of Blood from 1947 to 1974. Photo Fran Wollheim

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7.4 Washington University in St. Louis JW’s formal home base during his months in the U.S. was Washington, D.C. among the Swedish diplomats, but he spent very little time there. Instead, he crisscrossed the country, but in his memories he only mentions destinations in New York, Boston, St. Louis, Missouri and Minneapolis and Rochester in Minnesota. Certainly, there were other undocumented destinations, e.g., Johns Hopkins. Washington University in St. Louis was one of the places JW enlarges on [1]. The attractive campus was laid out in the 1890s by the Boston firm founded by Frederik Law Olmsted (1822– 1903), the creator of Central Park in New York City and Prospect Park in Brooklyn. Buildings were inspired by the college architecture of Oxford and Cambridge. Joseph Erlanger (1874–1965), a student of Sir Wiliam Osler at Johns Hopkins, was recruited as chairman of the department of medicine at Barnes Hospital in St. Louis in 1910. He was an eminent physiologist and awarded the Nobel Prize in 1944. At Jan’s visit, W. Barry Wood (1910–1971) and Carl V. Moore (1908–1972) shared the responsibility of chairing the Department of Medicine, each spending six months as chairmen leaving them six months for full-time research. This seemed to be an excellent arrangement between two young close friends. Jan wrote of Wood “He was a very active person, both as a professor and as a sportsman and was very popular among the students” [1]. Wood had attended Harvard College where he was an outstanding scholar as well as athlete. In 1932, while still an undergraduate senior he published his first scientific paper. It showed that the leukocyte counts in baseball players rose from 5000 at rest to 25,000 during intense physical activity. His visit to Oswald Avery during residency at Johns Hopkins inspired him to specialize in infectious diseases and start research on pneumococci [24]. Wood’s colleague Carl V. Moore shared Jan’s interest in iron deficiency [25]. They became close lifelong friends. In 1945 Jan showed Moore a slide of his work in Uppsala on iron loading which had only been published in Swedish. Moore remarked “That is a good curve”. Jan asked “Why do you say that?” Carl Moore replied “Because there is a kink on the level that must be a faulty analysis. It shows that the data have not been embellished”. At Barnes Hospital Jan was introduced to a form of teaching that was new to him, the clinical pathological conference, CPC. Wood and Moore alternated as discussion leaders. The department members and students were given a detailed case history at the beginning of the conference. After the oral case presentation, staff and students had to put a written diagnosis in separate urns. A board in the hall had a large figure with the heading “Where are we going?” It showed lines with the percent correct answers. It rarely happened that the students outperformed the teachers, but when it occurred it was taken as a good sign of both the quality of the students and the teaching by the staff (Fig. 7.15).

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Fig. 7.15 Brooking’s Hall, Washington University in St. Louis, Missouri. Built 1900–2 as administrative center of the 1902 World’s Fair. Public Domain https://sv.wikipedia.org/wiki/Washington_ University_in_St._Louis 6 February 2022

7.5 The University of Minnesota in Minneapolis The city of Minneapolis could proudly claim to have the tallest building west of the Mississippi river, the Foshay Tower, named after the business man Wilbur B Foshay and inspired by his visit to the Washington monument. The Art Deco building was opened less than two months before the crush of the stock market in 1929. Foshay was broken and lost the building and spent 15 years in prison for fraud. But the tower was for several years the tallest building west of the Mississippi. At the time of Jan’s visit in 1945 the Twin Cities of Minneapolis and St. Paul still were served by an extensive network of street cars, car tires were rationed as was gasoline the war (Fig. 7.16). Although the University of Minnesota Medical School could not boast Nobel Laureates on its staff like Washington University, it did not lack excellence. One example was the cardiologist W. George Fahr (1880–1959), who had collaborated with Wilhelm Einthoven before World War I on electrocardiography and was the first to described bundle branch block in 1915. Another was Ancel Keys (1904–2004), who founded the unique laboratory of Physiology and Hygiene in 1936. During Jan’s visit he was just starting a one-year Minnesota Starvation Experiment, a heroic study, using 32 conscientious objectors [26]. The 32 volunteers were losing 25% in weight on a diet restricted to 530 cal a day. Nutritional effects on health were his main field of interest, and he became famous for proposing that the consumption of unsaturated fat was an important risk factor for cardiovascular disease. JW had a special personal reason to visit Minneapolis. The chairman of medicine since 1943 was Cecil J. Watson (1901–1983), a familiar name to Jan since his year

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Fig. 7.16 A southbound Nicollet Avenue streetcar on Marquette Avenue between 9 and 10th Streets, with Foshay Tower in background. Photographer unknown. © Courtesy Minnesota Digital Library 24 July 2022

in Munich but whom he had not yet met in person although he was “a brother from the same father-house” [1]. Watson was the oldest of four children. His parents had both arrived to America at a young age from Ireland around the 1860s. His father had trained in Canada and practiced as eye, ear, nose, and throat doctor in Minneapolis. The parents were self-taught scholars in the classics. Watson learnt Latin and Greek and his favorite subject was classic mythology. He started to study English and French literature and writing at the University of Minnesota, but after attending an advanced course in comparative physiology and further inspired by reading Jacques Loeb’s classic book The Physical–Chemical Basis of Life, he changed his mind and switched to medicine. While still a student Watson fell ill with “catarrhal jaundice”, now recognized as infectious viral hepatitis, and was surprised by his pale stools and the passing of dark urine. This inspired him to perform his first experiments while still in medical school. As a result, he was awarded both an M.D. and Ph.D. degree in 1928. In 1930, he started two rewarding years as a Rockefeller fellow in the laboratory of Hans Fischer in Munich. There he succeeded in crystallizing stercobilin, the metabolite of bilirubin in feces [27]. He became fluent in German and with his young wife Joyce enjoyed both the culture of Munich and hiking and skiing in the nearby Alps. Watson established contacts with numerous clinicians, among them the chairman of

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Fig. 7.17 Cecil James Watson. © University of Minnesota 1956. National Academy of Science. 15 June 2022 http://www.nasonl ine.org/publications/biogra phical-memoirs/memoirpdfs/horsfall-frank.pdf

medicine Friedrich von Müller. After returning to Minneapolis, he was promoted in 1934 to assistant professor and in 1936 to associate professor and chief of the division of internal medicine. Subsequently, he was appointed professor and chairman of the new department of medicine in 1942. The only other full-time faculty member was Wesley W. Spink (1901–1988), a native Minnesotan who had graduated from Harvard Medical School and specialized in infectious diseases. He was a leading expert on brucellosis, not uncommon in Minnesota before penicillin. Liver diseases and porphyria were Watson’s primary fields of interest. He described a special form of prolonged cholinolytic hepatitis which often progressed to cirrhosis and was later renamed primary biliary cirrhosis. Together with Samuel Schwartz (1916–1997), his long-time laboratory collaborator, he published a method which became the standard assay for porphobilinogen in urine for many years [28]. It is not surprising that Jan and Cecil Watson became lifelong close friends, sharing both a common science focus and broad cultural interests and values. JW points out that they often could have conflicting views on scientific matters but adds that this did not affect their warm friendship (Fig. 7.17).

7.6 The Mayo Clinic in Rochester The Mayo Clinic was founded in 1864 and became a successful multispecialty establishment, and by 1919 a non-profit foundation. It was located in the then small town of Rochester, 85 miles southeast of Minneapolis. In 1901, William J. Mayo (1861–1939), “Dr. Will”, hired Henry Plummer (1874–1936), the man connected with the Plummer-Wilson syndrome (Chapter 6). In 1910, Plummer implemented a centralized patient-record system still in use at the Mayo Clinic and often mimicked.

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Fig. 7.18 Early 1914 building at the Mayo Clinic, demolished in 1986. From Hunter GG & Matteson EL. The History of Rheumatology at Mayo Clinic. © 2018 Mayo Foundation for Medical Education and Research. With permission

Although designed for patient care, with time it became a powerful research tool. Plummer was appointed chief of medicine in 1914. He contributed to the design of a new building completed in 1928 and still preserved in all its splendor as the Plummer Building. It is now a Mayo Historical Site containing a museum and an historic library. Jan must have enjoyed its qualities (Fig. 7.18 and 7.19). In 1920, Dr. Will recruited Leonard Rowntree (1883–1959) from the University of Minnesota as a second head of the section of medicine beside Henry Plummer [29]. Leonard Rowntree became professor at the Mayo Foundation in 1922. It was William Osler who stimulated Rowntree to give up private practice for research. At Johns Hopkins University he had worked with John J. Abel (1857–1938). They published two seminal papers in 1914. One was a method for hemodialysis in animals proposing its development into an artificial kidney in humans [30]and the other described a safe method of plasmapheresis [31]. Rowntree recruited investigators he knew from previous associations and together they formed “The Rowntree Group”, a fertilizer of investigative medicine at the Mayo Clinic. Rowntree left the Mayo Clinic in 1932. JW may have met with the biochemist Edward Kendall (1888–1972) who worked on suprarenal hormones in search of cortisone, but not the rheumatologist Philip Hench (1896–1965), with whom Kendall would share the Nobel Prize of Medicine or Physiology in 1950 for the discovery or cortisone treatment of rheumatoid arthritis.. Philip Hench had been drafted into the army and did not return to Rochester until 1946. Charles Slocumb was in charge of the rheumatology section during Hench’s absence. It was only at later visits to Mayo Clinic that he met Malcolm M. Hargraves,

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Fig. 7.19 Plummer building completed in 1928 is now a historic gem with many functions. https:// commons.wikimedia.org/wiki/File:Plummer_bldg_mayo_4988.jpg

the discoverer of the Tart cell, lupus erythematosus (LE) cell [32]. Over time JW developed a special friendship with Robert Kyle who became a lifelong May Clinic hematologist in 1961 and still is active there at present (2023). He had worked one year in Boston under Damechek but devoted to the. MAYO environment turned down an offer to join his group as a tenured member. One of Kyle’s early triumphs in Boston was the successful bone marrow transplantation to patient with agranulocytosis. Dr. Kyle still maintained annual contact in 2019 with healthy patient.

References

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7.7 Final Comments This long chapter is based largely on the rather incomplete narrative by JW at age 87 [1]. The extended visit to the states had a profound influence of his personal development and on his future performance as teacher and leader of a department. JW’s friendships in the U.S.A. were based on his already impressive standing in science, his outstanding instinct to spot equals in the new country, and of course on his personal charm and very special gift for developing friendships. JW returned to Sweden with fundamental knowledge regarding ongoing science. He had become impressed by the close links between clinical and basic science activities, and by undergraduate and postgraduate teaching routines. The expectations of his public employers in Stockholm were amply fulfilled. His seven months would inspire excellence and facilitate the ground for fellows and colleagues to establish their own contacts and collaborations in coming decades. By the time JW returned to Sweden in the summer of 1945, World War II had come to an end in Europe. In Uppsala he would find not only friends, but also animosity.

References 1. Waldenström JG. Reflections and recollections from a long life with medicine. Haematologica series, Ferrara Storti Foundation. Il pensiero scientifico Editore via Bradano, Rome; 1994. p. 1–137. 2. Griffith F. The significance of pneumococcal types. J Hygiene. 1928;27:113–59. 3. Avery OT, MacLeod CM, McCarty M. Studies on the chemical nature of the substance inducing transformation of pneumococcal type: Induction of transformation desoxyribonucleic acid fraction isolated from pneumococcus type III. J Exp Med. 1944;79:137–57. 4. Rivers TM. Filterable viruses: a critical review. J Bacteriol. 1927;14:217–58. 5. Hirst GK, Frank L. Horsfall Jr. A biographical memoir: National Academy of Sciences; 1979. 6. Horsfall F, Tiselius A. Mixed molecules of hemocyanins from two different species. J Exp Med. 1939;69:83–101. 7. Bearn AG. Robert Frederick Loeb 1895–1973. A Biographic Memoir: National Academy of Sciences; 1974. 8. Atchley DW, Stahl J, Loeb RF. The role of sodium in adrenal insufficiency. JAMA. 1935;104:2149–54. 9. Loeb RF. Activity of a new antimalarial agent, chloroquine (SN 7618). JAMA. 1946;130:1069– 70. 10. Schoenheimer R. The dynamic state of body constituents. Harvard University Monographs in Medicine and Public Health; 1946. p. 1–78. 11. London IM, Shemin D, Rittenberg D. The study of hemoglobin metabolism in man with the aid of the isotope technique. J Clin Invest. 1948;27(4):547. 12. Shemin D, Rittenberg D. Studies on the formation of heme and on the average life time of the human red blood cell. Fed Proc. 1946;5(1 Pt 2):153. 13. Heidelberger M, Pedersen KO, Tiselius A. Nature. 1936;138:165–216. 14. Albright F, Aub JC, Bauer W. Hyperparathyroidism: a common and polymorphic condition as illustrated by seventeen proven cases from the clinic. JAMA. 1934;102:1276. 15. Means JH. Clues to the aetiology of Grave’s disease. Lancet. 1949;2(6578):543–8. 16. Hertz S, Roberts A. Radioactivity as an indicator in thyroid physiology. V. The use of radioactive iodine in the differential diagnosis of two types of Grave’s disease. J Clin Invest. 1942;21:31–2.

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17. Krane SM, Browell GL, Stanbury JB, Corrigan H. The effect of thyroid disease on calcium metabolism in man. J Clin Invest. 1956;35:874–87. 18. Oransky I. George Widmer Thorn. Lancet. 2004;364(9433):496. 19. Anonymous. The Thorndike Memorial Laboratory of the Boston City Hospital. Science 1923;58:392–2. 20. Elrod JM, Karad AB. Boston City Hospital and the Thorndike Memorial Laboratory: the birth of modern haematology. Brit J Haematol. 2003;121:383–9. 21. Minot GW, Murphy WP. Treatment of pernicious anemia by a special diet. JAMA. 1926;87:470–6. 22. Castle WB. The aetiological relationship of achylia gastrica to pernicious anaemia. Proc R Soc Med. 1929;22:1214–6. 23. Zöllner N, Hofmann AF. Siegfried Thannhauser (1885–1962) Ein Leben als Arzt und Forscher in bewegter Zeit. Falk Foundation e. V. Freiburg 2006:3–99. 24. Wood WB Jr. The action of type-specific antibody upon the pulmonary lesion of experimental pneumococcal pneumonia. Science. 1940;92:15–6. 25. Moore CV, Dubach R, Minnich V, Roberts HK. Absorption of ferrous and ferric radioactive iron by human subjects and by dogs. J Clin Invest. 1944;23:755–67. 26. Keys A. Diet and blood cholesterol in population surveys-lessons from analysis of the data from a major survey in Israel. Am J Clin Nutr. 1988;48(5):1161–5. 27. Watson CJ. Über Sterkobilin und Pophyrine aus Koht. Zschr Phys Chem. 1932;204:57–67. 28. Schwartz S, Watson CJ. A simple test for urinary porphobilinogen. Proc Soc Exp Biol Med. 1941;47:393–4. 29. Hunder GG, Matteson EL. The History of Rheumatology at Mayo Clinic. The Mayo Clinic; 2018. 30. Abel JJ, Rowntree LG, Turner BB. On the removal of diffusible substances from the circulating blood of living animals by dialysis. J Pharm Exp Ther. 1914;5:271–316. 31. Abel JJ, Rowntree LG, Turner BB. Plasma removal with return of corpuscles (plasmapheresis). J Pharm Exp Ther. 1914;5:625–41. 32. Hargraves MM, Rochmon H, Morton R. Preparation of two bone marrow elements: the “Tart” cell and the L.E. cell. Proc Staff Meet Mayo Clin. 1948;23:25–28.

Chapter 8

Turbulent Final Years in Uppsala

Abstract In 1946 professor Gustav Bergmark was due to retire. JW an established scientist of international standing and an admired teacher was the star among ten applicants for the chair on medicine. But JW had not only friends. A defamation campaign was staged by the envoous Robin Fåhraeus. The dominating external reviewer Nanna Svartz was an outspoken adversary of JWs father. It came as a disappointing surprise for JW that he was bypassed by Erik Ask-Upmark. The faculty tried to console him with a personal chair named “Theoretical Medicine”. But the conditions became unbearable and JW, not inclined to work in the shadow of Ask-Upmark left Uppsala in 1950. While still in Uppsala he sent two promising scholars to prime institutions in US. They would join him in Malmö in 1950. Uppsala was left with a dysfunctional professor of medicine for two decades.

8.1 Selecting a New Professor and Chairman The success of the allied forces’ invasion in Normandy signaled that the end of World War II was in sight. JW was reunited with his family in June of 1945. After a mild winter and a cool spring, summer was pleasant and unusually warm with temperatures in the nineties Fahrenheit in much of Sweden. After happy holidays with his family Jan resumed work in Uppsala. The major epidemiology study on the prevalence of sarcopenia has been dealt with in Chap. 5 . His papers on purpura hyperglobulinemica [1] and macroglobulinemia [2] had been well received internationally. But in Uppsala a fierce attack brooded which would shake JW deeply. The atmosphere was so tense that when returning from work at the hospital, he could break down in tears in the lap of his wife Elisabet. Academic envy had taken hold of his former teacher Robin Fåhraeus (Fig. 8.1). Robin Fåhraeus (1888–1968) had obtained his M.D. and Ph.D. in 1922. His thesis dealt with the erythrocyte sedimentation rate (ESR) and showed its clinical usefulness. He also observed experimentally that blood flow through capillaries with a diameter of less than 0.3 mm resulted in a dramatic reduction of viscosity. This observation offered a new insight into the physiology of microcirculation [3]. Fåhraeus became assistant professor in 1923, associate professor in 1926, and full professor of © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Wollheim, Jan Gösta Waldenström and His World, Springer Biographies, https://doi.org/10.1007/978-3-031-36739-7_8

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Fig. 8.1 Robin Fåhraeus. Öppet bildariv Sydsvenska medicinhistoriska sällskaptet, BE200628-034paCpg.jpg. http://www.medicinhistoris kasyd.se›smhs_bilder

pathology in 1928. The ESR work established his international reputation, and it is said that he entertained hopes of winning the Nobel Prize just like his colleague The Svedberg with whom he had collaborated (Chap. 3). He was in fact nominated for the Prize several times without success between 1931 and 1941 by prominent Danish hematologists. JW’s discovery of two new diseases [1, 2] could be seen as a threat to such aspirations. In 1945, Fåhraeus sought to belittle JW and began spreading accusations among colleagues in Uppsala insinuating that JW was guilty of scientific misconduct and encouraged his student and later professor of pathology in Gothenburg, Stig Ranström (1914–2004), to publish a paper questioning part of Jan’s publications on hyperglobulinemia. The critique concerned some of the presented data and their interpretation, in particular regarding the connection between the gamma globulin changes and plasma cells and lymphocytes. Whereas Ranström stated that the cells were the source of the proteins, Jan had also considered the possibility that they were perhaps only the storage sites. Ranström suggested that one of JW’s cases of cryoglobulinemia instead was a case of systemic lupus erythematosus. Although the paper is written as a polite academic comment, it in fact repudiates JW’s description of two new diseases: “A survey of the literature shows that no one has yet put forward any factual basis for the thesaurismoasis theory as an explanation of the genesis of the myeloma. This casuistic ground on which Waldenström builds his assumptions on this matter proves hardly tenable on closer inspection” [4]. The accusations were in essence ungrounded, and Jan published an extended paper in response. Balanced and detailed, the paper contains eight parts [5]. Jan concedes some minor errors in his papers but convincingly strengthens their main messages. The paper included confirmatory results from reexamination of some sternal smears. “In the previous paper Ranström criticizes certain parts of my work on hypergammaglobilinemia and I shall use the opportunity that has been offered to discuss these questions at once. At the same time a few other points in my earlier publications on these subjects will be treated”. As we know, the international scientific community has fully corroborated JW’s original findings and attached the eponym “Waldenström” to both conditions. As will be seen JW’s defense did not prevent an

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upcoming academic injustice. Ranström in due time was promoted to professor of pathology in Gothenburg. In 1946, Gustaf Bergmark turned 65, the compulsory retirement age, and the chair of practical medicine in Uppsala became vacant. At that time only four chairs of medicine existed in Sweden, two in Stockholm and one each in Uppsala and Lund. The professors were appointed for the duration of their career by the government and given a document certifying the appointment signed by the King. Professors were in total command of their departments until retirement, and the salary was satisfactory and included honoraria from private patients. Naturally these positions were very attractive. The applicants were usually at least assistant professors. The merits of the applicants were assessed, and they were ranked by four external experts, whereupon the faculty voted on a suggested winner and informed the government which normally followed the majority vote in their appointment. There were 10 applicants for the chair, among whom Erik Ask-Upmark (1901–1985) was probably the most senior in age. His father, Fritz Ask, was professor of ophthalmology in Lund. Erik had studied medicine in Lund and developed an early fascination for morphology. He initially aimed to specialize in surgery but when the professor rejected his application he changed to medicine, the dominating non-surgical specialty. Medicine was still an undivided specialty and included all subspecialties including neurology. One of the reviewers was the professor of medicine in Lund since 1929 Sven Ingvar (1889– 1947), a charismatic neurologist. He had been sent the Charité in Berlin to complete knowledge of internal medicine. His international reputation was based on important discoveries on the development and function of the cerebellum using the tools of comparative embryology. Sven Ingvar was the unanimous appointee to the chair of medicine in 1929 (Fig. 8.2). Fig. 8.2 Ingvar, one of the outside experts for the chair in Uppsala while still in good health. Photo by the student nurse Elsa Arnberg. Copyright Henry Svensson. Öppet bildarkiv.Sydsvenska medicinhistoriska sällskaptet, 140510-003Copp.jpg. http:// www.medicinhistoriskasyd. se›smhs_bilder

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Fig. 8.3 Erik Ask-Upmark in 1932, embarking M/S Drottningholm for the U.S. as Rockefeller fellow with Harvey Cushing in Boston. From [7]. Öppet bildarkiv. Sydsvenska medicinhistoriska sällskapet, BE200628-016paCpg.jpg. http://www.medicinhistoris kasyd.se›smhs_bilder

Ask-Upmark worked in the Department of Anatomy in Lund on neural connections between the brain and the sinus caroticus. As a Rockefeller stipend recipient he spent six months in Boston in 1933 with Harvey Cushing, performing animal experiments. Back in Lund, he defended his Ph.D. thesis in 1935 [6]. It had 347 (!) pages, almost twice the volume of JW’s comprehensive thesis. In 1936, he became assistant professor and continued to publish clinical papers and attend a busy outpatient clinic at the hospital in Lund. In addition, he served as a full-time spa physician from June to August at Ramlösa Brunn on the west coast, 30 miles northwest of Lund. In 1945, he was promoted to chief physician at the Department of Medicine in Gothenburg. This was then still a non-teaching hospital (Fig. 8.3). Ask-Upmark published numerous papers on a variety of topics. They were often based on a small number of patients he had personally seen in his practice. The papers were always detailed and carefully written in an epical style, not omitting the medical history of the conditions, and contained detailed case reports and comprehensive concluding discussions and represented excellent state-of-the-art contributions. Often they pointed to possible psychologic factors in the pathogenesis. He could not resist catching also unscientific remarks. A paper on gout states “I have never encountered gout in a patient with a low IQ” [8]. Except for the animal work performed in Boston one does not find any experimental papers. Ask-Upmark authored several Swedish medical textbooks and popular texts. He was a celebrity in society. When Sven Ingvar died in 1947, Ask-Upmark published a four-page memorial praising his beloved mentor [9]. Ask-Upmark cherished his years in Lund, a city which he called “urs urbis”, the city of cities. It was no secret that he anticipated to become Sven Ingvar’s successor and live in Lund again. In their assessment of the applicants for the chair in Uppsala, it turned out that all four external reviewers judged Ask-Upmark and JW to be the most qualified among the ten applicants. However, they placed Ask-Upmark first because of his broader expertise in different fields of internal medicine. This was good news for Jan’s adversaries but bad news for his friends and for Uppsala. JW was devastated as

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Fig. 8.4 Nanna Svartz, Photogrpher unknown. © unretrivable. Unknown hotographer 1950. https:// history.rcplondon.ac.uk/inspiring-physicians/nanna-charlotta-svartz 7 February 2022

he feared he would be obliged to part from the scientific and cultural life in Uppsala. Working close to or under Ask-Upmark would be unbearable. It is likely that Nanna Svartz played dominating role in the appointment committee (Fig. 8.4). The reviewers had been selected among professors from the Scandinavian countries. They included Carl Ulaf Sonne (1882–1948), professor in Copenhagen, Sven Ingvar in Lund as mentioned Gustaf Bergmark, Uppsala, and. Nanna Svartz Stockholm. Ingvar was already severely ill with hypertensive encephalopathy and not mentally alert and in addition could be considered to have conflicts of interest since Ask-Upmark was his former fellow. Nanna Svartz (1890–1986), the first female professor in the medical field in Sweden, probably had a dominant influence among the reviewers. Years earlier she had been involved in a bitter fight with Jan’s father, Henning Waldenström, professor of Orthopedics at Karolinska. The issue concerned the leadership of a new research facility at Karolinska, the “Gustaf V Research Institute”. The mission of the institute was to perform research on chronic disabling diseases prevalent in the population, in particular arthritis and mental diseases. Henning and other professors wanted to advertise internationally for a leading scientist, but Nanna claimed that this was unnecessary. She claimed unwisely that the leader must be a clinician since research on diseases could only be fostered and supervised by an experienced clinician. Nanna prevailed and in the end she herself while continuing her full-time job a professor and chairman of medicine became appointed as director, a post she would hold until well after her retirement from the chair of medicine. In retrospect it is hard to understand the decision of the four professors. The decision may reveal a conservative mindset, but likely reflected personal conflicts and animosities. Gustaf Bergmark’s vote is more of a surprise and was a particular disappointment for JW. When the appointment of Ask-Upmark was confirmed by the King, the faculty in Uppsala realized that they risked losing their rising star and created a second, smaller Department of Medicine and a dedicated chair for JW. The faculty suggested the name “Clinical Biochemistry” but this was changed by the government officials to “Theoretical Medicine”. It came with a 100 m2 laboratory space and a limited number of hospital beds. Without applying Jan became a full professor in 1947. There were

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now two incompatible professors of medicine in Uppsala, an unhappy situation for both. The wards and the physicians were either part of JW’s smaller or Ask-Upmark’s larger domains. While the latter anticipated that his stay in Uppsala would be of short duration, JW continued his constructive work for a meaningful future. In his memoir, Ask-Upmark states that he encountered an unfriendly atmosphere when arriving in Uppsala. In 1969 he wrote: “I encountered rancor, spite, small-mindedness, and envy from his (Jan’s) friends who had convinced him that it (his appointment) would be an easy match” [7]. His wife was not allowed to attend a lecture he was giving. The welcome flowers on his desk were faded, the students hostile. He also writes that JW was a bad loser, although he did not want to go into details about this. Sven Ingvar’s untimely death in 1947 had vacated the chair of medicine in Lund seven years ahead of the expected time. Ask-Upmark was senior among several applicants and considered himself the obvious choice as Ingvar’s successor. There is a rule in Sweden that if a majority of the faculty can identify an exceptionally qualified candidate for a chair they can select such a person for the position and abstain from the tedious procedure of constituting a committee of external reviewers and wait for their verdict. Ask-Upmark had anticipated that Lund would invite him and abstain from the ordinary selection procedure. When this did not happen as described in Chap. 9, he felt disgraced. Apparently, he did not want to risk the embarrassment of not being the winner in a competition and withdrew his application. His hope for only a brief time in the unfriendly Uppsala turned out to last for the rest of his life. At this time, the Swedish health authorities had decided to increase the number of medical students in the country and enlarge support for medical research. Malmö General Hospital was converted into a teaching hospital of the medical faculty in Lund. JW applied for the new chair of practical medicine there. This time the reviewers uniformly gave him the first place. He was appointed in 1949 and started work in Malmö in January of 1950.

8.2 The Winner in Uppsala Ask-Upmark was a knowledgeable teacher with a special affinity for the odd. His lectures were elegant but also exposed his ego and vanity. He would spice up the lectures by asking sophisticated questions which often not even the brightest students could answer. After one such question, to his surprise one of the less ambitious students raised his arm as to answer and said: “Professor, there are some egg rests in your beard”. Ask-Upmark had only few but dedicated Ph.D. students who were not repelled by his sometimes-odd manners. His own scientific activity is evidenced by some 100 publications listed in PubMed. The titles bear witness to the author’s fluent pen and range of interests. Although the papers have educational qualities and continued to be based on personal experiences with patients, they lack deeper penetrations of pathogenetic mechanisms. An example is a 1977 letter on polymyalgia in the British Medical Journal [10]. He uses the term “polymyalgia arteritica” that had been proposed without success by JW’s Ph.D. student in Malmö Bengt Hamrin

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to replace the much less appropriate name polymyalgia rheumatica [11] (Chap. 22). This brief note informs on one of his “some 50 patients with polymyalgia arteritica” seen in Uppsala: “an old lady came to the clinic escorted by a St Bernhard dog which was entirely fictious. She wanted the dog placed in the bed next to her and this permission was of course granted. The following day after she had received a rather massive dose of cortisone, the dog had disappeared, much to her embarrassment. The subsequent treatment kept the dog away from her” [10]. In a paper from 1955, Ask-Upmark shows the increased number and volume of daily newspapers the time and then presents data on the prevalence of pulmonary cancer among typographers. The data were derived from the Department of Chest Surgery at Karolinska. The data suggested that such workers are a risk group that should be screened with chest radiography at least biannually [12]. Smoking was not mentioned in the paper. A brief report on four cases of vertebral artery occlusion in young women using contraceptives made a point of the fact that in three of them the affected vessel was the right-sided artery. In contrast, he cited work showing that arteriosclerotic vertebral artery occlusion more often affected the left-sided artery [13]. Starting in 1949, Ask-Upmark resumed his habit of spending three months every summer as the managing head of the noble spa Ramlösa Brunn in his home province, not far from “urs urbis”. The spa sold Sweden’s most popular sparkling mineral water. The label characterized it as “natural, alkaline and free of iron”, none of which was correct. The exiled professor enjoyed breathing southern air and meeting interesting people taking the waters. Except for Nanna Svartz, Ask-Upmark did not in general appreciate women as colleagues, and he could be very rude to female medical students. Many of them therefore avoided medicine in Uppsala and moved to Stockholm where they could expect fair treatment. Even worse, Ask-Upmark was a pronounced anti-Semite even after World War II [14]. In 1946, three Jewish medical students from communist Poland defected and arrived as refugees in Uppsala. They completed the preclinical years with honors, but when ready for the clinical part of the curriculum in 1948, Ask-Upmark did not allow them into his course. They had to transfer to Stockholm where one of them, Jerzy Einhorn, would become a prominent M.D., Ph.D. [15], and professor of oncology. However, in Ask-Upmark’s biography published in 1969 he claims that he was one of few doctors in the department in Lund who actively supported the admission of Jewish physicians from Austria in 1939 (Chap. 5). He also “remembers” how sad he was when looking out from his hotel window in Helsingborg in the summer of 1943 to watch the steamship Donau pass through the Sound on its way south. On board were rounded up Norwegian Jews on their way to Nazi concentration camps [7].

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8.3 The “Looser” JW’s scientific productivity continued uninterrupted despite the events related in the foregoing. He published papers on a gel formation test similar to the formal gel test, but simpler [16]. A detailed clinical paper dealt with acute neurologic complications in thyrotoxicosis [17]. Another detailed the clinical appearance of the tongue in patients with anemia documented with black and white photographs [18]. Encouraged by his chairman, professor Bergmark, JW embarked on a large epidemiological investigation of sideropenia in rural parishes in the Uppsala region. This was probably the first population-based epidemiologic study in Sweden. The study showed diets used by less affluent people to be an etiolgy of anemia and low serum iron. Other authors, among them the leading German hematologist Ludwig Heilmeyer, later a close friend, realized that low serum iron was the cause of “essential” hypochromic anemia. Heilmeyer called it the “Eisenmangelkrankheit”, iron deficiency disease. JW introduced the alternate term sideropenia. In 1941, JW had reviewed a book in which Heilmeyer described an improved iron assay [19]. JW was to use the method in his study. He selected a random parish dominated by sizeable farms and examined every one of its 152 female inhabitants above 14 years of age. Hemoglobin was obtained from all subjects, but serum iron was determined in “only” 142 /152, due to technical difficulties. The results showed pronounced sideropenia in 11% of the subjects, while somewhat subnormal serum iron was present in more than 20%. Sideropenia was also common in other parishes with smaller farms and a less affluent population. In contrast, the prevalence was lower in parishes where daily intake of fish was common and also among urban populations, even in low-income neighborhoods. These results pointed to the importance of previously neglected nutritional factors. Diurnal variation of serum iron with higher morning levels of serum iron was described. This finding was later explained by the normal hemo-concentration caused by capillary extravasation from dependent parts of the body rather than to some sophisticated diurnal regulating system. JW concluded that there was an unmet need for iron supplementation, in particular among women living in rural populations. JW acknowledges the help of medical students, a bishop and his wife, and nurses, one of whom was the research nurse Karin Nordsjö. She would become JW’s second wife in 1957 [20]. Invitations to serve as external reviewer at a Ph.D. thesis examination was then as now extended to individuals considered fair senior experts. For JW, two such assignments would turn out to be important for coming years in Malmö. The first was in 1947 when he was the invited reviewer at a thesis which was defended in Lund by Carl-Bertil Laurell (1919–2001). This event and Carl-Bertil’s contributions in Lund and Malmö are reviewed in Chap. 19. In 1949, another assignment was at Karolinska where Gunnar Biörck, GB, (1916–1996) was defending his thesis “On myoglobin and its occurrence in man” [21]. Biörck was a clinical scholar of Gustaf Nylin (1892–1961), the founder of Swedish cardiology, and the co-founder and first president of the Swedish Society of Cardiology as well as the European Society of Cardiology. The experimental work was performed in the laboratory of Hugo

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Theorell (1903–1982) at the Nobel Institute of Karolinska. Theorell had isolated myoglobin from animals. At the time a gifted beginner, Christian de Duve (1917– 2013) was in the laboratory to learn biochemical methodology and was given the task to isolate human myoglobin. He used minced heart tissue obtained from the adjacent morgue. Gunnar Biörck acknowledged the help of de Duve in his thesis. JW was attracted by the metabolic approach to the study of cardiac diseases. Although JW and GB had been on opposite sides in 1939, when GB opposed and JW supported granting immigration of 10 threatened Jewish physicians from Austria (Chap. 4), they became good friends. Both were extroverted aristocratic men with strong interests in the humanities, and they shared many ideas about the medical profession. Both strongly supported preserving internal medicine as a undivided unified specialty. In 1950, GB was recruited by JW to the department in Malmö to lead the division of cardiology. Like JW, GB was an early and enthusiastic visitor to North America [22] . Committee work was not JW’s favored past time but he had a strong interest in medical student education (Chap. 21). In 1946 he decided to make an exception. JW had a reputation as inspiring undergraduate teacher. The government’s secretary of health organized a committee of nine experts with the task of modernizing the curriculum at the Swedish medical schools of which JW became a member. Other experts were Haquin Malmros, Bertil Nosslin, and Helge Wullf, names which will appear in later chapters. The preparations started with a fact-finding visit to leading medical schools in the U.S., and clearly JW’s wartime experience made him an ideal member of the group. The work on the recommendations took several years. The committee’s report was not delivered until February of 1953 whereafter several of its suggestions were adopted and implemented in the 1950s [23] (Fig. 8.5). JW had now reached a stage in his career where it was time to choose his own scholars. His personal charm and scientific achievements made it easy to find them. JW was aware of the importance of psychologic factors and personal chemistry in a Fig. 8.5 The 1948 committee recommendations for a new medical school curriculum, delivered in 1953 [23]. Photo Frank Wollheim

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functional research community and how destructive even a single sociopathic personality could be. Therefore, he was then and later very careful in selecting collaborators, and his staff was never extensive. JW and Sven-Erik Björkman (1912–1996) had already found each other in 1940. Sven-Erik had graduated the previous year, and JW inspired his first scientific work, an experimental study of porphyrin excretion in lead-poisoned rabbits [24]. Björkman presented an impressive experimental Ph.D. thesis on spleen physiology in 1947 [25]. In essence, it dealt with the migration of red blood cells between the pulp and sinus areas of the spleen, a key mechanism regulating the splenic function of retaining and destroying aging and damaged erythrocytes from the circulation. These compartments are separated by fenestrated membranes. Björkman could show the importance of shape and dimensions of the erythrocytes and deduced that the circulation goes from the sinus areas to the pulp cords which feed into the splenic veins [26]. With help of JW’s recommendation to friends at the Rockefeller Institute, Björman spent an instructive postdoctoral year there in 1947–8 with Frank Horsfall (Chap. 7), studying the interaction of different influenza strains with erythrocytes [27]. Björkman shared JW’s clinical skills and the keen ability for translational observation. His memory for case histories of individual patients and his sense of humor also matched that of his mentor. Another of JW’s fellows was Bengt Skanse, BS, (1918–1963). BS was born in a small country village in V ärmland, the province of Selma Lagerlöf (1858–1940), as the oldest of three children. From age 11 he had to leave home and attend the gymnasium in Karlstad, the nearest town. He went to medical school in Uppsala and joined the department of medicine in the early 1940s. As related in Chap. 7, JW had been introduced to the medical use of radioisotopes by Robley Evans at MIT in 1945 and realized their potential for clinical practice and research (Chap. 7). In Uppsala, Jan sensed the potential of his enthusiastic young colleague and negotiated a Rockefeller Fellowship for him in 1946 to work at Harvard and learn the use of isotopes in the department of medicine under Howard Means and Robley Evans. BS’s fiancé Ingar Undén from Uppsala joined him some months later, and they were married in the Swedish church in New York City in 1947. She was daughter of the professor of law in Uppsala and later Swedish cabinet secretary of foreign affairs, Östen Undén (1886–1974). BS accomplished outstanding work and was highly appreciated by Means and his staff. As a result, he was awarded a Henry P. Walcott fellowship and could spend a productive second year in Boston. He published nine significant experimental and clinical papers on radioactive iodine and thyroid function and disease in collaboration with Evans’ group at MIT. In 1949, BS and his wife returned to Uppsala where he defended his Ph.D. thesis, a milestone in thyroid endocrinology [28]. The opponent was the professor of the still combined department of physiology and physiological chemistry, Gunnar Blix (1894–1981). BS described in great detail a new diagnostic method to examine thyroid function. It consisted of administering I131 mixed with inactive carrier iodine and measuring the urinary excretion after 24 and 48 h. This test, the “radio-iodine test”, was far superior in comparison with the basal metabolic rate, BMR. It measures the affinity of the thyroid gland for iodine, which is increased

References

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Fig. 8.6 Cover of Bengt Skanse’s Ph.D. thesis [28] Courtesy Beata Skanse

in thyrotoxicosis and reduced in myxedema. At the thesis ceremony the defendant following the tradition in Sweden by involving a friend as mock “third opponent”. The choice was Sverker Åström (1915–2012). Sverker criticized the thesis for being too egocentric, it contained far too many I-s (iodine). Sverker Åström was already a Swedish diplomat and worked in the ministry of foreign affairs. He would later work at the United Nations, close to Dag Hammarskjöld. BS’s thesis was awarded the highest grade. He had introduced the field of nuclear medicine in Sweden. Bengt was awarded the title of docent the same year. In 1950, Ingar’ wife gave birth to their son in Stockholm. The younger sister Beata Skanse often heard her parents mention that the years in Boston were the happiest of their life [29] (Fig. 8.6). Clearly the “bad looser” was instead an accomplished winner and built significant fundaments for a meaningful future. It will be seen that this contributed to his later success in Malmö. Intensive and productive work helped to ease the pain of being forced to leave his beloved alma mater for the unfamiliar provincial south of Sweden.

References 1. Waldenström J. Kliniska metoder för påvisande av hyperproteinämi och deras praktiska värde för diagnostiken. Nord Med. 1943;20:288–95. 2. Waldenström J. Incipient myelomatosis or “essential” hyperglobulinemia with fibrinogenopenia—a new syndrome? Acta Med Scand. 1944;117:216–47. 3. Fåhraeus R, Lindqvist T. The viscosity of the blood in narrow capillary tubes. Am J Physiol. 1931;96:562–8.

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4. Ranström, S. On the terms “Essential hyperglobulinemia and ”premyeloma”. Acta Med Scand. 1946;124:134–147. 5. Waldenström J. Some remarks on the previous paper by S Ranström. Acta Med Scand. 1946;124:148–59. 6. Ask-Upmark E. The carotid sinus and the cerebral circulation. An anatomical, experimental, and clinical investigation, including some observations on rete mirabilis caroticum. Acta Psych Neurol. 1935;suppl 6:1–3. 7. Ask-Upmark. Resa genom åren. Almqvist and Wiksell, Stockholm 1969:1–289. 8. Ask-Upmark E. Sven Ingvar (1889–1947). Acta Med Scand. 1948;130:213–8. 9. Ask-Upmark E. Gout and the pathogenesis of its attacks. Acta Med Scand. 1967;181:163–71. 10. Ask-Upmark E. Hallucinations in polymyalgia arteritica. Br Med J. 1977;10;2(6088):703. 11. Hamrin B. Polymyalgia arteritica. Acta Med Scand Suppl. 1972;533:1–131. 12. Ask-Upmark E. Bronchial carcinoma in printing workers. Dis Chest. 1955;27:427–35. 13. Ask-Upmark E, Bickerstaff ER. Vertebral artery occlusion and oral contraceptives. Br Med J. 1976;1(6008):487–8. 14. Högberg, U. Vita rockar och bruna skjortor (White coats and brown skirts). Universes Press Malmö. 2013. 7–318. 15. Einhorn J. Studies on the effect of thyrotropic hormone on the thyroid function in man. Acta Radiol Suppl. 1958;160:1–107. 16. Waldenström J. The, “alcacid reaction” a new qualitative test for serum globulins. Preliminary report Acta Med Scand. 1945;121:68–72. 17. Waldenström J. Acute thyrotoxic encephalo- or myopathy, its cause and treatment. Acta Med Scand. 1945;121:251–94. 18. Waldenström J. Examination of the tongue: a clinical and photographic study. Acta Med Scand. 1945;122:207–37. 19. Heilmeier L, Keiderling W, Stüwe G. Kupfer und Eisen als körpereigene Wirkstoffe. G. Fischer Jena, 1941. 20. Waldenström J. The incidence of “iron deficiency” (sideropenia) in some rural and urban populations. Acta med Scand. 1946;123(S 170):252–279. 21. Biörck GW. On myoglobin and its occurrence in man. Acta Med Scand. 1949;133(Suppl 226):7–216. 22. Biörck G. Cardiology in North America. Acta Med Scand. 1948;130(Suppl 206):66–75. 23. Waldenström J. Medicinstudierna I USA. (Studying medicine in the United States). Nord Med. 1946;32:2837–8. 24. Läkarutbildningen. Statens offentliga utredningar 1953:7. Ecklisiastikdepartementet. Digital at The National Library in Stockholm. 25. Björkman SE. Koproporphyrinurie und Hämoglobulinstoffwechsel bei experimenteller Bleivergiftung. Acta Med Scand. 1941;108:568–79. 26. Björkman SE. The splenic circulation, with special reference to the function of the spleen sinus wall. Acta Med Scand. 1947;127 (suppl 191):7–89. 27. Björkman SE, Horsfall FL Jr. The production of a persistent alteration in influenza virus by lanthanum or ultraviolet irradiation. J Exp Med. 1948;88:445–61. 28. Skanse B. Radioactive iodine in the diagnosis of thyroid disease. Acta Med Scand. 1949;135(suppl 235):1–186. 29. Beata Skanse. Personal communication. 2020.

Chapter 9

“The Great Faculty” in Lund

Abstract This chapter introduces some noted developments at the medical faculty in Lund during the first part of the twentieth century. It can be seen that research of international standing was performed at several departments. Some of the investigators later became Nobel Laureates, but by then had moved to other universities in Sweden.

9.1 Introduction As mentioned Uppsala University was founded in 1477. Lund University was opened in 1668, ten years after the capture of three southern provinces including Scania from Denmark. The government wanted to discourage youth from the area from enrolling at the nearby University of Copenhagen in enemy country and return with antiSwedish mindsets. The inhabitants in the new Swedish provinces soon realized that living conditions for ordinary people in Sweden were better than those in feudal Denmark. Therefore there was no strategical need to support the new university. That and a declining Swedish economy had the consequence that support for the new university dwindled. The medical faculty in Lund remained quite small until the mid-nineteenth century. It attained excellence in several fields in the twentieth century although the total number of professors in 1935 was still only 13. Yet local patriots later would call it the great faculty. This chapter will introduces some of this faculty up to the time of JW’s arrival and demonstrates some outstanding contributions to medical science (Fig. 9.1).

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Wollheim, Jan Gösta Waldenström and His World, Springer Biographies, https://doi.org/10.1007/978-3-031-36739-7_9

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Fig. 9.1 Main building of Lund University constructed 1876–1882. The architect was Helgo Zetterwall (1831–1907). The 4 female sculptures at the entrance represented the four faculties religion, law, medicine, and philosophy. They were removed in 1902. The (invisible) inscription on the top reads REGIA ACADEMIA CAROLINA. © Lund tourist information. Photo before 1902. https:// www.turistinformationlund.se/upplevelser/universitetsstaden/historia/ 12 February 2022

9.2 Pathology and Bacteriology Pathology and bacteriology were still united as a single specialty in the early twentieth century. Lund was fortunate to have an outstanding professor in this field. Magnus John C. A. Forssman (1868–1947) defended his Ph.D. thesis in Lund in1898. The experimental study showed that severed peripheral nerves had the potential to heal, provided the separated ends were brought into physical contact. The work predicted the later discovery of nerve growth factor. Forssman’s well-rounded training included studies in bacteriology in Copenhagen, Germany, and at the Pasteur Institute in Paris in 1898–99. Louis Pasteur (1822–1895) had recently died, and Ilya Ilyich Metchnikoff (1845–1916) was the new director. Infection and immunity became the main research interests of Forssman. He met his wife while studying a smallpox epidemic in London. In Lund, he began scientific collaboration with the chemist Ivar Bang (1869–1918) on the formation of specific hemolytic antibodies which would generate an unexpected result, bringing international fame but also leading to controversy with a prominent Nobel Laureate [1] (Fig. 9.2). In Germany, Paul Ehrlich (1854–1915) had proposed his “side-chain theory” in 1900, hypothesizing that antibody-forming cells have preformed sidechains, complementary to toxins and other foreign antigens [2]. Attachment of such compounds to the sidechains triggers the cell’s metabolic activity, resulting in release of specific antibodies. Ehrlich shared the Nobel Prize in 1908 with Ilyich Metchnikoff. Three years later Forssman found high titers of antibodies to sheep cells raised in rabbits immunized with guinea pig broth from animals who had never encountered sheep cells. The immunizing antigen therefore must be distinct from sheep red cells. When the experiments were broadly confirmed the unknown substance was soon called the

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Fig. 9.2 John Forssman at his desk 1910. © Sydsvenska Medicinhistoriska Sällskapet Öppet bildarkiv SMHS1368_ 000_02Copp.jpg. http:// www.medicinhistoriskasyd. se/smhs_bilder

Forssman antigen and the antibodies Forssman antibodies or heterophile antibodies. This was in apparent contradiction to Ehrlich’s hypothesis. Forssman visited him and tried to reconcile the findings without success. Forssman in reality had discovered the existence of haptens which are incomplete antigens, and the observation was not in conflict with Ehrlich’s specificity concept. The Forssman antigen much later was identified as a glycolipid, pentaglyosyl ceramide, which is expressed in several tissues but not in all species [3]. From 1909 to 1933, Forssmann was professor of pathology, bacteriology, and public health in Lund. The salary was meager, but he could supplement it by specializing in venerology in Copenhagen and start a dermatology practice in Lund. Forssman was a superb teacher and had some 70 postgraduate students, several of whom had distinguished academic careers. Forssman’s strong engagement in the well-being of university students with precarious finances initiated an initiative during World War I. There was widespread food shortage in Sweden due to blockade of shipping, and food prices soared. Forssman managed to organize a canteen providing affordable food for students, “Konviktoriet”. The canteen survived until 1968 to the benefit of many student generations, including that of the author. Forssman also had a strong interest in sports. He co-founded a tennis club with indoor courts and after retirement took up golf and co-founded the academic country club outside Lund [4]. Forssman’s colleague Einar Sjövall (1879–1964) was born in Lund. After finishing medical school in Lund in 1904, he worked two years in Stockholm and became a neuropathologist. In 1905, he returned to Lund, defended his Ph.D. thesis “Über Spinalgangliezellen und Markscheiden”, (On cells in spinal ganglia and on myelin sheaths), and was appointed assistant professor in 1906. He was professor of pathology and histology from 1914 until 1944. In addition, he was professor of forensic medicine, and his name appeared often in public when he had performed autopsies in connection with accidents or crimes. Sjövall was politically active as

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social democrat and worked for public support of health care for all and for the modernization of general practice. Realizing the negative effects of alcohol abuse, he became a teetotaler. His political activity met with disapproval from the conservative majority in the faculty. He was an early and outspoken opponent of the Nazi regime in Germany and their sympathizers in Sweden. During the years 1939 to 1944, he mantled the difficult task of assistant vice chancellor of the university. Sjöwall was an important mentor for the next generation of pathologists. Forssman´s and Sjövall’s departments shared a building with the address Paradisgatan, “Paradise Street”, named after the merchant who had once owned the land. The building became a popular and productive environment for the many students mentored there (Fig. 9.3). One of the brilliant mentees of Forssman was Arvid Lindau (1892–1958), who worked there from 1918. In 1921–2 he had performed autopsies on two cases with cyst formation of the cerebellum. He found preserved specimens of similar cysts in the department’s museum collection and started the search for additional cases elsewhere. He obtained a travel grant and visited several institutions in Sweden, Germany, and Czechoslovakia. After years of careful work Lindau presented an outstanding thesis in 1926 [5]. He observed that some cases of an otherwise benign retinal angiomatous

Fig. 9.3 The Department of Pathology and Bacteriology in Lund at “Paradisgatan 10”.The building left housed the Department of Bacteriology where Rune Grubb discovered the Gm system of gamma globulin genetics in 1956. From C. G Ahlströms archive at Lund University Library Permission obtained

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Fig. 9.4 Drawing of case 1. Stippled circle depicts the cyst and the vertically lined area, the angioma. From the thesis of Lindau [5]. Copyright unretrievable

condition, known among ophthalmologists as von Hippel’s disease, had died with cystic tumors of the cerebellum. Lindau amply documented that such lesions often were found in other organs as well, such as the spinal cord, pancreas, kidneys, and liver. Familial occurrence of this rare condition indicated a hereditary nature. The famous neurosurgeon Harvey Cushing (1869–1939) in Boston was working on hemangiomas of cerebellum. When he read the work of Lindau he was deeply impressed and published a paper in 1928 which acknowledged Lindau’s contributions and reported the first successfully operated case of the condition. He proposed the eponym “Lindau’s disease”[6] and invited Lindau to Boston. With Lindau he visited a successfully operated woman on a ward round. When she thanked the surgeon for having saved her life, Cushing responded: “Don’t thank me, thank this young man from Sweden” [7] (Figs. 9.4 and 9.5). With time the condition became known as Von Hippel-Lindau disease. In 1993, the genetic basis was identified as a mutation in the Von Hippel-Lindau tumor suppressing gene, VHL. The gene product, VHL protein, is essential for the oxygen sensing of cells and functions as a tumor suppressing gene. These discoveries resulted in the 2019 Nobel Prize to William G. Keilin, Sir Peter J. Ratcliffe, and Gregg L. Semeza. Lindau was promoted to professor as Forssman’s successor in 1933. In 1947, this chair was divided into one for pathology and one for bacteriology. Lindau choose bacteriology and worked on syphilis, tuberculosis, and central nervous system infections. One of his students, Rune Grubb (1920–1998), discovered the genetic Gm system of immunoglobulin G (IgG) in 1956. Grubb would succeed Lindau after his untimely death in 1958. Among the numerous other investigators at Paradise Street one can mention Carl Gustaf Ahlström (1905–1990) who became professor of pathology in 1944, and Ahlström’s first Ph.D. student Folke Linell (1913–1994), who became the professor of pathology in Malmö in 1953.

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Fig. 9.5 Angiomatosis retinae. From the thesis of Arvid Lindau [5] Copyright unretrievable

9.3 Anatomy and Histology Traditionally departments of anatomy had a prominent position at medical schools. In Lund, Ivar Broman (1868–1946), who graduated as M.D, Ph.D in 1899, was professor of anatomy and histology from 1905 until 1933. His main research interest was comparative embryology. He was the first to examine a human embryo only three mm in length and could show that at even at this early stage the brain had a segmented structure like that of adults and that the same applied to animal species. His interest in comparative embryology motivated extensive trips to Europe and Africa where he collected embryos from numerous species. He had a wealthy friend, the hotelier Hjalmar Tornblad (1867–1937), who donated money to build an institute for his research with space for the collection. The bylaws of the Tornblad Institute stipulated that Broman was to be its lifetime director. Broman was a strong admirer of German science and culture. He did not distance himself from the Nazi regime. In 1938, he became one of the funders of a society to foster friendship with The New Germany. Although he was never member of the Nazi party in Sweden, he turned a closed eye and silent tongue to the ongoing crimes in the Third Reich. Gösta Glimstedt (1905–1970), professor of histology 1943–1970, was Broman’s successor as chief of the Tornblad Institute (Fig. 9.6).

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Fig. 9.6 Tornblad Institute of Embryology, inaugurated in 1934. Fredrik Tersmeden, Lund, Sweden (= FredrikT)—Eget arbete. CC BY-SA 3.0. Photo by Fredrik Tersmeden. https://sv.wikipedia.org/ wiki/Tornbladinstitutet

9.4 Physiology, Medical Chemistry, and Pharmacology In 1905 the faculty was able to recruit an outstanding professor of physiology. Torsten Thunberg, (1873–1952). “TT” had graduated as M.D. in Uppsala in 1897. He defended his Ph.D. thesis there in1900, where he showed that cold, heat, and pain were sensed on different spots of the skin, indicating signaling by separate nerves [8]. TT also performed groundbreaking research on tissue respiration and showed that oxygen transport involves a series of transformations regulated by dehydrogenase enzymes. He introduced the use of methylene blue as a biochemical indicator of vitality. Similar discoveries were made independently by Otto Warburg (1883– 1970) in Berlin. Warburg was awarded the Nobel Prize in 1931 but TT was left out. Warburg was Jewish but retained his position a director at the Kaiser Friedrich Institut in Berlin-Dalem throughout the Third Reich. Why this “non-aryan” was not removed from office and persecuted has never been elucidated (Fig. 9.7). In the 1920s, poliomyelitis patients with palsy of the respiratory muscles rarely survived. This gave TT the idea to construct a barospirator in 1926 [9]. It enclosed the entire patient in a chamber in which the pressure was varied between one and eleven atmospheres in a rhythm similar to that of normal respiration. This provided adequate oxygen supply without any movement of the chest wall and helped the paralyzed patients to survive. Three years later Philip Drinker’s (1894–1972) “iron lung” respirator would replace the barospirator. But TT’s machine served for years as

98 Fig. 9.7 Torsten Thunberg. Photo 1940s by Olle Hammar, Department of Physiology, Lund. Öppet bildarkiv. Sydsvenska Medicinhistoriska Sällskapet. SMHS_2018_ OH002Copp.jpg. http:// www.medicinhistoriskasyd. se/smhs_bilder

Fig. 9.8 Torsten Thunberg with a patient in his barospirator. Unknown photographer 1926. Öppet Bildrkiv. Sydsvenska medicinhistoriska Sällskapet, Öppet bildarkiv. 09–09.jpg. http://www.medicinhistoris kasyd.se/smhs_bilder

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a lifesaving tool in the basement of the department of medicine. It created a very loud noise which could be heard throughout most of the four-story building (Fig. 9.8). TT was a humble, almost shy professor, but was a popular and proficient supervisor of Ph.D. students. Some of these and their achievements deserve mentioning. Erik Widmark (1889–1945) was attracted to the department while still a medical student and became a demonstrator for undergraduates. He defended his Ph.D. thesis in 1917 which described a new micro-assay for acetone [10]. Ivar Bang had worked with less success on the same task previously and disputed the new method and suggested that the dissertation should be flunked. Widmark mounted a successful defense and in the end was awarded the Ph.D. degree and created as “docent”/assistant professor. A year later Bang suddenly died, and ironically, Widmark was appointed to become his successor. Ulf von Euler (1905–1983) spent time with Thunberg in the late 1920s working on nerve transmission in sympathetic nerves. He moved back to Stockholm and continued work that resulted the discovery of noradrenalin as a transmitter substance in sympathetic nerves. The discovery was awarded the Nobel Prize in 1970. Gunnar Ahlgren (1898–1962) defended his Ph.D. thesis in 1925 and became TT’s favorite scholar. Jörgen Lehman (1898–1989) defended his Ph.D. thesis on dehydrogenases in 1929. He spent time with Landsteiner at the Rockefeller Institute before moving to Gothenburg in 1938 as chief of the hospital’s chemistry laboratory. There he developed two new important medicines, the anti-coagulant dicumarol, (warfarin), discovered contemporaneously by Karl Paul Link and colleagues (1901–1978) in the United States [11], and the tuberculostatic medicine para-amino-salicylate, PAS, both still in clinical use. PAS [12] equaled with streptomycin developed by Selman Waksman (1888–1973) at Rutgers University in the U.S. When Waksman received the message in 1953 that he had been awarded the Nobel Prize he congratulated Lehman, assuming that they were sharing the prize, but the Nobel committee had failed to recognize Lehman. TT’s importance for the faculty in Lund was profound, and his own scientific contributions while on the faculty were impressive. As mentioned, his discovery of the respiratory chain deserved a shared Nobel Prize. Thunberg was nominated 15 times between 1928 and 1950, both by Swedish and several international nominators to no avail (Figs. 9.9 and 9.10). A grand building from 1924 was shared by the Departments of Pharmacology and Medical Chemistry. The ground floor was the common educational area with the lecture hall and student laboratories. The first floor was devoted to chemistry and the second to pharmacology. The upper floors had space for special laboratories, social events, and living quarters for employees. The two young professors, Widmark and Ahlgren, both mentees of Thunberg, worked there in full harmony and had close contact with the nearby hospital. In this building much of the groundwork was performed for numerous advances in the second half of the century, including seeds leading to two Nobel Prizes. Several clinicians obtained their first experiences in experimental laboratory work in this building, including the author. Erik Widmark was 31 years old; at the time he was appointed professor of medical chemistry in 1920. His appointment was delayed because a majority of the faculty and two of the external assessors favored Leonor Michaelis (1875–1949), who had

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Fig. 9.9 Jörgen Lehmann. (sv.wikipedia.org). https://upload.wikimedia.org/wikipedia/commons/ c/c8/Lehman_1.jpg

Fig. 9.10 Department of Pharmacology and Biochemistry. Photo Per Bagge 1910. © Lund University https://www.med.lu.se/nyheter/160429_nobelskylt 12 February 2022

been invited to apply. After graduation in Berlin in 1897, Michaelis spent a year in Paul Ehrlich’s laboratory in Frankfurt where he discovered a method for staining of mitochondria in intact cells. Back in Berlin, he was unable to find a paid academic position and worked as bacteriologist in a municipal non-teaching hospital. There he set up a small research laboratory and studied enzyme–substrate interactions. He published a seminal paper with a Canadian fellow, Maud Menten (1879–1960),

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describing the kinetics of enzyme–substrate interactions which became known as the Michaelis–Menten equation. In the period from 1908 to 1921, Michaelis had attracted 40 fellows to this small laboratory. In 1914, he published a paper which put a definite end to his academic future in Germany in which he disclosed the fraud of the esteemed professor, Emil Abderhalden (1877–1950), who had launched a blood test that was purported to diagnose early pregnancy. The test was based on the formation of specific proteases, “Abwehrfermente”, defense enzymes and was widely applauded by gynecologists and other practitioners. Michaelis could not reproduce Abderhalden’s claims. Despite the fact that Dutch and American investigators later were also unable to reproduce the results [13], Abderhalden’s test remained in wide use. He was promoted to professor in Halle and elected president of the prestigious learned society Leopoldina for life. In 1921, Michaelis accepted a guest lectureship in Nagoya, and after a lecture tour in the United States in 1924, he remained for a stay at Johns Hopkins. In 1933 at age 54, he finally attained a permanent academic position at the Rockefeller Institute. He was elected to the National Academy of Science. One can understand that the faculty in Lund voted for this very able German scientist, but authorities in Stockholm dissuaded the appointment of a foreigner since this could discourage Swedes from starting research careers. Widmark was appointed and turned out to be a successful professor, much liked by colleagues and students. His main field of study was alcohol and its adverse biologic effects. In 1922, he published a micro-method for the accurate assay of ethanol concertation in blood which made him famous [14]. It was used by the traffic police to enforce the strict Swedish legislation against drunken driving. Widmark was an outspoken advocate for a healthy life style including sports, avoiding obesity, salt, and excessive carbohydrates. But he was a dedicated cigar smoker and had hypertension. Sadly, he died at age 49 from myocardial infarction [14]. As previously mentioned, Gunnar Ahlgren was a Ph.D. student of Thunberg [15], indeed his favorite student, and his thesis was awarded the highest mark. He had been associated professor of physiology in Uppsala from 1927, before his return to Lund as professor of pharmacology in 1930. As professor, he became involved in committee work and editor of an official book on licensed drugs together with the chief of medicine in Malmö, Malte Ljungdahl (1882–1957). Ahlgren mentored many talented Ph.D. students. Several of them continued strong careers in different clinical specialties, and others became the next generation of pharmacologists. Ahlgren’s most successful student was Arvind Carlson (1923–2018), who joined the department as junior demonstrator in 1944. He was initially assigned the task of studying neuro-stimulating drugs and analeptics. In collaboration with Folke Serin (1918–2010) he discovered that the efficacy of these agents had a diurnal variation [16]. This was years before chronopharmacology became established. Mentored by Ahlgren, Carlsson then started to work on calcium metabolism and vitamin D using isotope tracers. He defended a solid Ph.D. thesis in 1951[17] and in turn mentored two Ph.D. students on the calcium theme, one of whom became professor of orthopedics and one of pediatrics.

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In 1953, Carlsson applied for a position as associate professor in the department. The position was given to his friend Folke Serin. The committee told Carlson that his research on calcium did not belong to the field of pharmacology. Carlsson was on the verge of abandoning basic science and actually worked clinically in the department of medicine for a year. He enjoyed the new experience but yearned to go back to research and bench work. Helped by the recommendation of Sune Bergström (1916– 2004), the new professor of medical chemistry in Lund, he was able to work with Bernhard B. Brodie (1909–1989) at the National Institute of Health in Bethesda. The six months there turned out to be of crucial importance for his coming career. He was “introduced by Drs. Brodie and Shore to the most modern methods of biochemical pharmacology as well as to the hottest area of psychopharmacology at that time” [18]. Dr. Brodie gave him the task of investigating the effect of reserpine on platelets storage in vitro. The experiments were successful and demonstrated that the drug prevented the cellular uptake of adrenalin and noradrenalin. On his return to Lund, Carlsson could succeed his friend Folke Serin as associate professor of pharmacology. Serin had moved to the Department of Medicine in Malmö. Arvid Carlsson worked in Lund until 1960, when he was promoted to professor of pharmacology at Sahlgrenska University Hospital at the new medical school in Gothenburg. In 2000, he was awarded a Nobel Prize in medicine “for the for the discovery that dopamine is a transmitter in the brain and that it has great importance for our ability to control movements”. Much of the work on this groundbreaking discovery was based on research in Lund by his friends and collaborators in the Department of Histology, the later professor of histology at Karolinska NilsÅke Hillarp (1916–1961) and Bengt Falk (born 1927), later professor in Lund. In 1945 Hillarp had presented a dissertation on the fine histology of distal autonomic nerves showing that they branched and attached to different peripheral cells that also were innervated by other autonomic nerves. The discovery was soon confirmed and is basic for the understanding of how the autonomous nerve system works. Hillarp later showed that bioactive monoamines were stored as granules of white cells in blood and tissues. Physiology of synapses and identification of chemical transmitters then became the focus of Hillarp’s and Falk’s research. A genius histologic staining method was worked out making catecholamines and related substances including dopamine visible by fluorescence after treatment with formaldehyde [19]. The paper published in 1962 ranked as one of the 200 most cited articles. Although Carlsson acknowledged the importance of the Hillarp group’s contributions the Nobel Committee did not find it Prize worthy. In Stockholm Hillarp formed a new outstanding laboratory in a short time but sadly soon died of malignant melanoma (Fig. 9.11). Another of Ahlgren’s Ph.D. students was Georg Kahlson, “GK”, (1901–1982). He was born in Finland, but the family moved to Gothenburg where he finished high school. GK started medical school in Helsingfors, then moved to Jena in Germany where he lived with a brother who was a professional violinist. When the brother was recruited to Hollywood, GK moved to Munich and became assistant under Walther Straub (1874–1944), an eminent pharmacologist who had described the mouse tail reaction used to assay for opium in the early 1920s. The test was a crucial tool to

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Fig. 9.11 Bengt Falck and Åke Hillarp in 1961. Courtesy Bengt Falck. Öppet Bildarkiv.Sydsvenska Medicinhistoriska Sällskapet. SMHS6870_ 000_01Copp.jpg. http:// www.medicinhistoriskasyd. se/smhs_bilder

trace synthetic opioids like pethidine. GK worked on the biology of amines and on a determination method for acetylcholine. In Munich he met Louise, the daughter of a wealthy Jewish businessman and the couple was married in 1930. In his memories GK makes fun of German academic medicine where a department is under the command of a Geheimrat (ignoring the fact that this title vanished with the German Empire in 1918). “He gives lectures and makes rounds from 8 to 12, eats a sandwich and disappears from the hospital to see a large number of private patients. Then he returns to his office and dictates textbook chapters citing other investigators’ work as his own” [20]. This malicious portrait is unjust and totally ignores the excellence of German academic medicine before the Nazi takeover in 1933. Life in Germany with a Jewish wife became problematic and Georg and Louise moved to Lund. Here GK was adopted as a Ph.D. student by professor Ahlgren who also served as a benevolent reviewer at the examination in 1934 [21]. GK’s thesis was accepted, and he was appointed assistant professor (Fig. 9.12). In 1936, GK moved to the Department of Physiology as TT’s new adopted favorite, and in 1938 he was appointed as TT’s successor. GK became a powerful proponent for the academic position of physiology in the faculty. Its slot in the curriculum was increased from six weeks to a full semester. Plans for new extended premises were already initiated by TT, but GK could use his close contacts with leading social democrats in the cabinet to advance the project. This resulted in splendid new quarters in 1950, including a lecture hall with 190 seats. Already in 1941, GK started what is now called lobbying for increased public support for research. He wrote papers in the lay press, spoke publicly, and sent messages to cabinet members who were often

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Fig. 9.12 The Department of Physiology at Lund in 1950. Photographer unknown. The lecture hall is at the front the right. Sydsvenska Medicinhistoriska Sällskapet Öppet bildarkiv 130507004Copp.jpg. http://www.medicinhistoriskasyd.se/smhs_bilder Permission Holge Radner

his personal friends. The support from the basic science faculty was unanimous, but according to GK the clinicians were skeptical to the proposal. Sweden had a healthy economy after the war, and in 1945 the Swedish research council was formed, patterned after the corresponding agency in the United Kingdom. Governmental support for staffing, motivated by research needs and not only teaching, was boosted at all universities. This created the basis for expanding basic and translational research in Sweden and is widely acknowledged as GK’s major accomplishment. GK’s own research proved to be of modest significance and concentrated on various aspects concerning the biology and pathophysiology of histamine. But with his assistance, many of GK’s fellows in the new building went on to prominent academic careers. GK pushed for the creation of a new specialty called clinical physiology. The specialty became established, and three of his scholars became professors: Nils Johan Nilsson in Gothenburg, Håkan Westling (1928–2018) in Lund, and SvenErik Lindell (1927–2022) in Malmö. GK could also exercise strong influence in the faculty. When the candidates for the chair in medicine succeeding Sven Ingvar (see below) were discussed, a majority of the members suggested selecting “Kalla”, AskUpmark, as the most outstanding of the 10 applicants. GK strongly opposed this and characterized Ask-Upmark as a reactionary and conservative individual opposed to specialization in general and to the establishment of a chair of neurology in particular. The proposal was rejected with the narrow margin of one vote. GK had saved Lund from a major academic misfortune [20]. Ask-Upmark would thereafter only refer to

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GK as “the villain in Lund”. In contrast to Ask-Upmark GK was an early outspoken anti-Nazi fighter. He published articles in Göteborgs Handels- och Sjöfartstidning, the only major Swedish daily which, under its editor-in-chief Thorgny Segerstedt (1876–1945), condemned Hitler even before 1933. The newspaper was frequently censored during the war. GK and Sven Ingvar were the only medical professors in Lund who signed a public protest against the treatment of Norwegian colleagues during the occupation. Nazi sympathies or indifference lasted well into World War II. Börje Uvnäs (1913–2003) was tempted to abandon research and go to clinical practice but was inspired by Kahlson to remain in academic medicine. Working in GK’s department from 1938 on gastric secretion in cats, he showed that vagus stimulation caused secretion, but only if the antrum part of the stomach was intact and showed that gastrin was the stimulating substance produced by parietal cell in the antral mucosa. His thesis was defended in 1942. Although it represented a significant advance, it was accepted only after stiff opposition. In need of encouragement, Uvnäs spent a year at Northwestern University in Chicago. His research there progressed well. In 1949, a second chair of physiology was created in Lund and Uvnäs was appointed to it. He was looking forward to work in the new building of the department, but then “The partnership with my old teacher and benefactor came to a sudden end. I was made uncomfortable by this development and was looking for a way out. What I found, changed my life” [22]. In 1953, Uvnäs moved to Stockholm as professor of pharmacology. Three decades later he looked back on a very productive time at Karolinska as an internationally leading pharmacologist with numerous scholars. The basic reason for the rift with GK was the authoritarian leadership of GK. Uvnäs had rejected the request to join GK’s “histamine research club” [22]. Erik Jorpes (1894–1973) was a brilliant professor of chemistry at Karolinska, and a large number of excellent scholars were mentored in his busy laboratory, including Jan’s very first Ph.D. student in Malmö Inga Marie Nilsson. A new era in clinical chemistry began in 1947 when Sune Bergström (1916–2004), one of Jorpes’ gifted scholars, succeeded Widmark as professor in Lund. He had worked on the purification of heparin with Jorpes [23]. In Lund, Bergström mentored a number of successful fellows, several of whom worked on bile salts and cholesterol. In 1958, he would return to the Karolinska as professor of chemistry with some of his fellows, including Bengt Samuelsson (born 1933). Another eminent scholar of Jorpes, Pehr Edman (1916–1977), arrived in Lund in 1950. Edman invented a method for the stepwise degradation of amino acids from peptide chains and proteins that was developed into the automated Sequenator [24]. Edman left Lund for Australia in 1957 but returned to Europe as director of a Max Planck Institute in Martinsried outside Munich in 1967. One of his students, John Sjöquist, would later collaborate with JW using the Sequenator analyzing M-components [25].

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9.5 The Department of Medicine Sven Ingvar was mentioned in Chap. 8. Ingvar was a preeminent member of the faculty. In 1918 he defended a groundbreaking thesis on the functional structure of cerebellum [26], and in the following years he published a number of papers showing the similarities between the animal species from snakes to humans. His scientific importance was highlighted in 2019 at the centennial of his Ph.D. [27]. His work was often cited from the 1930s to the 1970s. A number of devoted trainees became known as the “Ingvar school”, and several became chief physicians at important district general hospitals. During his active years Ingvar also engaged in public debate and health initiatives, e.g., warning of the adverse effects of smoking, overeating, and alcohol. Four of his most noteworthy scholars would be applicants to the chair he vacated (Figs. 9.13 and 9.14).

Fig. 9.13 From Sven Ingvar’s thesis, figure 82, showing the cerebellar organization in different species (a) and in humans (b) [26]. Courtesy Christian Ingvar

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Fig. 9.14 Cartoon symbolizing staff members competing for academic promotion. Sven Ingvar far left, the ambitious Erik Ask-Upmark with his beard, far right. “Skall han nå upp?” translates Will he make it to the top? Cartoon by Stig Radner 1938. Öppet Bildarkiv. Sydsvenska Medicinhistoriska Sällskapet. BE170130-023Copp.jpg. http://www.medicinhistoris kasyd.se/smhs_bilder

Ingvar’s stimulating leadership fostered independent research in his department. Nils Alwall (1904–1986) had undergone basic laboratory training with TT and Ahlgren on tissue respiration. He joined the department as assistant professor in 1935 and began experimental work on hemodialysis in rabbits during World War II. In 1946, he performed the first human dialysis. After years of pioneering work, Alwall established collaboration with the industrialist Holger Crafoord (1908–1982). Alwall’s dialysis machine was refined and adapted as a commercial product by the new company GAMBRO in 1964. The company became very successful and the owner, Holger Crafoord and his wife Anna Greta, became generous donors supporting science and culture. As of 1983 the Swedish Academy of Science awards an annual Crafoord Prize of equal size as the Nobel Prizes in subjects not covered by these. Asthma and allergic conditions were cared for by Helge Colldahl (1911–1975), another of Algren’s Ph.D. students. It was elaborated in Chap. 8 that Thunberg’s student Carl Gottfried Holmberg was chief of a chemistry laboratory in the department. Haquin Malmros (1895–1995) defended his thesis in 1928 on glycosuria[28] and worked as associate professor in the department until named chief of medicine at the major city hospital in Örebro in 1937. This hospital was first in Sweden to create a centralized laboratory for all chemical tests. Olof Wilander (1907–1993), another of Jorpes’ Ph.D. students, was recruited as its chief. Wilander had discovered

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that heparin is stored in mast cells [29]. Malmros was able to continue significant research in Örebro [30]. One paper close to JW’s research interest dealt with hyperglobulinemia [31]. An important independent contribution was the observation of diminishing prevalence of cardiovascular diseases during the war in Scandinavia [32]. He was eventually returning to Lund as the successor of Sven Ingvar. Åke Nordén (1915–2002) performed research in hematology, fungal diseases, and diabetes and promoted academic activity in primary care. He was latter promoted to a new chair of primary care. Ingvar needed a deputy director for the division of rheumatology. Rheumatologists were short in supply but a specialist in physical medicine, Gunnar Edström (1898– 1988), was willing to come to Lund provided that he could still retain a position at one of the two spa institutions he worked at. Ingvar required in turn that Edström should qualify with a doctoral thesis. Edström accepted this and compiled a survey of the medical records of children that had been cared for in Lund with rheumatic fever. The work was completed in less than a year [33], and Sven Ingvar was the reviewer. The thesis did not contain much new information but was accepted, and Edström became assistant professor and formally qualified to teach undergraduates and graduates. He later became associate professor, and a strong promotor of rheumatology as an independent academic discipline. He used his influence as elected member of the Swedish parliament representing the Liberal Party (Folkpartiet). Another senior staff member was Erik Ask-Upmark (Chap. 8). Ingvar had asymptomatic hypertension for many years. In the 1940s he was diagnosed with hypertonic encephalopathy, and within a couple of years he died following several strokes at age 58. The “great faculty” had lost one of its most colorful personalities (Fig. 9.15). Fig. 9.15 Sven Ingvar 1929. Photo by Per Bagge. Library of Lund University. Public Domain Mark

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References 1. Forssman J. Die Herstellung hochwertiger spezifischer Schafhämolysine ohne Verwendung von Schafblut. Biochem Zschr. 1911;37:78–115. 2. Ehrlich P. On immunity with special reference to cell life. Proc Roy Soc London. 1900;66:424– 48. 3. Yoda Y, Ishibasi T, Makita I. Isolation, characterization, and biosynthesis of Forssman antigen in human lung and lung carcinoma. J Biochem. 1980;88:1887–90. 4. Forssman S. John Forssman – en biografi. Sydsvenska Meicinhistoriska Sällskapets Årsskrift. 1989;26:110–9. 5. Lindau A. Studie über Kleinhirncysten. Bau, Pathogenese und Beziehung zur Angiomatisis Retinae. (Studies on cerebellar cysts. Composition, pathogenesis and relation toretinal angiomatosis). Acta Path Microbiol Scand 1926;3(suppl 1):1–128 6. Cushing H, Bailey P. Hemangiomas of cerebellum and retina ILinau’s diease). Trans Am Ophthalmol Soc. 1928;26:182–202. 7. Gossage L, Eisen T, Maher ER. VHL, the story of a tumor suppressor gene. Nat Rev Cancer. 2015;15:55–64. 8. Thunberg T. Undersökningar öfver de köld- värme- och smärtproducerande nervändernas relativa djupläge huden samt öfver köldnervändarnas förhållande till värmeretmedel. (Examinations on cold-, heat-, and painproducing nerve endings relative deapth localising in skin, and on the relationship between cold nerrve tissue to the heatsensitive tissue). Dissertation. Uppsala 26 maj 1900. 9. Thunberg T. Der Barospirator, ein neuer Apparat für künstliche Atmung. (The barospirator, a new apparatus for artificial respiration). Skandinavisches Archiv für Physiologie. 1926;48:80– 94. 10. Widmark EMP. Acetonkoncentrationen i blod, urin, och alveolär luft och några därmed sammanhängande problem (Studies in the acetone concentration in blod, urine, and alveolar air and some related problems).Thesis for the doctoral degree (M.D.), University of Lund, Lund; 1917. p. 1–181 11. Stahmann MA, Huebner C F, Link KP. Studies on the hemorrhagic sweet clover disease: V. Identification and synthesis of the hemorrhagic agent. J Biol Chem. 1941;138(2):513–27. 12. Lehman J. On the effect of isomers of para-aminosalicylic acid and related substances on the tuberculostatic effect of PAS. Experientia. 1949;5(9):365–7. 13. Deichmann U, Müller-Hill B. The fraud of Abderhalden’s enzymes. Nature. 1998;393:109–10. 14. Andréasson R. Erik Matteo Prochet Widmark. Widmarks mikrometod och trafiknykterhetalagen. (E MP Widmark. The micro-method of Widmark and the legislation against drunken driving). Sydsvenska medicinhistoriska sälldskapets årsskrift. 1985;Suppl 5:7–150. 15. Ahlgren GJ. Zur Kenntnis der tierischen Gewebsoxydation sowie ihrer Beeinflussung durch Insulin, Adrenalin, Thyroxin und Hypophysepräparate. Thesis, Lund. 1925. 16. Carlsson A, Serin F. Time of day as a factor influencing the toxicity to nikethamide. Acta Pharmacol Toxicol. 1950;6:181–6. 17. Carlsson A. Metabolism of radiocalcium in relation to calcium intake in young rats. Acta Pharm Toccol. 1951;7(suppl 1):1–74. 18. Carlsson A. Autobiography. In: Larry RS, edotors. The History of Neuroscience in Autobiography, vol 2. 1999. p. 35–66. 19. Falck B, Hillarp N-Å, Thieme G, Torp A. Fluorescence of catecolamines and related compounds condensed with formaldehyde. J Hist och Cytochem. 1962;10:348–54 20. Georg Kahlson. GK Minns (GK remembers). Bokförlaget Signum, Lund 1981;2–100. 21. Kahlson G, Römer R. Der biologische Nachweis der Cholinkörper; ihre physiologische und pharmakologische Stellung. Mit einem Anhang über den chemischen Nachweiss von Acetylkolin im Blut. Berlin, Verlag Julius Springer, Braunschweig, 1934. 22. Uvnäs B. From physiologist to pharmacologist—promotion or degradation? Fifty years in retrospect. Ann Rev Pharmacol Toxicol. 1984;24:1–18.

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23. Jorpes E, Bergström S. On the relationship between sulphur content and the anticoagulant acivity of heparin preparations. Biochem J. 1939;33:47–52. 24. Edman P, Begg G. A protein sequenator. Europ J Biochem. 1967;1:80–91. 25. Sjöquist J, Eriksson S, Nilsson IM, Waldenström J. N-terminal aminoacids in normal and pathological human serum. Lancet. 1960;1:902–3. 26. Ingvar S. Zur Phylo- und Ontogenese des Kleinhirns nebst einem Versuch zu einheitlicher Erklärung der zerebellären Funktion und Lokalisation. Folia Neurobiol (Haarlem). 1918/ 1919;11:205–495. 27. Triarhou LC. Sven Ingvar (1889–1947) of Lund University and the centennial of his landmark dissertation on cerebellar phylo-ontogenity. Cerebellum. 2019;18:676–87. 28. Malmros H. The diagnostic and prognostic value of the blood sugar determination in chronic glycosuria. Acta Med Scand. 1925;62:294–318. 29. Wilander O. Studien über Heparin unter besonderer Berücksichtigung seiner physikalischen Chemie, seiner Lokalisation in den Geweben, und seines Vorkommens im Blute. Skandinav Arch f Physiol, 1938;suppl 15. 30. Winblad S, Malmros H, Wilander O. Studies on the pathogenesis of rheumatic fever. Acta Med Scand 1947;128(suppl 196):533–45. 31. Malmros H, Blix G. The plasma proteins in cases with high erythrocyte sedimentation rate. Acta Med Scand 1946;123(suppl 170):280–306. 32. Malmros H. The relation of nutrition to health: a statistical study of the effect of war-time on arteriosclerosis, cardiosclerosis, tuberculosis and diabetes. Acta Med Scand. 1950;(suppl 246:137–53) 33. Edström G. Febris Rheumatica. Eine Studie in Ihrer Epdemiologie, Klinik und Prognose, mit besonderer Berücksichtigung der Verhältnisseb in Schweden. A-B Gleerupska Universitetsbokhandeln. Lund, Sweden, 1935. p. 5–317.

Chapter 10

Malmö General Hospital—MAS

Abstract This chapter gives a brief presentation of growth and early development of the hospital in Malmö, leading up to the decision in 1947 to transform Malmö General Hospital into a teaching hospital affiliated with the medical school at Lund University. It shows that the ground was well prepared for the start of a dynamic academic environment equal to that in Lund.

10.1 The Early Years Malmö is said to have Scandinavia’s oldest heraldic city arms. The name Elbogen or Ellenbogen, German for elbow, was used since the early thirteenth century by the Hanseatics. Malmö was then an important Danish city, and Denmark controlled all seaways to the Baltic. With help of Hanseatic forces, after a series of wars Sweden defeated Denmark and Scania became a part of Sweden (Chap. 9). In 1775, Malmö inaugurated a modern harbor. Expanding trade, the establishment of textile factories, and a new shipping wharf followed. Completion of the railway to Stockholm in 1856 contributed to rapid growth, and Malmö became the third largest Swedish city. In 1870, the number of inhabitants exceeded 25000. Malmö could no longer rely on hospital services in Lund, and it became urgent to plan for a municipal hospital to meet the needs of the growing population (Fig. 10.1). Malmö Allmänna Sjukhus, MAS, (Malmö General Hospital), was opened in 1896 with 60 surgical and 50 medical beds. The population had now increased to 70,000. The new hospital was situated in the city outskirts, surrounded by farmland. It would soon become too small, and in 1907 it was enlarged to 328 beds. The chief physician (Styresman) was Fritz Jakob Bauer (1864–1956), born in Scania and a graduate of the Karolinska Institute. He was a skilled surgeon and widely recognized for successful abdominal operations. In 1907, he was awarded an honorary Ph.D. from the University of Uppsala. In 1917, he was promoted to chief physician of the military health system in Sweden and relocated to Stockholm (Fig. 10.2). Bauer was a demanding but respected chief. His professional competence and legendary dedication to every individual patient created a tradition of quality. The patients felt that they were receiving the very best of care. This tradition motivated © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Wollheim, Jan Gösta Waldenström and His World, Springer Biographies, https://doi.org/10.1007/978-3-031-36739-7_10

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Fig. 10.1 The earliest known hand-colored print of the coastal town Malmö [Elbogen], dating from the 1580s, illustrates the dominant position of St Petri church. The church originates from the early fourteenth century when the gothic building was constructed on the site of an even earlier brick-built church. During parts of the Medieval period and Reformation, Malmö was Denmark’s second largest town and became a Swedish region first in 1658 (Civitates orbis terrarum, Vol. IV, by G. Braun and F. Hogenberg). Public Domain: https://www.ikfoundation.org/itextilis/medievaltextiles-in-st-petri-church.html

fellows and nurses to give maximum effort in their work and made the administration give a keen ear to Bauer’s proposals for expansion. Separate resources were soon added for obstetrics, tuberculosis, venereal diseases, pediatrics, bacteriology, infectious diseases, and psychiatry. Physicians from the Department of Pathology in Lund performed the autopsies. Radiology was established early, at first in collaboration with Lund, but from 1922 Dag Carlsten became head of an independent department of diagnostic radiology. MAS became a highly ranked modern hospital. The department heads were usually recruited from Lund, and although not officially affiliated with the university, practice at the MAS departments would with time be engaged for clinical clerkships by medical students from Lund. The city councilors were proud of MAS, and chief physicians at the hospital would, like Bauer, often serve on the municipal council [1]. Mutual trust and respect created a win–win atmosphere in Malmö. This was less of a tradition in Lund but would continue in Malmö during following decades. Otto Gröné (1872–1960) specialized in obstetrics in Lund and joined Bauer´s department in 1906. Three years later he became chief of a new obstetrics and gynecology department, and in 1917 he succeeded Bauer as chief physician (Styresman) of MAS. He was also a city counselor. In 1923, his department moved into a new

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Fig. 10.2 Fritz Bauer with his son Allan. Photo 2011 by Mats Nilsson. Öppet Bildarkiv. Sydsvenska Medicinhistoriska Sällskapet. Fritz_Bauer_ pCpg.jpg. http://www.medici nhistoriskasyd.se/smhs_b ilder

and larger building [2]. After retirement, Gröné authored several books dealing with local medical history [1]. Ebbe Petrén (1878–1974) was the youngest of twelve siblings, all of whom contributed to society as noteworthy academics in the fields of mathematics, law, or medicine [3]. Two served as members of the national governing cabinet in Stockholm. Gustaf Petrén was professor of surgery, and Karl Petrén was professor of practical medicine in Lund. Ebbe Petrén had worked with John Forssman (Chap. 9). He arrived in Malmö in 1908 as chief of infectious diseases. The Department of Infectious Diseases had its own pavilion which also contained a laboratory for bacteriology tests. Petrén retired in 1942. S. Algot Pfannenstill (1859–1935) became the first chief of medicine in 1906. He had attended medical school in Lund, defended his Ph.D. thesis in 1892 titled “Neurasthenia and hyperacidity”, and was assistant professor in Lund until 1898. He had also worked at the Karolinska as assistant professor and been chief of medicine in Falun, the capital of Dalecarlia. His primary research interests were the gastrointestinal diseases [4]. Pfannenstill retired in 1923.

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10.2 The Next Generation Bauer’s successor as chief of surgery in 1920 was his student Otto Löfberg (1881– 1954). His technical skill matched that of his mentor. He was known as “the tiger” due to his vehement temper. Although abdominal surgery was his primary interest, he did not hesitate to tackle other demanding tasks within the specialty. He reformed the treatment of femoral neck fractures by a modified procedure of forceful reposition and fixation requiring physical help by a strong janitor. After a brief study visit in Boston with Harvey Cushing he even performed some brain surgery. Löfberg never presented a doctoral thesis but was awarded an honorary PhD degree in Lund in 1932. He mentored Fritz Bauer’s son Gunnar Bauer (1895–970) who defended a Ph.D. thesis in 1933 on peritonitis caused by appendicitis based on “only” 1252 cases [5]. He then became head of surgery in Mariestad 1937–1959 and pioneered management of deep vein thrombosis and the use of phlebography. He was the first to show the effectiveness of treatment with heparin, and he stressed the importance of early mobilization to avoid pulmonary embolism [6]. Löfberg had deep interests in the humanities, in particular in local artists and classical music. He retired in 1959 and devoted his remaining years to full-time promotion of the arts [7]. Sune Genell (1897–1960) became Gröné’s successor as chief of obstetrics and gynecology in 1938 (Chap. 11). Orthopedic surgery had already been separated from general surgery under Fritz Bauer, and in 1913 MAS was the first non-teaching hospital in Sweden with an independent department of orthopedics. Skeletal tuberculosis was then a leading cause of hospitalization. The head of the department as of 1941 was Sophus von Rosen (1898–1996), who earned his M.D. in 1928 and Ph.D. in 1939 in Lund on the subject of knee infections. Beginning in 1941, he was assistant professor with teaching commitments. Von Rosen was Styresman of MAS from 1951 to 1955.

10.3 Medicine Malte Ljungdahl (1882–1957) was the second chief of medicine at MAS from 1924 to 1948. His mentor was Karl Petrén, Sven Ingvar’s predecessor in Lund. He also spent time in the Department of Medical Chemistry under Ivar Bang and with John Forssmann in the Department of Pathology and Bacteriology. In 1914, he defended his doctoral thesis on arteriosclerosis of pulmonary vessels. He worked as assistant professor in Lund before his appointment in Malmö. In 1928, he described patients with a long history of recurrent pulmonary embolism whom he had autopsied. This was two decades before the condition could be diagnosed by radiography and use of heart catheters and be treated with heparin and other anticoagulants (Fig. 10.3). Ljungdahl was an academically well-rounded and demanding chief. His many responsibilities included running the hospital’s clinical laboratory. Ljungdahl was also the chief physician of MAS from 1931 to 1948. This was a period of significant expansion, culminating in the development of MAS as university hospital affiliated

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Fig. 10.3 Malte Ljungdahl. Svenskt biografiskt lexikon (art av Lars Öberg), unknown photographer 1930s. https://sok.riksarkivet.se/sbl/bilder/9571_7_024_00000001_3.jpg

with the medical faculty in Lund. For several years he was the main editor together with Gunnar Ahlgren of Pharmaconomia Svecica (Chap. 9), a book commissioned by the Swedish Health Board describing the composition, labeling, and dosing of all pharmaceuticals available by prescription in Sweden, mainly pills, powders, and fluid mixtures. Updated editions of this publication were regularly published, and the book was used as standard therapeutic guidance for decades after Ljungdahl’s retirement in 1948 (Fig. 10.4). For good reasons Ljungdahl was highly respected and was honored with the title of professor in 1947. He was a popular teacher and lecturer. Beginning in grammar school, he had developed a deep appreciation for classical languages and enjoyed reading Greek and Roman literature in the original languages. He authored papers on medicine in ancient times. He collected books on medical history and amassed a total of 1276 volumes. This collection was donated to MAS in 1947 but now is kept at the university hospital in Lund (Fig. 10.5). In 1948, the classes of students entering medical school in Lund increased to 30 admissions twice a year. Following the initial 2½ preclinical years at the campus in Lund, half of the students would continue their clinical training in Lund and the other half in Malmö at the new teaching hospital. A set of newly appointed enthusiastic professors there would become their teachers. These are presented in Chap. 11. JW would emerge as the star and the most charismatic among them.

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Fig. 10.4 Pharmaconomia Svecica. Left: a used copy. Right: title page with the editors and Malte Ljungdahl and Gunnar Ahlgren and their collaborators. Photo The author

Fig. 10.5 From the Malte Ljungdahl Library, now at the Scania University Hospital in Lund. http:// www.medicinhistoriskasyd.se/Skrifter/Om%20Malte%20Ljungdahl%20171028.html

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References 1. Gröné O.H. https://sok.riksarkivet.se/sbl/artikel/13266, Svenskt biografiskt lexikon (art av Bengt Willert), hämtad 2020–06–14. 2. Gröne, O. Malmö Allmänna Sjukhus Hundra År (Malmö General Hospital at One Hundred Years). Allhem, Malmö 1957, p. 207–19. 3. Petrén, släkt, urn:sbl:7164, Svenskt biografiskt lexikon (art av CHC), hämtad 2020–06–14. 4. Pfannenstill SA, Sjövall E. Ein Fall von Morbus Banti, begleitet von primärem Leberkrebs. Nord Med Arkiv. 1909;42:1–43. 5. Bauer G. Zur Behandlung der Appendicitis-Peritonitis mit besonderer Berücksichtigung der Frage nach Primärsutur und der Behandlung von postoperativem Ileus. Act 1–461 Chir Scand 1933;79(suppl 24):1–461. 6. Hallbök T. Gunnar Bauer - Föregångare inom trombosforskningen (Gunna Bauer- Pioneer of researth on threombosis). Lakartidningen. 2004;101:1730–1. 7. Löfberg, OL. urn:sbl:10032, Svenskt biografiskt lexikon (art av Bengt I Lindskog), hämtad 2020–06–15.

Chapter 11

Arrival in Malmö

Abstract JW moved to Malmö in January 1950 with his oldest son and took over from the experienced former deputy chairman Evald Ljungberg. JW inherited several scholars of his predecessor, some of which would become his PhD students, and some leave for other carriers. JW recruited Sven-Erik Björkman and Bengt Skanse from Uppsala and Gunnar. Biörck from Stockholm. The Malmö colleagues in surgery, gynecology, orthopedics, and pathology/bacteriology are introduced.

11.1 The Department of Medicine In November of 1949, Jan Waldenström, JW, was appointed professor of medicine and chairman of the Department of Medicine at Malmö General Hospital, MAS. He was unhappy to leave his friends and the scientific and cultural life in Uppsala but eager to establish his new working environment at Lund University. He rented a modern apartment in Tessin Street not far from the waterfront, accompanied only by his oldest son Magnus (Figs. 11.1 and 11.2). JW met with his highly esteemed predecessor and was pleased to learn that Malte Ljungdahl had donated medical history books would be deposited in the department (Chap. 9). JW also greeted the deputy chairman associate professor Edvard Ljungberg, who had been the locum chairman since the retirement of Ljungdahl in 1947. JW appreciated Ljungberg both as a talented physician and as an academic colleague. Ljungberg had defended a doctoral thesis in 1947 titled “On the reabsorption of chlorides in the kidney of rabbit” [1]. They developed a warm friendship. A very significant scientific collaboration happened a few years later when Ljungberg had moved as chairman to the Department of Medicine in Ängelholm 100 km north of Malmö (Chap. 14). At the hospital, JW met with Sophus von Rosen, chief of orthopedics and also Styresman, chief administrative physician of MAS, and also with Harald Lindvall (1897–1984), a respected social democratic politician, city councilor, and chairman of the hospital’s board of directors. Mutual respect characterized their relationship. The gentlemen shared cultural values. All three were ambitious to create a milieu of excellence at the new university hospital. A close and good relationship between the © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Wollheim, Jan Gösta Waldenström and His World, Springer Biographies, https://doi.org/10.1007/978-3-031-36739-7_11

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Fig. 11.1 View of Tessin Street in Malmö. Jan rented an apartment in the building on the far right. Note left-hand traffic. Sweden changed to right side traffic only in 1967. Unknown photographer, 1940s. © Pinerest.se Lisbeth Sjöstrand. 15 February 2022 https://www.pinterest.se/pin/332492384 965095710/

Fig. 11.2 Retired Malte Ljungberg celebrating with his staff in 1948. Sitting, from left: Hans Krook, Evald Ljungberg, Malte Ljungdahl, Ole Berg, unknown, Inge Edler, two unknowns. Standing on the left: Hans Östberg. Cigarette smoking was still kosher. © Universitetssjukuset MAS 1996

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administration and medical professionals was established. The physicians had a firm hold on decisions affecting their departments, which contribute to optimal patient care and job satisfaction. Lindvall and von Rosen were both lovers of classical music and members of the board of the city symphony orchestra. They would frequently meet JW at the city’s weekly symphony concerts. JW inherited a head secretary named Birgit Lundgren. She had obtained a lifetime university appointment in 1947 and had good formal qualifications. She was pleasant and easy going but slightly sloppy. She remained in her post longer than JW, who often wished for a less bohemian assistant. The staff soon learned to always keep a personal copy of material given to “Lunkan” for handling, as she was known to mislay documents. JW also inherited an outstanding head nurse, Judith Engstrand. She was exceptionally experienced and extremely loyal and devoted to JW and served as a strict guardian of the professor, filtering approaching visitors. If you wanted access to the professor, it helped to be on speaking terms with “Syster Judith” (Fig. 11.3). JW selected his staff with great care. He was well aware of the risk that a single sociopath can destroy the work climate for everyone else. At the start of his appointment, Jan recruited three key individuals from the north. Sven-Erik Björkman joined from the outset (Chap. 8) and was in many ways an ideal deputy to JW. JW was aristocratic: tall, vivacious, elegant, extroverted, and alert. Björkman was dignified: stocky, thoughtful, and stable, with common sense and a conspicuous dry humor. Both were blessed with an unusually sharp eye for clinical details and a phenomenal memory for individual patients. JW could be impulsive and become bored by too much routine. Björkman was the reliable guarantor of continuity and order in the department. Throughout his career JW was a frequent traveler, with Björkman as the dependable deputy at home. Björkman’s elegant laudation at the Festschrift Fig. 11.3 Head nurse Judith Engstrand. © Universitetssjukuset MAS 1996

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celebrating JW’s 60th birthday was a very warm manifestation of his devotion [2] (Chap. 23). Bengt Skanse (Chaps. 8 and 21), who joined the staff late in 1950, was a vivacious, stimulating independent and productive clinical investigator and one of the founders of endocrinology in Sweden. His happy image spread joy in the department. The cardiologist Gunnar Biörck (Chap. 8), “GB”, was no stranger to Malmö. His wife was a daughter of Malte Ljungdahl. GB was dynamic, ambitious, and had a fluent pen which produced a rich bibliography. Like JW, he enjoyed traveling and developed an extensive international network. GB’s contributions are dealt with in Chap. 20. GB would replace Inge Edler (1911–2001), an unassuming timid physician who had been the cardiologist in Malte Ljungdahl’s department. Edler was still an academic virgin in 1950. He moved to Lund that year where he and the outstanding physicist Hellmuth Hertz (1920–1990) only three years later introduced ultrasonography of the heart, a milestone advance in non-invasive imaging [3]. The investigators became recipients of the Albert Lasker Award in Clinical Research in 1977 and were nominated for the Nobel Prize. By letting Edler leave Malmö JW unknowingly catalyzed a monumental medical advancement “elsewhere” (Fig. 11.4). In 1950, professor was still a title of distinction in Sweden. Assistant professor (Docent) was just an unpaid title. A new professor was introduced in Lund at a public ceremony in the main auditorium of the university where the dress code for the main actors was gown or tails. JW had chosen the title “Deficiency diseases” for his inaugural speech at the ceremony, probably in part including his epidemiologic work in Uppsala on sideropenic anemia and other deficiencies caused by malnutrition. But the title could also allude to genetic defects and some of JW’s favorite diseases among the inborn errors of metabolism caused by enzymatic deficiencies. Fig. 11.4 Hellmuth Hertz and Inge Edler with the equipment used for the very first experiments with ultrasound examination of the heart. Öppet Bildarkiv © Sydsvenska Medicinhitoriska Sällskapet. Inge_Edler_och_Helmuth_ Hertz.jpg. http://www.medici nhistoriskasyd.se/smhs_b ilder/

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11.2 Department of Surgery Helge B. Wulff (1903–1986) was appointed professor of surgery in 1949. In 1946, Wulff had traveled together with JW to the United States. Both were members of the 1948 committee to reform the Swedish medical curriculum (Chap. 8). Helge Wulff was appointed as successor of “the tiger” Otto Löfberg in 1948. In Lund he had developed a special interest in thoracic surgery, and one of his major early projects was to establish heart surgery at MAS. He was a dynamic and popular son of Malmö. In medical school he had been a notable track and field athlete, and in Malmö he was a dedicated collector of contemporary art. In contrast to JW, Wulff favored the formation of independent subspecialty units. One of Wulff’s associate professors, Nils Carstam (1913–2014), had specialized in hand surgery in Gothenburg. He would within a few years become chief of an independent department of hand surgery. In 1950, Anders Wenckert (1909–1984) worked in the Department of Medicine on side-training to specialization as a surgeon and would later become the deputy chief of surgery and develop a special interest in the surgical treatment of Crohn’s disease. Thoracic surgery and urology would become independent sections and eventually independent departments. Bengt Olow would become in charge of proctology, and Knut Haeger was head of vascular surgery. The Department of Plastic Surgery would be established in 1955 under professor Karl-Erik Hogeman. Anesthesiology became a separate section in 1951 under Olle Lundskog. The Tiger was pleased to follow the growth and diversification of surgical services under the direction of the new professor (Fig. 11.5).

Fig. 11.5 Otto Lövberg and Helge Wulff in 1954. © Universitetssjukuset MAS 1996

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Fig. 11.6 Sune Genell, 1950s. Öppet Bildarkiv, Sydsvenska. Medicinhistoriska Sällskapet. SMHS8272_ 000_01Copp.jpg. http:// www.medicinhistoriskasyd. se/smhs_bilder/

11.3 Obstetrics and Gynecology Sune Genell (1897–1960) was appointed as the first professor of obstetrics and gynecology in Malmö in 1948 (Chap. 9). His exceptional gifts had already made him a leader in medical school where he was editor of a literary magazine. He received his medical degree in Lund in 1928 and became a fellow of the outstanding professor of obstetrics and gynecology Axel Westman (1894–1960) in Uppsala and worked in his endocrinology laboratory. In 1931, Genell studied with the famous endocrinologist Herman Zondek in Berlin. He followed professor Westman to Lund in 1935, earned a Ph.D. there in 1937, and was promoted to succeed Gröné at MAS in 1938, as mentioned in Chap. 10. In 1944, his department moved into a splendid new building. It contained a well-furnished hormone laboratory with resources that would be useful to research performed at other departments including medicine. Full of energy, enthusiasm, and scientific ideas, Genell would mentor a large number of fellows, some of which would become professors at other universities. His scientific and other skills made him an obvious choice in 1948 for the new chair of obstetrics and gynecology [5]. Genell was also Styresman of MAS from 1949 to 1951 (Fig. 11.6).

11.4 Orthopedic Surgery When Sophus von Rosen (1898–1996) arrived in Malmö in 1940 as chief of orthopedics, skeletal deformities, tuberculosis, and poliomyelitis still dominated the specialty. His 25 years as department head was a period of dynamic changes and

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growth. Traumatology, spinal diseases, osteoarthritis, and sports medicine became the dominate pursuits of the department. Von Rosen’s most important contribution in science was his work with congenital luxation of the hip. A pioneering routine to screen newborns for unstable hip was established at MAS in the early 1950s. The chief of pediatrics, Per Selander (born 1900), would examine all newborns with the method of Ortolani and refer all identified babies to von Rosen. Von Rosen had invented a simple cradle fixing the hips in abduction until the femoral head had become stabilized in the acetabulum several weeks later. The method became routine in Sweden and reduced the annual incidence from 100 to 150 permanent luxations to only three. The “von Rosen splint” was never patented, but has been adopted worldwide. Von Rosen could move into a lavish new building in the 1960s. One of his associates was Göran Bauer, a grandson of Fritz Bauer. After retirement, von Rosen worked as a volunteer for post-war rehabilitation of trauma victims in Algeria (Fig. 11.7). Fig. 11.7 Sophus von Rosen examining a newborn girl about to be placed in the “von Rosen splint”, seen on the right. Unknown photographer, 1950s. Sydsvsvenska Medicinhistoriska Sällskapet Öppet bildarkiv. SMHS5916_000_ 01Copp.jpg. http://www.med icinhistoriskasyd.se/smhs_b ilder/

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11.5 Pathology and Bacteriology Sten Winblad (1909–1987) was one of the pathologists who had commuted from Lund to perform autopsies in Malmö before 1944. That year Winblad was appointed as chief of the new Department of Pathology and Bacteriology. Winblad had earned his MD in 1936 in Lund and developed an early interest in the pathogenicity of hemolytic streptococci. Sulfa-based antibiotics had only just been introduced, and the advent of penicillin occurred only a decade later. Scarlet fever and its complications were rampant, and affected children and young adults were hospitalized for weeks and months. Winblad characterized the streptococci and immune response to the bacterium. The most ubiquitous antibody he found was anti-streptolysin O, ASO. His doctoral thesis focused on rheumatic fever. Thanks to Winblad, the ASO test became widely used in Sweden. In 1942–3, Winblad worked in Örebro under Haquin Malmros, and in 1947 they published a paper addressing risk factors for developing rheumatic fever [4]. Winblad was an independent and productive scientist. In 1947, he traveled to Norway on his honeymoon. The couple passed through Oslo where Sten spent time in the laboratory of the pathologist Eric Waaler (1903–1997) in order to learn first-hand about the technique of sheep cell agglutination. Waaler’s observations on sera from patients with rheumatoid arthritis date to 1937 and were published in 1940 [6]. While talking to Winblad, Waaler noticed a woman who was continuously walking outside the building. The visitor could inform him that it was his bride Anna-Stina, and that they were celebrating their honey moon trip that had been postponed due to the world war. Back in Malmö, Winblad introduced and popularized the rheumatoid factor assay in Sweden. He would become an important research partner of JW. In the years before 1953 he and his fellows also contributed to clinical research and quality of patient care as pathologists (Fig. 11.8). One can conclude that 1950 was a good time for a dynamic leader to embrace new initiatives at Malmö General Hospital. Sweden’s economy was not harmed by the war, and the local administrators had ambitions to support the creation of a first-class teaching hospital. The hospital had recruited talented experts, and JW proved to be the ideal chairman to lead a new academic departments of internal medicine.

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Fig. 11.8 Sten Winblad in 1950.Unknown photographer. © Universitetssjukhuset MAS 1996

References 1. Ljungberg BE. On the reabsorption of chlorides in the kidney of rabbit. Acta Med Scand Suppl. 1947;186:1–189. 2. Björkman SE. Jan Waldenström; April 1966. Acta Med Scand Suppl. 1966;445:5–8. 3. Edler I, Hertz CH. The use of ultrasonic reflectoscope for the continuous recording of the movements of heart valves. 1954. Clin Physiol Funct Imaging 2004;24:118–203. 4. Genell, urn:sbl:13008, Svenskt biografiskt lexikon (art av Alf Sjövall), hämtad 2020-06-15. 5. Winblad S, Malmros H, Wilander O. Studies on the pathogenesis of rheumatic fever. Acta Med Scand. 1947;128 (suppl 196):533–45. 6. Waaler E. On the occurrence of a factor in human serum activating the specific agglutintion of sheep blood corpuscles. Acta Path Microbiol Scand. 1940;17:172–88.

Chapter 12

Autoimmune Hepatitis

Abstract In September 1950 JW accepted an invitation from the German Society for Gastroenterology and Metabolic Diseases, DGVS, to give a talk at their first post-war congress in Bad Kissingen. German investigators, mostly Jewish, had been dominating contributors in the formation of gastroenterology, working in Germany until 1933, thereafter in forced exile. This was not mentioned in the introduction by the convenor of the congress. The program focused on liver diseases. JW presented his experience with hepatitis and included six cases of a new subset which he had identified in Uppsala which is now named autoimmune hepatitis. Similar patients were at the same time independently reported by Henry G Kunkel in the US.

12.1 The German Society for Digestive and Metabolic Diseases—DGVS When World War II ended in 1945 Germany an impoverished occupied country was divided into American, British, French, and Russian Occupation Zones. Its major cities were in ruins, the population exhausted, in shock and impoverished. The country was flooded by refugees and “displaced persons”. The universities were defunct with a large majority of the professors suspended by the allies as former members of the Nazi party or otherwise ethically suspect. Many medical professors had performed or sanctioned gravely unethical experiments on prisoners and “unworthy” adults and children. German factories which had survived the war were stripped of their machines. Living conditions of ordinary people were appalling. Within less than three years however, the situation in Germany changed dramatically. Most of the professors were reinstalled, and many resumed academic careers despite having been involved with culpable deeds. As christened by Winston Churchill, an Iron Curtain descended over Europe in 1946, signaling the start of the Cold War. The Marshall Plan (European Recovery Program) was approved by the U.S. Congress on April 3, 1948. West Germany received 11% of the 12-billion-dollar funding. That year, West Germany introduced a new currency, the Deutsche Mark, and launched a rapid building spree and industrial reconstruction which came to be called the

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Fig. 12.1 The old Town Hall in Bad Kissingen. Bildarchiv Roland Bergmann Public domain. https://upl oad.wikimedia.org/wikipe dia/commons/0/0f/Altes_Rat haus_in_Bad_Kissingen_01. JPG

Wirtschaftswunder, or economic miracle. “Visit Germany this summer. Last chance to see the ruins” became a slogan to attract potential oversees tourists (Fig. 12.1). In May, 1949 the West German Parliamentary Council declared the establishment of an independent democratic country, the Bundesrepublik Deutschland (Federal Republic of Germany). In the spring of 1950, JW received a letter from one of the reinstalled professors of medicine, Heinz Heinrich Berg (1889–1968) in Hamburg, with an invitation to speak at the 15th congress of the Deutsche Gesellschaft für Verdauungs- und Stoffwechsel-krankheiten, DGVS, (German Society for Digestive and Metabolic Diseases). The meeting was to be held that year on September 26–30 in the Bavarian Spa Bad Kissingen. The town had escaped bombardments during the war, and its army barracks from 1939 now housed U.S. troops. The gastroenterology meeting was devoted to liver diseases. JW was happy to accept the invitation, offering an opportunity to meet some old friends and to present his recent work including a new hepatic disease to the 470 delegates [1]. Until 1933, German gastroenterology occupied the forefront in science and could look back on a glorious history. Friedrich Theodor von Frerichs (1819–1885) published his magna opus on the liver, “Klinik der Leberkrankheiten” (Treatise on Diseases of the Liver), in 1858, and is considered founder of hepatology. Adolf Kussmaul (1822–1902) reported on the examination of esophagus and stomach with a rigid tube in 1868. In 1869, Paul Langerhans (1847–1888) published his thesis

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“Beiträge zur mikroskopischen Anatomie des Pankreasparenchyms” (Contributions to the Microscopic Anatomy of Pancreas Parenchyma). In 1883, Paul Ehrlich (1854– 1915) performed the first liver biopsy while working in the Department of Medicine at the Charité in Berlin where Frerichs was professor of medicine. In 1885, Carl Anton Ewald (1845–1915) and Ismar Boas (1858–1938) published their work on gastric acidity. Edward emigrated in 1889 to US and became a leading gastroenterologist at Lenox Hill Hospital in New York. In 1886, Boas opened his practice in Berlin as “Spezialarzt für Magen- und Darmkrankheiten” (Specialist for Diseases of the Stomach and Bowel). In 1889, Joseph von Mering (1849–1908) and Oskar Minkowski (1858–1931) published a paper titled “Diabetes mellitus nach Pankreasextirpation” (Diabetes mellitus following removal of the pancreas). In 1892, Bernhard Naunyn (1839–1925) published his studies on the prevalence and pathogenesis of gall stones. In 1898, Ismar Boas and Max Levy-Dorn (1863–1929) reported the radiographic diagnosis of gastric cancer. These milestones illustrate some of the groundbreaking work performed in Germany. The American Gastroenterological Association was founded in 1897 and the Japanese Society of Gastroenterology followed in 1902. The founding physicians in both countries had spent years studying in Germany or had emigrated from Germany. And yet the DGVS was not founded until 1913. One explanation of the delay was the strong position of the German Society of Internal Medicine which was founded in 1882 by Frerichs and Ernst von Leyden. There was a general reluctance to fragment internal medicine and establish independent subspecialties. The ideal of internal medicine as a single, comprehensive, and unified discipline was still firmly adopted by JW and his generation. The German Society of Internal Medicine, DGIM, with over 30, 000 members remains strong and successful in the 2020s (Figs. 12.2 and 12.3). Ismar Boas was one of the founders of the DGVS and contributed to its success as a comprehensive medical society. In 1932 Hermann Strauß was elected president of the DGVS congress in 1933, but this was revoked due to his Jewish background. He Fig. 12.2 Ismar Isidor Boas, 1920. Created Munich, J F Lehman. Public domain. https://commons.wikimedia. org/wiki/File:Ismar_Boas. jpg

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Fig. 12.3 Oskar Minkowski. Letvian stamp from 2012 Unknown author—http:// www.wnsstamps.post/en/sta mps/LT028.12.Public Domain

succumbed in the Holocaust. Boas fled from Berlin to Vienna, supported there by the Rockefeller Foundation and by his pupil Walter Zweig in 1936, now a refugee. When Austria became part of Germany in 1938, he committed suicide. A more fortunate Nazi victim was Rudolf Schindler (1888–1968). Born in Berlin, he developed the first semi-flexible gastroscopic instrument working in Munich between 1919 and 1934 and performed 400 consecutive examinations without any complications. He presented impressive results at a meeting in Munich in July 1932 [2]. Next year he was expelled as a “non-Aryan” and in 1934 while planning an international conference he was imprisoned after being denunciated. Following an invitation by colleagues in Chicago to become visiting professor at the University of Chicago, he was able to leave Germany in the summer of 1934. His life in Germany and later in the US is detailed by current gastroenterologists [3]. An English language paper was published in 2000 [4]. In the US Schindler expanded his work, wrote a textbook “Gastroscopy. The Endoscopic Study of Gastric Pathology” in 1937 [5], and founded the American Gastroscopy Club in 1941, which developed into the present American Society of Gastrointestinal Endoscopy. Since 1952 the Society gives out an annual Rudolf Schindler Award. Schindler himself was honored with this in 1962 [3] (Figs. 12.4 and 12.5).

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Fig. 12.4 Rudolf Schindler with the semi-flexible gastroscope. 1932/33. Private. Photo. Deutsche Gesellschaft. Für Verdauungs- und Schoffwechselkrankheiten. © Marianne Koch https://www.dgvsgegen-das-vergessen.de/en/biografie/rudolf-schindler/. With permission

Fig. 12.5 Mantel above the tympanum at the door of the Einhorn Auditory at the Lenox Hill Hospital NYC, commemorating from left Kussmaul, Boas, and Ewald in the tympanum. Einhorn was a Polish emigre and prominent gastroenterology working at Lenox who donated money for the auditorium in 1934. Courtesy Eric L. Matteson, photographer

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12.2 The 15th Congress of the DGVS In his opening message to the 1950 DVGS congress, Heinz Heinrich Berg did not mention the Nazi past nor any achievements by Jewish investigators. It would take a new generation to resurrect Ismail Boas and other important colleagues such as Siegfried Thannhauser (Chap. 7). It would take some further decades to fully acknowledge the history of persecution and contributions of Jewish scientists [1]. In 2013, the DGVS published an admirable and informative book on the history of German gastroenterology. The book starts with a quote from Wilhelm von Humboldt “Nur wer die Vergangenheit kennt, hat eine Zukunft” (Only those who know the past have a future). JW was not the only foreigner present in Bad Kissingen. Berg’s international network had delivered. The prominent bacteriologist G. M. Findlay from London[3] as well as colleagues from Scandinavia, Austria, Switzerland, and South America participated. One of the speakers was Ernst Wollheim (1900–1981), a naturalized Swede, professor of medicine in Würzburg since 1948 and father of the author.

12.3 A New Liver Disease JW was well prepared and arrived in Bad Kissingen with a written manuscript as requested by the organizers. This was published in a volume containing the proceedings from the congress but is one of the least accessible of his seminal papers. JW discussed the current methods of serum protein analysis and refers to collaborative studies with Kaj O. Pedersen in Uppsala (Chap. 6). He presented his experience with biliary and portal cirrhosis, both causing decreased albumin levels but only the latter associated with increased globulins. Then he presented six cases of chronic hepatitis in young women around or after puberty. All had spider varicosities and acne and amenorrhea. The patients gradually progressed to cirrhosis. JW also demonstrated the difference between the narrow gamma globulin peaks on electrophoresis in cases of macroglobulinemia and myeloma and the broad less homogeneous increase in hepatitis. This type of hypergammaglobulinemia is also seen in venereal lymphogranuloma, a disease known to be caused by a virus infection. One can conclude that already in 1950, JW was aware of the difference between monoclonal and polyclonal hypergammaglobulinemia, a theme which would come in focus in the early 1960s [6] (Fig. 12.6). In his presentation JW mentioned that eosinophils were absent in the blood of one of the six patients. This finding could indicate an adrenal dysfunction, and hence a stimulation test with adrenocorticotropic hormone (ACTH) was performed. This revealed normal adrenal function, but the test administration of ACTH also resulted in a transient improvement of her condition and lowered the hypergammaglobulinemia. As often happens, discoveries may be reported independently by two scientists at the same time. Henry G. Kunkel (1916–1983) from the Rockefeller Institute presented

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a paper in Atlantic City in May of 1950 on the effect of ACTH in patients with liver disease [7]. The abstract mentions low eosinophil counts that were further lowered by ACTH. Of particular interest is the mention of four women under the age of 35 years “with cirrhosis of undetermined etiology characterized by a marked increase in serum gamma globulin”, in whom administration of ACTH resulted in decreased bilirubin and increased serum albumin. The following year, Kunkel reported on eleven such women under the age of 32 with this condition. Their course was either steady or downhill. Biopsy of the liver showed a marked increase in plasma cells. Elevated gamma globulins could be measured with rabbit antiserum against normal human gamma globulin [8, 9]. By coincidence, Henry Kunkel was visiting scientist in Uppsala with Arne Tiselius 1949–50 and worked out a simple method of electrophoresis on filter paper published in 1951 (Fig. 12.7). JW and his close friend had independently described the same syndrome. When the news spread the patients were nicknamed “Kunkel-Waldenström girls”. The

Fig. 12.6 Program of the session in Bad Kissingen at which Jan spoke [3]. Courtesy Deutsche Gesellschaft für Gastroenterologie und Schtoffwechselkrankheiten, DGVS

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Fig. 12.7 Henry G Kunkel AAI Records, The American Association of Immunologists Collection, Special Collections, University of Maryland, Baltimore Cou UMBC, with permission. Courtesy John Emrich

condition has had several other names but is now labeled autoimmune hepatitis, AIH. Previous names include active chronic hepatitis, lupoid hepatitis, and Cirrhoses dysprotéinémiques d’origine inconnue chez la femme. A search in PubMed in 2020 yields more than 10, 000 hits. Dame professor Sheila Sherlock (1918–2001) was the first woman professor appointed in the UK in any medical field and a good friend of JW. She contributed a paper to the Festschrift for his 60th birthday where she summarized her material from the Royal Free Hospital between 1959 and 1965 [10]. Among a total of 561 cases of liver cirrhosis she had seen 139 cases of the condition which she named active chronic hepatitis. Almost half, 48%, of Sherlock´s patients were between 10 and 29 years of age, and 70% were women. The onset was usually insidious, and in contrast to other forms of cirrhosis the jaundice was stable and chronic, not intermittent. The liver histology in the early stages showed infiltration by lymphoid cells. Extra-hepatic involvement occurred in half of the patients. These manifestations included arthralgia, cutaneous lesions reminiscent of systemic lupus erythematosus, glomerulonephritis, thyroiditis, pulmonary hypertension, diabetes, and rheumatic heart disease. These features can be considered to be autoimmune manifestations and indicate a breakdown of immune tolerance and may be amenable to immune suppressive therapy with biologics [11] JW’s intrepid eye for new clinical conditions had again contributed an important discovery. An additional note of interest is that in the 1950s neither JW nor Henry Kunkel needed to publish full-length journal papers to receive full recognition for their groundbreaking discoveries.

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References 1. Bongiovanni ST, Blondheim WJ, Eisenmenger JH, Gerken G, Lerch MM. 100 Jahre Deutsche Gesellschaft für Verdauungs- und Stoffwechelkrankheiten DGVS (German Society for Digestive and Metabolic Diseases). August Dreesbach Verlag München 2012; 2012: 176 pp. ISBN 978-3-944334-17-2. 2. Schindler R. Eipn völlig ungefährliches Gastroskop. (A completely safe gastroscope). Münch Med Wochenschr. 1932;79:1268–1270 3. Jenss H, Klug L. In Ernnerung an Prof Dr. med. Rudolf Schindler. Z Gstroentereol. 2022;60:1195–1198 4. Modlin IM, Farhadi J. Rudolf. Schindler—a man for all seaons. J Clin Gastroenterol. 2000:3:95–102. 5. Schindler R. Gastroscopy. The endoscopic study of gastric pathology, 1937, 2nd edn. Chicago: The University Press, 1950;8(XIX): 433 pp. 6. Waldenström J. Leber, Blutproteine und Nahrungseiweiss. Verhandlungen der deutschen Gesellschaft für Verdauungs- und Stoffwechselkrankheiten. XV Tagung, Bad Kissingen 1950;113–119 7. Bongiovanni AM, Blondheim SH, Eisenmenger WJ, Kunkel HG. Effect of ACTH in patients with liver disease. J Clin Invest. 1950;29:798–798. 8. Kunkel HG, Ahrens EH Jr, Eisenmenger WJ, Bongiovanni AM, Slater RJ. Extreme hypergammaglobulinemia in young women with liver disease of unknown etiology. J Clin Invest. 1951;30:654–654. 9. Kunkel HG, Tiselius A. Electrophoresis on filter paper. J Gen Physiol. 1951;35:89–118. 10. Sherlock S. Waldenström´s chronic active hepatitis. Acta Med Scand 1976;171 (suppl 445):42633 11. Assis DN. Immunopathogenesis of autoimmune hepatitis. Clin Liver Dis (Hoboken). 2020;15:129–32.

Chapter 13

A Charismatic Leader

Abstract This chapter tells the daily routines at the department and of some initial members of the staff. It then informs on rounding customs and undergraduate teaching.

13.1 The Commander-in-Chief JW was now in charge of a department with ten wards and more than 200 beds and a busy outpatient clinic. Malmö Allmänna Sjukhus (MAS; Malmö General Hospital, now SUS, Skåne University Hospital) was the only hospital serving Sweden’s third largest city with a population of around 250,000. He was responsible for its administration and budget management as well as the routine care of patients and the teaching of undergraduate medical students. He was also expected to conduct and mentor research. Was it possible for one individual to master all these tasks? The following two decades would provide an indisputable answer of “yes” to this question. How was this possible? JW selected a limited staff and had a most trusted deputy in Sven-Erik Björkman (Fig. 13.1). JW realized that even a big ship should have only one captain and adopted an authoritarian leadership style. He always criticized the principle of diluted diffuse responsibility which was becoming popular in the country. From the very beginning he was prepared to be the one in charge and accountable. With time, a number of unwritten rules would come into effect and contribute to the special culture of the department. Jan disliked dry formality with written rules and would have despised current emergence of official recommendations and guidelines for classification, diagnosis, and management of both common and less prevalent conditions. The “regulatory system” in the department was simple: the staff would soon learn that their actions would be judged as either right or wrong according to the unwritten laws. This created an atmosphere of healthy alertness: one knew that sooner or later the professor would become informed of their dealings. A “wrong” action would result in a frank, sometimes loud reprimand. This culture could only be accepted and effective if the rules and behavior of the professor were consistent and made sense.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Wollheim, Jan Gösta Waldenström and His World, Springer Biographies, https://doi.org/10.1007/978-3-031-36739-7_13

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Fig. 13.1 Main building of the Department of Medicine. © Universitetssjukhuset MAS 1996

13.2 The Early Team Figure 13.2 shows most members of the staff after one of the daily radiology rounds in 1950. As mentioned in Chap. 11, Edvard Ljungberg (1905–1989) was the deputy chief and acting chairman following the retirement of Malte Ljungdahl. He moved to Ängelholm as chairman of medicine within months of Jan’s arrival. Jan often visited him there. One such visit triggered the discovery of a new syndrome (Chap. 14). Ole Berg (1910–1988) was the expert in neurology of the department. He had recently successfully defended a doctoral thesis in Lund [1], an experimental study of brain function following trauma. Berg’s ambition was to become head of and an independent department of neurology at MAS, a doomed goal in Malmö because JW felt strongly that it was important to preserve internal medicine as an indivisible specialty which should include subspecialties such as neurology [6]. Consequently, he moved to the independent Department of Neurology in Lund after some years as associate professor in Malmö. He was later promoted chairman of the Department of Neurology in Örebro. Neurology would only be established as a specialty at MAS in 1980 when Jörgen Malmquist had succeeded Jan’s successor Bertil Hood as chairman of medicine. Malmquist was able to recruit the highly qualified associate professor Bengt Hindfelt from Lund to create an independent Department of Neurology. Malmquist was one of JW’s notable early disciples. When he and JW met in JW’s later years, the matter neurology as independent from internal medicine was never discussed. Another staff member was Georg Theander, who had spent time in the Department of Pharmacology in Lund and would soon move to the Department of Radiology in Malmö where he advanced to the level of associate professor. He would participate

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Fig. 13.2 Members of the department after the daily radiology rounds. From left: Inga Marie Nilsson; Georg Theander; Bengt Skanse; Hjalte Hultén; Olof Forssman; Sven Johnsson; Edvard Ljungberg; Jan Waldenström; Ole Berg; Hans Krook; and Hans Östberg. © Universitetssjukuset MAS 1996

in several research project with the department. Sven G. Johnson (born 1918) earned his M.D. in 1941 and became PhD in Lund in 1946 with a thesis on diagnostic aspects of renal malignancy. He was recruited to Malmö from Helsingborg and had published papers on autoagglutinins[2] and leukemia [3], topics that were close to JW’s interests. He became docent (assistant professor) in 1951 and was one of the four senior physicians in the department before he was promoted to chairman of the Department of Medicine in the northern city of Sundsvall. He had a summer house close to Malmö and in the summer months would work as deputy physician in the department in Malmö in the 1960s. Olof Forssman and Hans Krook were the amanuenses (teaching assistants) in the department and would both become successful PhD students. Hjalte Hultén and Hans Östberg on the other hand would both soon open private practice in Malmö, well-groomed working first under Malte Ljungdahl and then JW. Inga Marie Nilsson (1923–1999), the only woman among only men, had just graduated as MD in Malmö. Attracted by Jan’s charisma, she boldly applied for a position in the department. Jan must have sensed her exceptional potential and promptly hired her. She was soon initiated to start research on bleeding disorders and hypergammaglobulinemia (Chaps. 15 and 18). Gunnar Biörck, GB (1916–1996), joined the department in 1950. GB had recently passed a doctoral thesis (Chap. 8) and already produced a significant bibliography of 27 papers in cardiology when he came to Malmö to head a productive division of cardiology for the next seven years. As mentioned, GB shared Jan’s view that the

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discipline of internal medicine should not be subdivided into multiple specialties. GB became an active participant in the heart surgery program of Helge Wulff with special interest in mitral stenosis, usually a complication of rheumatic fever [4, 5]. GB developed a substantial international network, and in 1958 he was appointed professor and chairman of medicine at the Karolinska. GB would also become a conservative member of the Swedish parliament and the personal physician-in-ordinary to the King of Sweden. The cardiology division will be more fully presented in Chap. 20.

13.3 New Routines As mentioned, the internal medicine department had ten wards each with between 20 and 30 beds. One ward was reserved for the professor’s private patients, and one would soon be designated for cardiology patients. Otherwise, there was no triage of the admissions to individual wards. The two largest wards were housed in older outside buildings on the campus. Six days a week at 8 o’clock, the respective attending physicians would carry out the morning rounds. On three days each week, the chief physician of the ward would come for rounds. At 9:30 the professor and all available physicians convened for a sitting X-ray round in the department of radiology where a senior radiologist showed all the investigations of the previous day. Starting in 1953 the demonstrator was usually the chairman of the department Sölve Welin. The senior physicians sat in the front row, the fellows in the middle rows and the medical students in the back row. These rounds could last from 30 min to one hour. They provided an overview of both outpatients and admitted patients to the different wards and were informative experience for all. Lively discussions characterized these sitting rounds. They served as excellent teaching events for juniors and students (Fig. 13.3). Back in the main building the staff continued with informal discussions assembled in the corridor outside the professor’s office. Then and there it was decided which ward was to be selected for the “professor’s round” of the day. This could start immediately or later that day. At the chosen ward the head nurse made sure that all patients were present at their beds. Most rooms had six beds. Empty beds were unusual. The senior attending or the ward’s assistant had to present the cases. This was followed by the professor’s questions, his direct interaction with the patient and often a relevant physical examination. Sometimes the professor would sit down on the bed for longer conversations with the patient. Previously unnoticed or misinterpreted signs could be revealed. Cases referred from other hospitals with unusual or undiagnosed conditions added to the interest of the rounds. Such cases, for example obscure hematologic disturbances, could give rise to discussions between JW and Sven-Erik Björkman, who often referred to similar cases they had seen in Uppsala, usually recalling the names of the patients. These rounds were both educational and entertaining. JW generously indulged in sharing experiences and anecdotes from recent visits abroad. Sensitive parts of the discussions were held in the corridor (Figs. 13.4 and 13.5).

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Fig. 13.3 The Department of Radiology at MAS, built in 1940. Photographer unknown, 1940s. Öppet Bildarkiv, SMHS. 231.jpg. www.medicinhistoriskasyd.se/smhs_bilder/

Fig. 13.4 Sölve Welin with Göran Nylander, a trainee1952. Öppet Bildarkiv, SMHS SMHS8315_ 000_01Copp.jpg

In his “Recollections and Reflections” JW wrote: “One of the most important sources of information regarding the medical policy of the department has been the rounds” [6]. For the younger staff the rounds were a significant part of their postgraduate clinical education. JW’s impressive overview of most fields of internal medicine and his legendary memory for individual patients and his skill to communicate made the rounds cherished by all. They engendered a feeling of belonging to a selected

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Fig. 13.5 Cartoon by Anders Steen “Rounds arriving!”. JW’s profile at the front was well known in Malmö. He was the tallest among the doctors and was sometimes nicknamed “Jan långben” (Jan long leg). Courtesy private archive of Anders Waldenström

privileged class, which even in retrospect is exactly what it was. In their future positions, the trainees would aim to mimic these rounds. JW’s first scholar, Sven-Erik Björkman, is also remembered for superb rounds on his ward in one of the outlying buildings, which was only rarely visited by JW’s “Professor’s Round”. A clinical pearl is remembered by a student: “If you see a patient sitting in bed with flexed legs, suspect cancer of the pancreas because this is the least painful position for them”. But equally important was the way all routines made every day into a teaching event where the younger learned from the more senior and the seniors learned from their superiors. It was a hieratical system and resulted in “continuing medical education” in the best sense of the term (Fig. 13.6).

Fig. 13.6 Ward round, 1960s. JW, Dr. Nyman, and two student nurses. Photo courtesy Ingemar Turesson

13.4 Exciting the Medical Students

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Fig. 13.7 Needle designed by JW for the safe performance of sternal marrow aspiration. It was produced for many years by the Stille Werner Company in Sweden. Courtesy Anders Waldenström, private archive

Before 1953 the department had a service laboratory for chemical analyses and morphological blood and bone marrow examination in the basement. After the establishment of the Department of Clinical Chemistry the diagnostic morphology of body fluids and bone marrow dominated. The laboratory moved to the top floor where the experienced nurse Signe prepared blood and bone marrow slides. After the round JW, Sven-Erik Björkman and other physicians went to the microscopes and deliberated on the interpretation of cells in blood and bone marrow. The senior nurse Signe was an experienced expert and appreciated instructor for juniors and students. JW, although characterized as technically “most inapt” by his son Anders, was particularly proud of an instrument he had designed in Uppsala for safe sternal puncture, preventing the risk of causing accidental damage to deeper structures [7] (Fig. 13.7).

13.4 Exciting the Medical Students The admission to medical school in Sweden was then and still is strictly regulated regarding the number of students. In Lund, the limit increased from 30 to 50 per annum in 1948. In 1950, when the first of the larger classes had finished the premedical curriculum, half of the students would continue in Lund and half would be “forced” to move to Malmö for the year of internal medicine and surgery. Originally most students would have preferred to stay in Lund where they had their accommodation and participated in social campus activities. Lund had all the basic science departments; it was the city of learning and culture. Malmö was the commercial metropolis and port, the “Piraeus of Athens” lacking academic tradition. It did not take long however, until enthusiastic reports from the students forced to move to Malmö made the new location competitive with Lund. This was largely based on the new professor’s dedicated teaching and charisma.

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In Lund medical students were commonplace and attitudes toward them from the hospital employees varied. In Malmö the students signaled new academic status, and they were given VIP treatment. Students in Lund encountered a more traditional atmosphere, while in Malmö there was more of a pioneering spirit. A dominant component of training in both locations was the work-up of new patients admitted to the department. The catchment area of Malmö was defined by the city borders. Lund was more rural, and patients came both from the city and from the surrounding countryside. Tertiary care patients dominated among in-patients. In Lund the students produced a handwritten draft for the chart which were typed by secretaries. The student’s draft had been corrected and supplemented by the physician in charge. In Malmö the students had to type the corrected draft themselves. The students in Malmö had to work a little harder and were exposed to a more comprehensive patient population enriched by referrals from distant hospitals of patients with unusual or unclear diagnoses and representing JW’s special clinical interests. Between 1950 and 1954 the student lectures in Malmö took place in an underground lecture room in the Department of Radiology. It was shabby and cramped but the lectures were educational and inspiring. JW always demonstrated one or two patients selected by the amanuensis. The case histories were presented by a student, and the professor then talked with the patients and demonstrated physical findings. The students were impressed by the superb ability of JW to communicate with patients unknown to him in front of the whole class. JW’s simple mantra was “You must convince the patients that they are more important to you than anything else, and that you have plenty of time just for them”. This approach is incompatible with current money-driven efficacy goals. JW’s lectures were far removed from conventional systematic textbook presentations. They were enriched by his personal experiences and unconventional statements, often illustrated by anecdotes. It was obvious to all that JW enjoyed student teaching. Between two and four students were allotted to each ward, and they had to be familiar with their share of the patients. The clerkship on a ward lasted for one to two months allowing the student to follow the course of their patients. They were under strict orders to maintain updated knowledge on history and findings. Failure to fulfill this expectation could lead to sharp reprimands from the professor on the teaching rounds where they had to present their patients. These rounds were JW’s more benign version of the “slaughter rounds” of his teacher Gustaf Bergmark in Uppsala (Chap. 2). The students had no advance information on when their ward would be selected for professor’s rounds. This forced them to always be prepared. The duration of clerkship on one ward allowed learning about the course of diseases. The initial clerkship period lasted one full semester. Toward the end of the curriculum the students served on one ward for two months as “medical assistants”. Then they prepared for the oral examination which could require another month or more of full-time textbook study at home. The student then made an appointment for oral examination with the professor via head nurse Judith. The student had to work up and present two patients. Having accomplished this part satisfactorily the oral examination by the professor continued usually in the evening at the professor’s apartment

References

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on Tessin Street. The care devoted to undergraduate education created well-qualified physicians during all years by JW, both as chairman in 1950–1972 and in the later years.

References 1. Berg O. A study of the effect of Evipan on the flicker fusion intensity in brain injuries. Acta Med Scand. 1947;126(suppl 186):3–186. 2. Johnsson S. On autoagglutinins active at body temperature. Acta Med Scand. 1949;134:180–8. 3. Johnsson S. Acute myeloblastic leukemia and insufficiency of the bone marrow. Acta Med Scand. 1949;136:148–56. 4. Biörck G, Winblad S, Wulff HB. Studies in mitral stenosis. II. Observations in incidence of active rheumatic carditis in left auricular appendages resected at operation for mitral stenosis. Am Heart J. 1952;44:325–32 5. Hall P, Dencker SJ, Biörck G. Studies in mitral stenosis. III. Observations on the incidence and distribution of cerebral emboli with regard to the possibilities of their prevention during operative procedures. Am Heart J. 1952;44:600–7 6. Waldenström JG. Reflections and recollections from a long life with medicine. Haematologica series, Ferrara Storti Foundation. Il pensiero scientifico, Rome 1994. p. 1–136 7. Waldenström JG. Die frühdiagnose der Myelomatose. Acta Chir Scand. 1942;87:365–79.

Chapter 14

The Carcinoid Syndrome

Abstract In a dramatic statement JW could date his discovery of the carcinoid syndrome to the very moment that he was exposed to a patient on a guest round in the town of Ängelholm. Others had encountered similar patients but JW was first to realize the condition as a paraneoplasia. He initiated the uncovering of the biochemical abnormality and the devise of a powerful screening test for carcinoid.

14.1 The Discovery “We believe that recent observations in Malmö may throw some light on the diagnostic and pathophysiological problem of the carcinoids”. With this sentence Jan Waldenström, JW, and Evard Ljungberg begin their paper on a new syndrome discovered by JW in January of 1952 when he was visiting Edvard Ljungberg in his department in Ängelholm [1]. The story begins the previous year when a 19-year-old cachectic man was admitted to Gunnar Biörck at the department in Malmö for investigation of weakness and cardiac failure. Already at age six the patient had developed exertional dyspnea, and at age eleven he started to suffer from asthma and reddish skin. As the years passed the dyspnea worsened, and some months before admission he could hardly walk. When examined by Åke Thorson and Gunnar Biörck, it was noted that he was poorly developed for age, weighed only 49 kg, had vermillion-colored skin with some pellagra-like spots, and that he had frequent episodes of flushing. The heart was enlarged, and systolic and diastolic murmurs were heard, most pronounced over the pulmonic artery area. The liver was enlarged and pulsating. Angiocardiography was performed under anesthesia, confirming the diagnosis of pulmonary stenosis and tricuspid insufficiency. During recovery from the procedure, the patient unfortunately suffered irreversible cardiac arrest and died. At autopsy Sten Winblad detected an intestinal carcinoid tumor the size of a bean with massive liver metastases. The authors published the case as congenital pulmonic stenosis and tricuspid insufficiency with unusual cyanosis and coincidental metastatic carcinoid [2]. However, in a note added in proof, it was mentioned that a 64-year-old man had recently been autopsied with pulmonic stenosis and metastasizing carcinoid. A patient of Ljungberg’s in Ängelholm was also mentioned, and JW’s insight was hinted at. © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Wollheim, Jan Gösta Waldenström and His World, Springer Biographies, https://doi.org/10.1007/978-3-031-36739-7_14

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In Ängelholm, JW was shown a 45-year-old woman with a 12-year history of flushing of the entire body that had worsened over time. Sometimes the attacks of flushing were combined with asthma-like symptoms, colic, and passing of watery stool. Abdominal surgery at another hospital 14 years previously had revealed a small intestinal carcinoid tumor with metastases to lymph nodes and liver. The symptoms were presented as being coincidental, but although this lady had no right side heart abnormality, Jan instantly thought of the young man in Malmö, and in his reflections 35 years later he could conclude: “At that very moment the carcinoid syndrome was born” [3, 4].

14.2 Intestinal Carcinoid Intestinal carcinoid tumors were first described in 1907 by the outstanding pathologist Siegfried Oberndorfer (1976–1944) who named them tumorlets (Geschwülstchen), “carcinoid” in Latin, since they had microscopic features of malignancy but were clinically benign. He had observed them already in 1901 as pie-size intestinal apparently benign tumors. They were characterized by the yellowish color of argentaffin enterochromaffin cells also known as Kulchitsky cells [1]. Oberndorfer later published 36 cases and noted that a minority formed metastases to the liver [5]. He was professor of pathology in Munich from 1911 and a prolific investigator. He had been a volunteer physician during World War I and had received several medals for his services during the war. This service did not help him in 1933 when he was forced into exile by the Nazis. In Istanbul he made most significant contributions as professor of pathology at the University of Istanbul, where he founded the Turkish Institute for Cancer Research in 1938. He was its director until his death in 1944 (Fig. 14.1).

14.3 A Meeting in Malmö In June of 1952, professor Waldenström was the host at a meeting of the Swedish Society for Internal Medicine in Malmö. Colleagues from all of Sweden must have been duly impressed by the nascent academic department. One of the sessions was devoted to carcinoid disease. Åke Thorson presented the case of the 19-year-old man related above who had died in 1951. JW demonstrated the woman from Ängelholm who had recently been admitted to the department for investigation. It was observed that during the attacks of flushing one could hear a loud systolic murmur. All delegates were able to witness an attack of flushing. During the discussion, the pathologist Sten Winblad mentioned that he had recently performed the autopsy on a man born in 1889 with a three-decade long history of abdominal pain who also had developed dyspnea, weakness, and “plethora”. The autopsy showed metastatic

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Fig. 14.1 Siegfried Oberndorfer with daughter Helene in Munich 1911. © Private collection Dr. Walter Castrillion-Oberndorfer, grandson of Siegrfied Obersdorfer. With permission [5]

intestinal carcinoid and pulmonic stenosis. Among the attendees were Olof Nordenfelt (1902–85), chief of medicine in Jönköping, and Olof Ljung (1909–1996) from Karlstad. Both later could report similar cases from their own departments which were published as case reports [6]. In 1953, JW highlighted the Malmö meeting in the Swedish weekly medical journal and asked for referral of similar patients [7]. Several new cases were subsequently brought to his attention, and in 1955 he and Ljungberg published a review of 17 Swedish patients [1, 3]. JW fully acknowledged that in 1953, two Swiss physicians independently published three cases of carcinoid tumors with metastases and right heart pathology and correctly concluded that the association was not coincidental but rather did represent a true syndrome [8].

14.4 Clinical Features In their 1955 paper, the authors reviewed clinical data of 11 Swedish cases and 19 from other countries including Switzerland, the U.K., U.S.A., Germany, and Denmark. They were surprised by how scanty the provided clinical information often was. Based on their own and this additional information, the dedicated clinicians with true Linnaean delight could list in detail features of the new syndrome. Not much has since been added to their clinical descriptions [1, 3]. Several investigators had

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Fig. 14.2 Carcinoid syndrome. Typical flushing face. © Domenico Coppola, Tampa FL USA. https://mof fitt.org/media/7564/3-gi-cop pola-rfs.pdf

observed similar patients, but like GB before JWs observation, had not realized that their patient represented a distinct clinical syndrome. After this thorough report, it did not take long before the literature was flooded with additional cases confirming the features of the clinical syndrome. PubMed lists some 200 publications on the carcinoid syndrome during the 1950s. The appearance of these reports illustrates nicely one of JW’s favorite quotes from a poem by Johann Wolfgang von Goethe (1749–1832): “Was ist das Schwerste von allem? Was dir das Leichteste dünket: Mit den Augen zu sehn, was vor den Augen dir liegt” (What is the hardest to recognize? It is what you think is the easiest: to make your eyes aware of what is in front of them.) (Fig. 14.2). As late as 1948, a publication stated that the diagnosis can only be proven by surgery, although, as realized by JW, the cutaneous symptoms are “a most remarkable” diagnostic feature in patients with malignant carcinoid. They are initially transient but later the skin develops a permanent reddish discoloration, with telangiectasia and cyanosis. The transient flush is quite dramatic. It starts in the face but then spreads to the skin of the legs and other parts of the body as brick-red hot spots. Patients feel weak and hot and often have tachycardia. Jan points out that several patients initially had been suspected to suffer from polycythemia because of the plethoric facies. Facial swelling and edema are common. Fibrotic pellagra plaques may develop with time [9]. Abdominal symptoms including colic, diarrhea, and borborygmi are common and have been misinterpreted as mechanical effects of the gastrointestinal tumor. JW correctly judged that they were instead induced by chemical signals from the tumor cells. Ascites was common. One interesting subset was carcinoid tumors in the appendix region. As a rule, these had a better prognosis, perhaps because they caused appendicitis-like symptoms and were subjected to early curative surgery. Several patients experienced atypical asthma associated with attacks of flushing. This had not been reported earlier, and JW suspected that a vasoconstricting agent might be the cause. JW’s PhD student Åke Thorson would explore this in depth in his thesis [9]. Right heart disturbances were a characteristic feature in a majority of cases. Fibrotic thickening and stiffness of blood vessels could be observed at

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autopsy. The fibrosis resulted in tricuspid regurgitation and pulmonary stenosis. Left heart involvement was less common.

14.5 From Bedside to the Bench True to his habit from Uppsala, JW realized the need for support from the basic sciences in order to get a better understanding of the clinical condition. His friend in Stockholm, the professor of physiology Ulf von Euler, connected JW with his assistant Bengt Pernow (1924–2009). Pernow had defended an excellent thesis on substance P in 1953. The first result of the collaboration was a brief Lancet paper in 1954, reporting the presence of increased amounts of 5-hydroxytryptamine (=serotonin) in the blood and urine of two patients with a carcinoid syndrome using an in-house bioassay [10]. The Austrian pharmacologist Fred Lembeck (1922–2014) had recently reported the presence of large amounts of this indole in the tissue of a carcinoid tumor [11]. Lembeck was an assistant in the Department of Pharmacology in Graz and would become professor and later its chief there in 1969. It was the same position that Otto Loewi had held before he was forced to leave for the Rockefeller Institute, where he and JW met in 1944 (Chap. 7) (Fig. 14.3). The 5-hydroxytryptamine had originally been isolated from enterochromaffin or argentaffin cells in the gut wall of rodents by a young student of pharmacology, Vittorio Erspamer (1909–1999), a graduate from the University of Pavia. In 1935, he showed its powerful effect on contractility in intestinal tissue preparations, and two years later he showed it to be different from adrenaline and named it enteramine [11]. In 1948, Maurice Rapport (1919–2011) together with Irvine Page (1901–1991) in Cleveland, Ohio, isolated a compound from beef blood which increased blood pressure and named it serotonin [12]. In 1949, now at Columbia, Rappaport could show that serotonin was 5-hydroxytryptamine, 5HT, a metabolite of the amino acid tryptophan [13]. In 1951, research in Melbourne confirmed the work from the United States and also showed that almost all 5HT in the blood was carried in the platelets [14]. Erspamer also replicated the work and in addition showed that that 5HT was an antidiuretic and could cause asthma-like symptoms [12]. These actions of 5HT corresponded well to the edema and asthmatic symptoms of patients with carcinoid disease [15]. Erspamer continued to produce outstanding research in several fields and was twice nominated for the Nobel Prize (Fig. 14.4). The 1954 Lancet report of Pernow and Waldenström was soon confirmed. In 1955, it was shown that after release, 5HT was rapidly converted by oxidative deamination to 5HIAA (Fig. 14.3), and that 5HIAA was the dominant derivative in the urine. The 5HIAA was present, albeit in small amounts in the urine of healthy individuals, ranging from 2 to 8 mg/24 h. Patients with carcinoid excreted as much as 350 mg 5HIAA daily [16, 17]. The discovery of 5HIAA was the first scientific breakthrough for a young investigator, Albert Sjoerdsma (1924–2014). He would be one of the founding fathers of clinical pharmacology. He discovered alpha-methyl dopa (methyldopa; Aldomet) in 1960. And he would be a visiting scientist from the

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Fig. 14.3 Tryptophan metabolism and formation of 5-hydroxyindole acetic acid, 5HIAA. Figure 1 from Reference 18 with permission

Fig. 14.4 Vittorio Erspamer. Fondazione Ghislieri, Pavia. Unknown photographer, 1940s. https:// en.wikipedia.org/wiki/Vit torio_Erspamer18 February 2022

Experimental Therapeutics Branch of the National Heart Institute in Washington, D.C., with JW in Malmö in 1958–1959. The staff was impressed by his American efficiency both at work and leisure. It may have been his first time in Europe, and he was eager to see it all. His method was to visit at least one new country each weekend (Fig. 14.5).

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Fig. 14.5 Cover of the biography of Albert Sjoerdsma by his daughter Ann G Sjoerdsma. www.imp robablebooks.com 2009

In further studies done at the NIH, Sjoerdsma and colleagues showed that administration of tryptophan in healthy individuals caused abdominal cramps and asthma but not flushing. Using tracer studies they found that 60% of administered tryptophan was excreted as 5HIAA in patients with carcinoid, whereas only 1% appears as 5HIAA in healthy individuals. The tryptophan is metabolized by the tumor tissue and high levels of serotonin are formed. This can cause tryptophan/niacin deficiency, explaining the pellagra that often complicates the carcinoid syndrome [17, 18]. In 1957, Pernow and Waldenström published a series of 33 carcinoid cases examined in Malmö. Twenty-two of these had abundant metastases and high 5HIAA output. Eleven had been cured by surgery and excreted normal or marginally elevated 5HIAA. Assays for histamine in urine were also carried out in nine of the patients. Of these, seven had elevated histamine levels ranging from 27 to 6800 μg/24 h. This could be a consequence of histamine production in the tumor, but could also have been caused by formation of histamine in other tissues upon stimulation by 5HT from the tumor [19]. Meanwhile, Åke Thorson was making good progress with his Ph.D. thesis and would defend it in May 1958 [9]. It was a comprehensive presentation of all 103 confirmed cases of carcinoid tumors listed in the registries of the hospitals in Lund and Malmö between 1944 and 1957 and included 12 of his own cases. All diagnoses were confirmed histologically, and postmortem examination had been performed on deceased 70 patients. The detailed thesis is informative but perhaps a little dry to read. It confirms that most tumors originated in the distal third of the ileum, and that carcinoid tumors constituted a substantial proportion of all intestinal malignancies. On the occasion of JW’s 60th birthday in 1966, one of his London friends, Sir Stanley “Stan” Peart (1922–2019) concluded: “One of the outstanding examples of clinical acumen and biochemical knowledge shown by Jan Waldenström has been

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the elucidation of the carcinoid syndrome” [20]. Like JW, Sir Stanley managed to combine basic clinical research with outstanding leadership as clinician and educator. Ulf von Euler had discovered the presence of noradrenaline in sympathetic nerves in 1948. In 1949, Peart showed that noradrenalin was a neurotransmitter, and in 1954 he elucidated the involvement of the renin–angiotensin–aldosterone system in hypertension. In 1956, he succeeded his mentor Sir George Pickering as professor of medicine at St. Mary’s Hospital in London. Hypertension and renal diseases were at the center of his interests. His department was among the first to offer peritoneal dialysis and renal transplantation. In the Festschrift paper for JW he emphasized the still limited understanding of the mechanisms causing the cellular overproduction of 5HT in carcinoid disease but he favored a hypothesis of de-repression of a controlling gene. An unusual case of carcinoid in the ovary was published in 1958 [21]. It is a splendid example of interdisciplinary collaboration. The patient was a female inn keeper diagnosed at the city hospital in Karlstad in her 50s with a three-year history of progressive systemic signs of a carcinoid syndrome. In addition, she had noticed abdominal swelling. She was referred to Malmö where an encapsulated ovarian carcinoid tumor was excised. The patient recovered to full health in the following years. There were no signs of intestinal or hepatic metastases. The detailed report illustrates the slow progression before diagnosis and the regression of all signs and symptoms following surgery. It demonstrates the relevance of the associated laboratory test results. The list of co-authors mirrors the interdisciplinary connetions. Dr. Thorson was JWs PhD student, Arne Hansson was the clinical chemist behind the HIAA test, Bengt Pernow was the clinical physiologist behind the 5HT bioassay, Nils Söderström was the chief of medicine in Karlstad who first identified the patient, Sten Wimbled was the chief of pathology, Helge Wulff was the chief of surgery, and JW was the man behind it all. Nils Söderström would be appointed as professor and chairman of medicine in Lund in 1962 [21]. In 1958, JW summarized the state of the art when he delivered the Fourth Annual Memorial Lecture of the American Gastroenterological Association at their 59th meeting in Washington, D.C. [22]. JW co-authored his last paper on the subject of carcinoid heart disease in 1973. His last Ph.D. student, Erik Trell (born 1938), reported the clinicopathological findings and outcome of 11 cases with carcinoid heart disease. Two of these were ovarian carcinoids, and both patients died due to severe tricuspid insufficiency [23].

14.6 Recent Contributions in the Carcinoid Syndrome Interest and recognition of the carcinoid syndrome have increased substantially since the initial reports from the 1950s. A search in PubMed yields 4860 hits (16 July 2022). JW had published evidence that histamine was an additional mediator to 5HT producing the syndrome, but by 2018, a review listed 40 potential mediators. They can either be released by the tumor or be released by other tissue cells upon stimulation

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from a substance released by the tumor [24]. The review summarizes impressive developments in the understanding of the pathobiology of the carcinoid syndrome and lists 90 references, but regrettably none cites the founding father. Table 14.1 lists the main manifestations and some of the identified mediators. Little has been added to the main clinical features of the carcinoid syndrome or to the overall concept of its pathophysiology since the early descriptions by JW and others (Table 14.1). A better recognition of risk factors for a carcinoid crisis, the complication that killed the 19-year-old man in 1951, can prevent such poor outcomes. The diagnostic tools have been improved. Clinical examination and the urinary excretion of 5HIAA still have a dominant role, but echocardiography, the method introduced by Inge Edler and Hellmuth Hertz in Lund (Chap. 11), provides an outstanding non-invasive technique for diagnosing cardiac involvement [25]. Improved diagnostic tools and perhaps increased awareness have resulted in an increase in reported incidence and earlier diagnosis of carcinoids. A larger number of successful radical surgeries can now be performed of tumors appearing at various sites in the body. Fatal carcinoid crisis precipitated by surgery or diagnostic events can be prevented in most cases. A major advance dating to 1978 was the realization that somatostatin was an inhibitory hormone produced in the gut and that somatotropin receptors on carcinoid cells were upregulated. Somatostatin administration was shown to inhibit flushing and diarrhea [26], and long-acting somatotropin analogues soon became anchor drugs, controlling the carcinoid related symptoms in affected patients [27, 28]. These advances have significantly improved symptoms and Table 14.1 Frequency and mediators of carcinoid manifestations Symptom

Frequency

Characteristics

Mediators

Flushing

90%

Foregut: long-lasting Midgut: frequent short-lasting attacks, pink to red face and trunk

Catecholamines, 5HT, histamine substance, prostaglandins

Diarrhea

60–80%

Secretory: intermediate, accompanied by abdominal cramping

Gastrin, 5HT, histamine, prostaglandins, VIP

Abdominal pain

35%

Progressive

Small bowel obstruction? Hepatomegaly? Ischemia?

Bronchospasm

15%

Wheezing

Histamine, 5HT

Pellagra

5%

Skin induration and pruritus

Niacin deficiency

Carcinoid heart disease

19–60%

Dyspnea, murmur radiating to right side of the chest, progressive

5HT, bradykinins, tachykinins, activin-A, tissue growth factor

Mesenteric fibrosis

50%

Malabsorption, ascites, and intestinal and ureteral obstruction

5HT, TGFβ

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quality of life for the majority of patients, but ultimately the progression of the malignancy causes refractory symptoms. New targeting compounds such as inhibitors of 5HT synthesis and tryptophan hydroxylase have emerged [29, 30]. JW would indeed marvel if he could witness what has become of the paraneoplastic snowball born at a ward round with Edvard Ljungberg in Ängelholm in 1953.

References 1. Waldenström J, Ljungberg E. Studies on the functional circulatory influence from metastasizing carcinoid (argentaffine, enterochomaffine) tumours and their possible relation to enteramine production. I. Symptoms of carcinoids. Acta Med Scand. 1955;152:293–309. 2. Biörck G, Axén O, Thorson Å. Unusual cyanosis in a boy with congenital pulmonary stenosis and tricuspid insufficiency. Fatal outcome after angiocardiography. Am Heart J. 1952;44:143–8. 3. Waldenström J, Ljungberg E. Studies on the functional circulatory influence from metastasizing carcinoid (argentaffine, enterochomaffine) tumours and their possible relation to enteramine production. II. The chemistry of carcinoid tumours. Acta Med Scand. 1955;152:311–31. 4. Waldenström JG. Reflections and recollections from a long life with medicine. Haematologica series, Ferrara Storti Foundation. Il pensiero scientifico, Rome; 1994. p 1–136. 5. Klöppel G. Oberndorfer and his successors: from carcinoid to neuroendocrine carcinoma. Endocr Pathol. 2007;18:141–4. 6. Thorson A, Nordenfelt O. Development of valvular lesions in metastatic carcinoid disease. Br Heart J. 1959;21:243–8. 7. Waldenström J, Ljungberg E. Carcinoidtumörer och vasomotorik. Ett påpekande. (Carcinoid tumors and vasomotor function; a note). Sven Läkartidn. 1953;50:690–2. 8. Isler P, Hedinger C. Metastatic carcinoid of the small intestine with severe valvular defects especially in the right part of the heart with pulmonary stenosis; a peculiar syndrome. Schweiz Med Wochenschr. 1953;83:4–7. 9. Thorson Å. Studies on carcinoid disease. Acta Med Scand Suppl. 1958;334:1–132. 10. Pernow B, Waldenström J. Paroxysmal flushing and other symptoms caused by 5hydroxytryptamine and histamine in patients with malignant tumours. Lancet. 1954;821:591. 11. Lembeck F. Über den Nachweis von 5-hydroxytryptamin (Enteramine, Serotonin) in Carcinoidmetastasen. Arch Exper Path Pharmakol. 1954;221:50–66. 12. Erspamer V. Historical introduction: the Italian contribution to the discovery of 5hydroxytryptamine (enteramine, serotonin). J Hypertens Suppl 1986;4(1):S3–5. 13. Rapport MM, Green AA, Page IH. Partial purification of the vascoconstrictor in beef serum. J Biol Chem. 1948;174:735–41. 14. Rapport MM. Serum vasoconstrictor (serotonin) the presence of creatinine in the complex; a proposed structure of the vasonstrictor principle. J Biol Chem. 1949;180:961–9. 15. Rand M, Reid G. The source of “serotonin” in serum. Nature. 1951;168:385. 16. Page IH, Corcoran AC, Szoerdsma A, Weissbach H. Argentaffinoma as endocrine tumour. Lancet. 1955;268(6859):198–9. 17. Udenfriend S, Titus E, Weissenbach H. The identification of 5-hydroxy-3-indoleacetic acid in normal urine and method for its assay. J Biol Chem. 1955;216:499–506; Sjoerdsma A, Udenfriend S. Studies on indole metabolism in patients with malignant carcinoid (argentaffinoma). J. Clin Invest. 1955;34:194. 18. Sjoerdsma A, Weissenberg H, Udenfriend S. A clinical, physiologic and biochemical study of patients with malignant carcinoid (argentaffinoma). Am J Med. 1955;20:520–32. 19. Pernow B, Waldenström J. Determination of 5-hydroxytryptamine, 5-hydroxyindole acetic acid and histamine in thirty-three cases of carcinoid tumor (argentaffinoma). Am J Med. 1957;23:16– 25.

References

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20. Peart WS. Carcinoid tumours. Acta Med Scand. 1966;172(suppl 445):371–6. 21. Thorson A, Hanson A, Pernow B, Söderström N, Waldenström J, Winblad S, Wulff HB. Carcinoid tumour within an ovarian teratoma in a patient with the carcinoid syndrome (carcinoidosis); clinical picture and metabolic studies before and after total resection of tumour. Acta Med Scand. 1958;161:495–550. 22. Waldenström J. Clinical picture of carcinoidosis. Gastroenterology. 1958;35:565–9. 23. Trell E, Rausing A, Ripa J, Torp A, Waldenström J. Carcinoid heart disease. Clinicopathologic findings and follow-up in 11 cases. Am J Med. 1973;54:433–44. 24. Rubin de Celis Ferrari AC, Glasberg J, Riechelmann RP. Carcinoid syndrome: update on the pathophysiology and treatment. Clinics (Sao Paulo). 2018;73(suppl 1):e490s. https://doi.org/ 10.6061/clinics/2018/e490s 25. Lichtenauer M, Pichler T, Eder S, Mirna M, Magnes T, Wernly B, Paar V, Jung C, Prinz E, Seitelberger R, Hoppe UC. Carcinoid heart disease involving the left heart: a case report and biomarker analysis. ESC Heart Fail. 2+19;6:222–7. 26. Frölich JC, Bloomgarden ZT, Oates JA, McGuigan JE, Rabinowitz D. The carcinoid flush. Provocation by pentagastrin and inhibition by somatostatin. N Engl J Med. 1978;299(19):1055– 7. 27. Öberg K, Eriksson B. Medical treatment of neuroendocrine gut and pancreatic tumors. Acta Oncol. 1989;28:425–31. 28. Ruszniewski P, Ducreux M, Chayvialle J-A, Blumberg J, Cloarec D, Michel H, Raymond JM, Dupas JL, Gouerou H, Jian R, Genestin E, Bernades P, Rougier P. Treatment of the carcinoid syndrome with the long acting somatostatin analogue lanreotide: a prospective study in 39 patients. Gut. 1996;39:279–83. 29. Herrera-Martinez AD, Hofland J, Hofland LJ, Brabander T, Eskens FALM, Gálvez Moreno MA, Luque RM, Castaño JP, de Herder WW, Feelders RA. Targeted systemic treatment of neuroendocrine tumors: current options and future perspectives. Drugs. 2019;79:21–42. 30. Gade AK, Olariu E, Douthit NT. Carcinoid syndrome: a review. Cureus. 2020;12: e7186. https:// doi.org/10.7759/cureus.7189.

Chapter 15

Beginning of a Golden Age

Abstract In 1954 improved premises included a main auditory and a new wing containing the Department of Clinical Chemistry with animal quarters, expanded outpatient space, an enlarged library, the hospital pharmacy, and the transfusion central. Important interactions with diagnostic radiology and pathology are illustrated. Waldenstöm’s family moved to Malmö. JW with wife Elisabet visited Dag Hammarskjöld in New York. Two PhD students graduated and became assistant professors (docents).

The New Wing The year 1954 was an important year in the transformation of Malmö Allmänna Sjuhus, MAS, into a well-endowed academic hospital. In 1947, the city council had decided to enlarge the premises of the department of medicine in order to meet the increased demands for teaching and research. The addition was also intended to contain a central department of clinical chemistry and an enlarged hospital library. The construction only began in 1952, and in March of 1954 a four-story new wing and an Aula were completed. The architect Stefan Hornyánzky (1905–1974) had formed the Aula in the shape of an amphitheater, ideal for demonstrations visible even from the back rows and also well suited for discussion among the attendees. It would serve for decades not only as venue for student and other lectures, but also for public PhD procedures and for the monthly “Demonstration Association”, where interesting patients were presented by and for a mix of hospital-based physicians, practitioners from town, and medical students. Unfortunately, lecture halls with this shape with antique roots are gone out of fashion. Recent new constructions have transformed this Aula into a monument of earlier days of excellence (Figs. 15.1, 15.2 and 15.3). JW now had a worthy venue for his acclaimed undergraduate lectures which he enjoyed as much as did generations of students and house staff. The Aula had a lower entrance at the culvert level. Here was a room where the patients waited before being demonstrated to the audience and through which the teacher arrived. At least one patient would be demonstrated at each lecture as a live illustration of the subject of

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Wollheim, Jan Gösta Waldenström and His World, Springer Biographies, https://doi.org/10.1007/978-3-031-36739-7_15

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15 Beginning of a Golden Age

Fig. 15.1 Malmö General Hospital in 2012. The nearest building in the center is the Department of Diagnostic Radiology (1940). The center background is the Department of Medicine (1935) with the new wing to its right. The round building on the right is the Aula. The buildings except the Aula were demolished in 2019 when a new hospital was constructed Photo Matts Rydén with permission. https://mattsryden.wordpress.com/tag/malmo-allmanna-sjukhus/

Fig. 15.2 Inauguration of “The Aula” on April 5, 1954. JW at the rostrum. Photo by Björn Henriksson. Sydsvenska Medicinhistoriska Sällskapet. Öppet bildarkiv SMHS7698_000_ 01Copp.jpg. http://www.medicinhistoriskasyd.se/smhs_bilder/

15.1 The New Wing

163

Fig. 15.3 The man with spectacles in the middle of the first row is Sweden’s Prime Minister Tage Erlander. To his right in profile is Harald Lindvall, chairman of the hospital board. To his right is Artur Thomson, the University Chancellor of Sweden. Photo by Björn Henriksson. Sydsvenska Medicinhistoriska Sällskapet. Öppet bildarkiv SMHS8098_000_ 01Copp.jpg. http://www.med icinhistoriskasyd.se/smhs_b ilder/

the day. The upper public entrance was at the level of the ground floor where there was an elegant hall suitable for minor social events. It was connected with the main building of the Department of Medicine. JW exposed a masterful interaction with the patients he demonstrated to the students who often remembered individual patients that were demonstrated. An example is a man with heart problems who happened to have a hand with two merged fingers. JW mentioned that such abnormalities were dominantly inherited. The patient admitted that the finger abnormality had been present from birth, but that it was not inherited in his case. The cause was that his mother had been scared at one occasion by a neighbor with the same abnormality. JW tactfully pretended to accept this story (Fig. 15.4).

15.1 The New Wing Hornyánzky’s new wing would host activities of paramount importance for the new academic hospital. They housed the Department of Clinical Chemistry. The ground floor was occupied by the new Department of Medicine’s outpatient clinic. The second floor contained the hospital’s library where a shelf was filled with new journals every Monday. This was a place where industrious physicians from internal medicine and other departments would keep updated with the literature before the time of internet. Some would leave their initials on the cover page when they had read a journal number. Index Medicus was an important comprehensive list of titles listing all recognized journals, the majority of which were only available at other libraries.

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Fig. 15.4 Student lecture by JW in 1954. In front row: Sten Olle Larsson, Hans Krook, Folke Serin, and Karl Gydell. Photographer Olof Liljeroth. https://digitaltmuseum.se/011013844258/professorjan-waldenstrom-overlakare-vid-medicinska-kliniken-som-forelaser/media?slide=0

When needed, these had to be borrowed from other institutions. This was a service offered free of charge for students and hospital employees. The library’s subscribed journals were available on shelves in the large reading room where one could browse recent back issues and bound back volumes. Physicians could visit the library at all hours using their personal key. Thefts were not unknown but fortunately rare. The third and fourth floors housed the new Department of Clinical Chemistry which is presented in Chap. 19.

15.2 Radiology Diagnostic radiology had for decades been an independent department. In 1952, Sölve Welin (1901–1994) was appointed as its chief physician. In 1942 he defended a PhD thesis in Lund in 1942. From 1943 onward, he worked in Stockholm. In Malmö he was promoted to full professor in 1957. He introduced a new technique to image the colon called the “double-contrast method” [1]. Following an enema with a sticky contrast material, the colon was inflated with air under pressure. It was an improved method to visualize small polyps and early detection of malignancy. The method was mandatory in Malmö but considered too sensitive clinical use in Lund. Welin recruited several academically active staff members. The daily demonstration sessions provided have been mentioned (Chap. 13). A Christmas Eve Glögg Reception soon became an appreciated tradition hosted by professor Welin. Glögg is

15.3 Pathology

165

Fig. 15.5 The Glögg Reception following the daily radiology rounds on Christmas Eve. From left: Bengt Skanse and Sven-Erik Björkman, JW, and Sölve Welin. © Universitetssjukuset MAS 1996

a traditional sweet drink around Christmas time in Sweden, served in small glasses and spiced with almonds and raisins (Fig. 15.5).

15.3 Pathology In 1953, Sten Winblad, assisted by Folke Linell (1913–1994), started the planning of a new building for pathology and bacteriology. At the time of its inauguration in 1957, many thought that it was vastly oversized, but soon time proved that it was rather on the small side. Linell was an outstanding pathologist, excelling in elegant autopsies but also interested in bacteriology. His diagnostic acuity at the microscope was legendary. He was not impressed by subject matter authorities and would not hesitate to dispute their diagnostic decisions. While still in Lund, he had discovered atypical tubercle bacilli as the cause of an endemic skin disorder among customers who had visited a public swimming pool [2] (Fig. 15.6). After arriving in Malmö, Linell soon realized the potential of careful postmortem examinations to yield quality epidemiologic studies in a sizable community served by only one hospital. He implemented the widest possible use of detailed postmortem examinations. Including forensic autopsies, within a short time over 90% of all persons dying in Malmö were autopsied. A number of unique studies were initiated which revealed the true prevalence of various diseases. They often showed them to be far more prevalent than suggested by epidemiologic studies based on registries of clinical diagnoses. An example from later years is a study of carcinoid tumors in Malmö. Among 16,292 autopsies from a 12-year period, carcinoid tumors were found in 199 cases. Only 44 of these had been diagnosed before death. The prevalence

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Fig. 15.6 Folke Linell 1978. Photographer unknown. Sydsvenska Medicinhistoriska Sällskapet. Öppet bildarkiv SMHS10803_000_ 01Copp.jpg. http://www.med icinhistoriskasyd.se/smhs_b ilder/

was seven times that noted in the national cancer register [3]. Sadly, within few years after his retirement in 1978, near-universal autopsy was abandoned in Malmö and lead to decline in its use not only in Malmö. JW’s unhappy relations with the pathologists in Uppsala (Chap. 8) were transformed into a good friendship and close interactions in education and science when he encountered Linell and his team. The demonstrations in the morgue were faithfully attended by all involved and always produced important information. Patterned after JW’s experiences in the United States, regular clinical-pathological conferences were instituted and developed into exquisite, well-attended educational events. Linell emerged as an enthusiastic and generous mentor and attracted numerous fellows and generated productive research. It was appealing and very useful for young clinicians in training to spend time in the department during specialization. The working week was still six days. The author remembers a half-holiday in Sweden, the day before Christmas Eve, in the 1970s. Upon entered the morgue Linell greeted the visitors from medicine with a big smile: “Today it is really Christmas here. I have just autopsied my very first case of Chaga’s disease”. The autopsy case that day which he was about to demonstrate concerned a man in his late 40s who had been admitted with abdominal pain, heart failure, and skin thickening. The clinicians had diagnosed systemic sclerosis. The patient died of heart failure. The correct diagnosis would have escaped later generations [4]. The clinicians had based a diagnosis of myocardial infarction on scintigraphy, a finding they published without acknowledging the pathologist’s contribution or even mentioning their own incorrect diagnose of scleroderma [5]. Unfortunately, the use of autopsies has fallen out of fashion. This is serious loss for

15.5 Private Life

167

clinicians to obtain correct diagnostic information and leaves students without an ideal teaching source. Likewise an important research tool is lost.

15.4 The First Ph.D. Students The year 1954 was also the year in which JW’s first Ph.D. students graduated in Malmö. On February 26, Anders Wenckert defended a study titled “The activation of prothrombin”. As mentioned in Chap. 11, he would soon continue his career as a surgeon. It is intriguing that both his thesis and that of Inga Marie Nilsson (Chap. 18) were triggered by their study of a single female patient affected with a rare familial bleeding disorder [6]. JW’s contributions to understanding bleeding disorders are a subject of Chap. 18. Olof Forssman (1914–2000) acknowledges in his thesis that already in January of 1950, JW had induced him to investigate the adrenal function of patients with myocardial infarction. He studied all patients admitted to the department during the period 1950 to 1953, 123 men and 62 women, about outcome, fever, erythrocyte sedimentation rate, white blood cells, eosinophils, blood sugar, urinary catecholamine, and 17-ketosteroids. The description of characteristic changes is well known to later generations, but they were new at the time [7]. Forssman then spent a year with experimental work at the Rockefeller Institute with Frank Horsfall [8]. A later paper on myocardial infraction showed that the majority of cases were men with hypertension, overweight, and high cholesterol. A less common phenotype was patients without these risk factors but with higher education and social standing [9]. In 1956 he left Malmö and became head of medicine at the city hospital in Borås.

15.5 Private Life On April 3, 1953, JW sent a long letter to Dag Hammarskjöld congratulating him on his election as Secretary-General of the United Nations. “From amongst an unusually happy and rich store of common memories many surface at this moment. No doubt you will appreciate that (my) mother and her pathos for a unified Europe and for appeasement among nations often comes to mind. How happy she would have been to learn that little Dag whom she trusted so much, in such a splendid way continued and complemented the efforts to which her great idol Hjalmar [Dag’s father] devoted so much of his life … Do you remember an evening in June in the tower of the castle in Uppsala when the white beam had just started blooming. We sat there with your matchless mother and talked about life, and all four of us felt closer than human beings normally are allowed to feel?” [10] (Fig. 15.7). The following summer, JW and his wife Elisabet were the guests of Dag Hammarskjöld, the new Secretary-General of UN in New York. Elisabet had now moved to the Tessin Street apartment in Malmö with the three youngest children.

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Fig. 15.7 JW and Elisabet visiting Dag Hammarskjöld in 1954. Courtesy Anders Waldenström

Elisabet and Jan traveled by ship to New York. The visitors savored the time spent together in Jan’s favorite city. They also enjoyed visiting with Dag in his countryside retreat in the company of his pleasant bodyguard William (Bill) Ranallo (1922–1961), who always carried his weapon. A thank-you letter written on “M/S Kungsholm” is preserved in the Hammarskjöld archive. This was the last time the friends would meet. The trip to the United States also included visits in Philadelphia, St. Louis, and Chicago. Elisabet was impressed by museums and galleries which she could visit while Jan spent time in hospitals [10, 11] (Fig. 15.8).

References

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Fig. 15.8 Kungsholm II outside Manhattan. Postcard 1950s, Swedish American Line © DigitaltMuseum. Photographer unknown. https://digitaltmuseum.se/021188696278/svenska-amerikalinien

References 1. Andren L, Frieberg S, Welin S. Roentgen diagnosis of small polyps in the colon and rectum. Acta radiol. 1955;43(3):201–8. 2. Nordén Å, Linell F. Mycobacterium balnei, a new acid-fast bacillus occurring in swimming pools and capable of producing skin lesions in humans. Acta Tuberc Scand Suppl. 1954;33:1– 84. 3. Berge T, Linell F. Carcinoid tumors. Frequency in a defined population during a 12-year period. Acta Pathol Microbiol Scand A. 1976;84:322–30. 4. Wollheim FA. Message from the morgue to rheumatology: from Chagas disease to giant cell arteritis. Arthritis Res Ther. 2013;15(6):131. https://doi.org/10.1186/ar4418. 5. Lessem J, Persson B. Myocardial scintigraphy in Chagas’ disease. Lancet. 1977;310(8032):310. 6. Nilsson IM, Wenckert A. Hyperglobulinemia as the cause of hemophilia-like disease. Blood. 1953;8:1067–77. 7. Forssman O. Myocardial infarction and adrenal function. Acta Med Scand Suppl. 1954;296:1– 133. 8. Tyrrell DA, Tamm I, Forssman OC, Horsfall FL Jr. A new count of allontoic cells of the 10-dy chick embryo. Proc Soc Exp Biol Med. 1954;86:594–8. 9. Forssman O, Lindegård B. The post-coronary patient: a multidisciplinary investigation of middle-aged Swedish males. J Psychosom Res. 1958;3:89–169. 10. Excerpt from a letter by Jan Waldenström in the Dag Hammaskjöld file at the National Library in Stockholm. Translation by the author. 11. Waldenström A. Personal communication 2020.

Chapter 16

Gammopathies—Jewel in the Crown

Abstract In 1955 JW divorced Elisabet and in 1957 he remarried a research nurse from Uppsala. He moved into a nice house and would within 4 years be the father of two boys. In close collaboration with Carl-Bertil Laurell systematic clinical and biochemical research relating to conditions with hypergammaglobulinemia progressed. Malmö became an internationally noted research center. The concept of polyclonal and monoclonal gammopathies was launched in a 1961 Harvey Lecture. Familial SLE and so-called benign or essential gammopathy, later named MGUS by Robert Kyle, were delineated. A registry of M-components was created at the Clinical Chemistry laboratory and became an important resource for further investigation. The Belgian investigator Joseph Heremans who had discovered IgA participated as a guest researcher in Malmö.

16.1 A New Family In 1955, Jan and Elisabet Waldenström were divorced. Elisabet left for Paris and spent a year there with the younger children. She became a student with the prominent cubist artist and teacher André Lhote (1885–1962) and then moved back to Uppsala. The following year JW married Karin Nordsjö, the research nurse he had collaborated with in Uppsala (Chap. 8). They moved into a home in a pleasant residential area of Malmö and started a happy marriage. Two sons were born in 1957 and 1962. JW had been suffering from migraine attacks which often triggered feared tantrums. Such unhappy episodes became markedly less frequent. The department was thriving. It had become very attractive to work there, and hopeful candidates for fellowships usually starting with a trial period as locum were lining up from all parts of the country. The reputation for excellence also resulted in enrichment of the department by referral of patients with unusual or unclear diagnoses from many outlying hospitals. Various lines of research ranging from hematology to hepatology, inflammatory bowel disease, and renal disease were exploited in the new department. Autoimmune disorders and patients with abnormal gamma globulins, however, were at the forefront of JW´s own interest in continuation of his earlier studies in Uppsala [1, 2]. This chapter will cover some of the developments in this area. In 1961 JW was © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Wollheim, Jan Gösta Waldenström and His World, Springer Biographies, https://doi.org/10.1007/978-3-031-36739-7_16

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Fig. 16.1 New home of Jan and his second wife Karin at Sånekullavägen 17 in Malmö, designed by the internationally noted architect Sigurd Lewerentz (1885–1975). Photo The author

invited to deliver an important lecture which demonstrates his insight of the field at the time (Fig. 16.1).

16.2 The Harvey Lecture “Gammopathies” The Harvey Lecture is defined as “a series of distinguished lectures in the life sciences” and organized by the Harvey Society in New York under the patronage of the New York Academy of Sciences. The prior year, Peter Medawar (1915–1987) had been invited speaker at a similar distinguished event. JW’s lecture on gammopathies was delivered on May 18, 1961, and provided an opportunity to summarize the field and his contributions to this topic in a landmark document titled “Studies on conditions associated with disturbed gamma globulin formation (Gammopathies)” [3]. The discovery of two new diseases in Uppsala in 1943 had come to fruition in the following decades and the audience in New York was listening to a milestone in the history of gammopathies by one of the frontline movers. The lecture received much attention and inspired new research (Fig. 16.2).

16.3 Monoclonal and Polyclonal Gammopathy In retrospect it had become clear that purpura hyperglobulinemica and macroglobulinemia and all the other conditions characterized by extremely high erythrocyte sedimentation rates combined with hypergammaglobulinemia were either neoplastic and due to myeloma, macroglobulinemia or other malignancies, or reactive and due to infections, autoimmunity or other exogenous triggers. Work by Frank Horsfall and Elvin Kabat related in Chap. 6 performed in part in Uppsala in collaboration with

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Fig. 16.2 New York Academy of Sciences, Fifth Avenue and 103rd Street. https://en.wikipedia.org/ wiki/New_York_Academy_ of_Medicine. 17 July 2022

Arne Tiselius and Kai O Pedersen had shown that gamma globulins consisted of antibodies. Astrid Fagraeus (1913–1997) had in 1943 provided evidence that plasma cells were producing antibodies. In Paris, Pierre Grabar (1898–1986) had introduced immune electrophoresis in 1953, providing a new simple immunochemical method with which new proteins in blood could be identified [4]. In Malmö, Carl-Bertil Laurell, CB, had perfected paper electrophoresis according to Kunkel/Tiselius [5] and launched it as an informative and simple clinical routine method. It separated plasma into distinct fractions and allowed quantification of albumin, α1 , α2 , ß1 , ß2 , and γ fractions [6]. Paper electrophoresis allowed the distinction between neoplastic narrow band and reactive broad band hypergammaglobulinemia. It was accurate, fast, and inexpensive method yielding information with high clinical relevance (Fig. 16.3). A biobank collection of all sera with narrow bands was started by CB in Malmö in 1954. In 1959, a third class of immunoglobulin, β2A, later named IgA, was discovered by Joseph F. Heremans (1927–1975) [7]. IgA molecules are richer in carbohydrate Fig. 16.3 Astrid Fagraeus. Unknown photographer. Public domain. https://en. wikipedia.org/wiki/Astrid_ Fagraeus#/media/File:Ast rid_Fagraeus.jpeg

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than IgG and IgM. This explains why IgA producing plasma cells stain more intensely with eosin and become “flaming” red in the bone marrow. Heremans spent extended periods working in Malmö the following years and was the senior author of a landmark publication presenting nearly 300 M-components from the biobank of CB in 1961 [8]. Relation of the immunochemical classification and the clinical diagnosis established without knowledge of the biochemical finding is shown in the table from the paper (pages 111–119). Sir Frank Macfarlane Burnet (1899–1987) had shared the Nobel Prize in 1960 with Sir Peter Medawar (1915–1987). In 1959 Burnet published a monograph on his hypothesis of clonal selection postulating that antibody diversity originates in different “clones” of plasma cells. This immediately caught the attention of JW and gave him the brilliant idea for a new nomenclature [9]. It was known from work in Uppsala and at the Rockefeller Institute done by Frank Horsfall, Elvin Kabat, and Kai O Pedersen that gamma globulins were antibodies. JW did not like the label paraprotein because all evidence indicates that M-components are normal proteins formed in excess. He introduced the more adequate term monoclonal for the narrow peak and polyclonal for the broad band type of hypergammaglobulinemia. The M in M-component originally referred to “myeloma” [10] but came now instead to stand for monoclonal. The concept of mono- and polyclonal disturbances with seeds in the 1940s has stood the test of time and remains as a contribution of lasting significant by JW (Figs. 16.4 and 16.5). The table drawn from a lecture by JW shows that M-components in myeloma are most often typed as IgG. Not shown are sera from 20 patients with myeloma but without a detectable M-component. In these patients the malignant plasma cells secreted only Bence-Jones protein which is small enough to escape in the urine. This condition can be named “light chain disease” [11]. It can be seen from the table that 39 of 276 patients had a macroglobulin M-component. This was, according to JW, due to pronounced referral bias. In unselected populations of M-components, IgM is Fig. 16.4 Frank Macfarlane Burnet. By N. Murray 1945. Public Domain Mark. https:// commons.wikimedia.org/ wiki/File:Burnet_in_the_lab. jpg

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Diagnosis Myeloma Myeloma? Macroglobulinemia Possible Macroglobulinemia Leukemia, lymphatic Reticulosis, and similar Cancer Varia: Liver cirrhosis, Splenomegalia, Myelofibrosis “Essential” hyperglobulinemia

IgG 91 11 2 3 2

IgA 30

6

2

2

2

1

1

Apparently healthy Grand total 267

39 171

Total

15

IgM 2 2 20 14 3

L

1

3 7 40

11 61

1

Fig. 16.5 M-component typing and clinical diagnoses as reported by JW in 1961

rarer. But a registry from Iceland identified at total of 713 cases with M-components from the whole country. Of these 55% were typed as IgG, 32% as IgM, and 13% IgA. About 29 cases were classified as manifest macroglobulinemia and 177 as myeloma [12]. Another important result from the Malmö registry was recognition of the categories “essential hyperglobulinemia” and “apparently healthy individuals” followed for a long time. Some of these cases had been under observation for 10 or more years. JW always stressed that such patients should only be kept under supervision with no therapy. This subset of patients has later been extensively studied in Malmö and other centers around the world, initially by Robert Kyle at the Mayo Clinic in Rochester, Minnesota, who introduced the term “Monoclonal gammopathy of undetermined significance”, MGUS [13]. He extended the observations made in Malmö and followed 241 subjects from Olmsted County in a prospective study concluding that there was no simple way to predict who would remain asymptomatic and who was to progress to myeloma, macroglobulinemia, lymphoma, amyloidosis, or any other frank malignancy. Consequently “guarded expectancy” still is the best strategy to deal with MGUS (Fig. 16.6). The improved quality of paper electrophoresis in Malmö leads to the important observation that in sera with M-components the “background” normal gamma globulins with the diffuse type of migration were attenuated. This resulted in low titer or absence of diverse common antimicrobial antibodies present in most normal serum samples. It had been confirmed by JW’s collaboration with Sten Winblad. This collaboration turned out an early surprise. One serum from a patient with myeloma showed the extremely high titer of 1:12,800 anti-streptolysin-O reactivity most likely located in the M-component [14]. Some other serum samples contained high titer

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Fig. 16.6 Paper electrophoresis with M-components of different mobility. Normal pattern to the very left [8]. © Private archive Anders Waldenström

anti-complement activity and cold agglutinin, as shown in the figure. This observation was an additional support for JW’s view that M-components are the result of excessive synthesis of otherwise normal proteins and not abnormal “paraproteins”. The monoclonal nature of their serologic activity was later studied in detail by Olle Zetterwall [15] (Fig. 16.7). In his Harveyan Lecture JW also addressed hereditary gammopathies. In 1952, the pediatrician Ogden Bruton (1908–2003) working at the Walter Reed Army Hospital in Washington D.C. had published a family of two male siblings with absence of gamma globulins who suffered from extremely frequent airway obviously caused by inability to produce antibodies [16]. The first Swedish cases of the new disorder agammaglobulinemia were found in a family by the pediatrician Nils Kulneff. He

Fig. 16.7 M-components with serologic activity. Note the weak staining of “background” gamma globulin [3]. © Private archive Anders Waldenström

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became a fellow of JW, and they published a study on this family in 1955 confirming X-linked recessive inheritance [17]. In the following years rare cases of “antibody deficiency” were described in adult patients of both sexes. They were categorized as idiopathic or acquired [18]. Two women with this condition were referred to JW from different hospitals in the late 1950s. Talking to the patients, he noticed that both had ancestors in Visseltofta, a small village in the north of Scania. A less observant physician would probably not have uncovered or put significance to this fact. But JW instructed the author, still a beginner in the department, to trace their ancestors and find out if they perhaps were relatives. This can be done in Sweden thanks to preserved church registers. After some months exploring such registers in archives a pedigree could be constructed showing that the patients indeed were offspring of common ancestors born in 1694 and 1703, five and six generations back. Just as JW had suspected, this pedigree suggested the presence of a genetic component in the pathogenesis of the rare condition and cast doubt on the designation “acquired”. When JW approved the young house officer’s brief manuscript, he erased his own name as co-author and said: “Send it to The Lancet”. The paper was accepted [19, 20]. The world-famous mentor abstained co-authoring the paper although he had initiated the investigation. This act of a generous mentor was intended to support the advancement of a young fellow. Two years later the author was received with open arms at the Department of Medicine of the University of Minnesota in Minneapolis and spent two career defining years there, mentored by Ralph C. Williams, Jr. (1928–2020). The chairman of medicine was Cecil Watson. Williams had just spent two years with another of JW’s close friends, Henry Kunkel at the Rockefeller Institute. This is one of many examples of the advantage of choosing distinguished mentors with a comprehensive network (Fig. 16.8). Fig. 16.8 Pedigree of two patients with common variable hypogammaglobulinemia. From [19] with permission

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16.4 Epidemiology of Gammopathies In 1960, Jan Hällen (1929–2019) joined the department. He had earned good credentials after working four years under the chairman of medicine Per J. Wising at the Department of Medicine in Västerås. Wising was an acquaintance of JW from Uppsala. Jan Hällén spent eleven years in Malmö and would eventually move back to Västerås as a highly respected successor of his former chief. As mentioned, paper electrophoresis was a sensitive method to detect presence and concentration of M-components [8]. The method was extensively used in clinical routine. CB personally inspected each analysis and gave the clinicians information regarding possible diagnoses. CB also made the method available for research without charge. CB as mentioned had a biobank containing frozen serum samples with all M-components diagnosed in the laboratory. JW suggested that Hällén should further characterize the subset of patients with “essential” monoclonal hypergammaglobulinemia as his doctoral thesis (Fig. 16.9). Hällén was able to include serum samples from all patients from Malmö with Mcomponents diagnosed between January 1950 and July of 1965 belonging to one of three groups. Group I consisted of 108 patients with IgG or IgA M-components but not diagnosed as having myelomas or lymphoma. Group II contained all cases with an IgM component, and Group III all cases of leukemia, lymphosarcoma, or reticulum cell sarcoma. The resources of CB and his assistant Rolf Bachmann were utilized and supplemented with serologic data from Sten Winblad, and histologic examinations by Folke Linell. Sölve Welin provided assistance with radiologic expertise. The 108 cases in Group I were compared with 92 consecutive patients with confirmed myeloma. The follow-up time was between 2 and 10 years, during which time two individuals developed myeloma and a few exhibited high concentration of Fig. 16.9 Jan Hällén. Courtesy Mrs. Gudrun Hällén

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the M-component but remained healthy. The concentration of the M-components was markedly lower and stable in comparison with the patients who developed myeloma. The amount of plasma cells in the bone marrow was lower than among the myeloma cases but the proportion of IgG and IgA components corresponded to the normal distribution. Bence-Jones proteinuria was present in only 5% in contrast to 35% among the patients with myeloma. Serologic activity included anti-complementary activity in 10–15% of both groups. Group II consisted of 27 patients. The bone marrow contained an excess of lymphocytes in half the cases. Lower concentrations of the M-components were the rule but in 4 cases macroglobulinemia evolved. Group III consisted of 8 patients from a cohort of 59 consecutive patients with lymphatic leukemia. An additional random group of 671 individuals older than 70 years were also examined. The prevalence of M-components among these individuals was 3%, but none had myeloma or macroglobulinemia [21]. Guarded surveillance remained the method to manage asymptomatic subjects with M-components. This very careful work, presented with modesty and balance, was well received by the assessors, and in 1967, Jan Hällén received his doctoral hat and was awarded the title “docent”.

16.5 The Värmland Study Uno Axelsson (born 1927) was another young physician recruited from the medical department in Karlstad, the capital of the province of Värmland. Like Hällén, he had a solid previous knowledge of internal medicine and although one foot shorter than the professor, well matched to him intellectually. JW learnt from his friend Artur Engel that the Swedish Health Authority which he chaired since 1952 had decided to sponsor a study investigating the general population health in four parishes in Värmland. Carl Bertil Laurell and JW suggested that Axelsson together with Rolf Bachmann from clinical chemistry and Hällén should survey the prevalence of gammopathies in the selected parishes. CB organized laboratory resources. Blood samples from 6995 individuals were collected, representing 70% of the adult population in the four Värmland parishes. The specimens were shipped to Malmö by train and arrived within less than 10 h in the Malmö laboratory. Sera were stored at −20 °C. A special “electrophoresis factory” was organized by CB and managed by Hällén at a laboratory in the school of dentistry where Hällén was a part-time instructor. A trained technician performed Malmö quality filter paper electrophoresis, employing the method of CB. Two independent observers inspected the stained strips. A total of 64 M-components were identified, the majority of which in low concentration as seen in the figure. Many would have escaped detection with a less precise technique [22] (Figs. 16.10 and 16.11). The presence and type of each M-component was identified by immunoelectrophoresis by Rolf Bachman using antisera made “in house” using purified Mcomponents as antigen and absorbed to be specific for IgG, IgA, and IgM by absorption [23]. Thirty-nine components were classified as IgG, seventeen as IgA, and five

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Fig. 16.10 Sweden map showing the location of Värmland by Lapplänning which was based on SWE-Map Kommuner2007.svg by Lokal_Profil, CC BY-SA 2.5. https://commons.wikimedia.org/ w/index.php?curid=7028777

Fig. 16.11 Concentration of 64 M-components from the Värmland study. Note that the most Mcomponent were present in low concentration blood samples from 6995 individuals [22]

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as IgM, corresponding to 61%, 27%, and 8%, respectively. This distribution corresponded roughly to the proportion of M-components found in large clinical materials. This was supporting that the collected samples matched the whole population. The distribution also closely mirrored the concentration of immunoglobulin classes in normal serum samples, supporting the contention that they represented dysregulated production of normal immunoglobulin and should not be called paraproteins. Axelsson traveled to Värmland and examined each patient. Sternal puncture and radiologic examination of the skull and spine were also performed. Myeloma was suspected in three cases, one of which had radiographic skeletal lesions. One patient had lymphatic leukemia, and three had other malignancies. The remaining 57 individuals appeared healthy [24]. Axelsson was promoted to head of the Outpatient Department of Medicine in Karlstad in 1973. He continued to follow up the patients and was able to trace the fate of all 64 subjects for up to 20 years [25]. By then, 45 patients had died, two with myeloma and one with lymphatic leukemia. Three of the 19 survivors had progression of the concentration of the M-component and more pronounced suppression of the background gamma globulin, but none satisfied a diagnosis of myeloma. In 1966, JW was honored on his 60th birthday with a 466-page Festschrift published as a supplement of Acta Med Scand. One-third of the volume contains papers on protein disturbances. In one of the contributions, Axelsson and Hällén presented further data on 12 patients from the Värmland study in whom polyclonal hypergammaglobulinemia, defined as more than 2 g/100 ml gamma globulin, was present [22]. All but one of the patients were women. Details of these patients and

Fig. 16.12 Data on the 12 cases from the Värmland study with polyclonal hypergammaglobulinemia. FIIA is Sten Winblad’s rheumatoid factor test [24]

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analyses are given in the table. Notably, eight of the sera were rheumatoid factor positive, three patients had rheumatoid arthritis, and two patients had purpura hypergammaglobulinemica. These findings provide further support for the notion of polyclonal hypergammaglobulinemia as a reactive condition. These results were reproduced and expanded upon in studies performed at the Mayo Clinic [23]. A more recent publication concerning a new entity of IgG4-related diseases from Canada is added to the list of conditions that are clinical manifestations of polyclonal hypergammaglobulinemia [24] (Fig. 16.12).

16.6 Genetics of Monoclonal IgM One paper in the Festschrift was by Maxime Seligmann, a leading French immunologist, who contributed a manuscript on 65 patients with macroglobulinemia and 192 first-degree relatives. In 7 of the 65 families a second individual with an M-component was found. This suggests a genetic component to the development of this condition [28]. In following decades, studies on the genetics of malignancies developed with break-neck speed. A starting point was the accidental discovery of the Philadelphia chromosome in 1960, a deletion of chromosome 22 later shown to be the result of a translocation of genetic material from chromosome 22 to chromosome 9 [29]. JW’s interest in genetics began when he worked on his doctoral thesis in Uppsala dealing with acute intermittent porphyria (Chap. 3). Lund had a great tradition of genetic research. In 1956, Albert Levan (1905–1998) and Joe Hin Tjio discovered that the correct number of chromosomes in humans was 46 and not 48. In 1965, the more recent star geneticist, Felix Mitelman, published his first of several hundred scientific papers [30]. He later became professor of clinical genetics. When JW was in his 80s he approached his friend Mitelman and suggested a project examining the genes of patients with macroglobulinemia. A considerable number of patients were screened with negative results. Finally however, in a patient with unusual bone lesions and hypercalcemia, a chromosomal translocation was detected, t(1;3(36;q21). The young doctor from Lund, Bertil Johansson, was the first author on the resulting paper, one of the last publications co-authored by JW. Dr. Johansson remembers that when talking to him on the phone, JW insisted on a meeting in person. This occurred in October of 1994. During the conversation, JW asked whether he had been abroad, and the young doctor told JW that he had spent time in a laboratory in Cambridge. This was the beginning of a long dialogue which both greatly enjoyed. The paper was submitted to the prestigious journal Leukemia and accepted without changes. The editor was proud and delighted to publish a paper co-authored by Jan Waldenström. The patient had a unique chromosomal abnormality and also an unusual clinical picture with bone destructions which are not commonplace in macroglobulinemia [31].

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16.7 MGUS, SMM, and MM The condition identified by JW as “essential” hypergammaglobulinemia and named MGUS (monoclonal gammopathy of undetermined significance) by Robert Kyle has been the subject of a host of studies during the last half century and presently is addressed in numerous full-length papers almost every year. As already mentioned, MGUS has been studied at the Mayo Clinic in Rochester, Minnesota, starting in 1961 and continuing to this day [32, 33]. The prevalence in the Värmland study was estimated to be 3%. In Olmsted County it is 5%. MGUS is thus a common condition. However as described by JW, subjects with “essential hypergammaglobulinemia” most often are asymptomatic. The M-components are often accidental findings in patients examined for unrelated complaints. MGUS is therefore underdiagnosed. Confirming its high prevalence in a defined Minnesota population, it was concluded that MGUS is a premalignant condition with a risk of progression to myeloma, lymphatic leukemia, amyloidosis, or other conditions at an annual rate of approximately 1%. This confirms the findings in Hällén smaller material from 1966 [21]. It is now realized that most if not all cases of myeloma are preceded by a period of MGUS. Smoldering disease, SMM, has been recognized as a transitional phase preceding full malignancy. Important risk factors for MGUS are the presence of MGUS, or myeloma in close relatives. MGUS is more prevalent in Black people both in Africa and America, and the age dependence is less pronounced. Japanese populations have lower risk but those exposed to radiation from the atomic bomb in 1945 have a higher risk for MGUS and malignancy. Some clinical features associated with MGUS have been identified which may help in predicting progression. These include peripheral neuropathy, vertebral fractures, and unexpected osteoporosis [34]. The risk of progression of MGUS is strongly correlated with the concentration of the M-component and also with unbalanced presence of kappa and lambda light chains in serum or urine. Results of more recent research efforts give hope that preventive strategies may be within reach. There is evidence that metformin may diminish the risk of progression [35]. A consensus meeting in 2019 dealt with new information, much of which has been generated by decades of solid epidemiological studies at the Mayo Clinic in Rochester [31, 32]. The man who recognized “essential hypergammaglobinemia” in 1952 [36] and his school predicted important features that later studies did extend and confirm.

16.8 Familial Autoimmunity In the Festschrift honoring the Danish physician Erik Warburg (1882–1969), JW contributed an extensive paper on purpura hyperglobulinemica, the condition he had discovered in Uppsala in 1943 [37]. He describes three new patients referred to him in Malmö, one of which had a twin sister with systemic lupus erythematosus (SLE).

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This could indicate familial susceptibility and triggered the amanuensis Tore Leonhardt (1928–2011) to contemplate a doctoral thesis project. He saw that of the 14 siblings of this patient two turned out to have SLE. Another had 3.8 g/100 ml IgG on paper electrophoresis which is 4 times above the normal upper limit [38]. Leonhardt was able to trace 109 patients with SLE and 225 of their first-degree relatives. The overall conclusions were: SLE may be considered as a heterogeneous syndrome; it may be the consequence of a genetically based lower tolerance to environmental or endogenous antigenic triggers; that hypergammaglobulinemia, antinuclear factors, and rheumatoid factor are what we now call biomarkers of this abnormality; and that Sjogren’s syndrome, rheumatoid arthritis, and systemic sclerosis are more prevalent among first-degree relatives. All these conclusions have stood the test of time. Leonhardt defended his thesis in 1964 and moved to the department of medicine in Vänersborg. He became its chief when his predecessor, Hans Krook, was called to become head of the department of medicine in Helsingborg. In Vänersborg Leonard emerged as a model of the Waldenström school of internal medicine (Figs. 16.13 and 16.14). The investigations instigated by JW on gammopathies stand out as a paradigm shifting important contribution to medical science. An essential component of the

Fig. 16.13 Tore Leonhardt 1980s. © Courtesy Merete Leonhardt

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Fig. 16.14 Pedigree of proband KG and her 14 siblings from the family triggering Tore Leonhardt’s Ph.D. thesis. © The Lancet [38], with permission

developments in Malmö was the constant outstanding contribution from the “Parnassos” by Carl-Bertil Laurell and his team at the Department of clinical Chemistry. CBs friend Rune Grubb in Lund had a son who qualified to CBs standard of clinical chemists. In his doctoral thesis defended in 1974 he described the technique of crossed immuno-electrophoresis in agarose gel which became a sensitive and simple analytic method to detect protein heterogeneity for many years [39]. In 1975 JW had the pleasure to recommend a paper co-authored by Olle Zetterwall describing a patient with three M-components typed as respectively IgG, IgA, and IgM. All three had kappa-type light chains, and all had the same idiotypic group in the Fab region [40]. Anders Grubb was later recruited to replace a defunct professor of clinical chemistry in Lund. Recent major scientific contributions are the cystatin C method for better assessment of glomerular filtration rate [41] and the discovery of the shrunken pore syndrome, a frequent renal abnormality [42] (Figs. 16.15 and 16.16).

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Fig. 16.15 Three M-components in the same patient. © The authors Anders Grubb and Olof Zetterval†. Figure 1 [40]

Fig. 16.16 Jan Waldenström visiting his friend Elliot Osserman at Columbia University, New York, 1963. Sydsvenska Medicinhistoriska Sällskaptet, Öppet bildarkiv

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24. Axelsson U, Hällén J. The frequency of pronounced polyclonal hypergammaglobulinaemia in a random population. Acta Med Scand Suppl. 1966;445:97–101. 25. Axelsson U. A 20-year follow-up study of 64 subjects with M-components. Act Med Scand. 1987;219:519–22. 26. Dispenzieri A, Gertz MA, Therneau TM, Kyle RA. Retrospective cohort study of 148 patients with polyclonal gammopathy. Mayo Clin Proc. 2001;76(5):476–87. 27. Zhao EJ, Carruthers MN, Li CH, Mattman A, Chen LYC. Conditions associated with polyclonal hypergammaglobulinemia in the IgG4-related disease era: a retrospective study from a hematology tertiary care center. Haematologica. 2020;105(3):e121–3. https://doi.org/10.3324/ haematol.2019.219725. 28. Seligmann M. A genetic predisposition to Waldenström’s macroglobulinemia. Acta Med Scand Suppl. 1966;445:140–6. 29. Nowell PC, Hungerford DA. Chromosome studies on normal and leukemic human leukocytes. J Natl Cancer Inst. 1960;25:85–109. 30. Mitelman F. Preferential chromosome loss in a Rous rat sarcoma in response to environmental changes. Hereditas. 1965;54(2):202–12. 31. Johansson B, Waldenström J, Hasselblom S, Mitelman F. Waldenström’s macroglobulinemia with the AML/MDS-associated t(1:3)(p36;q21). Leukemia. 1995;9:1136–8. 32. Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006;354:1362–9. 33. Kyle RA, Leung N, Muchtar E, Go RS. Monoclonal gammopathy of undetermined significance: Indications for prediagnostic testing, subsequent diagnoses, and rollow-up practice at Mayo Clinic. Mayo Clin Proc. 2020;95(5):944–54. 34. Ravindran A, Lackore KA, Glasgow AE, Drake MT, Hobbs MA, Kourelis T, Kumar S, Mouhieddine TH, Weeks LD, Ghobrial IM. Monoclonal gammopathy of undetermined significance. Blood. 2019;133(23):2484–94. 35. Tomasson MH, Ali M, De Oliveira V, Xiao Q, Jethava Y, Zhan F, Fitzsimmons AM, Bates ML. Prevention is the best treatment: the case for understanding the transition from monoclonal gammopathy of undetermined significance to myeloma. Int J Mol Sci. 2018;19(11):3621. 36. Waldenström J. Abnormal proteins in myeloma. Adv Intern Med. 1952;5:398–440. 37. Waldenström J. Three new cases of purpura hyperglobulinemica. A study in long-lasting benign increase in serum globulin. Acta Med Scand Suppl. 1952;266:931–46. 38. Leonhardt T. Familial hypergammaglobulinemia and systemic lupus erythematosus. Lancet. 1957;270(7007):1200–3. 39. Grubb AO. Crossed immunoelectrophoresis and electroimmunoassay of IgM. J Immunol. 1974;112(4):1420–5. 40. Grubb AO, Zettervall OH. Immunochemical evidence for a common variable region in three immunoglobulin classes in the same individual. Proc Natl Acad Sci U S A. 1975;72(10):4115–8. 41. Grubb A. Diagnostic value of analysis of cystatin C and protein HC in biological fluids. Clin Nephrol. 1992;38(Suppl 1):S20–7 PMID: 1284235. 42. Grubb A. Shrunken pore syndrome—a common kidney disorder with high mortality. Diagnosis, prevalence, pathophysiology and treatment options. Clin Biochem. 2020;83:12–20.

Chapter 17

Porphyria Research from Malmö

Abstract The chapter summarizes JW’s and his scholar Birgitta Haeger-Aronsen’s contribution to the field in Malmö and covers some Swedish and international developments resulting in establishing characteristics of different forms of porphyria and a long list of dangerous triggers. Some impressive new targeted therapies are presented. The chapter also contains some remarks on diabetes insipidus.

17.1 Introduction In 1957, a leading periodical at the time, the American Journal of Medicine (often referred to as the “green journal”), published a 170-page issue with a symposium titled “Inborn errors of metabolism”, a subject that had been a keen interest of JW’s since medical school when he read Sir Archibald Garrod’s book with the same title (Chap. 3). The symposium was edited by Charles Enrique Dent (1911–1976), who also authored the introductory paper [1]. Dent was professor of human metabolism at University College in London. He pioneered partition chromatography and applied it to the study of familial kidney diseases. Dent identified a number of inborn errors of metabolism including a variety of the Fanconi disease known as Dent’s disease [2]. This is a predominantly male disease characterized by hypercalcinuria, renal calcinosis, kidney stones, and rickets resulting in progressive renal damage. It is caused by a mutation of the Xlinked gene CLCN5N which encodes the chlorine channel CNC-5 in proximal tubules making the channel non-functional and causing intracellular acidosis [3] (Fig. 17.1). Dent gives a succinct overview of the principle pathogenetic mechanisms of a growing number of conditions described by that time. Citing the classical Croonian Lecture of Sir Archibald Garrod from 1908, he illustrates the consequences of a metabolic block combined with renal dysfunction for the concentration of circulating and excreted intermediate metabolites. Identification of these conditions is often straight-forward based on pronounced phenotypic abnormalities. Other famous contributors to the symposium were Alexander Bearn, JW’s friend from the Rockefeller Institute (Chap. 6), and Victor McKusick (1921–2008), a prolific investigator © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Wollheim, Jan Gösta Waldenström and His World, Springer Biographies, https://doi.org/10.1007/978-3-031-36739-7_17

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Fig. 17.1 Pathophysiology of Dent’s disease in a mouse model. © Reference 3 licensee Biomed Central permission. http://www.creativecommons.org/licenses/by/2.0

of genetic disturbances in the Department of Medicine at Johns Hopkins University. When offered to chair a new clinic for chronic diseases he accepted on the condition that he could create a division of medical genetics within the department. Groundbreaking new developments made possible with the advances in molecular biology. The division became the leading site for research on genetic diseases, attracting fellows from all over the world. The enigmatic leader became a “father of medical genetics” and his institution is still at the forefront in its field. In 1999, it was redesignated as the McKusick-Nathans Institute of Genetic Medicine and housed in the Department of Genetic Medicine.

17.2 The Porphyrin Diseases as Inborn Errors of Metabolism JW’s early contribution to the knowledge of acute intermittent porphyria, AIP, and the discovery of porphobilinogen, PBG (Chap. 3) made him an international esteemed leader in porphyria research. AIP became known as “the Swedish form of porphyria”—JW’s contribution to the symposium [4]. For some time, it appeared to be the only form of porphyria occurring in Sweden. JW began with pointing out that inborn errors of metabolism remain “true to type” within individual families. This is

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true for the cystinurias described by Dent as well as the bleeding disorders studied by Inga Marie Nilsson (Chap. 18). It also applies to families with porphyria. This observation can now be explained as a consequence of different pathogenetic mutations in individual families. Abnormality of porphyrin metabolism can be induced by exposure to lead causing symptomatic porphyria, a condition which had been known since the early 1900s and which JW liked to call “pyrroluria”. The parish of Arjeplog where AIP is endemic also had a lead mine but lead poisoning was never suspected as causing the endemic AIP (Chap. 3). In the review JW dealt only with the genetic forms of porphyria. New analytical methods such as partition chromatography and radioactive tracer techniques were mentioned in passing when JW continued to mention Roland G. Westall’s isolation of PBG in pure crystalline form in 1952 [5] and Claude Rimington’s (1902–1993) discovery in 1953 that the formula of PBG was 2-aminomethyl-4-2’-carboxymethyl-pyrrole. Remington correctly predicted that PBG participated in the biosynthesis of several different porphyrins [6]. David Rittenberg and David Shemin (Chap. 7) at Columbia University in NYC showed that porphyrins were formed by condensation of active succinate generated via the Krebs cycle and glycine formed by the succinate-glycine cycle, Fig. 17.2. Furthermore, ∂-amino-levulinic acid (ALA) was identified as a precursor in the synthesis of porphyrins [7]. ALA emerged as an important marker in the study of porphyria. Next, JW presented his tentative classification of porphyria. Congenital porphyria is the rarest form. Only 34 published cases fulfilled strict diagnostic criteria at the

Fig. 17.2 Tricarboxylic acid and succinate-glycine cycle. A pathway for the generation of porphyrin. Figure 1 from Reference 9. © https://creativecommons.org/licenses/by/4.0/

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Fig. 17.3 Swedish AIP family. X indicates individuals examined for ALA and PBG. From [4] with permission

time, 19 of which were female. The young children pass red urine containing uroporphyrin and some coproporphyrin but never porphobilinogen (PBG). Six families with affected siblings had been documented suggesting autosomal recessive inheritance. Teeth and bones were stained brown or red from porphyrin deposits. The patients suffer from extreme photosensitivity and may develop pellagra. Erythropoiesis is affected leading to anemia and splenomegaly. Porphyria cutanea tarda, PCT symptomatica, is more common and more prevalent in men older than 40 years of age. The photosensitivity is less severe, liver cirrhosis is often present, and alcoholics are overrepresented. Uroporphyrin is increased in blood and urine, but PBG is not augmented. Porphyria cutanea tarda, PCT hereditaria (protocoproporphyria), becomes symptomatic around puberty and is accompanied by excretion of large amounts of proto-, copro-, and uroporphyrin in the feces. Blisters develop in sun exposed areas of the skin. The photosensitivity occurs only when porphyrin is found in the urine, sometimes together with PBG. Such cases may be accompanied by colics. Acute intermittent porphyria, AIP, described in JW’s thesis, is endemic in northern Sweden. In South Africa a similar type of porphyria occurs in which abdominal attacks are less frequent, but these patients often exhibit cutaneous symptoms that are never observed in Swedish patients with AIP. Both forms are characterized by asymptomatic periods and attacks of acute abdominal colics with neurologic and neuropsychiatric complications. Attacks can be severe and fatal and are triggered and exacerbated by exposure to barbiturates and other drugs or surgical trauma. JW described several pedigrees of Swedish families with AIP demonstrating autosomal dominant inheritance (Fig. 17.3).

17.3 Enter Birgitta Haeger-Aronsen In the review JW acknowledges support by the Rockefeller Foundation and help from the former head of the Department of Medicine in Boden, Arthur Engel (Chap. 3), who now had become the Director General of Sweden’s health authority, from Dr.

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Gösta Neander, nurse Ragnhild Blomquist, but also by his new disciple in Malmö, Dr. Birgitta Haeger-Aronsen (1926–2008). She was born in Malmö where her father was a respected practicing pediatrician. Haeger-Aronsen graduated from medical school in 1954 and was directly recruited by JW. She started to work on porphyria and extended JW’s genealogic work with the Swedish families of AIP. Patients with AIP requiring hospitalization were often referred to Malmö, where trainees could get the false impression that AIP was a common disease. After three years of clinical work, Haeger-Aronsen was attracted to the Parnassus and its research laboratory. She spent the years 1957 to 1960 working full time on a doctoral thesis under Carl-Bertil Laurell in the Department of Clinical Chemistry which she defended in 1960. The title was “Studies on urinary excretion of ∂-amino-levulinic acid and other haem precursors in lead workers and lead-intoxicated rabbits” [10], a meticulous monograph. It starts with a general chapter on lead toxicology and then presents research on methods for the assay of ∂-amino-levulinic acid (ALA), porphobilinogen (PBG), coproporphyrin, coproporphyrogen (CP), and lead (Pb) in urine. Previously ALA had been shown to be stable at acid pH, while PBG and CP were now demonstrated stable at alkaline pH. Therefore, urine samples to be assayed had to be divided and adjusted to different pH before storage. Reference levels were established for normal ALA and PGB excretion. Increased excretion of ALA was found in both poisoned rabbits and lead workers, but PBG was excreted only by lead-poisoned rabbits. As shown in Fig. 17.4, ALA excretion varied with the type of lead exposure. Administration of chelating agents, EDTA or d-penicillamine, was followed by a rapid decline in ALA levels and an increase in lead excretion. Assay of ALA in urine was found to be a more sensitive screening test for lead intoxication than CP excretion. Elevated levels were found in some asymptomatic workers and demonstrated the need to prevent further lead exposure. This observation is still valid although more recent epidemiologic work employs measurement of blood lead levels rather than urine ALA as the screening method. Haeger-Aronsen received the title of assistant professor (docent) in 1961 and returned to the Department of Medicine for the next ten years. She emerged as Sweden’s leading international expert on porphyria. Patients suffering from AIP continued to be referred to Malmö from distant hospitals in Sweden. Residents would often care for young women who were severely symptomatic and had been errantly subjected to unnecessary surgery or exposure to barbiturates or other toxic drugs. JW’s encouraging bedside mastery helped them to recover. Depressed and miserable patients were told “I have cared for patients who were worse off than you, and regained full health”. Medical treatment still merely consisted of high fluid and caloric intake combined with pain relief with more appropriate medications including opiates and chlorpromazine. With increasing awareness, AIP mortality was diminishing in Sweden, largely a result of JW’s pioneering work in Uppsala (Table 17.1). Haeger-Aronsen embarked on a new career in 1971 when she moved to the Department of Occupational Medicine in Lund, a new specialty not yet established at MAS. She was uncertain of what JW’s upcoming retirement the following year would entail for her niche in the department. She was well qualified for a career in the new specialty through her thesis work on lead poisoning. In 1977, she returned to Malmö as the

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Fig. 17.4 ALA excretion in urine of lead exposed workers in a factory and its relation to the type of their job. © Birgitta Haeger-Aronsen Thesis and Estate

chairman and later full professor of a new Department of Occupational Medicine. She was an energetic, charming, respected, and sometimes feared investigator and performer of inspections at industries (Fig. 17.5).

17.4 Neuropsychiatry and Genetics of Porphyria In Chap. 3 we learnt that JW’s very first encounter with porphyria was an unfortunate woman who was mentally affected and committed suicide during the acute attack. The psychiatrist Lennart Wetterberg (born 1931) received his MD in Lund in 1959, specialized in psychiatry, and became an eminent scholar of AIP in Uppsala. He studied several of the families from JW’s thesis in his own thesis which he defended on December 8, 1967, in Uppsala [15]. He also examined a random sample of 1907 patients with mental disease hospitalized in northern Sweden. Among these, he found three cases of manifest AIP and 170 (!) who excreted abnormal amounts of PBG in the urine. He also examined 40 randomly selected families from a registry of all families with AIP in Sweden and found that the risk of mental disorders differed between them. The frequency of manifest AIP in Sweden in 1964 was 1/13,000, but in the two northernmost counties it was 1/1500. JW had a pleasant assignment as external

17.4 Neuropsychiatry and Genetics of Porphyria

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Table 17.1 Porphyrin presence in different forms of porphyria Type

Urine

Urine

Urine

Urine

Feces

Feces

Serum

Red cells

ALA

PBG

UP

CP

CP

PP

ALA

PP

AIP latent

(+)

++

++*

+

+

+

(+)

N

AIP manifest

++

+++

+++*

++

+

+

+

N

PP P variegata latent

N

N

N

N

+++

++

N

−

PP P variegata manifest

++

+++

+++*

++

+++

+++

+

−

PCT latent

N

N

++

(+)

+++

++

N

N

PCT manifest

(+)

N

+++

++

++

+

N

N +

P congenita

N

N

+++

+++

+++

(+)

−

P erytropoetica

N

N

N

N

(+)

(+ + )

N

+++

Lead induced

+++

N

N

++

N

N

++

+++

Sedormid ind

+

+++

++*

+

+

++

(+)

N

Hexachlor-benzene ind

++

+++

++*

+

+

+

−

N

DDTD ind

+

+++

+++*

+++

+

++

(+)

N

Legend: (+) to +++ = increased. N = normal. − No information. * = chiefly made from PBG in vitro. ALA = Delta-amino-levulinic Acid. PBG = prophobilinogen. UP = uropophyrin. CP = coproporphyriAIP = acute intermittent porphyria. P = porphyria. PP = protoporphyria. PCT = porphyria cutana tarda. The table is based mostly on the doctoral thesis by Birgitta Haeger-Aronsen

Fig. 17.5 Professor Birgitta Haeger-Aronsen in 1985. Photo Björn Henriksson. © Sydsvenska Medcinhistoriska Sällskapets Öppet Bildarkiv SMHS8866_000_01Copp.jpg. http://www.medici nhistoriskasyd.se/smhs_bilder/

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examiner at the public thesis event. Wetterberg would continue porphyria research applying molecular medicine methodology at Karolinska Hospital as professor of psychiatry 1973–1996 [16].

17.5 Diabetes Insipidus Wetterberg’s mentor in Uppsala was Hans Forssman (1912–1994) who was professor of psychiatry there before relocating to his city of origin, Gothenburg where he assumed the same function at the newly founded medical school. Forssman had defended his doctoral thesis on diabetes insipidus in 1945 and showed that this inborn error of metabolism was sometimes inherited as an X-linked recessive disease [17]. It had previously only been reported to be autosomal dominant. Forssman discovered two different X-linked recessive forms of the condition, one which could be treated with antidiuretic hormone and another which was resistant and was named nephrogenic [18]. His father Axel Forssman (1877–1942) was a respected liberal lawyer in Gothenburg and owner of a major daily newspaper, Göteborgs Handelsoch Sjöfartstidning. As mentioned in Chap. 9, its editor, Torgny Segerstedt (1876– 1945), was an upright, intrepid defender of democracy. During World War II the paper was put under pressure by the government to be less frank about the crimes of the Nazi regime. Several issues were censored by the government to appease Nazi Germany. Like JW’s father Henning, Axel Forssman had a Jewish wife. Hans Forssman shared his father’s liberal views. JW’s first wife Elisabet was a close friend of the Forssman family from early years and considered Hans almost as a brother. The friendship became extended to JW and their children. In Gothenburg Hans Forssman published a case report on a new form of diabetes insipidus in 1957. A co-author was Bengt Heister (1927–1986), a trainee from Malmö who at the time was specializing in internal medicine in Gothenburg [20]. Forssman recommended Heister for further training to his friend JW who hired him as amanuensis, anticipating that he would continue research on the pathophysiology of diabetes insipidus in Malmö. Heister started experiments exposing volunteer medical students (one of whom was the future wife of the author) to forced water intake for 24 h. The heroic experiments, long remembered by the volunteers, did not yield interpretable findings, and Heister gave up the difficult research on diabetes insipidus. He left the department in 1961 and started a respected private practice in town. Heister was a strong proponent of undivided internal medicine as a comprehensive “mother” specialty. Imaginative and talented with unusual administrative skill and energy, he served several terms on the board of the Swedish Society of Internal Medicine. He was made an honorary member of the society. After his untimely death the society created an annual prize in his name. Heister was a dedicated Free Mason and interested in heraldic symbols. He introduced the logotype of the society, featuring a maple leaf, symbolizing the different subspecialties encircled by a uniting serpent, preventing fragmentation of internal medicine. A desktop flagpole with a flag decorated with the logotype was created. Copies of the flag and pole are awarded to

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Fig. 17.6 The “pole” of the Swedish Society of Internal Medicine inspired by Bengt Heister. Photo The author

individuals providing special services to the society. Hospital departments became ranked as “one pole”, “two pole”, or “three pole” departments based on the number of honored individuals that worked there. JW was pleased and never reproached Heister for abandoning academic medicine (Fig. 17.6).

17.6 Pathogenesis of Porphyria and Its Rational Therapy In the 1960s the molecular defects underlying porphyria were still largely unknown. This changed in the following decades thanks to molecular methodology. JW was able to follow the developments of this technology and present them at a meeting in Stockholm in 1975 [21]. The results of this method to identify AIP by testing for PBG in urine have recently been supplemented by examining the frequency of the mutated AIP gene on chromosome 11. A surprise finding was that only 10% of carriers of the mutated ALA synthase gene develop manifest disease [23]. Early on, JW realized the importance of exogenous factors in triggering or worsening of attacks. The list of dangerous and safe drugs is extensive but important

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for proper management [23]. Avoiding exposure to environmental triggers is still a mainstay of AIP management. The new knowledge enabled development of biologic therapies directly influencing steps in the pathogenic pathway leading to porphyria. Cecil Watson in Minneapolis can be credited with introducing infusion of heme to critically ill patients with porphyria. This regimen was based on evidence for the feedback effect of heme on porphyrin biosynthesis. Initially four patients with AIP and congenital erythropoietic porphyria were treated with hematin or with packed erythrocytes with favorable results [24, 25]. A form of hematin called panhematin was introduced and is still used in the U.S. It is not stable in solution, however, and can cause harmful effects on coagulation and generate thrombophlebitis [26]. Another hemin arginate in the form of a Finnish product called Normosang™ was introduced in 1986 [27] and is used in Europe. Heme therapy diminishes ALA synthesis and dramatically reduces the excretion of ALA and PBG, resulting in clinical improvement of attacks. Attempts to replace the inactive PBG deaminase enzyme in AIP by gene therapy have not been successful [22]. However, in 2014, eight decades after JW’s first encounter with AIP, a breakthrough was achieved when scientists in New York, Utah, and Massachusetts reported that silencing of hepatic ALA synthase 1, ALAS1, in mouse AIP could suppress the induction of acute attacks [28]. The authors used a synthetic double-stranded siRNA which specifically targets ALAS1 mRNA in hepatocytes. The small interfering RNA, siRNA, was linked with N-acetyl-galactosamine residues. The compound specifically targets hepatocytes. Based on a successful sixmonth phase III trial, U.S. Food and Drug Administration licensing was obtained in November 2019 [29, 30]. Although not without adverse effects, the early therapeutic response was dramatic in acute hepatic porphyria, common AIP, and in less common porphyria variegata and in hereditary coproporphyria. This elegant therapeutic triumph would have excited JW. A recent review of the now more complete understanding of the different porphyria forms provides a scholarly overview of the subject. It deals with the central pathogenic and diagnostic roles of porphobilinogen but does not mention the name of our hero who discovered the compound in 1934 [22] (Table 17.2).

References

199

Table 17.2 Heme synthesis and eight enzymes involved and eight forms of porphyria resulting from identified enzymatic defects. In the liver heme is the precursor of cytochrome P-450 and in the bone marrow of hemoglobin Intermediate metabolite

Dysfunctioning enzyme

Related porphyria condition

Succinyl and glycine

ALA synthase 1

X-linked proteoporphyria

Delta-amino-levulinic acid

ALA dehydratase

ALA dehydratase deficiency porphyria

Porphobilinogen

PBG deaminase

Acute intermittent porphyria

Hydroxymethylbilane

Uroporphyrinogen synthase

Congenital erythropoetic porphyria

Uroporphyrinogen III

Uroporphyrinogen decarboxylase

Porphyria cutana tarda

Coproporphyrinogen III

Coproporphyrinogen oxidase

Hereditary coproporphyria

Protoporphyrinogen IX

Protoporphyrinogen oxidase

Variegate porphyria

Protoporphyrin IX

Ferrochelatse

Protoporphyria

Heme

Heme oxygenase

Biliverdin + Carbo monoxide + Iron Bilirubin Simplified table based mostly on data in Reference 22

References 1. Dent CE. Inborn errors of metabolism. Introduction. Am J Med. 1957;22:671–5. 2. Dent CE, Friedman M. Hypercalcuric rickets associated with renal tubular damage. Arch Dis Child. 1964;39:240–9. 3. Devuyst O, Thakker RV. Dent’s disease. Orphanet J Rare Dis. 2010;5:28. https://doi.org/10. 1186/1750-1172-5-28. 4. Waldenström J. The porphyrias as inborn errors of metabolism. Am J Med. 1957;22(5):758–73. 5. Westall RG. Isolation of porphobilinogen from the urine of a patient with acute porphyria. Nature. 1952;170(4328):614–6. 6. Cookson GH, Rimington IC. Porphobilinogen. Biochem J. 1954;57(3):476–84. 7. Neuberger A, Muir HM, Gray CH. Biosynthesis of prophyrins and congenital prophyria. Nature. 1950;165(4207):948–50. 8. Wittenberg D, Shemin D. The location in protoporphyrin of the carbon atoms derived from the alpha-carbon atom of glycine. J Biol Chem. 1950;185(1):103–16. 9. Shemin D, Russell CS, Abramsky T. The succinate-glycine cycle. I. The mechanism of pyrrole synthesis. J Biol Chem. 1955;215(2):613–26. 10. Haeger-Aronsen B. Studies on urinary excretion of 5-aminolaevulic acid and other haem precursors in lead workers and lead-intoxicated rabbits. Scand J Clin Lab Invest. 1960;12(Suppl 47):1–128. 11. Boström H, editor. Ärftliga ämnesomsättningsrubbningar: symposium den 25 April 1975. (Inborn errors of metabolism). Scandia Int Symp. 1975;10:1–175 12. Waldenström J, Haeger-Aronsen B. Different patterns of human porphyria. Br Med J. 1963;2(5352):272–6.

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13. Dean G, Barnes HD. Porphyria in Sweden and South Africa. S Afr Med J. 1959;33:246–53. 14. Barnes HD. Porphyria in South Africa: The faecal excretion of porphyrin. S Afr Med J. 1958;32:680–3. 15. Haeger-Aronsen B. Erythropoetic protoporphyria. A new type of inborn error of metabolism. Am J Med. 1963;35:450–4. 16. Wetterberg L. A neuropsychiatric and genetic investigation of acute intermittent porphyria. Svenska bokförlaget/Nordstedts, Stockholm 1967;3–88. 17. Wetterberg L. Acute intermittent porphyria. A thesis and 68 follow-up publications. Stockholm; 2016. p. 250. ISBN 978-91-980751-4-4 18. Forssman H. On hereditary diabetes insipidus. Acta Med Scand Suppl. 1945;159:6–196. 19. Forssman H. Two different mutations of the X-chromosome causing diabetes insipidus. Am J Hum Genet. 1955;7(1):21–7. 20. Ellborg A, Forssman H, Heister B. A case of the pituitary type of genetic diabetes insipidus simulating the nephrogenic type. Acta Paediatr. 1957;46(3):294–300. 21. Waldenström J. Farmakogenetik illustrerad av porhyrisjukdomarna. In: Boström H, Ljungstedt N, Waldenström J, editors. Skandia international symposis. Almqvis & Wiksell, Stockholm; 1975. p. 105–18 22. Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. N Engl J Med. 2017;377:862–72. 23. Wetterberg L. Internationell enkät om farliga och ofarliga läkemedel vid akut intermittent porfyri [International survey of safe and hazardous drugs in acute intermittent porphyria]. Lakartidningen. 1976;73(47):4090–2. 24. Granick S. The induction in vitro of the synthesis of ò-aminolevulinic acid-synthetase in chemical porphyria: a response to certain drugs, sex hormones and foreign chemicals. J Biol Chem. 1966;241:1359–75. 25. Watson CJ. Hematin and porphyria. (Editorial). N Engl J Med. 1975;293:605–7. 26. Bonkowsky HL, Tschudy DP, Collins A, Doherty J, Bossenmaier I, Cardinal R, Watson CJ. Repression of the overproduction of porphyrin precursors in acute intermittent porphyria by intravenous infusions of hematin. Proc Natl Acad Sci USA. 1971;68(11):2725–9. 27. Watson CJ, Pierach CA, Bossenmaier I, Cardinal R. Use of hematin in acute attack of the ‘inducible’ hepatic porphyrias. Adv Intern Med. 1978;23:265–86. 28. Mustajoki P, Tenhunen R, Tokola O, Gothoni G. Haem arginate in the treatment of acute hepatic porphyrias. Br Med J (Clin Res Ed). 1986;293(6546):538–9. 29. Yasuda M, Gan L, Chen B, Kadirvel S, Yu C, Phillips JD, New MI, Liebow A, Fitzgerald K, Querbes W, Desnick RJ. RNAi-mediated silencing of hepatic ALAS1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice. Proc Natl Acad Sci USA. 2014;111:7777–82. 30. Balwani M, Sardh E, Ventura P, Peiró PA, Rees DC, Stölzel U, Bissell DM, Bonkovsky HL, Windyga J, Anderson KE, Parker C, Silver SM, et al. for the ENVISION Investigators. Phase 3 trial of RNAi therapeutic givosiran for acute intermittent porphyria. N Engl J Med. 2020;382(24):2289–2301.

Chapter 18

Inga Marie Nilsson—“The Queen of Coagulation”

Abstract JW recruited Inga Marie Nilsson in 1950 promptly after her graduation as MD. This chapter is devoted to her remarkable career as investigator of bleeding disorders. She had close interaction with Erik Jorpes and Margareta and Birger Blombäck in Stockholm. She was the first physician who administered Factor VIII infusions to patients with von Willebrand’s disease and hemophilia A. She founded a worldfamous center of bleeding disorders in Malmö. Several of the 34 Ph.D. students she mentored continued to superb academic careers.

18.1 A Rising Star Getting Help from Stockholm As mentioned, Inga Marie Nilsson (1927–1999) started as fellow of JW in 1950 and was stimulated to explore coagulation defects in gammopathies. JW was aware of her potential for research and facilitated her early career. It started with her investigation of one unusual patient and culminated by her becoming a decorated world-famous professor of coagulation research. A 44-year-old woman was admitted with cutaneous bleedings and sedimentation rate of 100 mm at room temperature. A diseased sister of the patient had suffered from pleuritis, both superficial and deep dermal bleedings and anemia. The patient had arthralgia and several episodes of pleuritis and pronounced fatigue as well as hypergammaglobulinemia. Like her sister the patient had hemophilia-like bleeding manifestations and a prolonged bleeding time. An anticoagulant factor could be located to the patient’s elevated gamma globulin, and it was blocking the coagulation cascade at an early phase. A study was co-authored by Inga Marie and Anders Wenckert and published in the Boston-based journal Blood. The authors suggested that the condition was a hereditary “essential” hypergammaglobulinemia and related to purpura hyperglobulinemica although they did not document purpura hyperglobulinemica type leg pigmentation. But Jan Waldenström’s (JW’s) mentoring presence is evident [1]. During the laboratory exploration of this case JW and Inga Marie Nilsson realized the need of external advice. This was found in the Karolinska Institute where Erik Jorpes was professor of chemistry. She rented an apartment in the Solna borough of Stockholm close to the Karolinska Institute and became a regular guest in the lab of the productive professor. The insights and © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Wollheim, Jan Gösta Waldenström and His World, Springer Biographies, https://doi.org/10.1007/978-3-031-36739-7_18

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Fig. 18.1 Inga Marie Nilsson 1950s © Private archive. Courtesy Per Björkman

friendships in this stimulating environment were fundamental for her future success (Fig. 18.1).

18.2 Erik Jorpes Erik Jorpes (1895–1973) had an unusual background. He was born on Kökar, an island in the Åland archipelago, a Swedish-speaking part of Finland which was ruled by the Russian Empire from 1809 until 1917. His father was a fisherman and his mother contributed to the tight household budget by farming. While in school, a student from Åbo (Turku) working as a supplemental summer teacher noted how studious Erik was, and persuaded Jorpes’ parents to let him attend the Swedish gymnasium in Åbo, where he graduated with honors. In 1914 he started medical school in Helsingfors (Helsinki), receiving top grades. In 1917 Finland declared its independence. The Finnish Civil War started while Jorpes was still a medical student. He was recruited as a doctor on the “red” side based on his strong sympathy with the poor people in society. But the “white” side prevailed, and Erik escaped to the Soviet Union. In Moscow he co-founded the Finnish communist party. But soon he realized that the new Soviet leadership cared little to improve the living conditions for poor people in Russia. Consequently, he fled to the west in

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Fig. 18.2 William Howell who discovered heparin. Public Domain Mark. https:// wellcomecollection.org/ works/ja3ud6da

1919 via Kökar in Åland to Sweden. In Stockholm he wanted to complete his medical studies. As a foreigner he had to obtain special government permission to be accepted to medical school. This was granted when he promised the acting minister of finance Hjalmar Branting (1860–1925) at a personal interview that he would abstain from all political activities while in Sweden, a promise which he honored. Admitted to the Karolinska Institute Jorpes was now in need financial support. Fortunately, he was in possession of his academic credentials from Helsingfors. They contained the exceptional grade in physiology given by the famous professor and discoverer of renin, Robert Tigerstedt (1853–1923). The associate professor of chemistry, Einar Hammarsten (1889–1968), was a scientist of international standing and appreciated the weight of Tigerstedt’s words. Jorpes was hired and Hammarsten never regretted this recruitment. Jorpes became his leading scholar and successor as full professor when he retired in 1947 [2]. Jorpes obtained his medical doctorate in 1923. He carried out studies on the composition of nucleic acids and defended an outstanding doctoral thesis in 1928. From 1928 to 1929 he worked as recipient of a Rockefeller stipend with Phoebus Levine (1869–1940) at the Rockefeller Institute [3]. In New York he became familiar with carbohydrate chemistry. He also visited Charles Best (1899– 1978) in Toronto, learned about the preparation of insulin, and noted the ongoing work on purification of heparin (Figs. 18.2 and 18.3) .

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Fig. 18.3 Erik Jorpes who purified and made heparin a reliable prophylactic anti-coagulant. Hufvudstadsbladet, August 1, 2021, p. 25. Photographer unknown. Public Domain. https://sv.wikipedia.org/wiki/ Erik_Jorpes

After returning to Sweden, Jorpes helped the local Vitrum Company to set up production of high-quality insulin. During World War II Vitrum scaled up its insulin production and made Sweden self-sufficient. He also started independent work on characterizing heparin and could show that it was composed of uronic acid with glucosamine and esterified sulfur. Heparin’s anti-coagulant activity was linked to the amount of sulfur in the molecule. Heparin was stored in mast cells and released from these. Sune Bergström (1916–2004), the 1982 Nobel Laureate in physiology or medicine, was his fellow at the time [3, 4]. Based on Jorpes’ work heparin could be manufactured as a reliable anti-coagulant by Vitrum, and Jorpes became a wealthy man [5]. Much of the new income was used to support his research laboratory. He also was able to lend economic support to farmers in need in Åland. Making heparin into an effective tool for prevention of thrombo-embolism was of fundamental importance for the development of the heart–lung machine which was essential in modern open-heart surgery. The thoracic surgeons Clarence Crafoord (1899–1984) and Åke Senning (1915–2000) could with the help of heparin perform the first successful repair of an aortic coarctation in 1944 [5, 6]. Jorpes was a popular and effective mentor for a large number of excellent scholars. In 1950 Jorpes recruited the medical students Birger Blombäck (1926–2008) and his wife Margareta (born1926) for work on heparin assays [8, 9]. JW often mentioned Jorpes’ achievements with admiration and respect. In 1994 Åland dedicated a stamp to Jorpes [7] (Fig. 18.4).

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Fig. 18.4 Åland stamps issued in 1994, celebrating Erik Jorpes and Erik von Willebrand to commemorate their work on heparin and von Willebrand’s disease, respectively

18.3 The Doctoral Thesis of Inga Marie Nilsson The title of the thesis was “Demonstration of a heparin-like anticoagulant in normal blood”. It consists of two publications and a printed a summary in Swedish [10– 12]. The starting observation was the finding that the coagulation time of plasma is longer than that of serum, indicating the presence of a physiological factor in plasma antagonizing coagulation which is not present in serum, both when it was obtained by oxalate or citrate addition to whole blood. Complex fractionation yielded both fractions with anti-coagulant and metachromatic features and such with thrombotic activity. The extensive experiments, in part using horse blood, resulted in the conclusion that normal blood contains a clotting inhibitor with features similar to if not identical with heparin. Jorpes had been a helpful adviser throughout the work, but he regretted not being able to attend the act in Malmö. Reviewers there were the famous professor in Copenhagen Tage Astrup (1908–2006) and Sven-Erik Björkman from her own department. Both were impressed by the work, and Sven-Erik thought that the defendant had very convincing data regarding the presence of heparin in normal blood and that the title could have been “heparin” rather than “heparin-like”. Inga Marie Nilsson received the title of “docent” (assistant professor) in 1955.

18.4 Anti-hemophilic Globulin With the blessing of JW Inga Marie spent several postdoctoral months in the laboratory of Jorpes with research in the laboratory in Stockholm with “the father of heparin” as Jorpes was often called. The initial aim was to work further on isolation of heparin from normal blood, but soon the subject of hemophilia took the center stage. As her Blombäck friends later noted, “she was suddenly there with her joyful nature and Scania accent, loud at times” [13]. In Malmö Inga Marie had attained expertise regarding assays of coagulation factors, including those for the fragile “still exotic” anti-hemophilic globulin, AHG, later renamed AHF or coagulation factor

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Fig. 18.5 Margareta and Birger Blombäck with the first sterile 1-0 fraction vial in 1955. © Photo courtesy Ulla Hedner. Photographer unknown

VIII, FVIII. It had been known for some years that the Cohn fraction I contained AHF, but due to its instability it was not used for treatment of hemophilia. Blood transfusion was still the only available therapy for hemophilia. It was a happy surprise when Inga Marie’s assays showed that a new fraction named I-0 contained the bulk of still intact AHF [14]. The reconstituted fraction I-0 contained 20 to 50 times more AHF per gram of protein than normal plasma. Conventional sterile filtration however inactivated AHF. Therefore, a seamless closed sterile system had to be employed in order to allow its use in patients. It was obvious to the young investigators that fraction I-0 could be of potential use in hemophilia. Animal tests in rabbits and mice had showed that it was well tolerated and free of pyrogens. But was it effective and safe if administered to human patients? Preparation of a full dose of fraction I-0 required 1000 to 1400 ml fresh plasma and the product had to be preserved as a dry frozen powder in the cold. Important details of the preparation of pure fibrinogen and AHF were published in Birger and Margareta Blombäck’s individual Ph.D. thesis publications in 1958 [15, 16]. They represented a breakthrough achievement at the bench, performed by a creative young married couple working in an inspiring environment. The stage was set to test FVIII in hemophilia patients (Fig. 18.5).

18.5 Early Use of Cohn Fraction I-0 (AHF) in Von Willebrand’s Disease With new knowledge Inga Marie returned to Malmö and established her state-of-theart coagulation laboratory in the basement of the main building of the Department of Medicine. Her salary and research budget were provided by the Swedish Medical Research Council, enabling her to pursue full-time clinical and laboratory research. Word got around that an enthusiastic expert on bleeding disorders was working in Malmö, and referral of patients from other hospitals commenced. Very soon Inga

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Marie and Margareta Blombäck functioned as the responsible physicians for patients in the country with hemophilia. Inga Marie devoted much empathic care and time with her patients at her clinic and when cared for in internal medicine, pediatric, and orthopedic wards, both weekdays and holidays, regardless of the hour of day. In May of 1956, Birgitta, a 17-year-old woman, was referred from Örebro, a town in the middle of Sweden, with life-threatening menstrual bleeding. Since birth Birgitta had been afflicted with a hemophilia-like bleeding disorder causing bruises, gingival bleeding and joint bleedings, although she was spared from permanent joint deformities which were crippling hemophilia boys. After menarche her condition worsened. Profuse menstrual bleedings became life-threatening and required frequent hospitalizations. She had received 82 blood transfusions in the preceding year. Severe allergic reactions made further transfusions dangerous. The patient’s AHF activity was only 2% of normal. Hemophilia patients have a normal bleeding time, but Birgitta’s exceeded 60 min. Her mother had a similar hemophilia-like history but was in stable condition after a hysterectomy at age 38. Mother and daughter were members of a family with von Willebrand’s disease, a familial bleeding disorder. This condition was first described in 1926 and named pseudo-hemophilia by the Finnish professor Erik von Willebrand (1870–1949) in Åbo. His index patient came from the island Sottunga in the Åland archipelago [17, 18]. The condition is now recognized as von Willebrand disease, VWD. Including all subsets, it is the most common inherited bleeding disorder with a total prevalence of up to 1%. But the severe subset which affected Birgitta has a prevalence of only between three and six cases per million [19]. Birgitta’s precarious medical condition prompted Inga Marie to contact the Blombäcks in Stockholm who immediately started the processing of fraction I-0, using only plasma from donors with the ABO blood group identical to Birgitta’s. JW happened to be in Stockholm when the material was ready and served as the personal courier carrying the precious specimen on the evening flight to Bulltofta Airport in Malmö. Early the next morning, fraction I-O was given intravenously to the patient. Inga Marie was very tense, but the infusion was uneventful. The historic date was the May 11, 1956. The menstrual bleeding stopped, the bleeding time became normal, and the plasma level of AHF/FVIII was restored to nearly 60% of normal. A phone call informed the collaborators in Stockholm, and soon they could celebrate the therapeutic success in champagne [13]. In Malmö it was decided that a hysterectomy would be the preferred therapeutic option. In Stockholm work again started “day and night” [13] in order to produce enough fraction I-0 for protection at the surgery. An uneventful hysterectomy was performed on May 16 (Fig. 18.6). Ten days later an alert medical student, Jan Erik Niléhn, was sitting for the important oral examination in internal medicine with the professor in his flat on Tessins väg (Chap. 11). During his senior clerkship in the department, the assiduous student had trained in the ward where Sven-Erik Björkman was attending. The accomplished teacher had a special interest in blood coagulation, and the student was well prepared, not least regarding details of coagulation factors. Impressed by the student’s knowledge in a complicated field of medicine, he was awarded an extra high mark. Jan Erik

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Fig. 18.6 First patient ever to be treated with Cohn fraction I-0 in Malmö on May 11, 1956. © Per Björkman, private archive [21]

Niléhn was soon recruited as a house officer and sometimes served as a messenger, picking up new shipments of fraction I-0 at Bulltofta Airport [20]. Within a year eight additional patients with the same diagnosis and severe bleeding problems were treated both in Stockholm and Malmö. It was found that Cohn fraction I, although without active AHF normalized the bleeding time and prevented capillary bleeding symptoms in von Willebrand patients. The pedigrees of the familial disease indicated an autosomal dominant inheritance with varying penetrance and severity. Although the Swedish patients had features similar to the original patients described by von Willebrand, the authors still suspected the condition in Sweden to be a distinct entity [21]. To clarify if this was the case, Jorpes organized an expedition with Inga Marie and Margareta Blombäck in June 1957 portrayed as “quite dramatic and with a whole laboratory of equipment” [13]. In Mariehamn, the capital of Åland, they examined 15 local patients including some from the original report of von Willebrand. It turned out that these patients also had reduced AHF levels. Fraction I-0 administered to one of the patients normalized both bleeding time and AHF, confirming that Birgitta and the other Swedish patients actually had VWD [22] (Fig. 18.7). It was now clear that fraction 1-0 contained another component besides fibrinogen and AHF, named the von Willebrand factor, VWF [24]. Extensive research has revealed that VWF acts as a carrier protein for FVIII. It also attracts platelets to sites of vascular injury, resulting in structural changes through interaction with a proteinase, ADAMTS-13 [25]. Current knowledge regarding VWD expression and severity was comprehensively summarized in 2015 at an expert meeting in Mariehamn [23]. In her very last publication Inga Marie Nilsson compares her mentor JW with Erik von Willebrand: “I regard von Willebrand as an eminent scientist and he had some of the properties that I saw in my boss—the late professor Jan Waldenström. He was intelligent and observant, with good knowledge of what was happening at

18.6 Hemophilia in Sweden

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Fig. 18.7 Map of Åland. Erik Jorpes was born on Kökar. Erik von Willebrand’s first patient lived on Föglö. The founding father of the disease was traced to Sottunga. Mariehamn is the capital of Åland, an archipelago in the Baltic Sea between Sweden and Finland. https://en.wikipedia.org/ wiki/%C3%85land#/media/File:Topographic_map_of_%C3%85land.CCBY-SA4.0svg

the research front, he had intuition, imagination, and the talent to form associations. I also feel that he was quite courageous, which is necessary for a researcher putting forward something new” [26].

18.6 Hemophilia in Sweden Encouraged by the success with the first patient in May of 1956, Inga Marie treated the first boy with severe hemophilia A within weeks. This patient was an 11-year-old boy admitted with a painful hematoma in the region of the right heel. The ongoing bleeding ceased when the patient’s serum AHF level was restored to 50% of normal. Five months later the boy was readmitted with a large new hematoma which could be uneventfully evacuated under protection with new infusions with AHF. In Stockholm, Margareta Blombäck also started treatments. In 1958 Inga Marie and Margareta published good results in 12 patients with severe hemophilia A. Surgical procedures and tooth extractions could be performed safely, and acute bleeding episodes were stopped. Three of the patients were also given monthly preventive infusions with

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Fig. 18.8 The 11-year-old boy who was the first patient with severe hemophilia A to receive fraction I-0 in June of 1956. Contracture of elbows, hips, knees, and deformed ankles is due to chronic recurrent hemarthrosis. Photographer unknown. Courtesy Per Björkman, private archive

lower AHF doses. The results were encouraging but not perfect. The study was summarized with the statement: “By increasing the AHG level to 40–80% of normal and by maintaining it at 20–30% of normal the necessary surgical operations could be performed and the healing completed without abnormal bleeding” [27]. No adverse reactions were observed, but the short half-life of AHF was a problem. The halflife was further shortened in connection with inflammation, e.g., surgery, ongoing bleeding, and infection (Fig. 18.8). News of the favorable results spread. Physicians from all over Sweden contacted Inga Marie and the Blombäcks. The demand for AHF very soon far exceeded the production capacity of the department of professor Jorpes which amounted to 15 batches monthly and used plasma from 120 donors [28]. The Federation of the Swedish County Councils (Landstingsförbundet) agreed to purchase the preparation, which further increased demand. When the Karolinska Institute celebrated its 150th anniversary in 1960, a new research building was added to the department of chemistry and there the fractionation capacity could be scaled up [28]. But the demand for AHF increased further, and in 1966 the production was commercialized by KABI (Fig. 18.9). Comprehensive investigation of patients with hemophilia in Sweden began in 1940 when Dr. Erik Sköld, a disciple of Jorpes, then head of the transfusion unit at St. Erik’s City Hospital in Stockholm, asked colleagues at transfusion units in the country to inform him of their patients with hemophilia. Life expectancy of patients with severe hemophilia A at that time was 16.5 years. In 1957 it was still only 23.2 years, approximately one-third of that in the general population. A majority of patients became more or less disabled and unable to earn their livelihood. In 1957

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Fig. 18.9 Fractionation unit in the Department of Chemistry at the Karolinska [26]. © Sydsvenska medicinhistoriska Sällskapet with permission

it was still discussed whether carriers should be discouraged from childbearing. But in his monograph that year on Hemorrhagic Diseases, Armand James Quick (1894– 1978) commented on this issue as follows: “Had Queen Victoria known that she was a carrier and had foregone marriage, England would not have its beloved royal family and their gracious Queen Elisabeth II (1926–2022). Furthermore, over 85 normal and 10 hemophilic descendants would not have been born” [29]. In 1957 it was still not possible to determine whether a woman in a hemophilia family was a carrier or not. The improved accuracy of AHF assays in the hands of Inga Marie however enabled physicians to provide anxious potential mothers with appropriate counseling regarding the disorder and its management [30]. By 1962 Inga Marie and her co-workers had accumulated experience from administering AHG 818 times to 63 patients with hemophilia A. Of these, 26 had been Inga Marie’s patients in Malmö, 21 had been treated in Stockholm, 12 at their local hospitals elsewhere in Sweden, and 4 in other countries. AHF levels had been assayed before and after the infusions only in Malmö and Stockholm. Inga Marie’s first patient had received 86 half and 20 full doses. He was one of the patients selected for preventive monthly infusions. The detailed tables, figures, case histories, and concluding narrative evidenced dramatic beneficial effects. Both major and minor surgery could be performed safely, and painful joint bleedings cleared faster. New permanent joint damage was prevented in the patients that had received prophylactic infusions. The only adverse reactions were two cases of infectious hepatitis, one of which may have been caused by previous blood transfusions [31]. JW must have been proud, enjoying the impressive independent achievements of his young disciple. He would only once co-author a paper from her group on hemophilia. This concerned the unusual case of a 16-month-old girl referred to Malmö in 1959 with severe recurrent bleedings. Her mother was a proven carrier of severe hemophilia A, and the girl had a brother who had died from bleedings soon after birth. The patient had suffered from bruises and large hematomas requiring blood transfusion since birth. The coagulation time was prolonged, and AHF was

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Fig. 18.10 Chromosome map of the “female” patient with hemophilia [32]. © The Lancet with permission

0.1% of normal. This was corrected in vitro by addition of normal plasma or plasma from patients with hemophilia B, but not from a patient with hemophilia A. All tests confirmed a diagnosis of severe hemophilia A. JW became interested and suggested contact with genetic expertise in Lund. It was found that the girl had male chromatin staining pattern of neutrophils and a male chromosome map showing a normal number of 46 chromosomes with one X chromosome and one Y chromosome [32]. This case was much discussed in the corridors among the junior doctors. Was the baby a boy or a girl? Today one can conclude that it probably was a case of androgen insensitivity syndrome, AIS, which is most often caused by a mutation of the androgen receptor gene on the X chromosome [33]. The gonads of such “boys” remain intraabdominal, and their phenotype is female (Fig. 18.10).

18.7 Professor of Coagulation Research In the 1960s the expanding activities in the over-crowded basement laboratory came to an end. After refurbishment of the main building in 1966 Inga Marie and her laboratory moved from the basement to more spacious quarters on the top floor, and when the Department of Blood Transfusion moved to a new building Inga Marie took over the premises, creating space for both the outpatient clinic and the laboratories in

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Fig. 18.11 Malmö General Hospital in 1956. 1. Pathology and Bacteriology under construction; 2. Infectious Diseases; 3. Gynecology and Obstetrics; 4. Internal Medicine; 5. Orthopedics; 6. Radiology; 7. Surgery; 8. The adjacent park Pildamsparken; 9. Clinical Chemistry; 10. Pharmacy and Transfusion Medicine and from 1966 Coagulation Center; and 11. Chronic Diseases. © Sydsvenska Medicinhistoriska Sällskapet Öppet bildarkiv. Foto 1950s AB Flygtrafik, Dals Långed. BE200616-001FlygfotoMAS1956Cpg.jpg

the 1954 wing adjacent to the Laboratory of Clinical Chemistry. In 1965 Inga Marie was given a personal chair of coagulation research (Fig. 18.11). The population of identified hemophiliacs in Sweden increased with improved screening and management. As mentioned, in 1942, life expectancy was 16.5 years. Patients could die even after minor procedures such as tooth extraction. Olof Ramgren (1911–1990), a scholar of Erik Jorpes at the Blood Bank in Stockholm, took up work in the field in 1960. By then, the number of diagnosed patients in Sweden was 253 coming from 180 families [34]. In 1990 the numbers had risen to 412 families and 666 living hemophiliacs. Life expectancy was now 60 years [24], and quality of life of patients with bleeding disorders had improved dramatically in the subsequent decades. A notable finding was that 40% of the patients were born in families without previous cases, indicating that they were caused by new mutations. The overall prevalence in Sweden was 16/100,000 men, similar to that in other countries [35]. About 20% of the cases had hemophilia B, Christmas disease, described in 1952 [36]. In 2013 the number of patients with hemophilia in the Swedish registry had risen to 1431 [37] (Fig. 18.12). Ulla Hedner (born 1939) followed the advised by her father Erik Flodmark, the director of the hospital’s Pharmacy to spend her first summer vacations in medical

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Fig. 18.12 Life expectancy 1831–1990 for Swedish men, compared to Swedish patients with mild, moderate, and severe (svår) hemophilia [24]. © Sydsvenska Medicinhistoriska Sällskapet

school as an unpaid apprentice technician in Inga Marie Nilsson’s basement laboratory. There she was instructed to work on diagnostic methodology. She was so appealed by the warm atmosphere in the laboratory, the devotion of the leader, and the presence of all the young patients. In 1972 she could start as resident in the coagulation unit. Hedner defended her Ph.D. thesis in 1974 and became associated professor and deputy chief until 1983. She was the first of 34 Ph.D. students mentored by Inga Marie (Fig. 18.13). In 1994 Inga Marie could look back at four decades of outstanding work, making Malmö an “International Hemophilia Treatment and Training Center” [38]. Prophylactic therapy with AHF was pioneered in Sweden from the late 1950s. Initially it aimed to lessen disease severity but not fully control it, thereby preventing new occurrence of spontaneous joint bleedings and irreversible joint damage. When the

Fig. 18.13 Erik Flodmark with Inga Marie Nilsson and Erik’s daughter Ulla Hedner at the inauguration ceremony after her “Berömlig” (Laudable) Ph.D. thesis in May of 1974 © Ulla Hedner’s private archive

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drug company KABI had taken over the production of AHF dosing could be more generous, allowing patients with severe hemophilia to live normal lives in professions of their choice and participate in sport activities [24]. However the risk of acquiring hepatitis could not be entirely eliminated since the hepatitis C virus was not identified until 1965, why no donor screening was possible. A major disaster hit the program with the outbreak acquired HIV infection. In the early 1980s KABI used donor blood from the US, which contaminated some batches of their AHF. Since each batch contained blood product from 10,000 donors, contamination from a single donor could spread HIV to a large number of recipients. No Swedish patient with hemophilia A was infected by the Swedish AHF product. Sadly however, 100 hemophiliacs came down with AIDS in Sweden [19, 24]. They had been treated with AHF produced in USA. Another problem was the development of inhibiting antibodies. This occurs in 30% of hemophilia A and 6% of patients with hemophilia B. They became resistant to the administered coagulation factors. Inga Marie saw that this only occurred in certain families, an example of the “true to type” principle embraced by her master JW. It shows how detailed knowledge of each individual patient, and their background generates meaningful information and suggested the involvement of a genetic component. This was amply confirmed years later in the age of molecular genetics and identification of mutations which influenced susceptibility for immunization [39]. Attempts to overcome resistance were use of large overdoses of AHF. With her co-worker Ulla Hedner it was found that some efficacy could be restored by combining infusion of high doses of AHF or factor IX with cyclophosphamide [40]. A surprising observation was made in a patient with hemophilia B with antibodies against factor IX. The patient needed a tooth extraction. Treatment with factor IX and cyclophosphamide caused an unexpected normalization of the bleeding time and lowered antibody titer [41] But there was still urgent need for improvement (Fig. 18.14). Fig. 18.14 A 16-year-old man with severe hemophilia A on prophylactic AHF since age 2 [24]. © Sydsvenska Medicinhistoriska Sällskapet. Photographer unknown

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In 1985 Erik Berntorp was recruited, and with Inga Marie and the expert hematologist Olle Zettervall a new protocol was developed. This combined administration of a high dose of intravenous IgG, cyclophosphamide, and high doses of factor IX was able to induce tolerance in four cases of hemophilia B. JW, as a member of the National Academy of Science, was pleased to recommend the paper by his academic children and a grandchild to be published in PNAS, the Proceedings of the National Academy of Sciences of the U.S.A [42]. The same protocol with AHF was proved to be effective in hemophilia A patient with inhibitor [43]. When especially high levels of anti-AHF were present, apheresis and passage of the patient’s plasma through sepharose columns loaded with staphylococcal protein A were added to the management protocols [44]. The expensive columns provided by Pharmacia retained all IgG including the anti-AHF antibodies and restored sufficient therapeutic efficacy to allow major surgery. Figure 18.14 shows details in the therapy of a patient with hemophilia B treated according to “The Malmö method”. The protocol was soon adopted by other centers. Formation of immune complexes between the administered coagulation factor and IgG were probably contributing the treatment success although the complete understanding is still lacking [45] (Fig. 18.15).

Fig. 18.15 Case of hemophilia B treated with “The Malmö method” [43]. © The authors with permission by the surviving author Erik Berntorp

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18.8 Factor VIII Bypass with Activated Factor VII Antibody induction however remains as a serious complication even in the 2020s. Different protocols have been developed, and some are still under investigation [46] One of Inga Marie’s early scholars, her depute as associate professor between 1979 and 1983, was reluctantly given leave of absence to work on fibrinolysis as guest investigator in Seattle in the laboratory of the super expert Earl Davie (1927–2020). Inge Marie’s condition was “Only if you can recruit someone to replace you”. In Seattle Hedner happened to share office with Walter Kisiel (1942–2013) who was working on purification of coagulation factors. Dr. Hedner confronted him with her brainchild that factor VII, a contaminant of factor IX preparations used to treat hemophilia B [41], could be of possible therapeutic use in patients with factor VIII resistance. Although then working on factor V he became interested of collaborating. Back in Sweden Ulla Hedner obtained a grant from the Swedish Research Counsel, and he could spent a year in the coagulation laboratory in Malmö. Here he participated in the development of the extracorporeal absorption of antibodies included in the “Malmö method” [47]. With Ulla Hedner he managed to produce a purified factor VII preparation which allowed a proof-of-concept testing of Ulla Hedner’s bypass hypothesis. It turned out as a dramatic success, much like that with fraction I-0 by her mentor in 1956. Factor VII protection was used to stop bleeding episodes and facilitate tooth extraction in two boys with pronounced Factor VIII resistance in 1981. After rejection by the journal Blood a paper was later published by JCI [48]. Unfortunately, Professor Nilsson’s attitude toward her deputy had become strained, and Ulla Hedner’s situation in Malmö became uncomfortable. She was recruited to develop a coagulation laboratory focusing on development of low molecular heparin by Novo Nordic in Copenhagen in 1983. There she managed to convince the management to support the high-risk expensive development of recombinant factor VII. The decision was based on success in only two patients in Sweden and on confidence in their new Swedish employee. This eventually resulted in the successful licensing of NovoSeven® in 1996 in Europe and 1999 in the USA. Dr. Hedner has given a complete account of an impressive 30-year story of the development of NovoSeven® [49, 50].

18.9 A Royal Bleeding Condition On August 18, 1973, King Gustav VI Adolf of Sweden at age almost 91 fell ill with persistent gastric bleeding while staying at his summer castle Sofiero outside Helsingborg. He underwent surgery for gastric ulcer on August 21 at the local hospital closely attended by Professor Gunnar Biörck, the Royal Personal Physician (Chaps. 8, 11, 13, and 14). He consulted Inga Marie who had described conditions with local fibrinolysis. She confirmed the presence of activated fibrinolysis in the King’s gastric mucosa [51]. Despite heroic anti-fibrinolytic therapy, the condition did not improve,

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Fig. 18.16 Rhododendron in the garden of Sofiero Castle, introduced to the site by Crown Princess Margret (1888–1920) and enlarged by her husband the future King Gustaf VI Adolf (1882–1973) after her untimely death. The King was a dedicated gardener and botanist. © Jsdo 1980—Eget arbete, public domain. https://commons.wikimedia.org/w/index.php?curid=2304788

and the popular monarch died on September 15, 1973. The King was almost 91 years old (Fig. 18.16).

18.10 The Legacy Thirty-four Ph.D. students were supervised by Inga Marie. Several came from the department of JW, others from pediatrics, gynecology, surgery, and orthopedics. Many continued an academic career as prominent investigators. Lars Holmberg became chairman and professor of pediatrics in Lund and Birger Åstedt (1931– 1998) of gynecology and obstetrics, also in Lund. Several other scholars pursued similar carriers in medical and surgical departments. For years Inga Marie’s Ph.D. students were supposed to thank their mentor with a charm for her bracelet in the shape of a miniature golden doctor’s hat engraved with their initials and the date of the defense. She was very attached to this bracelet with its growing number of charms. Unfortunately, when she had received 14 charms and was in Florida for a meeting the motel room she was sleeping in was burglarized during the night. When she woke up the bracelet was gone. Fortunately, no violence occurred, and she could mentor twenty more Ph.D. students in Malmö.

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Fig. 18.17 Inga Marie Nilsson surrounded by her group in 1989. Standing from left: Stefan Lethagen, Erik Berntorp, Inga Marie, Gun Wikstrand (social worker). Front row: Ulla Wikström (nurse), Margareta Carlsson (technician), Claes Pettersson (orthopedic surgeon), and Erik Waldenström (JWs younger son). Sydsvenska Medicinhistoriska Sällskapet Öppet Bildarkiv. Photo by Björn Henriksson. SMHS6796_000_ 01Copp.jpg

Inga Marie formally retired in 1989. During all her years as leader of the worldclass coagulation unit, clinical care, and research had been closely integrated as a section in the Department of Medicine, continuing ideal conditions for translational medicine. In 1990 the services were officially reorganized as International Coagulation Center. The clinical service became part of the Division of Hematology in the Department of Medicine with Erik Berntorp as head. The laboratory became a division in the Department of Clinical Chemistry, and its chief was Björn Dahlbäck. Inga Marie is said to have been reluctant to vacate her office in discussing the matter with her technicians asked them: “Where shall we accommodate the new professor?” But she could not have passed on her world-class unit into better hands. Importantly, the branches remained tightly integrated initially in shared premises by the two new professors. This fostered mutually fertilizing and close intellectual contacts. Productive decades on highest international level continued as highlighted in a commissioned review for the Finnish Medical Society in 2020 [52]. In 1983 Inga Marie was the recipient of the prestigious Main Nordic Jahre Prize, two decades after her mentor. The “Queen of Coagulation” died from cancer of the colon in 1999. In 2012, one of the main streets on the hospital grounds in Malmö was named Inga Marie Nilssons Gata (Inga Marie Nilsson’s Street) (Fig. 18.17).

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References 1. Nilsson IM, Wenckert A. Hyperglobulinemia as the cause of hemophilia-like disease. Blood. 1953;8(12):1067–77. 2. Mutt V, Blombäck M. Erik Jorpes—a pragmatic physiological chemist. In: Semenza G, Jaenecke R, editors. Selected topics of biochemistry: personal recollections VI. Comprenehnsive biochemistry Vol. 41. Elsevier Science B.V; 2000. p. 363–89. 3. Levene PA, Jorpes E. A method of separation of ribopolynucleotides from thymonucleic acid and on conditions for a quantitative separation of the purine bases from the ribopolynucleotides. J Biol Chem. 1930;86:389–401. 4. Jorpes E, Bergström S. On the relationship between the sulphur content and the anticoagulant activity of heparin preparations. Biochem J. 1939;33(1):47–52. 5. Crafoord C, Jorpes E. Heparin as a prophylactic against thrombosis. JAMA. 1941;116:2831–5. 6. Jorpes JE. The origin and the physiology of heparin; the specific therapy in thrombosis. Ann Intern Med. 1947;27:361–70. 7. Shampo MA, Kyle RA. J Erik Jorpes—Pioneer in the identification and clinical 54) application of heparin. Mayo Clin Proc. 1997;72:1056. 8. Blombäck B, Blombäck M, Corneliusson EV, Jorpes JE. On the reliability of the methods used in the assay of heparin. J Pharm Pharmacol. 1953;5(12):1031–40. 9. Jorpes JE, Blombäck M, Blombäck B. An in vivo method for the assay of heparin. J Pharm Pharmacol. 1954;6:694–701. 10. Nilsson IM, Wenckert A. Demonstration of a heparin-like anticoagulant in normal blood I. Human blood. Acta Med Scand Suppl. 1954;297:1–146. 11. Nilsson IM. Demonstration of a heparin-like anticoagulant in normal blood II. Horse blood. Acta Med Scand Suppl. 1954;298:1–16. 12. Nilsson IM. Demonstration of a heparin-like anticoagulant in normal blood. Lund, Berglingska Boktryckeriet; 1954. p. 1–14 (Swedish summary of reference 13). 13. Blombäck B, Blombäck M. Recollections of times past: remembering Inga Margareta Nilsson in Stockholm in the 50s. Thromb Res. 2000;98:231–2. 14. Blombäck B, Blombäck M. Purification of human and bovine fibrinogen. Arikv kemi. 1956;10(29):415–43 15. Blombäck B. Studies on fibrinogen: its purification and conversion into fibrin. Acta Physiol Scand Suppl. 1958;43(148):1–51. 16. Blombäck M. Studies on antihemophilic globulin. Acta Paediatr Suppl. 1958;47(Suppl 114):1– 32. 17. von Willebrand EA. Hereditär pseudohemofili. Fin Läkaresällsk Handl. 1926;68:7–112. 18. von Willebrand EA. Über hereditäre Pseudohaemophile. Acta Med Scand. 1931;76:521–50. 19. Berntorp E. Personal communication 2020 20. Niléhn JE. Personal communication 2020 21. Nilsson IM, Blombäck M, von Francken I. On an inherited autosomal hemorrhagic diathesis with antihemophilic globulin (AHG) deficiency and prolonged bleeding time. Acta Med Scand. 1957;159(1):35–57. 22. Nilsson IM, Blombäck M, Jorpes E, Blombäck B, Johansson SA. Von Willebrand’s disease and its correction with human plasma fraction 1–0. Acta Med Scand. 1957;159(3):179–88. 23. Berntorp E, Peake I, Budde U, et al. von Willebrand’s disease: a report from a meeting in the Åland islands. Haemophilia. 2012;18:1–13. 24. Nilsson IM. Blödarsjuka—förr och nu. (Hemophilia then and now). Sydsvenska Medicinshistoriska Föreningens årsbok. 1994;33–52. 25. South K, Lane DA. ADAMTS-13 and von Willebrand factor: a dynamic duo. J Thromb Haemost. 2018;16(1):6–18. 26. Nilsson IM. Commentary to Erik von Willebrand’s original paper from 1926 “Hereditär pseudohemofili”. Haemophilia. 1999;5:220–1. 27. Blombäck M, Nilsson IM. Treatment of hemophilia A with human antihemophilic globulin. Acta Med Scand. 1958;161:301–21.

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28. Jorpes JE, Blombäck B, Blombäck M, Magnusson S. A pilot plant for the preparation of a human plasma fraction containing the human antithaemophilic factor A (factor VII) and v. Willebrand’s factor. Acta Med Scand. 1962;171(suppl 379):7–21. 29. Quick JA. The haemorrhagic diseases. Lea & Febiger; 1957. p. 159. 30. Nilsson IM, Blombäck KM, Thilen A, Francken IV. Carriers of hemophilia A: a laboratory study. Acta Med Scand. 1959;165:357–70. 31. Nilsson IM, Blombäck M, Ramgren NO. Haemophilia in Sweden. VI. Treatment of haemophilia A with the human antihaemophilic factor preparation (fraction I--0). Acta Med Scand Suppl. 1962;379:61–110. 32. Nilsson IM, Bergman S, Reitalu J, Waldenström J. Haemophilia A in a “girl” with male sexchromatin pattern. Lancet. 1995;2(7097):264–6. 33. Mitelman F. Personal communication 2020 34. Jorpes E, Ramgren O. The haemophilia situation in Sweden. Acta Med Scand Suppl. 1962;379:23–33. 35. Larsson S. Life expectancy of hemophiliacs in Sweden 1830–1980. Brit J Haemtol. 1985;59:593–602. 36. Biggs R, Douglas AS, Macfarlane RG, Dacie JV, Pitney WR, Merskey E. Christmas disease: a condition previously mistaken for haemophilia. Br Med J. 1952;2(4799):1378–82. 37. Lövdahl S, Henriksson KM, Baghaei F, Holmström M, Nilsson JÅ, Berntorp E, Astermark J. Incidence, mortality rates and causes of deaths in haemophilia patients in Sweden. Haemophilia. 2013;19(3):362–9. 38. Astermark J, Berntorp E, White GC, Kroner BL, Group MS. The Malmo International Brother Study (MIBS): further support for genetic predisposition to inhibitor development in hemophilia patients. Haemophilia. 2001;7(3):267–72. 39. Astermark J, Donfield SM, Gomperts ED, Schwarz J, Menius ED, Pavlova A, Oldenburg J, Kessing B, DiMichele DM, Shapiro AD, Winkler CA, Berntorp E on behalf of the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort.The polygenic nature of inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort. Blood. 2013;121(8):1446–54. 40. Nilsson IM, Hedner U, Björlin G. Suppression of factor IX antibody in hemophilia B by factor IX and cyclophosphamide. Ann Intern Med. 1973;78(1):91–5. 41. Nilsson IM, Hedner U. Immunosuppressive treatment in haemophiliacs with inhibitors to factor VIII and factor IX. Scand J Haematol. 1976;16(5):369–82. 42. Nilsson IM, Berntorp E, Zettervall O. Induction of split tolerance and clinical cure in high-responding hemophiliacs with factor IX antibodies. Proc Natl Acad Sci U S A. 1986;83(23):9169–73. 43. Nilsson IM, Berntorp E, Zettervall O. Induction of immune tolerance in patients with hemophilia and antibodies to factor VIII by combined treatment with intravenous IgG, cyclophosphamide, and factor VIII. N Engl J Med. 1988;318(15):947–50. 44. Nilsson IM, Berntorp E, Zettervall O, Dahlbäck B. Noncoagulation inhibitory factor VIII antibodies after induction of tolerance to factor VIII in hemophilia A patients. Blood. 1990;75(2):378–83. 45. Astermark J. Symposium in memory of professor Inga Marie Nilsson. Haaemophilia. 2001;7:401–10. 46. Brackmann HH, White GC 2nd, Berntorp E, Andersen T, Escuriola-Ettingshausen C. Immune tolerance induction: what have we learned over time? Haemophilia. 2018;24(Suppl 3):3–14. 47. Theodorsson B, Hedner U, Nilsson IM, Kisiel W. A technique for special removal of Factor IX alloantibodies from human plasma: partial characterization of the alloantibodies. Blood. 1983;61:973–81. 48. Hedner U, Kisiel W. Use of human factor VIIa in the treatment of two hemophilia A patients with high-titer inhibitors. J Clin Invest. 1983;71(6):1836–41. 49. Hedner U. Recombinant activated factor VII: 30 years of research and innovation. Blood Rev. 2015;29(Suppl 1):S4-8.

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50. Hedner UKE. Treating life-threatening bleedings. Development of Factor VIIa. Academic Press; 2017. p. 1–199. 51. Nilsson IM, Bergentz SE, Wiklander O, Hedner U. Erosive hemorrhagic gastroduodenitis with fibrinolysis and low factor XIII. Ann Surg. 1975;182(6):677–82. 52. Berntorp E, Dahlbäck B. Personliga historiska reflektioner över koagulationsenheten i Malmö. Finska Läkarsällskapets Handlingar. 2020;180:10–1.

Chapter 19

Carl-Bertil Laurell and His Outstanding Laboratory of Clinical Chemistry

Abstract The chapter covers Carl-Bertil Laurell’s (CB’s) achievements starting in Uppsala with a paper on the location of vitamin B1 in wheat grains, continuing in Lund where he defended a thesis describing total iron binding capacity, TIBC. He also discovered transferrin and ceruloplasmin. Working in Malmö from 1954 he created Sweden’s leading laboratory of Clinical Chemistry. His interaction with JW started immediately. Three of his first five PhD students were trainees from JW’s department. Paper electrophoresis became an early signal method perfected by CB. The discovery of alpha-1-antitrypsin deficiency was another milestone discovery made by CB in 1962. Sten Eriksson and Eriksson’s student Chister Larsson discovered intracellular retention of defect alpha-1-antitrypsin as background for the deficiency in 1975.

19.1 Introduction Carl-Bertil Laurell (1919–2001), CB, was briefly introduced in Chap. 8 when he had JW as opponent in his doctoral dissertation on iron transport. CB and JW were both exceptionally brilliant in their different roles and both children of medical professors, but their personalities were very different. CB was the dedicated “bench side” companion for JW, the virtuous “bedside” physician. At the end of his life CB summarized the essence of his contributions, experiences, and advice to juniors in two documents, both written in Swedish and published as extended pamphlets for friends and scholars in his academic community [1, 2]. Regrettably JW never cared to provide a similar service. The close interaction between JW and CB became the nave for two decades of excellence (Fig. 19.1).

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Wollheim, Jan Gösta Waldenström and His World, Springer Biographies, https://doi.org/10.1007/978-3-031-36739-7_19

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Fig. 19.1 Carl-Bertil Laurell 1970s. Photo Björn Henriksson. © Öpet Bildarkiv Sydsvenska medicinhistoriska Sällskapet. SMHS10162_000_01Copp.jpg. http://www.medicinhistoriskasyd.se/ smhs_bilder/

19.2 Carl-Bertil Laurell in Uppsala CB’s father Hugo Laurell (1884–1959) was the prominent first professor of diagnostic radiology in Uppsala. JW admired him both as teacher and as scientist. CB started his academic career in Uppsala while still a medical student in 1939. During WWII nutrition and health became a subject of lively debate. The health prophet Are Waerland (1876–1955) began a crusade against consumption of sugar and wheat which provided only “empty calories”. Although not supporting the message of the fanatic Waerland, CB was interested in healthy food. He was annoyed that all mills in the country produced mostly highly refined wheat flour devoid of most vitamins, whereas whole-wheat, later named “organic”, was only used as fodder for pigs and poultry. He approached Sten Abdon (1909–1984), a chemical engineer and brother of the pharmacologist Nils-Olof Abdon (Chap. 9), who oversaw the laboratory in the local mill. CB asked why they produced such unhealthy flour. The answer was that it was more “bakeable”. But Abdon also invited the medical student to work in the well-equipped laboratory at the mill. In 1943, CB could show that vitamin B1 was exclusively present in the subcapsular region shielding the sprout of the grains. This layer is rich in proteases and other enzymes which interfere with baking. CB’s maiden paper did not attract much attention. It was decades ahead of its time [3] (Fig. 19.2).

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Fig. 19.2 Cover of the summaries of Carl-Bertil Laurel’s account of his professional work. Photo The author

19.3 Carl-Bertil Laurell in Lund In 1944, CB transferred studies from Uppsala to Lund and completed three full semesters there. It is unusual in Sweden to move between medical schools. One could speculate that he was repelled by professor Ask-Upmark and attracted by the department of Sven Ingvar in Lund and wanted to spend the final medical assistant months in the department of the charismatic chairman Sven Ingvar (Chap. 9). CB’s publication on vitamins in flour could have come to the attention of Ingvar who was interest healthy diets. Ingvar had noticed a connection between low consumption of fibers and constipation in the elderly. When CB had passed the final oral examination in medicine with honors, Ingvar hired him in a paid position as “assistant amanuensis”. This was an unusual favor at a time when even bright young doctors often had to work as unpaid apprentices for months before qualifying for a paid position. Obviously Ingvar had spotted the unusual talent of CB. The new amanuensis started to work in the recently endowed Rockefeller laboratory in the basement of the medical building. The laboratory was managed by associate professor Carl Gottfrid Holmberg (1902–1986), a scholar of Thorsten Tunberg (Chap. 9). Holmberg was interested in metal transport in the blood and had repeated JW’s work in Uppsala with iron loading showing that there was a maximal Fe2+ concentration which could not be exceeded. He extended JW’s experiments in humans to in vitro studies adding Fe2+ to plasma and confirmed JW’s observation of an upper limit for solubility of iron. But in contrast to JW, he concluded that iron was insoluble and required a binding carrier for solubility. With CB, he published a seminal paper coining the term “total

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iron binding capacity” [4]. CB was given the task of isolating the unknown carrier in a doctoral thesis. The task turned out to be difficult or impossible with the technology available at the time. Instead, CB worked out an improved simple assay for total iron binding capacity, TIBC, and some clinical applications of the test. He defended his thesis with honors with JW as the admiring opponent (Chap. 8) [5]. The observations were soon confirmed by the group of Clement Finch (1915–2010) at Harvard in Boston [6]. The precise TIBC method became a widely used and valuable routine clinical test for decades. Already before the Ph.D. ceremony CB had started to use pig blood from the slaughterhouse in an effort to isolate the elusive iron-binding carrier. Fast growing pigs need large amounts of iron and poses high level of iron binding in circulation. Aided by a pink color, the new cold centrifuge in the laboratory, the new fractionation technique of Edwin J. Cohn (1872–1953) at Harvard utilizing precipitation by addition of ethanol, a protein was isolated and its purity confirmed with help of CB’s friend in Uppsala, Björn Ingelman (1917–2000). The paper was published in a new Scandinavian journal [7], and the finding was soon independently confirmed [8]. CB adopted the name transferrin, suggested by Gerhard Bendz (1908–1985), professor of Latin in Lund. In the United States, the less descriptive name siderophilin was used for some years. In 2022 (25 July), a PubMed search for “transferrin” yields 43,929 hits. Elucidation of the molecular action of transferrin had to await the arrival of 59 Fe (Fig. 19.3). Fig. 19.3 Edwin Joseph Cohn. No known copyright. https://digital.sciencehistory. org/works/p8418n224

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During the purification efforts for the iron-binding purple substance a blue stained fraction was noticed. This was purified and sent to Kai Pedersen in Uppsala who performed an ultracentrifuge run. This showed that only a minor part was blue and that it was a macroglobulin. The blue fraction was named ceruloplasmin, and it turned out to be the major oxidizing enzyme present in serum [9–11]. A further finding of significance was the unequivocal demonstration that copper and iron are transported by different carrier proteins. Based on the finding that the concentrations of these metals vary inversely, it had previously been assumed that they competed for binding sites on the same carrier. The new discoveries caught the attention of Edvin Cohn at Harvard, the leading pioneer in protein research since the 1920’s. Thus CBs international fame was established. Cohn’s fractionation method was used during WWII to produce large amounts of serum albumin and saved the lives of countless allied soldiers injured on the battlefields (Chap. 7). CB quickly became familiar with the spectrum of routine chemical tests in use, but he was less interested in the examination of blood morphology which constituted a fair proportion of the service provided by the laboratory. Originally, CB’s plan was to specialize in internal medicine. He spent the following year as clinician in the department. He enjoyed patient work but missed the bench. Consequently, he returned to the laboratory and was appointed as one of the few three-year paid assistant professorships (docenttjänst) of the faculty and could spend most time in research. The only obligation connected with the position was to deliver 60 hours of undergraduate lectures each year. The undergraduate curriculum did not yet embrace lectures in clinical chemistry. Student attendance therefore was voluntary. In order to avoid the embarrassment of an empty lecture hall CB announced the series as “pathophysiology” and addressed disease mechanisms and laboratory tests used in clinical practice for diagnosis and management of patients. The attendance concerns turned out to be a non-issue since the students soon realized how relevant and useful information CB presented both for their examination and their future work as doctors. The armamentarium of the laboratory was upgraded in 1947–8, financed by grants from the newly formed Swedish Medical Research Council. Modern equipment was installed including a Beckman spectrophotometer, a cooled centrifuge, an LKB machine for free electrophoresis, and a Warburg apparatus for measuring of oxygen consumption. A flame photometer was also acquired simplifying the assay of sodium, potassium, and other metals. CB became an enthusiastic expert on the use of these new tools for a state-of-the-art clinical chemistry. In 1950, he also introduced the use of the brand new method of paper electrophoresis in Lund. He had picked up the method during a visit to Uppsala, where he had become acquainted with Henry Kunkel who was working in the lab of Arne Tiselius (Chap. 6) [12]. The method was used by CB’s wife, Anna-Britta Laurell (1918–2000) in her PhD thesis on Wasserman antibodies in 1955 [13] (Fig. 19.4). A new learning experience appeared when Professor Holmberg was chosen as opponent on a thesis examination at the Department of Physiology in Lund. The defendant was a scholar of Georg Kahlson (Chap. 9). He had studied histamine in blood and claimed presence of high levels of free histamine. Holmberg was skeptical and asked CB and Helge Colldahl (1911–1975) to review the work. It was easy for

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Fig. 19.4 Carl Gottfrid. Holmberg in white coat shows his new laboratory to visitors in 1968. © Private archive Bernt Eriksson. Öppet bildarkiv Sydsvenska Medicinhistoriska Sällskapet. SMHS14656Copp.jpg. http://www.medicinhistoriskasyd.se/smhs_bilder/

them to perform animal experiments showing beyond doubt that the defendant had overestimated the amount by a potence of ten to one hundred. This was brought up at the public thesis ceremony, much to the chagrin of the mentor. Sometime later another thesis was presented from Kahlson’s department again reporting very high levels of histamine, this time in blood during pregnancy. CB recalculated the results using data from the defendant’s thesis and found that the results could not be correct. He brought up the matter “ex auditorio” during the public act and also submitted a written statement regarding the problem to the faculty of medicine. Rather than making productive use of the critique and improve the department’s methodology, Kahlson reacted with lasting enmity toward CB extended to the specialty of clinical chemistry in general. Due to Kahlson’s dominating influence in the faculty, both dissertations were awarded with high grades, leading to CB’s lasting distaste for the grading of doctoral thesis work.

19.4 Carl-Bertil Laurell Arrives in Malmö In 1953, CB was appointed as chief of the hospital’s new Department of Clinical Chemistry responsible for organizing and offering chemistry analyses for all departments of the hospital and of developing research and undergraduate teaching. CB was a trained MD and a model example of the advantage when physicians rather than non-medical chemistry specialists oversee central laboratories. Some familiarity of patient work is essential to provide optimal service for the clinicians. Before his arrival, CB was involved in the planning and outfit of the new facilities in Malmö.

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He could select the most modern instruments and influence building details at the blueprint stage of planning. He completely revised the existing old-fashioned inventory of instruments. CB saved much money by refraining from buying the expensive commercial instrument for moving-boundary electrophoresis in free solution which was then installed in many hospitals. CB realized that the new simple and inexpensive method of paper electrophoresis was superior for routine clinical as well as research use [1, 2]. The government committee of 1948 overseeing the medical curriculum (Chap. 8) had in 1953 decided that hands-on laboratory teaching and lectures in clinical chemistry should be compulsory for all medical students. In Malmö this mandate was implemented in 1954. CB’s lectures were relevant and up to date, and he became highly respected by the students. But they could also be scared by the questions he posed during the lectures. Often, they did not know whom he was asking in class. CB had a pronounced squint from childhood and mastered the unusual feat of retaining full vision on both eyes by using them alternatively. Consequently, the students were unable to tell whom he was looking at when asking the question (Fig. 19.5). CB obtained funding for a junior staff position in 1954 and recruited Bertil Nosslin (1919–2014) whom he knew from the Department of Medicine in Lund. Nosslin was a man with many skills. He had spent 12 (!) years in medical school from 1938 to 1950. However, he had not been idle. Nosslin had been amanuensis in anatomy, bacteriology, and pathology, served as editor of the student union’s monthly magazine, served as chairman of the student’s union, served as expert in the government’s curriculum reform committee of 1948 of which JW was also a member, and had studied mathematics and statistics. The author experienced him during a two-month clerkship in 1953 as an outstanding bedside instructor and keeper of linguistic quality in case records. His laboratory proficiency was demonstrated when he became the first physician in the region to master the new LE cell technique of Hargraves used diagnostically in suspected cases of systemic lupus erythematosus, SLE. He was an Fig. 19.5 Bertil Nosslin. © Photographer unknown. Family archive. Courtesy Sussi Nosslin Kyle

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outstanding organizer, knowledgeable in statistics, and a master of structured scientific writing. In Malmö he pioneered meticulous quality control of all outgoing test results. In addition, he was an expert botanist and conducted surveys of local fauna in Smolandia. He rediscovered a flower in a cemetery which had been considered extinct by experts. CB also recruited a school friend of Nosslin, the chemist and toxicologist Arne Hansson who was educated at laboratories in Germany and Switzerland and had worked as a chemist at the Sorbonne and Scotland Yard before founding the first National Laboratory of Toxicology in Stockholm. These two individuals with unusual all-round proficiency and CB made the department into a model academic and clinical facility, delivering high-class reliable daily service, outstanding teaching, and state-of-the-art research. The lively and productive interaction between JW and CB is well illustrated by the following episode. In 1953 CB visited JW who took him to a ward and demonstrated a female patient from Ängelholm who suffered attacks of peculiar flushing and abdominal colic (Chap. 14). CB was amazed to discover that he had seen this patient before when he cared for “Miss P” during his clinical year in Lund. She had been admitted with the strange question “Why is Miss P still alive?”. Miss P had been discharged from the hospital in Ängelholm four years previously when an exploratory laparotomy had shown the presence of multiple metastatic carcinoids in the liver. Informed that she was to die shortly, the patient adopted permanent bed rest. The physicians in Lund could not find any obvious disability and interpreted the disability as functional. Rehabilitation from bed rest was started, and the patient was discharged [1]. The reader may have guessed that “Miss P” was identical with the patient Edvard Ljungberg had shown JW at his visit in Ängelholm (Chap. 14). The episode triggered collaboration between Arne Hanson and JW’s new amanuensis Folke Serin coming from the Department of Pharmacology in Lund (Chap. 9). Together they described an assay for the diagnosis of carcinoid, 5-hydroxyindoleacetic acid, 5-HIAA in urine. It was published in December of 1955 in the Lancet [14]. JW had learned of 5-HIAA in May of that same year when the discovery was presented by Albert Sjoerdsma at the annual American “Young Turks” meeting in Atlantic City [15]. The simple semi-quantitative test was based on colorimetry of the blue color which formed when Ehrlich’s aldehyde reagent, p-dimethylaminobenzaldehyde, was added to urine from a patient. CB was aware of JW’s need for enhanced clinical service focusing on protein analyses and was working on improving paper electrophoresis. This involved modifications of the buffer, size of the buffer vessels, and better application techniques of the samples. These adaptations resulted in more distinct bands and even allowed semi-quantitative measurement of the fractions. Electrophoresis became a signature method of the laboratory. CB had useful help from Otto Olofsson, master at the instrument workshop of the hospital, who produced the required equipment. Nancy Skoog, a skilled but grumpy technician taken over from the medical department’s laboratory became the laboratory’s expert on electrophoresis, working closely with CB on the research floor. She was already introduced in Chap. 16 for having used tap water when preparing a new batch of buffer. After admitting her mistake, systematic

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Fig. 19.6 Carl-Bertil Laurell in 1959 with the equipment provided by Tor Olofsson for paper electrophoresis. The power supply is shown on the upper shelf, and a glimpse of the buffer vessels can be seen below. © Universitetssjukhuset MAS 1996

research into improved methodologies followed [16, 17]. The modifications were adopted at other laboratories only much later. Paper electrophoresis, “elfores”, was soon included as standard in the diagnostic work-up of patients by clinicians in the hospital. The referral slip contained brief clinical data on the patient. The following day, a copy of the clinician’s referral slip with an attached stained electrophoretic strip was sent back from the lab along with a comment by CB or his proxy on the possible clinical significance of the pattern. Only years later was this kind of service provided at some, but not all, other central laboratories. Many hospitals continued to use the expensive work intense method of moving-boundary electrophoresis in free solution in their central laboratories [1]. But other hospitals had started to send specimens to the Malmö laboratory requesting paper electrophoresis (Fig. 19.6). The routine clinical laboratory service was soon functioning smoothly, allowing CB and his team to start research projects. As the table shows, the first Ph.D. students were all MDs. Three came from JW and were specializing in internal medicine. Two were pursuing an academic career as clinical chemists and were required to work on a project they had identified themselves, while the three clinicians were either given a topic or helped to continue a project already in progress (Fig. 19.7). Karl Gydell (1920–2006) had joined the department of JW in 1952. He had published several clinical papers but had not identified a suitable subject for a doctoral thesis. In 1956 he was helped by CB who, while still working in Lund had observed that administration of 50–100 mg of nicotinic acid intravenously resulted in increased serum iron and bilirubin, suggesting the possible induction of breakdown of erythrocytes [18]. Gydell expanded this observation to a thesis defended in 1959 titled “Studies on erythrocyte and hemoglobin destruction with special reference to changes induced by nicotinic acid”. The work resulted in a clinically useful test measuring the

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The first doctoral thesis projects Name Margareta Nyman Karl Gydell Birgitta HaegerAronsen, Wilfried von Studnitz Bertil Nosslin

Title Serum haptoglobin Studies on erythrocyte and hemoglobin destruction Studies on urinary excretion of ∂-aminolevulic acid and other haeme precursors in lead workers and lead-intoxicated rabbits Methodische und klinische Untersuchungen über die Ausscheidung der 3-Methoxy-4hydroxymandelsäure im Urin The direct diazo reaction of bile pigments in serum

Date of completion 1959 1960 1960 1960 1960

Fig. 19.7 The five first doctoral dissertations at the Department of Clinical Chemistry in Malmö

amount of exhaled carbon monoxide hemoglobin as a test for suspected hemolytic anemia [19–21]. Gydell returned to the department of Medicine as associate professor and much appreciated clinician and teacher for a decade before he was promoted as chairman of medicine in Kalmar. A devoted ambassador of JW, Gydell stayed in close contact with Malmö from where he recruited one of the staff members, Ulla Evaldsson (1928–2020) as deputy chairman. JW liked to visit his department in Kalmar for guest rounds and social contact. The preferred season for visits was June when rare orchids were in bloom nearby. Edvaldsson would drive with him to the island of Öland and remembers how delighted JW was while kneeling on the ground to inspect rare protected and hidden orchids. Bertil Nosslin (1919–2014) elected to explore bile pigments as his dissertation theme. He focused on the direct bilirubin test. Hijmans van den Bergh (1869–1943) had described the direct and indirect diazo reaction in 1916 [22]. In the following decades the use of bilirubin tests suffered from imprecise methodology, limiting their clinical usefulness. Nosslin performed a penetrating investigation of the stability of the diazo reagent and other critical factors influencing the test. He ran the test under different conditions and generated reliable information regarding differentiation between prehepatic, hepatic, and posthepatic jaundice. The direct reaction was only positive in patients with post-hepatic jaundice, for example due to obstruction of the bile duct by gallstones or cancer. This exhaustive thesis restored testing for indirect and direct bilirubin as a reliable and informative assay [23]. Margareta Nyman (1921–2011) had an Austrian father and a Swedish mother. She spent much of her early life in France and earned high school diplomas both in France and Sweden. She attended medical school in Lund from 1940, graduated as MD in 1952, already the mother of two children. She joined the Department of Medicine in Malmö in 1952. After some years she wanted to perform experimental research and joined CB in 1957, initially as an unpaid PhD student. Experience from routine use of paper electrophoresis had shown that some patients had a subnormal α2 -fraction. The lowest levels had been observed in patients with hemolytic anemia

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[24]. A clue to the background was uncovered by the francophone PhD student. Scrutinizing French journals, she found that already in the 1940s Max-Fernand Jayle (1913–1978) in Paris had discovered that plasma contained a protein with high affinity for hemoglobin that could be quantified by its peroxidizing features. Jayle named the protein haptoglobin [25–27]. The president of France Charles de Gaulle had dissuaded investigators of his country from publishing science in English and knowledge about haptoglobin had escaped non-francophone scientists. Jayle’s research was temporarily interrupted by an explosion in the lab resulting in his loss of vision [1]. CB noted that several investigators had reported variability in the highest concentrations of serum hemoglobin before hemoglobinuria was detected. CB sensed that there could be an explanation of the discrepancies, namely that hemoglobin could be retained in circulation bound to Hp. Free hemoglobin escapes quickly through normal pores in the renal glomeruli. In contrast, haptoglobin-bound hemoglobin is eliminated from blood and rapidly taken up in the liver and spleen where the complexes are metabolized for re-use. The variability in the “renal threshold” of hemoglobin could be explained by variable concentrations of haptoglobin. A critical self-experiment was then performed. Sterilized human hemoglobin was prepared in ampules and samples sent to the pharmacy to check whether the substrate was toxic administered to animals. CB had calculated that 7 g of hemoglobin would be needed to saturate circulating haptoglobin in normal people. When no information had been obtained from the pharmacy after 7 days, the impatient investigators injected themselves with 7-g hemoglobin intravenously. The calculation turned out to be correct and their haptoglobin levels decreased in a linear fashion to zero. Excess hemoglobin then appeared in the urine. It took a week for their Hp levels to return to normal [1, 28]. A few days after completion of the experiment the information came back from the pharmacy that all injected rabbits had died. Human hemoglobin is lethal when given to rabbits! (Fig. 19.8). In 1959, Nyman defended her comprehensive doctoral thesis with honors. She reported that Jayle’s original peroxidase method and the paper electrophoretic method developed in Malmö generated identical results. She described clinical conditions where measurement of Hp was useful and where it was not. She defined an assay for Hp binding capacity in analogy to the total iron binding capacity described in the thesis of her mentor [29]. Returning to the bedside, Nyman introduced immune suppressive therapy of inflammatory bowel diseases in the department and initiated a collaboration with gastrointestinal surgeons. In 1965, she was promoted to associate professor and became an anchor in undergraduate teaching and often replaced JW as oral examiner. Her devotion to patients and students, her spontaneity and her constant intense activity combined with ever-present characteristic laughter made her much liked by all colleagues. After retirement in 1987, she took over JW’s private practice in the city. In her obituary she was hailed as Une Grande Dame. Wilfried von Studnitz (born 1927), came to Sweden from Germany in 1951. He had recently graduated as MD from the University of Göttingen and wanted to complete his education abroad. His professor advised him to contact the professor of medicine in Malmö. Von Studnitz was received amiably by JW, who recommended

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Fig. 19.8 Margareta Nyman at Torup Castle in 1986. © Photo courtesy of Gunilla Berglund

him to start with a paid locum position at the hospital laboratory in Kalmar and come back when he could speak Swedish. After returning to Malmö, von Studnitz decided to specialize in clinical chemistry. He joined CB in 1954 and was initially assigned the task of examining lipoproteins and protein changes in pregnancy, applying results obtained with the routine use of the new “poor man’s electrophoresis” on paper [30]. It was von Studnitz who first had noticed the low α2 fraction in patients with hemolytic anemia [24]. His early publications would have qualified him for a doctoral thesis in Sweden some decades later. However, as we have learned, CB demanded that PhD students aiming to specialize as clinical chemists independently select their own original topic. Consequently, von Studnitz had to find another subject for his dissertation. The inspiration for his choice probably emanated from contacts with JW. Hypertension was a common disease for which treatment was usually only symptomatic. But among hypertensives occasional patients experienced attacks of pallor, excessive perspiration and spiking blood pressure. Arthur Engel and Ulf von Euler had recently described two patients with tumors of the adrenal medulla named pheochromocytoma. Bioassay had revealed that they excreted large amounts of adrenaline and noradrenalin with the urine. The levels returned to normal after surgical removal of the tumors [31]. The symptoms could be atypical and there was a need for a reliable screening test for pheochromocytoma. The adrenal glands are endocrine organs producing the catecholamines adrenaline and noradrenaline. With new histochemical methods von Euler and Hillarp (Chap. 9) discovered noradrenaline as transmitter substance in sympathetic nerves [32]. The

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Fig. 19.9 Formula of noradrenalin, adrenalin, and the metabolite 3-hydroxy-4-metoxy vanillic acid

following year Armstrong et al. published evidence that increased amounts of 3methoxy-4-hydroxy-d-mandelic acid, a catecholamine metabolite, were found in patients with pheochromocytoma [33]. This discovery triggered von Studnitz’s Ph.D. project (Fig. 19.9). With Arne Hanson, von Studnitz entered a hot field of research and published a simplified method to assay 3-methoxy-4-hydroxy-d-mandelic acid using highvoltage paper chromatography followed by staining with a diazo reagent [34]. In his thesis, von Studnitz presented the method with details on its performance, including drug interactions. The normal excretion in children and adults, sex-independence, and variation in several diseases were addressed. Very high levels were found in patients with pheochromocytoma that became normal after removal of the adrenal tumor. Increased post-operative levels indicated presence of residual tumor tissue or tumor relapse. 3-methoxy-4-hydroxy-d-mandelic acid was thus useful both for screening and follow-up of patients with pheochromocytoma [35]. Children with neuroblastoma excreted high amounts of 3-methoxy-4-hydroxy-d-mandelic acid, and sometimes also another previously undescribed metabolite, 3-methoxy-4-hydroxyphenyle alanine [36]. It was mentioned in Chap. 14 that Albert Sjoerdsma at the NIH in Washington D.C. had worked with carcinoids and serotonin and had discovered its metabolite 5HIAA, and that he would come to Malmö as visiting professor in 1958. By then Inga Marie Nilsson, the “Queen of Coagulation” had started work on increased fibrinolysis as a pathogenic mechanism [37]. Bleeding manifestations in such patients could be stopped by treatment with ε-aminocaproic acid, εACA. To study this further, an assay of εACA was needed. Sjoerdsma and Hanson worked out a simple highvoltage electrophoretic assay [38]. The test was used in a paper co-authored by JW confirming the beneficial effect of εACA [39].

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Fig. 19.10 Wilfried von Studnitz in 2011. Photo The author

Aado Vendsalu (1921–2014) shared an interest in pheochromocytoma with Sjoerdsma and von Studnitz. He came to Malmö from Stockholm and joined Gunnar Biörck in the cardiology section in 1954. In 1960, he defended a thesis in which he used a sensitive spectrophotofluorometric method for direct measurement of minute amounts of adrenalin and noradrenalin in serum. The laborious test could localize the tumors by sampling venous blood from different parts of vena cava [40]. In 1960–61 he spent a postdoctoral year at NIH. In 1963 he left Malmö to become the cardiologist in the Department of Medicine in Falun. Von Studnitz succeeded Vendsalu at NIH and spent a productive year as visiting scientist working on catechol metabolism [41]. He returned to Malmö in 1963 where his competence resulted in fruitful collaborations with other departments in translational research in the following decade (Fig. 19.10).

19.5 Alpha-1 Antitrypsin Deficiency Cutting-edge research and comprehensive fast and reliable service fulfilling all needs of clinicians were hallmarks of CB’s department. Other hospitals began sending specimens for analysis, foremost serum proteins. Each afternoon CB personally examined all the electrophoretic patterns produced that day. One day in the fall of 1962 he noticed the near absence of the alpha-1 band in a serum sample sent for electrophoresis from a Eksjö Sanatorium for care of pulmonary diseases in Smolandia. Some weeks later a serum sample from another patient sent from the same hospital showed a similar absence. The referral slips for both samples informed that both patients suffered from pronounced pulmonary emphysema. The tests had been ordered by a curious Danish locum physician for no obvious reason. CB realized that some kind of protein abnormality was present which needed to be explored as a

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Fig. 19.11 Eksjö Sanatorium, a former tuberculosis hospital, built in 1918. It was demolished in 1988 and replaced by residential homes. Postcard. Photographer unknown. Public Domain https:// sv.wikipedia.org/wiki/Eksj%C3%B6_sanatorium

possible cause for pulmonary disease, and that this should be performed by a clinician. He contacted JW who selected Sten Eriksson (1932–2022) for this attractive task. Eriksson had recently been recruited from the Department of Medical Chemistry in Lund where he had participated in a study on M-components [42] (Fig. 19.11). Eriksson became CB’s clinical partner and started on his PhD thesis with enthusiasm, realizing that he was onto something of great interest. The first step was a search of the electrophoresis archives in the clinical service laboratories in Malmö and Lund where he was able to find three more cases, one of which had emphysema and also a brother and a sister with emphysema. CB performed chemical and immunochemical investigations of the alpha-1 region and showed that the alpha-1 antitrypsin content of the five sera amounted to only few percent of normal. In the resulting publication in 1963 CB and Eriksson described alpha-1 antitrypsin as a new inborn error of metabolism [43]. Eriksson defended his forefront Ph.D. thesis in 1965 [44]. A test measuring the total trypsin inhibitory capacity, TIC, was developed. Fourteen probands, 110 relatives, and 103 control subjects showed a trimodal distribution of TIC. The patients had only 10% TIC, several first-degree relatives had around 50% TIC although they were apparently healthy. This indicated a recessive inheritance of alpha-1antitrypson deficiency [44]. In following years, Eriksson mentored multiple Ph.D. students and authored almost 100 papers dealing with alpha-1 antitrypsin. Liver cirrhosis was a common complication of alpha-1-antitrypsin deficiency. In 1975, Christer Larsson co-authored three papers in the New England Journal of Medicine showing intracellular presence and retention of alpha-1 antitrypsin in hepatocytes and in granules of leukocytes in the blood of patients [45–47]. The diseased

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Fig. 19.12 Sten Eriksson at his desk with his PhD student Christer Larsson in 1975. © Courtesy Hilde Eriksson

protein lacked stretches of the molecule needed for export from the cell. Soon after his outstanding dissertation Larsson left Malmö and became deputy chief of medicine in Simrishamn on Scania-east coast where he unfortunately soon succumbed due to bipolar disease (Fig. 19.12). Important work in the field of M-components was performed by Rolf Backman (Chap. 16) who later became deputy head of medicine in Trelleborg, and on alpha2 macroglobulin and other serum proteins by Per-Olof Ganot (1935–2018) who finished his career as chairman of the Department of Clinical Chemistry in Örebro. In the following decades CB had the gratifying experience of witnessing independent groundbreaking achievements by new scholars. He would enjoy daily bench work in the laboratory until he had to stop due to failing eye sight. CB was conferred the Edwin F. Ullman Award from the American Association for Clinical Chemistry in 2001. He was persuaded by his son Martin to travel to Seattle, received the prize, and gave an excellent lecture with the technical help of Martin Laurell. CB was recently widowed and could no longer perform bench work. He could not stand idle life and departed from life within months after returning from Seattle [48].

References 1. Laurell CB. “Axplock” från min tid som klinisk kemist. Lund 1944–1953. Malmö 1954– 1983 (Selection from my time as clinical chemist. Lund 1944–53. Malmö 1954–83.). Malmö, published privately; 1996. p. 1–73.

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2. Laurell CB. Om utvecklingslinjer inom klinisk kemi under min Malmöperiod. (Developments in clinical chemistry during my time in Malmö). Department of Laboratory Sciences in Malmö; 2000. p 1–84. 3. Abdon S, Laurell CB. Über den B1-Vitamingehalt der Vermahlungsprodukte des Weizens und über Möglichkeiten, die B1-vitaminreichsten Mehlfraktionen als Menschennahrung auszunutzen. Acta Physiol Scand. 1945;7(suppl 19):1–36. 4. Holmberg CG, Laurell CB. Studies on the capacity of serum to bind iron. Acta Physiol Scand. 1945;10:307–19. 5. Laurell CB. Studies on the transportation and metabolism of iron transport in the body. Acta Physiol Scand. 1947;14(suppl 46):1–129. 6. Rath CE, Finch CA. Chemical, clinical, and immunological studies on the products of human plasma fractionation XXXVIII. Serum iron transport. Measurement of iron-binding capacity of serum in man. J Clin Invest. 1949;28:79–85. 7. Laurell CB, Ingelman B. The iron binding protein of swine serum. Acta Chem Scand. 1947;1:770–6. 8. Schade AL, Caroline L. An iron-binding component in human blood plasma. Science. 1946;104(2702):340–1. 9. Holmberg C, Laurell, CB. Investigation in serum copper I. Nature of serum copper and its relation to the iron binding protein in human serum. Acta Chem Scand. 1947;1:944–50. 10. Holmberg C, Laurell, CB. Investigation in serum copper II. Isolation of the copper containing protein and description of some of its properties. Acta Chem Scand. 1948;2:550–6. 11. Holmberg CB, Laurell C-B. Investigation in serum copper III. Coeruloplasmin as an enzyme. Acta Chem Scand. 1951;5:476–8. 12. Kunkel HG, Tiselius A. Electrophoresis of proteins on filter paper. J Gen Physiol. 1951;35:89– 118. 13. Laurell AB. On antibodies separated by paper electrophoresis with special reference to the Wassermann reagins. Acta Pathol Microbiol Scand Suppl. 1955;103:1–92. 14. Hansson A, Serin F. Determination of 5-hydroxy-indole-acetic acid in urine and its excretion in patients with malignant carcinoids. Lancet. 1955;269(6905):1359–61. 15. Sjoerdsma A, Udenfriend S. Studies on indole metabolism in patients with malignant carcinoid (argentaffinoma). (Abstract). J Clin Invest. 1955;34:914. 16. Laurell CB, Laurell S, Skoog N. Buffer composition in paper electrophoresis. Clin Chem. 1956;2:99–111. 17. Laurell CB, Skoog N. Quantitative determination of the glucoprotein pattern of normal serum after electrophoretic separation on filter paper. Scand J Clin Lab Invest. 1956;8:21–5. 18. Laurell CB. Influence of nicotinic acid on the intermediary metabolism of iron and bilirubin. Acta Pharm Toxicol. 1953;9:86–92. 19. Gydell K. On the hyperbilirubinemic and hypersideremic action of nicotinic acid on normal subjects and on patients with some hematologic disorders. Acta Med Scand. 1958;162:9–27. 20. Gydell K. Transient effect of nicotinic acid on bilirubin metabolism and formation of carbon monoxide. Acta Med Scand. 1960;167:431–41. 21. Gydell K. Nicotinic acid induced hyperbilirubinemia and hypersideremia. I. Observations in hemolytic disease and allied conditions. Acta Med Scand. 1959;164:305–20. 22. Hijmans van den Bergh AA, Müller P. Über eine direkte und indirekte Diazoreaktion auf Bilirubun. Biochem Zschr. 1916;77:90–103. 23. Nosslin B. The direct diazo reaction of bile pigments in serum. Experimental and clinical studies. Scand J Clin Lab Invest. 1960;12(Suppl 49):5–176. 24. von Studnitz W. Über die Verminderung der alpha-Globuline im menschlichen Serum bei verschiedenen Krankheiten [Lowering of alpha-globulin in human serum in various diseases]. Klin Wochenschr. 1956;34(13–14):371–3. 25. Polonovski M, Jayle MF. L’haptoglobine et sa signification clinique. Recherches médicales en France pendant la guerre 1939–1945. Paris; 1945.

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26. Jayle MF, Said I, Gillard P. Action de l’haptoglobine sur la catalyse peroxydasique de l’hémoglobine: nouvelle théorie sur la constitution des enzymes. (Action of haptoglobin on the peroxidase catalysis of hemoglobin: new theory on the constitution of enzymes). Bull Soc Chim Biol (Paris). 1946;28:63–80. 27. Jayle MF, Boussier G. Les serómucoides du sang, leur relations avec leur mucoprotéines de la substance foundamentale du tissue conjunctif. Exp Ann Biochim Méd. Masson et cie. 1955.16.Série 157. 28. Laurell CB, Nyman M. Studies on the serum haptoglobin level in hemoglobulinemia and its influence on renal excretion of hemoglobin. Blood. 1957;12:493–506. 29. Nyman M. Serum haptoglobin: methodological and clinical studies. Scand J Clin Lab Invest. 1959;11(Suppl 39):1–169; von Studnitz W. Studies on serum proteins in pregnancy. Scand J Clin Lab Invest. 1955;7:324–8. 30. von Studnitz W. Studies on serum lipids and lipoproteins in pregnancy. Scand J Clin Lab Invest. 1955;7:329–35. 31. Engel A, von Euler US. Diagnostic value of increased output of noradrenaline and adrenaline in phœochromocytoma. Lancet. 1950;6630:387. 32. von Euler US, Hillarp N-A. Evidence for the presence of noradrenalin in the microscopic structures of adrenergic axons. Nature. 1956;177:44–5. 33. Armstrong MD, McMillan A, Shaw KNF. 3-Methoxy-4-hydroxy-d-mandelic acid, a urinary metabolite of norepinephrine. Biochim Biophys Acta. 1957;25:422–3. 34. von Studnitz W, Hanson A. Determination of 3-methoxy-4-hydroxymandelic acid in urine by high-voltage paper electrophoresis. Scand J Clin Lab Invest. 1958;11:101–5. 35. von Studnitz W. Methodische und klinische Untersuchungen über die Ausscheidung von der 3-Methoxy-4-Hydroxymandelsäure im Urin (Methodical and clinical studies on the excretion of 3-methoxy-4-hydroxymendelic acid in the urine). Scand J Clin Lab Invest. 1960;12(Suppl 48):3–73. 36. Käser H, Bettex M, von Studnitz W. Further observations on the determination of cathecolamine metabolites in tumours of sympathetic nervous system. Arch Dis Childh. 1964;39:168–71. 37. Björkman SE, Laurell CB, Nilsson IM. Serum proteins and fibrinolysis in polycythemia vera. Scand J Clin Lab Invest. 1956;8:304–8. 38. Sjoerdsma A, Hansson A. Determination of ε-aminocaproic acid in urine by means of highvoltage paper electrophoresis. Acta Chem Scand. 1959;13:2150–1. 39. Nilsson IM, Sjoerdsma A, Waldenström J. Antifibrinolytic activity and metabolism of ε-aminocaproic acid in man. Lancet. 1960;1(7138):1322–6. 40. Vendsalu. Studies on adrenaline and noradrenaline in human plasma. Acta Physiol Scand Suppl. 1960;49:1–123. 41. Sjoerdsma A, von Studnitz W. Dopamine-beta-oxidase activity in man, using hydroxyamphetamine as substrate. Br J Pharmacol Chemother. 1963;20:278–88. 42. Sjöquist J, Eriksson S, Nilsson IM, Waldenströmm J. N-terminal-aminoacid pattern in normal and pathological human serum. Lancet. 1960;275(7130):902–3. 43. Laurell CB, Eriksson S. The electrophoretic 1-globulin pattern of serum in alfa1-antitrypsin deficiency. Scand J Clin Lab Invest. 1963;15:132–40. 44. Eriksson S. Studies in alpha 1-antitrypsin deficiency. Acta Med Scand Suppl. 1965;432:1–85. 45. Jeppsson JO, Larsson C, Eriksson S. Characterization of alpha1-antitrypsin in the inclusion bodies from the liver in alpha 1-antitrypsin deficiency. N Engl J Med. 1975;293:576. 46. Eriksson S, Larsson C. Purification and partial characterization of pas-positive inclusion bodies from the liver in alpha 1-antitrypsin deficiency. N Engl J Med. 1975;292:176–80. 47. Eriksson S, Larsson C. Letter: role of sialyltransferases in alpha-1-antitrypsin deficiency. N Engl J Med. 1975;292:925–6. 48. Laurell M. Personal communication; 2021.

Chapter 20

The Division of Cardiology

Abstract Gunar Biörck leads the division from 1950 to 1958 when he was promoted to professor and chairman at Serafimer Hospital/Karolinska in Stockholm. Bengt W Johansson expanded the activities with own research and that of several mentees. The division remained part of internal medicine all the time in full harmony with JW. Johansson’s interest in hibernation as Societas Erinacea is introduced.

20.1 The Period 1950–8 Gunnar Biörck (Chaps. 8 and 11) was, like JW, a firm champion of undivided departments of medicine including all branches of the specialty. Thus, he was comfortable in the position as urbane head of the Division of Cardiology in the Department of Medicine. Elegant, ambitious, and extroverted, he was keen to preserve traditions and style. Students had to be properly dressed; jeans and clogs were not welcome. He was soon known as “GB” among colleagues and sometimes characterized as detached and cold. His international reputation resulted in invitations as author in influential publications [1]. Like JW, he attracted capable staff members, allowing himself to spend less time in daily routine work and more on leadership and research, make use of his fluent pen, and traveling (Fig. 20.1). GB did not perform heart catheterization himself but supported its introduction in Malmö. Hans Krook initially performed most procedures, well aware of the risks involved [2]. JW had hoped that after arriving in Malmö, GB would continue his basic research on myocardial metabolism which he had started with Christian de Duve in Nobel Laureate Hugo Theorell’s Department of Biochemistry (Chap. 8). But open-heart surgery was just taking off in Malmö, and a large part of his work and that of his division was to provide necessary back-up for Professor Wulff and his team at the Department of Surgery. Several papers bear witness of the collaborative research effort with cardiac surgery [3–6] (Fig. 20.2). GB realized the unique opportunities in Malmö for epidemiologic research with a stable population of over 200 000 inhabitants served by only one hospital where medical records including clinical charts and postmortem results were available. The opportunity to pursue a detailed epidemiologic study of acute rheumatic fever © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Wollheim, Jan Gösta Waldenström and His World, Springer Biographies, https://doi.org/10.1007/978-3-031-36739-7_20

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Fig. 20.1 Painting of Gunnar Biörck in 1966 by Ulla Wachtmeister. The original was displayed in a corridor of the Karolinska hospital. This copy is donated to the Swedish Society of Medicine by the Biörck family and is displayed in the staircase of the headquarters is the Socety, Klara. Öatra. Kyrkogatan 10, Stockholm. With permission

Fig. 20.2 Paul Hall in 1966. © Håkan Westling archive at Lund University Library

in Malmö was given to his favored PhD student and close collaborator in the ensuing years, Paul Hall (1924–2013). Hall had entered medical school in Lund in 1947 and initially split time between studies and campus life, playing the clarinet as leader of a jazz orchestra. He was one in the first class of medical students transferring to Malmö for the clinical years of their curriculum. There he was soon drawn to GB, and while still a student was enticed to participate in a survey of patients with valvular heart disease treated at the hospital. Mitral stenosis following acute rheumatic fever was the most common diagnosis [7]. These were the early years of computer applications in medicine, and Hall developed a strong interest in their use not shared by many contemporary colleagues. The bulky computers arrived and were at that time only occasional intruders in the daily business. This interest slowed the progress of his PhD project on the epidemiology of rheumatic fever in Malmö. The thesis covered the years 1945 to 1950 [8]. Progress

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Fig. 20.3 Gunnar Blomqvist, portrait photo in laboratory, around 1990 where he designed several experiments for NASA space flights. Creator unknown. © University of Texas with permission. C. Gunnar Blomqvist, M.D., Ph.D, portrait photo in laboratory, circa 1990 - UT Southwestern Images 1943-Present - UT Southwestern Image Archives (oclc.org)

reports were published during the 1950’s [9–11], but the detailed investigation was only finished in 1961 [12]. By then, his mentor GB had left Malmö and was professor and chairman of the Department of Medicine at the Serafimer Hospital of Karolinska Institute in Stockholm. GB recruited Hall as associate professor to his department in Stockholm, There his research focused on the computerizing of patient records. Computers still were large and heavy. When Hall acquired a processor weighing one ton, it had to be placed close to a wall in order to diminish the risk of crashing through the floor of the eighteenth century building at “Serafen”. He also worked with several projects to streamline hospital routines. Jazz music remained a favored pastime of his, and he often played informal sessions with friends during visits in Lund. The talented young physician Gunnar Blomqvist (1931–2011) also joined GB in Stockholm where he started a PhD project on digitizing of the electrocardiogram. He was recruited to the University of Texas Southwestern School of Medicine and concluded an eminent career as head of its Space Medicine Laboratory (Fig. 20.3).

20.2 Bengt W. Johansson as Leader The successor of GB was Johan Karnell from Stockholm, who within few years returned to a leading position in Stockholm. Bengt W. Johansson (born 1930), BWJ, would become his successor. He was another of the early medical students recruited to the department in Malmö following a successful oral examination with

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JW. In contrast to Hall, BWJ would remain attached to the department throughout his professional life. BWJ grew up in one of Sweden’s smallest villages, Hög, counting less than 300 inhabitants. It is surrounded by farms and located ten miles north of Lund. His parents were teachers in the local school. His father was “my best teacher” and his mother animated him to learn to cook after he complained about a dish she had prepared, telling him to “do it yourself ”. BWJ graduated from high school in Lund and started medical school there in 1948. He joined the group of GB soon after graduating and was present in the operating room when professor Wulff performed open-heart surgery on patients with congenital heart disease. This was before the advent of the heart–lung machine. Circulation had to be arrested while the heart was opened; four minutes was the maximum time of arrest. By reducing the patient’s body temperature to 300 C the time could be prolonged to eight minutes, but further cooling caused cardiac arrhythmias including ventricular fibrillation and risk of cardiac arrest. The idea came up that it might be possible to learn more about the tricks of safe cooling to lower body temperatures by studying hibernation in hedgehogs, an idea which immediately appealed to BWJ. He learned to monitor hedgehog electrocardiograms during hibernation and while awake, he also studied metabolic differences between hedgehogs and non-hibernating guinea pigs [13] (Fig. 20.4). With the invention of the heart–lung machine in 1953, this line of research became less relevant for heart surgery. Nevertheless, BWJ remained obsessed by hedgehogs and cryobiology for life. It was firmly established that hearts of hibernating animals were resistant to induction of ventricular fibrillation and other arrhythmias [14]. He founded a society called “SOCIETAS ERINACEA” to encourage interest in the subject. The bylaws state that to become a lifetime member one must deliver a talk

Fig. 20.4 A traditional nineteenth-century farmhouse from Hög, the home village of Bengt Johansson I. The farm was moved to Skansen, the open-air museum in Stockholm in1974-8. © Public Domain://digitaltmuseum.se/021057935520/skanegarden

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mentioning the word “hedgehog” at least once. BWJ collected hedgehog paraphernalia in his home, and by 2012 his collection consisted of 495 (!) objects. This achievement resulted in inclusion by the Guinness book of world records that year. The interest in cryobiology resulted in several significant publications from 1955 until the end of the 1990s [13–19]. GB was not able to mentor BWJ for a PhD project. As time passed, GB sought to pass on the daily duty to review all electrocardiograms performed at the hospital. One day Hall and BWJ slipped in a hedgehog electrocardiogram to the stack of tests to be reviewed. GB was not fooled, but his prompt revenge to the gag was to excuse himself from the routine work and entrust it to BWJ. Indirectly this routine finally helped BWJ to identify a thesis project which he considered worthwhile. After GB’s departure to Stockholm in 1958, JW assumed the role of mentor and suggested studying the significance of bundle branch block. But BWJ had a better idea. Resuscitation of patients with cardiac arrest by external heart massage was introduced in the early 1960’s [20]. Many of the resuscitated patients had relapses and their mortality rate was staggering. Adams-Stokes syndrome is characterized by repeated attacks of syncope, often described as fainting fits, epilepsy, or pseudoapoplexy, and its cardiologic etiology was not generally accepted. In 1961, BWJ published a comprehensive review where he defined the Adams-Stokes syndrome as “attacks of acute cerebral ischemia in non-anesthetized patients on the basis of a sudden change in cardiac rhythm”. Following a review of the literature, he presented forty-two of his own cases from Malmö among which coronary heart disease was the dominating but not exclusive diagnosis. Electrocardiography recordings during an attack were obtained from sixteen patients. Tachyarrhythmia was almost as common as bradyarrhythmia and asystole. Fully 50% of the patients died within one year of the attack [21] (Fig. 20.5). Fig. 20.5 Bengt W. Johansson 1970s. © Öppet Bildarkiv Sydsvenska Medicinhistoriska Sällskapet. Photo Lars Stavenow, 131,120-007Copp.jpg

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BWJ realized that the treatment of patients with Adams-Stokes attacks needed improvement. The Swedish physician and engineer Rune Elmqvist (1906–1996) had recently invented an improved pacemaker, but its use was met with widespread skepticism. One night in September 1961 when BWJ was on call, a 44-year-old man was admitted with an Adams-Stokes episode. Without consulting his senior, BWJ contacted the thoracic surgeon on call and urged him to consider insertion of a pacemaker. Otto Holen was just having dinner but arrived within minutes, still chewing his meal. He performed the requested surgery and transplanted an Elema Schönander pacemaker. Surgery was followed by a smooth recovery and an uneventful followup. The patient was working full-time 18 months later. Åke Senning (1915–2000) in Stockholm had performed a similar procedure at about the same time. In December 1962, a paper was submitted from Malmö reporting on nine implants [22]. Two patients had died but seven survived in good health (Fig. 20.6). BWJ now decided that complete heart block was to become his theme for a dissertation and JW became his supportive mentor. The comprehensive study was defended in 1966 and was based on almost 200 cases of complete heart block found in the ECG registry from 1951 to 1964. The estimated incidence was 6,3/100 000/ year, and the overall 1-year mortality was 50%. It was even higher in patients with

Fig. 20.6 Implantable pacemaker. Wikipedia https://upload.wikimedia.org/wikipedia/commons/b/ b0/PPM.png © Npatchett-own work. CC BY SA-4.0

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myocardial infarction. The average atrial frequency was 93 beats per minute (bpm), and the ventricular response rate was 43 bpm. Digitalis therapy reduced the atrial tachycardia and augmented cardiac output. Importantly, the use of an “artificial pacemaker” in 17 patients dramatically improved outcomes and return to work, confirming the previous report [23]. The thesis soon captured international attention and BWJ was invited as a contributor to several prime international meetings, such as the New York Academy of Science [24], and at the universities of Copenhagen, Lausanne, and Tokyo. In Boston at Harvard around 1970, his visit overlapped with one of JW’s, who was pleasantly surprised to discover his scholar in the audience during a lecture. Although other centers reported more favorable outcomes of medical treatment, the use of pacemaker soon was the favored treatment for patients with Adams-Stokes syndrome [25]. Because episodes of syncope can have non-cardiac causes, BWJ realized the need for better diagnostic screening. The advent of long-term ECG monitoring in the 1970’s filled this need [26]. It was strongly promoted by BWJ and Nils-Johan Abdon (born 1941) who, working in a nonteaching hospital in in Uddevalla had published a Lancet paper on hidden bradyarrhythmia as cause for neurologic disturbances [27]. In Malmö Abdon worked on a doctoral thesis titled “Cardiogenic neurology” [28]. Undiagnosed atrial fibrillation and other arrhythmias were uncovered and correlated with femoral neck fractures, “senile” dementia, and morbidity in athletes. The 24-h ECG monitoring frequently resulted in implantation of a pacemaker. As a result, the prevalence of pacemakers in the Malmö population was higher than anywhere else at the time since the high screening activity policy was initially received with great skepsis. In retrospect it has saved countless lives. Abdon returned to the Uddevalla hospital and continued as the leading cardiologist in the province of Bohuslän (Fig. 20.7). Management of patients with myocardial infarction in the 1960’s still called for complete bedrest for weeks and very slow mobilization. But this tradition had disadvantages. It increased the risk of deep vein thrombosis and slowed recovery to an Fig. 20.7 Nils-Johan Abdon. © Private, N-J Abdon

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Fig. 20.8 BWJ and Tore Leijon, chairing the Malmö Patient’s Club in 1968. © Personal files of BWJ

active life [29]. BWJ boldly introduced early mobilization and adapted physical therapy in 1968 on his ward, initially to the shock of JW when he came for rounds. But the new routine turned out to be safe, and it was soon popular among the patients and spread countrywide as “The Malmö Model” [30] (Fig. 20.8). Another colleague in the Division of Cardiology was Jan Sievers (born 1930), a nephew of Hans Forssman in Gothenburg (Chap. 17). His father Olle Sievers (1899– 1982) was a physician from Finland who came to Sweden in 1950 and worked as chief of bacteriology in Gothenburg. There he helped Jörgen Lehman (Chap. 9) to develop para-amino-salicylic acid, PAS, for treatment of tuberculosis. Sievers Junior started medical school in Lund but was “demoted” to continue the third year in Malmö. As a freshly minted physician he was attracted by GB, who asked him to review some records of patients with myocardial infarction. Under the guidance of BWJ, when GB had moved to Stockholm, this undertaking grew into a doctoral thesis in which he surveyed the over 3000 cases of patients that had been hospitalized in Malmö between 1935 and 1961. Although only addressing hospitalized cases the work could almost qualify as a population-based study, since most symptomatic patients were hospitalized in the city’s only hospital. Male patients dominated the younger age groups, and diabetes was four times more common than in the general population. Careful postmortem examinations were performed on 97% (!) of the patients who died. The autopsies performed provided essential sources of information. Scars left by presumably asymptomatic older myocardial infarctions were found in more than one third of the 811 autopsied patients and cardiac rupture was the ultimate cause of death in 13% [31]. Sten Winblad, Folke Linell, and their colleagues thus contributed fundamental scientific information about this topic in that period. Sievers included their data, but surprisingly their work was not acknowledged in the dissertation. Such a lapse was never committed by his mentors. When the position as leader of the Division of Cardiology as associate professor became vacant this was awarded to BWJ.

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Sievers then chose to leave Malmö. JW was pleased when he learned that Sievers had been appointed assistant head at the Department of Medicine in Linköping, where his friend from Uppsala, Ragnar Berlin (1910–1994), would become professor of medicine in 1970 when the University of Linköping was founded. In Linköping, Sievers would generate a cardiology division and make a career as physician administrator, but he gave up research. In 1985, he became the chief physician of the hospital. JW was wise when he selected BWJ and not Sievers to lead cardiology in Malmö. A number of other PhD. students were trained under BWJ. Alf Torp (1937–2020), an immigrant from Norway had worked in an illustrious group of cell biologists including Åke Hillarp, Bengt Falk, and Arvid Carlsson in Lund as a medical student. They all would become noted professors and chairmen, and Carlsson would be a Nobel Laureate in 2000 [32–34] (Chap. 9). However, Torp chose to abandon this fertile environment and become a clinician. He joined the Division of Cardiology as an able investigator and boldly introduced endomyocardial biopsy using a new Japanese method [35, 36]. It found diagnostic application in amyloidosis [37] and carcinoid syndrome [38], but the technique would only gain wider importance in the era of heart transplantation. A patient with carcinoid tumor and liver metastases was followed up by Torp. Only marginal progression was observed during eight years following non-radical surgery, illustrating the limited aggressiveness of this disorder. [39]. In another paper Torp showed that ambulatory oxygen therapy was both feasible and beneficial [40]. As a well-trusted cardiologist, Torp spent his final active years running a busy private practice where he excelled in the art of attentive listening and state-of-the-art management (Fig. 20.9). Erik Trell (born 1939) joined the division in the 1960’s. He had indicated that his original plan was to specialize in psychiatry. At the oral examination with JW, his performance pleased the professor and the examination turned into a conversation and invitation to start as a house officer. Trell switched to medicine and JW became his lifetime hero. He would become an assiduous worker who in rapid succession Fig. 20.9 Alf Torp, 1980s. Photo Lars Stavenow. Öppet Arkiv Sydsvenska Medicinhistoriska Sällskapet 131,120-003Copp.jpg

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Fig. 20.10 Erik Trell 1989s. © Private file of Erik Trell

authored an impressive number of papers on different aspects of pulmonary hypertension [39–42]. He also published papers with JW on a series of patients with carcinoid syndrome [38, 43]. Thereafter, Trell developed an interest in medical sequelae of alcohol abuse [44]. He became assistant professor in 1973. In 1982, he switched to Community Medicine in Malmö and from 1987–2006 he was professor and chairman at the Department of Family Medicine in Linköping [45] (Fig. 20.10). In the 1990s BWJ mentored Ole Hansen’s doctoral dissertation. Hansen could use the Malmö myocardial infarction (MI) registry which remained meticulously maintained by BWJ and his wife and show detailed unbiased population-based figures on the improved MI prognosis starting in the 1970s [46]. Another relevant contribution was that in an experimental myocardial infarction model nonselective betablockers were superior to selective betablockers in preventing stress-induced lowering of potassium and magnesium. Low potassium and magnesium may induce serious arrhythmias in myocardial infarction [47]. Hansen remains an anchor of outstanding cardiology in Malmö (Fig. 20.11).

20.3 Concluding Comment No tensions ever developed between JW and BWJ. The issue of separating the cardiology division from internal medicine never was raised. Fellows were groomed as internists and were mentored as cardiologists, stayed on as senior staff members, moved to other hospitals, or went into private practice. Following the example of his mentor, BWJ remained fully active long after retirement, becoming the most respected senior cardiologist in Sweden, and at age 90 years was celebrated as the very first Gustav Nylin Prize awardee. Gustav Nylin (1892–1961) is recognized as the first Swedish cardiologist. He was a founder of the European Society of Cardiology. A book published by BWJ in 2020 titled “Kyla i konst och vetenskap” (Chill in science and art) was well received in the press. Its attractive cover was adorned by

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Fig. 20.11 Ole Hansen. © Private Ole Hansen

his artist wife Anita Johansson. As someone who treasured the world of humanities, JW would have enjoyed this engaging treatment of the subject matter. And it is very obvious that JW had selected the right leader of the division when he appointed BWJ and not the formally more merited competitor (Fig. 20.12). Fig. 20.12 Cover of “Kyla I vetenskap och konst”, Chill in science and art. Edited by Bengt W. Johansson, 2020. Painting by accomplished artist Anita Johansson, the wife of BWJ. Photo Th author

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References 1. Biörck G. Heart. Annu Rev Physiol. 1952;14:283–314. 2. Biörck G, Krook H. Myocardial injury at cardiac catheterization: report of a case. Acta Cardiol. 1951;6:101–6. 3. Wulff HB, Biörck G, Bergh NP, Krook H, Axén O, Lundskog O. Studies in mitral stenosis. I. Results of one year’s series of surgically treated cases. Acta Med Scand. 1953;144:274–83. 4. Biörck G, Winblad S, Wulff HB. Studies in mitral stenosis. II. Observations on incidence of active rheumatic carditis in left auricular appendages resected at operation for mitral stenosis. Am Heart J. 1952;44:325–32. 5. BiörckG, Axén O, Krook H, Andrén L, Wulff HB. Studies in mitral stenosis. IV. The relative merits of various diagnostic methods in mitral valvular disease. Am Heart J. 1953;45:13–39 6. Werkö L, Biörck G, Crafoord C, Wulff H, Krook H, EliaschH H. Pulmonary circulatory dynamics in mitral stenosis before and after commissurotomy. Am Heart J. 1953;45:447–90. 7. Biörck G, Hall P, Jansson I. Synpunkter på 1950 års vitiematerial vid Malmö allmänna sjukhus; några kommentarer till frågan om mitralisstenosens operativa behandling [Observations on heart defect cases at Malmö general hospital 1950; comments regarding surgical therapy of mitral stenosis]. Sven Lakartidn. 1951;48:2214–24. 8. HallL P, Dencker SJ, Biörck G. Studies in mitral stenosis. III. Observations on the incidence and distribution of cerebral emboli with regard to the possibilities of their prevention during operative procedures. Am Heart J. 1952;44:600–7. 9. Björck G, Hall P. Follow-up studies in rheumatic fever patients; a preliminary report. Acta Rheumatol Scand. 1955;1:119–26. 10. Hall P, Biörck G. The natural history of rheumatic valvular heart disease and its bearing upon the results of surgery for mitral stenosis. Acta Rheumatol Scand. 1958;4:70–8. 11. Hall P, Biörck G, Ohlsson NM. Roentgenological evaluation of the left atrium in early mitral stenosis. Acta Med Scand. 1961;169:313–22. 12. Hall P. On the prognosis and natural history of acute rheumatic fever and rheumatic heart disease. A study based upon a 25-year material in a Swedish town served by a single hospital. Acta Med Scand Suppl. 1961;S362:1–122. 13. Biörck G, Johansson B. Comparative studies on temperature effects upon electrocardiogram in some vertebrates. Acta Physiol Scand. 1955;34:257–72. 14. Duker GD, Olsson SO, Hecht NH, Senturia JB, Johansson BW. Ventricular fibrillation in hibernators and nonhibernators. Cryobiology. 1983;20:407–20. 15. Johansson BW, Biörck G, Veige S. Some laboratory data on hedgehogs, hibernating and nonhibernating. Acta Physiol Scand. 1956;37:281–94. 16. Biorck G, Johansson B. Influence of anoxia on the hypothermic electro-cardiogram of hedgehog and man. Cardiologia. 1957;30:344–8. 17. Johansson BW. Brown fat: a review. Metabolism. 1959;8:221–40. 18. Biörck G, Johansson BW, Nilsson IM. Blood coagulation studies in hedgehogs, in a hibernating and a non-hibernating state, and in dogs, hypothermic and normothermic. Acta Physiol Scand. 1962;56:334–48. 19. Johansson BW. The hibernator heart-nature’s model of resistance to ventricular fibrillation. Arctic Med Res. 1991;50 Suppl 6:58–62 20. Johansson BW, Sievers J, Svanberg L, Bjerre I. Cronberg, Eriksson S, Lindh J, Mansson T, Wollheim F, Zettervall O [External heart massage]. Sven Lakartidn. 1962;59:1285–302. 21. Johansson BW. Adams-Stokes syndrome. Review and follow-up study of forty-two cases. Am J Cardiol. 1961;8:76–93 22. Swedberg J, Johansson BW, Karnell J, Malm A. Implantation of pacemaker for Adams-Stokes syndrome. Acta Chir Scand. 1963;125:547–56. 23. Johansson BW. Complete heart block. A clinical, hemodynamic and pharmacological study in patients with and without an artificial pacemaker. Acta Med Scand Suppl. 1966;451:1–127 24. Johansson BW. Longevity in complete heart block. Ann NY Acad Sci. 1969;167:1031–7.

References

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25. Edhag O, Swahn A. Prognosis of patients with complete heart block or arrhythmic syncope who were not treated with artificial pacemakers. A long-term follow-up study of 101 patients. Acta Med Scand. 1976;200:457–63 26. Johansson BW. Long-term ECG in ambulatory clinical practice. Analysis and 2-year follow-up of 100 patients studied with a portable ECG tape recorder. Eur J Cardiol. 1977;5:39–48. 27. Abdon NJ, Malmcrona R. Symptomatic patients with bradyarrhythmias hidden in the population. Lancet. 1973;2(7829):607–9. 28. Abdon NJ. Cardiogenic neurology. Clinical studies using long-term electrocardiographic recording. Thesis, Malmö. 1981; 1–46. 29. Early mobilization after myocardial infarction. Lancet. 1969;1(7599):821. 30. Ragnarson P. 80 år 936–2016. Historik om hjärt- och lungsjukas förening i Malmö. (80 years 1936–2016. History of the Malmö Club of Heart- and Lung Disease Patients). Malmö 2016; Private document:1–25. 31. Sievers J. Myocardial infarction: clinical features and outcome in three thousand thirty-six cases. Acta Med Scand. 1964;175 Suppl 406:5–123 32. Falck B, Hillarp NA, Torp A. A new type of chromaffin cells, probably storing dopamine. Nature. 1959;183(4656):267–8. 33. Falck B, Torp A. A fluorescence method for histochemical demonstration of noradrenalin in the adrenal medulla. Med Exp Int J Exp Med. 1961;5:428–32. 34. Carlson A, Falck B, Hillarp NA, Torp A. Histochemical localization at the cellular level of hypothalamic noradrenaline. Acta Physiol Scand. 1962;54:385–6. 35. Torp A. Endomyocardial biopsy. Scand J Thorac Cardiovasc Surg. 1973;7:253–6. 36. Torp A. Special investigations in COCM: biochemical analysis of cardiac biopsies. Postgrad Med J. 1978;54:494–9. 37. Hedner P, Rausing A, Steen K, Torp A. Diagnosis of cardiac amyloidosis by myocardial biopsy. Acta Med Scand. 1975;198:525–8. 38. Aronsen KF, Torp A, Waldenstöm JG. A case of carcinoid syndrome followed for eight years after palliative liver resection. Acta Med Scand. 1976;199:327–9. 39. Malmquist J, Trell E, Torp A, Lindström C. A case of drug-induced (?) pulmonary hypertension. Acta Med Scand. 1970;188:265–72. 40. Johansson BW, Torp A, Trell E. Prolonged ambulatory oxygen therapy in pulmonary hypertension of various etiology. Acta Med Scand. 1971;189:155–9. 41. Trell E, Lindström C. Pulmonary hypertension in systemic sclerosis. Ann Rheum Dis. 1971;30:390–400. 42. Trell E, Johansson BW, Linell F, Ripa J. Familial pulmonary hypertension and multiple abnormalities of large systemic arteries in Osler’s disease. Am J Med. 1972;53:50–63. 43. Trell E, Rausing A, Ripa J, Torp A, Waldenström J. Carcinoid heart disease. Clinicopathologic findings and follow-up in 11 cases. Am J Med. 1973;54:433–44. 44. Trell E, Kristenson H, Fex G. Alcohol-related problems in middle-aged men with elevated serum gamma-glutamyltransferase: a preventive medical investigation. J Stud Alcohol. 1984;45:302–9. 45. Moidu K, Wigertz O, Trell E. A multicenter study of data collection and communication at primary health care centers. J Med Syst. 1991;15:205–20. 46. Hansen O, Johansson BW. Epidemiologic aspects of coronary heart disease in Malmö, Sweden, 1935–1988. Am J Epidemiol. 1991;133(7):721–33. 47. Hansen O, Johansson BW. Benefits of non-selective versus cardioselective beta-blockers in acute myocardial infarction in hypertensive patients. J Hypertens Suppl. 1993;11(4):S55-60.

Chapter 21

Bengt Skanse and Endocrinology in Malmö

Abstract In 1950 Bengt Skanse started 12 years of brilliant contributions in Malmö not only in the field of endocrinology. His remarkable international network outstanding knowledge and winning personality was a great asset for the department. Liked by colleagues, students, and outside collaborators he added greatly to the reputation of the department. In 1963 he died of drowning and was succeeded by Berndt Hökfelt from Karolinska. Pharmacotherapy of hypertension and diabetes became new areas in focus. Endocrinology became an independent department named Department of Medicine II.

21.1 Bengt Skanse Metabolic research as a tool to understand pathogenetic mechanisms had been seeded in the mind of JW in childhood during the Sunday walks with his father in Stockholm. Some decades later JW encountered of Bengt Skanse (1918–1963), BS, and recognized him as a gifted prosing man of the future with interest in metabolic diseases. It has been mentioned (Chap. 8) that JW sent him to Harvard in 1947 and that this resulted in a thesis on radio-iodine in 1949. In 1950 JW was pleased to recruit him to his permanent staff in Malmö. The young Skanse family started life in Malmö in an apartment, but when more children arrived the family moved to a larger home with a view of the sound separating Sweden and Denmark. BS was liked by all. He generously shared his large knowledge and was endowed with a warm and charming personality. He was also an empathic physician and consequently much appreciated by staff and undergraduate students as a teacher and dedicated colleague (Figs. 21.1 and 21.2). The introduction of cortisone and ACTH for treatment of rheumatoid arthritis at the Mayo Clinic in 1948–9 was a paradigm shift in medical practice and a milestone in the history of rheumatology and endocrinology. By the time Philip S. Hench delivered his Nobel Lecture in Stockholm on December 11, 1950, thousands of patients with rheumatoid arthritis had already been treated with the new drugs cortisone and ACTH. But adverse effects had become evident, and he wisely stated that “These hormones still belong to the physiologist and to the clinical investigator as much as, if not more © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Wollheim, Jan Gösta Waldenström and His World, Springer Biographies, https://doi.org/10.1007/978-3-031-36739-7_21

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Fig. 21.1 Row houses at Bülow Hybes Väg, where the Skanse family lived from 1957 onward, close to the Sound in Malmö. The houses are designed by the noted architects Samuelsson & Jaenecke and are now protected buildings. Photographer The author

Fig. 21.2 Bengt Skanse in 1960. Courtesy Beata Skanse. Also available at Öppet Bildarkiv Sydsvenska Medicinhistoriska Sällskapet 140108_Bengt_Skanse_Copp.jpg. http://www.medicinhi storiskasyd.se/smhs_bilder/

than, to the practicing physician” [1]. Cortisone and ACTH were expensive drugs, and their supply was limited. In Malmö, JW obtained a special grant to cover the costs for local patients in need of the new therapy. Prednisone and prednisolone first became available in 1954 [2]. BS contributed to the field with a study of chemical changes in the adrenals induced by ACTH [3], with a paper on the beneficial use of cortisone in patients with polymyositis [4], and later with one on the use of ACTH to test adrenal function [5].

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21.2 Thyroid Diseases The main trust of Skanse’s research, however, focused on diseases of the thyroid gland which he had begun in Boston. JW proudly managed in October of 1951 to obtain licensing from the radiation agency allowing BS to establish the first hospital unit in Sweden authorized for handling and medical use of radioactive material. The paper BS had published in 1948 showing 131 I uptake in the thyroid gland [6] constituted a breakthrough in the field. The new diagnostic method exposed the patient to 200 times less radiation than previous methods, and it was in wide use for decades. BS collaborated with the brilliant young nuclear physicist in Lund Sven Johansson (1923–1994) on a historic paper describing a forerunner of the gamma camera [7]. Its sensitivity was too low for clinical use at the time, but it foreshadowed the development of scintigraphy with gamma cameras decades later [8]. Sven Johansson was elected vice chancellor of the university from 1970 to 1977 and was able to restore the trust between students and teachers after the painful rift caused by social and political unrest in 1968 (Fig. 21.3). Another of BS’s important contributions addressed the problem of how to distinguish normal thyroid function from borderline hyperthyroidism. Patients selected from the thesis of BS in Uppsala and followed up diagnostically were tested with three methods to determine their power to discriminate among these thyroid activity states. Conventional basic metabolic rate, BMR, was compared with the 24-hour excretion of 131 I, a measure of rate of iodine uptake in the gland, and protein bound iodine, PBI, a measure of synthesized thyroxin. The table shows the relative performance of the tests individually and in combination. BMR contributed only marginally and could be abandoned. PBI was still a time-consuming, laborious test when this paper was published, making the radio-iodine uptake assay most useful [9]. But then, in collaboration with the laboratory engineer Inge Hedenskog, BS devised a simple and reliable method to measure PBI [10]. This made PBI the preferred standard test in clinical practice [11] (Fig. 21.4). Fig. 21.3 Nuclear physicist Sven Johansson, vice chancellor of Lund University 1970–72. From http://history.fysik.lu.se/ima ges/FysicumsHistoriaBok_ pdf/SV_FysikILund_web/ SV_Bok_09_SvJ_web.pdf 28 February 2022

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Fig. 21.4 Comparative discriminative efficiency of individual tests and of a combined score for borderline hyperthyroidism, RI = 24 h. excretion of 131 I. Table II from [9]. © The authors

21.3 Other Contributions Professor James H. Means, who hosted BS in Boston, had described a rare type of myxedema that did not respond well to thyroxin [12]. These patients also had other endocrine deficiencies caused by hypophysial insufficiency. In Malmö, BS developed a new test which could distinguish such patients from those with primary hypothyroid myxedema. The test employed determination of serum PBI before and after administration of thyroid stimulating hormone, TSH. A seminal paper based on simple, logical reasoning, and careful clinical analysis examining some 200 patients showed that the test clearly differentiated between normal function, primary hypothyroidism, and secondary hypothyroidism related to hypopituitarism, low thyroid reserve, and cases in which clinically suspected hypothyroidism could be excluded [13]. Sadly, when this excellent paper was published, the author was no longer alive. A popular view that excess body weight was a feature of hypothyroidism was investigated in 76 consecutive untreated patients and shown to be incorrect. Body weight did not deviate from the norm, and BMR did not correlate with body weight [14]. In an editorial on the therapeutic use of 131 I irradiation in hyperththyriodism, BS advises against its use in patients under age 45 years. In an invited lecture delivered in Finland in August of 1961, BS summarized the Malmö experience with PBI based on more than 1000 patients. BS showed its value both in distinguishing marginal hypofunction from normal function and in distinguishing between primary and secondary hypothyroidism. The major shortcoming of the BPI test is that it cannot distinguish exogenous from endogenous iodine, which precludes its use in patients recently exposed to exogenous iodine [14]. In 1955, BS cared for a patient suffering from thyrotoxicosis and epileptic seizures. He was reminded of a paper by his Uppsala mentor JW on neuropsychiatric involvement in patients with thyrotoxicosis [15]. This observation formed the basis for a collaboration by BS and a psykiatrist in Lund, Eberhard Nyman (1922–2005) resulting in a report on electroencephalograms (EEGs) of 44 patients with thyrotoxicosis. Abnormal EEG patterns were present in 19 of the patients, and abnormal focal activity was found in four. Most abnormalities disappeared after treatment [16]. Two other papers addressed EEG in Addison disease [17] and in patients with Vitamin D toxicity [18].

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21.4 Aldosterone Conn syndrome or primary hyperaldosteronism is present in a fair number of people with hypertension. The discovery by Jerome W. Conn (1904–1994) is a splendid example of JWs thesis that individual patients are signposts for fruitful research. Conn was a graduate of the University of Michigan in Ann Arbor, where he became professor of endocrinology in 1943. During World War II he noticed that armed forces service members exposed to the heat of South East Asia excreted perspiration containing less sodium than normal indicating a sodium-sparing defense mechanism. At a meeting in Chicago in October of 1954, he presented a 34-year-old female patient with a 4-year history of hypertension, tetanic cramps, leg weakness, and fainting. Conn found a 24-h aldosterone excretion of 1500 μg, 10 times the upper limit of normal. Slightly high sodium and very low potassium were found in plasma. He predicted that the condition could be caused by a hormone-producing tumor. At the spring meeting of the Endocrine Society next year in Atlantic City, Conn reported that indeed an encapsulated adrenal tumor, rich in aldosterone, had been removed and the patient was healthy [19]. An editorial in the Lancet weeks later had the title “Conn’s syndrome (Primary hyperaldosteronism)”. It assessed the significance of this observation as equal to that of the discovery of Cushing’s syndrome [20] (Fig. 21.5). In April of the following year, a 45-year-old woman was referred to BS for further evaluation from a military hospital in Sollefteå, a city 1100 km to the north of Malmö, where the chief of medicine Dr. Folke Möller had diagnosed hyperaldosteronism, probably the first case in Sweden. The explanation of Dr. Möller’s referral of the patient to such a distant hospital was probably the reputation of BS and the department in Malmö. The patient had a 12-year history of hypertension, occasional vomiting, and had been experiencing attacks of pronounced muscle weakening and paresis for five years. Low potassium in serum of 2.2–2.5 mEq/l was noted in Malmö. The Fig. 21.5 Jerome W Conn. © University of Michigan. https://medicine.umich.edu/ sites/default/files/IntMed MENDJeromeConn.jpg

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tendon reflexes were incresed. Elevated excretion of aldosterone in the urine was confirmed in the laboratory of Bernt Hökfelt at Karolinska in Stockholm. The presence of a suprarenal nodule was visualized by abdominal radiography enhanced with retroperitoneal insufflation of air. An encapsulated tumor was extirpated by professor Wulff. The aldosterone excretion became normal and the spasticity improved, but the hypertension persisted [21]. It is likely that sustained hypertension over the years had resulted in irreversible vascular sclerosis. A decade later, aldosterone producing tumors were found to be present in eight of 700 consecutive postmortem examinations done in Malmö, a number far exceeding that claimed in previous reports [22]. The opposite of hyperaldosteronism was predicted by Conn in 1954. In 1957, BS encountered a 56-year-old housewife with a history of fatigue, obstipation, attacks of dizziness, insomnia, and weight loss. Her blood pressure was 100/70 mmHg, and the orthostatic test was normal. The level of serum potassium was at the lower range of normal, and sodium was subnormal. Bernt Hökfelt at Karolinska Hospital, a friend of BS, performed a laboratory test confirming the absence of aldosterone in the patient’s urine [23]. At this time the condition had only been described in a single patient in whom the condition was complicated by cardiovascular comorbidity [24]. A final proof of aldosterone deficiency in the Mamö patient was the successful treatment by parenteral administration of synthetic aldosterone for six weeks. Lasting improvement was achieved by added sodium chloride to the diet and prescription of fludrocortisone [25]. This is still the current therapy for hypoaldosteronism. A number of enzyme mutations leading to various forms of congenital and adult hypoaldosteronism have later been identified in children [26].

21.5 Continued Growth of Endocrinology BS was the permanent attending physician at “Ward E”, and it became the embryo of a comprehensive metabolic unit. He strived for the formation of an independent department of endocrinology, an effort not immediately adopted by JW. Service on the ward of BS was highly sought after by medical students and house staff thanks to the warm friendly atmosphere and outstanding clinical knowledge and dedicated teaching that BS provided. The productivity of BS in various fields as well as his contributions to development of the field of endocrinology is reflected by the papers described above. Additionally, in collaboration with Wilfried von Studnitz and Nancy Skoog in the Department of Clincal Chemistry, BS studied still unexplored influences of ACTH and cortisone on the metabolism of lipids and lipoproteins [27]. In collaboration with Inga Marie Nilsson and Karl Gydell, augmented fibrinolysis was described as a new cause of bleeding in sarcoidosis [28]. On February 24, 1958, a 15-year-old girl was referred to BS from another hospital with a one year history of atypical Raynaud’s phenomena in form of monthly attacks of painful numbness of fingers and sometimes toes, lasting up to seven days. The sedimentation rate was elevated to 40 mm/1 h. Two months before admission, she had also experienced syncopal episodes lasting a few miutes. Physical examination revealed

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pale fingers and toes. The patient had no dyspnea and could climb three flights of stairs without becoming breathless. The first heart sound was loud at the apex, and a grade 3/6 mid-systolic murmur was heard. The pulse rate was 80–88 beats per minute and blood pressure 115/75 mmHg. ECG and chest radiographs were normal. Serum eletrophoresis showed signs of inflammation with normal gamma globulins, and the LE test for lupus was negative. One week after admission the patient lost consciousness and developed right-sided hemiplegia. The EEG showed a left-sided focus and left carotid angiography visualized extatic arteries. Ventricular drainage was performed but the patient died within days. On postmortem examination, a friable 4 × 6 cm large atrial myxoma was found along with multiple tumor-derived emboli in the brain, liver, and kidneys. The authors urged vigilance for this rare condition in view of possible surgical cure [29]. In October–November of 1957, Malmö with a population of approximately 220 000 noted 8117 registered cases of influenza. Ten patients died, nine of them while inpatients. These underwent autopsy, the results of which are shown in Fig 21.6. Three of the patients had untreated Addison disease, and one had pituitary fibrosis. One patient had rheumatoid arthritis and impaired adrenal response to ACTH secondary to cortisone therapy [30]. This publication can be read with special interest during the COVID-19 pandemic which started in 2020 (Fig. 21.6). BS reflected on the presence of flushing, sweating, fatigue, palpitation, dyspnea, and diarrhea in patients with thyreotoxicosis. They reminded him of symptoms in patients with the carcinoid syndrome recently described by JW. This prompted a publication with Arne Hanson in 1959 showing levels of 5HIAA above 10 mg/24 h before treatment in 19 of 23 patients. After adequate therapy consisting of surgery in 15, 131 I in seven, and thiouacil in one of the patients, lower levels of 5HIAA were observed in 20 of the patients [31]. This Lancet paper must have been satisfying reading for JW, the man who discovered the carcinoid syndrome (Fig. 21.7).

Fig. 21.6 Fatal cases of influenza in Malmö in 1957. © From Ref. [30] with permission

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Fig. 21.7 Urinary excretion of 5HIAA in 23 patients with thyrotoxicosis. © From Ref. [31] with permission

21.6 The Tragedy Clinical service demands for endocrinology and the laboratory of diagnostic nuclear medicine continued to increase. BS who managed both, as mentioned, desired the creation of an independent department of endocrinology. JW, a firm advocate of unified internal medicine, was hesitant. Consequently, when Haquin Malmros (1895– 1995), the professor and chairman of medicine in Lund, retired in 1962, BS applied for the chair. The assessors placed him in the top position, and BS had the option of becoming professor and chairman of medicine in Lund. Post hoc or propter, JW agreed to the creation of an independent department of endocrinology named Medicine 2. Waiting for this to materialize, BS decided to update his familiarity with developments in clinical chemistry. CB was delighted to employ BS as an overqualified regular amanuensis. They had been close friends since medical school when both were supplemental employees in the Department of Histology in Uppsala where Erik Agdur (1886–1942) was the respected professor and investigator of endocrine tissues. A collaborative research project now started addressing the effect of synthetic steroids used in treatment of breast and prostate cancer on plasma proteins. The ambitious study was complicated, since inflammation caused by the malignancies also influenced protein synthesis. Among the main conclusions from the investigation was that haptoglobin, orosomucoid, and transferrin levels increased out of proportion after androgen stimulation, while ceruloplasmin and α-lipoprotein were predominantly augmented by estrogens. The manuscript was entered anonymously in 1962 for the prestigious Alvarenga Prize competition awarded for not yet published manuscripts by the Swedish Society of Medicine. The Prize Committee selected the

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manuscript for the Prize in 1963. By then BS was already deceased. The paper had been submitted to the Scandinavian Journal of Clinical and Laboratory Investigation but unfortunately was rejected. Only a summary of this study has been published by CB [32]. As previously mentioned, the Skanse family home was not far from the waterfront in Malmö. BS was a lover of nature, and it was his habit to take a walk in the field bordering the shore before work. On a winter morning in late January of 1963, he failed to return from his morning stroll. It was still dark and slippery when he started out on this cloudy day. His cap was found in the water where he had drowned. This accident shocked everyone in the department. Details of how this healthy 45-year-old man perished have never been clarified. The tragedy is remembered as a monumental loss to family, to friends, to colleagues, to endocrinology, to patients, and not least to Jan Waldenström who had to shoulder the heavy task of composing the obituary. It is known that until the tragic death of BS, JW had nourished a secret hope that he would one day become his successor as department chairman.

21.7 Endocrinology After Bengt Skanse The responsibility for managing the laboratory of diagnostic nuclear medicine was transferred to Bertil Nosslin, who did outstanding work developing it over coming decades. It started as a division of the Department of Clinical Chemistry and eventually became an independent unit named Diagnostic Isotope Laboratory. Nosslin’s unique competence in mathematics, physics, statistics, and clinical medicine as well as his outstanding capacity for work and administrative skill developed the laboratory into a leading national and international center (Fig. 21.8). Bernt Hökfelt (1924–2006) was appointed to the position aimed for Bengt Skanse as head of the Department of Medicine 2, Endocrinology. Hökfelt was a scholar of Professor Rolf Luft (1914–2007) at Karolinska [33]. Luft had spent several postdoctoral years with Fuller Albright in Boston. Diabetes became his main area of Fig. 21.8 Berndt Hökfelt 1980s. © Kungliga Fysiografiska Sällskapet i Lund. https://docplayer.se/ 76831921-Kungl-fysiograf iska-sallskapet-i-lund-inmemoriam.html

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investigation in Stockholm, and this eminent physician is considered “the father of endocrinology” in Sweden. In Malmö Hökfelt became a competent leader of a productive department. He was serious, formal, and perhaps a bit stiff. Under his leadership one focus of the department became new and emerging therapies for hypertension [34, 35]. Diabetes was another main field, and the department would later develop into an international center of excellence in diabetes [34]. Two fellows close to BS who lost their scientific mentor with his death were Torsten Denneberg (born 1928) and John Fredrik Dymling (1931–2007). Bone metabolism and calcium were the initial field of “Jonte” Dymling. His new mentor became the orthopedic surgeon Göran Bauer (1923–1994), later chief of research at the Hospital for Special Surgery in New York. Bauer returned to Sweden as professor and dynamic chairman of the Department of Orthopedics in Lund. After obtaining his Ph.D. [36], Dymling worked on bone metabolism with a new isotope techniques and followed Bauer to New York for a postdoctoral year [37]. He then became the deputy of professor Hökfelt and continued clinical research [38]. He was a kind of superior leader and advanced to become the chief administrative physician of the hospital (Fig. 21.9). Torsten Denneberg would follow another path stimulated by BS and a visiting friend of BS, the pioneer of nuclear medicine working at UCLA, George V. Taplin (1910–1975), he embarked on investigating the use of isotopes to assess renal function. Denneberg remembers the profound confidence and guidance emanating from BS, based on his extensive knowledge, his remarkable network of experts in matters of interest, and his friendliness and patience with the scholar. It was hard to replace BS as mentor, and a number of different experts were needed to fill the gap. Experimental and human studies guided first by BS and with help of Inge Hedenskog, the pleasant engineer from clinical chemistry, and throughout by Bertil Nosslin [39–42], resulted in Denneberg’s doctoral thesis in 1964 [43]. Renography became a reliable method to assess renal uptake and elimination of 131 I Hypaque and became a local standard clinical method replacing inulin clearance for a short time until Hypaque was replaced by 131 I Hippuran [44]. Dennenberg was promoted to associate professor. Fig. 21.9 John Fredrik “Jonte” Dymling in 1988 Öppet bildarkiv, Sydsvenska Medicinhistoriska Sällskapet. Photographer Björn Henriksson. SMHS9198_000_ 01Copp.jpg

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With help of Fleming Raaschou (1915–1983), the expert in Copenhagen, Denneberg introduced peritoneal dialysis in Malmö in 1966 and hemodialysis two years later. Collaboration with Inga Marie Nilsson’s group was close [45, 46]. Starting with a single patient, Denneberg began investigations of the rare disease cystinuria in collaboration with J O Jeppsson (1937–2020) in the Department of Clinical Chemistry [47]. Denneberg mentored two Ph.D. students in Malmö, Gunnar Sterner and Mats Ekberg [45]. In 1983, he moved to Linköping as head of the Department of Nephrology and started productive research at the young university [48]. Five of his PhD students there investigated cystinuria. Developments set in motion by Bengt Skanse came to fruition during many years following his untimely and tragic death.

References 1. Hench PS. The reversibility of certain rheumatic and non-rheumatc conditions by the use of cortisone or of the pituitary adrenocorticotropic hormone. Nobel Lecture December 11, 1950. 2. Bunim JJ, Pechet MM, Bollet AJ. Studies on metacortandralone and metacortandracin in rheumatoid arthritis: antirheumatic potency, metabolic effects, and hormonal properties. J Am Med Assoc. 1955;157:311–8. 3. Johnsson S, Skanse B. ACTH and bronchial asthma: adrenal cortical function and therapeutic effect. Acta Med Scand. 1952;143:83–97. 4. Skanse B. The effect of cortisone in polymyositis; report of two cases. Acta Med Scand. 1954;150:169–74. 5. Denneberg T, Skanse B. Use of intramuscular injection of ACTH in the diagnosis of adrenocortical insufficiency: value of adequate dose of ACTH for the eosinophil response. Acta Med Scand. 1958;161:477–85. 6. Skanse BN. Radioactive iodine. Its use in studying the urinary excretion of iodine by human in various states of the thyroid function. Acta Medica Scand. 1948;131:251–68. 7. Johansson SA, Skanse B. A photographic method of determining the distribution of radioactive material in vivo. Acta Radiol. 1953;39:317–22. 8. Larsson SA. Gamma camera emission tomography. Development and properties of a multisectional emission computed tomography system. Acta Radiol Suppl. 1980;363:1–75. 9. Zieve L, Skanse B, Schultz AL. Comparative value of the basal metabolic rate, chemical protein-bound iodine, and radioactive iodine excretion or uptake in the diagnosis of borderline hyperthyroidism when used individually or in combination. J Lab Clin Med. 1955;45:281–5. 10. Skanse B, Hedenskog I. The determination of serum protein-bound iodine by alkali incineration: values in normal subjects. Scand J Clin Lab Invest. 1955;7:291–7. 11. Skanse B. Tolkning av PBJ-värden [Interpretation of PBI values]. Nord Med. 1962;68:1234–8. 12. Means JH. Hypothyroidism: diagnosis and treatment. Bull N Y Acad Med. 1940;16:14–9. 13. Skanse B. Value of the TSH-PBJ test in diagnosis of hypothyroidism. Acta Med Scand. 1964;175:335–9. 14. Skanse B. Kroppsvikt vid hypothyreos [Body weight in hypothyroidism]. Nord Med. 1957;57:463–5. 15. Waldenström J. Acute thyreotoxic encephalo- or myopathy, its cause and treatment. Acta Med Scand. 1945;121:251–94. 16. Skanse B, Nyman GE. Thyrotoxicosis as a cause of cerebral dysrhythmia and convulsive seizures. Acta Endocrinol (Copenh). 1956;22:246–63. 17. Skanse B, Nyman GE. Electroencephalographic abnormalities in Addison’s disease and its response to cortisone. Acta Endocrinol (Copenh). 1958;27:469–81.

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18. Skanse B, Nyman GE, Tornegren L. Electroencephalographic abnormalities in vitamin D intoxication and the effect of cortisone. Acta Endocrinol (Copenh). 1959;31:282–90. 19. Conn JW. Presidential address. I. Painting background. II. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med. 1955;45:3–17. 20. Conn’s syndrome; primary aldosteronism. Lancet. 1955;268(6875):1167. 21. Skanse B, Möller F, Gydell K, Johansson NS, Wulff HB. Observations on primary aldosteronism. Acta Med Scand. 1957;158:181–92. 22. Hedeland H, Östberg G, Hökfelt B. On the prevalence of adrenocortical adenomas in an autopsy material in relation to hypertension and diabetes. Acta Med Scand. 1968;184:211–4. 23. Hökfelt B, Skanse B. Effect of aldosterone in a case of hypoaldosteronism. Acta Endocrinol (Copenh). 1960;33:511–9. 24. Skanse B, Hökfelt B. Hypoaldosteronism with otherwise intact adrenocortical function, resulting in a characteristic clinical entity. Acta Endocrinol (Copenh). 1958;28:29–36. 25. Brown JJ, Chinn RH, Fraser R, Lever AF, Morton JJ, Robertson JI, Tree M, Waite MA, Park DM. Recurrent hyperkalaemia due to selective aldosterone deficiency: correction by angiotensin infusion. Br Med J. 1973;1:650–4. 26. Rajkumar V, Waseem M. Hypoaldosteronism. 2021 Feb 10. In: Stat Pearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–. PMID: 32310452. 27. Skanse B, von Studnitz W, Skoog N. The effect of corticotrophin and cortisone on serum lipids and lipoproteins. Acta Endocrinol (Copenh). 1959;31:442–50. 28. Nilsson IM, Skanse B, Gydell K. Fibrinolysis in Boeck’s sarcoid. Acta Med Scand. 1957;16:463–70. 29. Skanse B, Berg NO, Westfelt L. Atrial myxoma with Raynaud’s phenomenon as the initial symptom. Acta Med Scand. 1959;164:321–4. 30. Skanse B, Miörner G. Asian influenza with adrenocortical insufficiency. Lancet. 1959;1(7083):1121–2. 31. Skanse B, Hansson A. Increased thyroid function and the urinary excretion of 5hydroxyindoleacetic acid. Lancet. 1959;1(7238):1072. 32. Laurell CB. Riksföreningen för Cancer Årbok 1963–5. 33. Hökfelt B, Luft R. The effect of suprasellar tumours on the regulation of adrenocortical function. Acta Endocrinol (Copenh). 1959;32:177–86. 34. Hedeland H, Ostberg G, Hökfelt B. On the prevalence of adrenocortical adenomas in an autopsy material in relation to hypertension and diabetes. Acta Med Scand. 1968;184:211–4. 35. Hökfelt B, Hedeland H, Dymling JF. Studies on catecholamines, renin and aldosterone following Catapresan (2-(2,6-dichlor-phenylamine)-2-imidazoline hydrochloride) in hypertensive patients. Eur J Pharmacol. 1970;10:389–97. 36. Dymling JF. Calcium kinetics in osteokinetics and parathyroid disease. Acta Med Scand. 1964;175(Suppl408):1–56. 37. Mautalen CA, Dymling JF, Horwith M. Pseudohypoparathyroidism 1942–1966. A negative progress report. Am J Med. 1967;42:977–85 38. Ljungberg O, Dymling JF. Pathogenesis of cancer-cell neoplasia in thyroid gland. Ccell proliferation in a case of chronic hypercalcaemia. Acta Pathol Microbiol Scand A. 1972;80:577–88. 39. Denneberg T, Hedenskog I. The radioactive hypaque renogram. Assessment of renal function with automatic external scintillation detection equipment. Acta Med Scand. 1959;165:61–70. 40. Denneberg T. The radioactive hypaque renogram in acute renal obstruction. Acta Chir Scand. 1960;118:231–9. 41. Denneberg T, Hansson E, Hedenskog I. On the distribution and excretion of some I 131-labelled renal contrast media. An experimental study in cats. Acta Med Scand. 1960;166:351–6. 42. Denneberg T, Ek J, Hedenskog I. Comparison of the renal excretion of I-131-labelled hypaque and inulin. Acta Med Scand. 1961;170:169–81. 43. Denneberg T. Clinical studies on kidney function with radioactive sodium diatrizoate (Hypaque). Acta Med Scand Suppl. 1966;442:1–134.

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44. Denneberg T, Nosslin B. Renografi: evaluering och kliniska resultat [Renography: evaluation and clinical results]. Nord Med. 1971;85(25):784. 45. Ekberg M, Nilsson IM, Denneberg T. Coagulation studies in hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. Acta Med Scand. 1974;196:373–82. 46. Denneberg T, Ekberg M, Welin CO. Erfarenheter av ett peritoneal- och hemodialys material (Experience from a peritoneal- and hemodialysis material). Nord Med. 1971;85:785–6. 47. Ekberg M, Jeppsson JO, Denneberg T. Penicillamine treatment of cystinuria. Acta Med Scand. 1974;195:415–9. 48. Endsley JK, Phillips JA 3rd, Hruska KA, Denneberg T, Carlson J, George AL Jr. Genomic organization of a human cystine transporter gene (SLC3A1) and identification of novel mutations causing cystinuria. Kidney Int. 1997;51:1893–9.

Chapter 22

Hematology

Abstract In 1962 JW had been elected to host the tenth Congress of the International Society of Hematology in 1964. Despite JW’s lifelong defiance of fragmented internal medicine he took part in the foundation of a Swedish Society of Hematology and even arranged its first official meeting in Malmö in 1963. The international congress in Stockholm in 1964 was a well-attended great success. Leading experts delivered invited lectures before noon and afternoons were filled with submitted abstracts from 450 delegates. The 1960s and 70s were hay days for academic dissertations supervised by JW. Topics included gammopathies, polymyalgia rheumatic/arteritica, and the description of Hb Malmö. The scholars could spread the JW legacy to a large number of major hospitals in Sweden.

22.1 The International Society of Hematology See (Fig. 22.1). Jan Waldenström, JW, although a stalwart of undivided internal medicine, never denied that he also was a hematologist at heart. Fresh out of medical school, he began his career with investigations of topics related to blood. Guided by Elsa Segerdahl he became familiar with bone marrow morphology. His early studies in Uppsala of myeloma, macroglobulinemia, and sideropenia have been dealt with in Chaps. 5, 7, and 8. JW was an early delegate at the meetings of the International Society of Hematology, ISH. The society was founded in 1946, and its 6th meeting was organized in 1956 in Boston where William Dameshek was the president and JW one of 450 delegates. For the 1964 Xth ISH congress JW was elected president in 1962. Since no Swedish society existed, 15 Swedish hematologists at a meeting in Stockholm in November 1962 decided to form one. It was the first in Scandinavia. JW was elected president and Lars-Erik Böttiger secretary. The Society had its first open meeting in Malmö on May 16, 1963, with four speakers (Table 22.1): The 10th ISH meeting in Stockholm in September of 1964 was both well-attended and productive. The scanty documentation of this meeting available to the author does not allow a comprehensive covering, but it is known that in addition to JW’s prominent © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 F. Wollheim, Jan Gösta Waldenström and His World, Springer Biographies, https://doi.org/10.1007/978-3-031-36739-7_22

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Fig. 22.1 Cover of the abstract book of the Xth Congress of the International Society of Haematology. Private archive. Courtesy Gösta Gahrton

Table 22.1 Presentations in Malmö 16. May 1963 Speaker

Title

Sven-Erik Björkman, Malmö

Corticosteroid therapy in chronic lymphatic leukemia

Nils Söderström, Lund

“Hyaline droplets” in lymph nodes

Jan Waldenström, Malmö

Modern treatment of myeloma

Åke Nordén, Lund

The PAS reaction in leukocytes

international friends few “elephants” in hematology were absent. In the leading national newspaper “Svenska Dagbladet” one can read that the oncologist Joseph H. Burchenal (1912–2004) from Sloan Kettering in New York participated with a leukemia talk. Burchenal had introduced 6-mercaptopurine as a chemotherapeutic agent in 1953 [1]. In Stockholm he talked on treatment of an African malignancy later named Burkitt lymphoma and the successful use of methotrexate. He was awarded with the Lasker Prize in 1972 (Fig. 22.2). The thymus was a hot topic at the meeting. Robert A. (Bob) Good (1922–2003) from Minneapolis was the brilliant presenter of exciting frontline immunology. The bursa of Fabricius in chicken was considered a rudiment of little importance until Bruce Glick in 1956 showed that neonatal extirpation caused immunodeficiency. This stimulated new interest in the human equivalent, the thymus. Observations in

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Fig. 22.2 Robert A. Good National Academy of Sciences. © University of Minnesota Archives Photograph Collection. Good, Robert 1967 (una568243). http://purl. umn.edu/216647

Good’s laboratory that the same happened after thymectomy in newborn rabbits and mice were presented at a 1961 meeting in Atlantic City [2]. Good presented new insights in the field of immunology, including the distinction between B (bursa) and T (thymus) lymphocytes and new immune deficiency diseases caused by B and/or T cell dysfunction. He fully acknowledged the contributions of J. F. Miller published in the Lancet that same year [3]. Good had visited JW in Malmö in 1963 and presented some of these thrilling results [4]. It was also mentioned in the Stockholm newspaper that Johan August Hammar, the professor of histology in Uppsala and admired teacher of JW, believed that increased activity of the thymus gland resulted in criminality. This misconception was based on observations of large thymus glands at autopsies of executed criminals. Felix Milgrom was another speaker at the meeting and introduced the new concept of autoantibodies as a failure of tolerance [5]. He was photographed in the Svenska Dagbladet with Astrid Fagraeus. Professor G.C. de Gruchy from Melbourne, an expert on hemolytic anemia and co-founder of the Australian Society of Hematology, was in Stockholm as elected president of the XIth ISH congress in Sydney in 1966. The list of delegates in Stockholm has some 1700 names, and there were 800 printed abstracts, which reflects the popularity of hematology, of Stockholm as the venue, and of JW’s standing in international hematology. Another participant at the congress was Louis W. Sullivan (born 1933), then working in the Thorndike laboratory in Boston with William Castle on intrinsic

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factor [6]. In Stockholm, he presented ongoing work showing that ethanol in vitro and in vivo inhibited folic acid and caused megaloblast proliferation in bone marrow and macrocytic anemia [7]. Dr. Sullivan and his wife stayed with his Swedish friend, Gösta Gahrton (born 1932). Sullivan was just at the beginning of a brilliant career, as department head and founder of a medical school in Atlanta. He was also the first black Secretary of the Department of Health and Human Sciences of the United States in the cabinet appointed by President George H.W. Bush. For his own part, Gahrton presented his work showing that a sophisticated technique of microspectrography could be used for accurate measurement of the glycogen content of neutrophil leucocytes. The method could distinguish between normal and leukemic cells [8]. Two years later, in his Ph.D. thesis Gahrton showed that high levels in chronic myeloid leukemia became normal on treatment with busulfan [9] (Figs. 22.3 and 22.4).

Fig. 22.3 Main topics of the ISH congress meeting in Stockholm. Courtesy Gösta Gahrton Fig. 22.4 Gösta. Gahrton, © Private archive, Gösta Ghrton

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Fig. 22.5 Jan Niléhn, Fibrinogen split products visualized by immunoelectrophoresis. © Courtesy Jan Niléhn, personal archive

The list of main topics at the ISH meeting mirrors the cutting-edge research at the time. Invited main speakers filled the morning sessions. The afternoon program consisted of 800 submitted and accepted abstracts. Chester Alper from Boston and a visiting scientist with JW and Carl-Bertil Laurell in Malmö, showed ultracentrifuge and paper-electrophoretic data of IgA in myeloma proteins, demonstrating heterogenic molecular polymers. Alper worked with this project in Malmö with Tristram Freeman from London, who was another visiting scientist guest in Carl-Bertil Laurell’s laboratory. Their work using radioactive tracer methodology revealed that while IgG and IgA myeloma proteins from patients with the disease were metabolized both in the intra- and extravascular space, IgM components were only metabolized in the extravascular compartment [10]. Jan-Erik Niléhn, working with Inga Marie Nilsson in Malmö, presented data on fibrinogen split products using immunoelectrophoresis. The method was developed as a useful clinical diagnostic test for the detection of increased fibrinolysis [11] (Fig. 22.5).

22.2 Hematology Research in Malmö Jan-Erik Niléhn (born 1928) defended his thesis on fibrinogen and fibrin split product in 1967 [11]. It illustrates the close interactions between the Department of Medicine, its Division of Coagulation Disorders, and the Department of Clinical Chemistry in Malmö where Nihlén and other clinicians performed experimental bench work. Fruitful interactions at this time also involved the Department of Surgery. As mentioned, while still a medical student Niléhn was stimulated to investigate coagulation by Sven-Erik Björkman. Formally he was a Ph.D. student of Inga Marie Nilsson, but was performing much of the work in Carl-Bertil Laurell’s department. Together with Per-Olov Ganrot (1935–2018) he showed that the primary physiologic elimination mechanism for activated plasminogen, plasmin, was by forming complexes with α2-macroglobulin. Such complexes were rapidly cleared from the circulation [12]. In 1970 Niléhn moved to the new University of Linköping as associate professor in the Department of Medicine where insights acquired in Malmö were passed on to the new teaching department and its undergraduates. Haquin Olof (Olle) Zettervall (1931–2018) was acquainted with JW through his student friend JW’s son Johan Waldenström. Zettervall inherited a love for nature

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from his father and an aptitude for mathematics from his mother. He had studied mathematics before entering medical school and immunology after finishing medical school. He also worked in the Department of Neurology in Lund before joining the department in Malmö in 1961. Although his given name was Olof/ Olle, in Malmö he was soon known only as “Hacke”. He impressed everyone with his subtle humor, competence, and inquisitive mind. As mentioned in Chap. 16, extreme titers of specific serologic antibodies were present in some myeloma sera [13]. Zettervall decided to investigate a serum from such a patient with a high antistreptolysin titer. The patient was treated with plasmapheresis. He could use the ample volumes of plasma to address fundamental questions regarding the nature of the M-component because the patient underwent frequent therapeutic plasmapheresis procedures. Were M-components abnormal proteins or were they excessive amounts of a deregulated normal protein? JW was an adherent of the latter hypothesis and did not like the designation “paraprotein” suggesting that they were abnormal proteins. By the meticulous study of the isolated IgG M-component and its fractions, Zettervall was able to show that the antibody activity was localized to the antibody-binding part of the IgG lambda component. The activity was lost when the heavy and light chains were separated enzymatically and reappeared when the chains were united again. The same was shown with another antistreptolysin and one antistaphylolysin IgG M-component. Some parts of the work were published [14, 15]. Zettervall was a perfectionist and kept performing more control experiments. JW grew impatient, but finally the thesis was completed in the summer of 1968 [16]. As associated professor Zettervall became a stalwart mentor at a new hematology laboratory located on the top floor of the medical building. He also stayed in touch with his former neurology colleagues in Lund. He inspired efforts to establish in vitro growth of spinal fluid lymphocytes from patients with multiple sclerosis, MS. A Ph.D. student in neurology managed to achieve this and could recover secreted oligoclonal bands of IgG.in the culture supernatant identical to those present in the patient’s native spinal fluid. Such bands offer support to a diagnosis of MS. This work was direct evidence that the cells in the spinal fluid were involved in the pathogenies of MS [17]. Zettervall continued to work in the department as an erudite senior hematologist until long after retirement (Fig. 22.6). Folke Lindgärde (1936–2021), one of Zettervall’s Ph.D. students, could claim a special relationship to the Waldenström name. From childhood he was, like his parents, a faithful member of “Missionsförbundet”, the Mission Covenant Church, the large free church congregation founded by JW’s great-uncle Paul Peter Waldenström (Chap. 1). The congregation had many proselytes in the province Smolandia north of Scania where Lindgärde was raised. As an active member he became the chief officer of the congregation in Lund and organized the construction of a new church building and an adjacent student residence called “Miklagård”. Diligence combined with organizational skill also enabled his active participation in politics as an officer in the liberal party. The starting point of Lindgärde’s thesis was again a single patient with an unusual M-component [19]. JW and others had noted that serum calcium levels could be elevated in patients with myeloma although they had no symptoms of Ca+ toxicity.

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Fig. 22.6 Olle Zettervall in 1997. © Photographer The author

Their apparent serum calcium was measured as elevated, but the ionized (diffusible) calcium level was normal as reported in a 1948 paper [18]. Patients with hypercalcemia due to other causes were usually treated with phosphate infusions. Whenever JW discovered that a patient with hypercalcemic myeloma had been treated with a phosphate infusion, he would regularly get one of his much-feared rages. The patients that triggered the doctoral thesis project of Lindgärde was a 62-year-old woman who had been admitted to the department in 1971 with a 6-year history of increasing erythrocyte sedimentation rates and moderate anemia. She complained of fatigue and skeletal pain but had no symptoms of hypercalcemia. Electrophoresis revealed an M-component of 6.5 g/100 ml, typed as IgGλ. The Bence-Jones test in urine was positive and immunoelectrophoresis showed abundant presence of λ light chains. The serum calcium was elevated at 7.2 g/100ml, normal level being 4.9+/−0.4. The ionized calcium level was 2.04–2.44; normal level 2.33+/−0.28.2. The bone marrow contained 20–30% plasma cells. Treatment with mephalan was started. [20]. Serum electrophoresis (figure) showed that the bulk of isotope 45 Ca migrated with the M-component [21]. Further analysis localized the 45 Ca to the antibody biding region [22]. Splendid as it was, the investigator missed one thing. A careful scrutinizing of the literature would have revealed that a patient with myeloma who had a total calcium of 19 mg/100 ml and a normal level of free serum (diffusible) calcium of 2.1 mekv/l had been identified in a paper cited above [18]. But this shortcoming is excusable in the time before computers and PubMed (Fig. 22.7). As a productive associate professor in following years, Lindgärde was involved in several areas of clinical and research interest, including vascular diseases, diabetes, physical activity, diet, and other environmental health factors. His interest in smoking,

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Fig. 22.7 Two-dimensional agar gel electrophoresis of a normal serum (left), and the abnormal myeloma serum (right). Protein staining in the left and radioactivity in the right half, showing prominent 45 Ca affinity in the albumin and in the beta- and gamma globulin regions of the myeloma serum, but only in the albumin region of the normal serum [21]. © Clin Chim Acta with permission

obesity and in the physiology of high altitude adaptation materialized in an impressive two-year study showing that lifestyle education could improve the health of overweight in women with type II diabetes in Ecuador and Peru, a truly herculean achievement [23, 24]. Lindgärde was a dedicated follower of the Waldenström family role models, both of JW in science and of P.P. Waldenström in religious faith (Fig. 22.8). Ingemar Turesson, (born 1937) also a Smolandia native, is remembered by classmates in medical school as a serious, quiet, hardworking, conscientious, but a little dry fellow. However, his peers in the Department of Medicine spotted a man of the future. Turesson was rewarded by the unusual favor of being hired as a paid locum house officer while still a senior medical student. He passed a successful oral examination with JW at which he correctly diagnosed scurvy, a rare condition in Sweden. He was promptly included in the group of “regular” locums, in contrast to most who had to spend some months or years before being considered worthy of a permanent one- or three-year appointment. Ingemar Turesson was soon attracted by hematology and the projects of Uno Axelsson and Jan Hällén (Chap. 16) and joined the myeloma team. On a visit to the Netherlands, JW had met Willy Hijmans, (1921–2018), a world leading expert in the new technique of fluorescence microscopy [25]. Realizing the potential of the method, JW arranged for Turesson to spend time with Hijmans in Rijswijk. A fluorescence microscope was acquired for the department’s hematology laboratory and soon became an important and much used tool [26].

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Fig. 22.8 Folke Lindgärde in the 1980’s Öppet bildarkiv, Sydsvenska Medicinhistoriska Sällskapet. Photographer Lars Stavenow 131120-006Copp.jpg. http:// www.medicinhistoriskasyd. se/smhs_bilder/

Years of assiduous work and eight full-length papers later, in 1979 Turesson presented a successful Ph.D. thesis [27]. The external reviewer was Hijmans himself, who was surprised and delighted to be accommodated in style by Margareta Nyman (Chap. 19) in her medieval Torup castle. The main emphasis of the thesis was on identifying then novel surface markers on B lymphocytes in malignant disorders. The comprehensive studies were well received and Turesson was soon promoted to associate professor. His skill with the fluorescence microscope and other merits made him an anchor in the laboratory. The international standing of hematology in Malmö was maintained after JW’s retirement. Turesson participated in several national and international multicenter studies and published significant papers on myeloma and MGUS well into the new century, based on large representative samples from local and regional populations, longtime observation, international and national cooperation [28–31] (Fig. 22.9). Jörgen Malmquist (born 1937) was actively recruited to the department in the 1960’s. He had contributed to basic science publications in Lund on germfree rats [32] and on Wasserman reagins and complement with Anna-Brita Laurell [33]. Malmquist soon acquired clinical competence and was looking for a suitable Ph.D. project perhaps related to the carcinoid syndrome. JW knew that Albert Sjoerdsma’s collaborator at NIH, John Oates (1932–2019), had worked in this field and moved to Vanderbilt University as professor of pharmacology in 1963. Oates was happy to accommodate a scholar of JW’s as visiting scientist. Malmquist spent a year in

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Fig. 22.9 Ingemar Turesson © Private archive. Courtesy Ingemar Turesson

the laboratory at Vanderbilt Medical School. Although he published three papers there, the year did not result in initiation of a doctoral thesis. Two of his publications concerned the carcinoid agent bradykinin [34, 35], whereas the third dealt with mitochondrial pharmacology. This was a subject Malmquist had been working on previously in Sweden [36]. Upon return to Malmö, he started working in the research laboratory of the Department of Medicine on proteins released from leukocytes. This work ultimately resulted in his dissertation titled “Leukocytic proteins in serum and urine: Studies in leukemia and polycythemia”. Carl-Bertil Laurell served as co-mentor. The enzymes studied were lysozyme, lactoferrin, and myeloperoxidase [37]. The successful defense in February of 1972 made him assistant professor. One of his several mentees was Folke Lindgärde, with whom he shared liberal political interests and developed a special lifelong friendship. After years in research as associate professor and in the 1980’s as administrative chairman of the department, Malmquist entered a different phase of life and became a successful fulltime popular science author and esteemed public discussant on medical matters [38] (Fig. 22.10). Another dissertation completed around this time was that of Stig Cronberg (1935–2023). He was a cousin of Margareta Blombäck (Chap. 18), and had spent years studying rat mast cells with Bengt Gustafsson, (1916–1986) the master of germfree animals in the Department of Histology in Lund. His thesis titled “Investigations in haemorrhagic disorders with prolonged bleeding time but normal number of platelets with special reference to platelet adhesiveness” was mentored by Inga Marie Nilsson and focused on platelets in bleeding disorders [39]. Cronberg moved to the Department of Infectious Diseases in 1970 where he later became its popular chairman. Lars-Olof Almér (born 1936) had spent the year 1968–9 as a fellow with Cecil Watson in Minneapolis (Chap. 7) where he was rated as “one of the most mature and best residents I have experienced”. Back in Malmö he worked on the cardiac ward under Bengt Johansson, where he noted the frequent occurrence of coronary disease in obese diabetic women. This bedside observation enticed him to study a possible

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Fig. 22.10 Jörgen Malmquist © Courtesy Jörgen Malmqust, private archive

connection with defective fibrinolysis. He approached Inga Marie Nilsson, and in her laboratory, he could actually document subnormal fibrinolytic activity in the blood and the vessel walls of patients with diabetics as well as in obese individuals, and defend a very focused and well written thesis in 1975 [40–42]. Almér continued his work in the department performing diabetes research and became a much appreciated director of undergraduate and house staff continued education. He was honored as “Master teacher” by the students in the 1970s (Fig. 22.11). Frank Wollheim (born 1932) started as locum house officer in 1959. His first endeavors with adult “acquired” hypogammaglobinemia have been mentioned (Chap. 16). With this single contribution and coming from the department of JW Fig. 22.11 Lars-Olof Almér 1990 Öppet bildarkiv, Sydsvenska Medicinhistoriska Sällskapet. © Photo Björn Henriksson SMHS9196_ 000_01Copp.jpg. http:// www.medicinhistoriskasyd. se/smhs_bilder/

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he was accepted for an instructor position at the Department of Medicine at the University of Minnesota where he worked for two years under Ralph C. Williams Jr. (1928–2020) from 1963 to 1965. Williams had recently arrived from the Rockefeller Institute and Henry Kunkel (Chaps. 12, 14 and 25) as the first academic rheumatologist at the University of Minnesota and established his own laboratory in July of 1963. After a rewarding stay, Wollheim returned to Malmö and spent two years, 1966–7, in the Department of Clinical Chemistry as amanuensis. The doctoral thesis, defended in 1968, dealt with polyclonal and monoclonal conditions with increased formation of IgM [43, 44]. When Wollheim returned to clinical work in the department, JW noted that he had become familiar with “the Mayo technique of examining joints” and decided “You shall be our rheumatologist”. Obedient to the master, he was in charge of the division of rheumatology from 1972 to 1982, benefiting from the advantages to be part of an undivided department of medicine for teaching, research, and comprehensive patient care. Reluctantly, he moved to Lund as chairman of the large independent Department of Rheumatology in 1982. The attraction was an increased potential to conduct research. The rheumatology division in Malmö survived in good health for another two decades before meddlesomeness by politicians, administrators, and unwise professionals resulted in an unhappy forced merger of the hospitals in Lund and Malmö burdened by oversized and confusing administration. The stated motivation was to save money and at the same time improve the standard of care but it resulted in increased costs, widespread dysfunction, and loss of several competent displeased specialists and allied health professionals. Fortunately, some quality of care survived despite the administrative turmoil (Fig. 22.12). Stig Berglund (born1934) was a medical school classmate of Johan Waldenström in Lund, and together they moved to the new medical school in Gothenburg to complete their studies. While Johan Waldenström stayed in Gothenburg, Berglund returned to Malmö as senior medical assistant. There he caught the favorable attention of JW. After passing the oral examination, he was promptly hired Fig. 22.12 Frank Wollheim in 1998 Öppet bildarkiv, Sydsvenska Medicinhistoriska Sällskapet. Photo Brorsson. SMHS15217Copp.jpg. http://www.medicinhistoris kasyd.se/smhs_bilder/

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as amanuensis and remembers two duties that came with the assignment. One was to select patients from the emergency room suitable for demonstration at student lectures by JW and other teachers. The other was to collect money from the staff and organize the orchid and bottle of Hennessy XO cognac for the New Year’s gift to the professor. After some limited research tasks relating to autoimmunity, Berglund elected to study an unusual family with erythrocytosis as the subject for his doctoral thesis. Berglund was to be the last Ph.D. student mentored by JW. The index family had originally been spotted by Tore Leonhard, but he had left for Vänersborg (Chap. 16). The index patient presented with pulmonary fibrosis and erythrocytosis. Relatives in four generations were similarly afflicted, suggesting a dominant heredity. A pathologic hemoglobin was suspected. JW facilitated contact with the master of molecular hemoglobin abnormalities, the professor of clinical biochemistry in Cambridge, Herman Lehmann (1910–1985). Lehmann had worked with the Nobel Laureate Otto Fritz Meyerhof (1884–1951) in Heidelberg, who had sent him to Sir Frederick Gowland Hopkins (Chap. 2) in Cambridge in 1935 thereby sparing him Nazi regime persecution. Meyerhof himself escaped to the United States via France in 1938. Initially Lehmann was unable to find an abnormality in the Malmö patient’s hemoglobin. But Jan Olof Jeppsson coming from Umeå to the Department of Clinical Chemistry in Malmö had developed a sensitive analytic method of isoelectric focusing with which he could detect a discrete hemoglobin abnormality [45]. Confronted with the data from Malmö, Lehmann discovered a single nucleotide mutation, histidine to glutamine (His→Gln) substitution in codon 97 of the beta chain in the patient’s hemoglobin. The abnormality results in a firmer binding of oxygen causing tissue hypoxia, which in turn stimulates erythropoietin production and explains the erythrocytosis. The new mutation was named Hemoglobin Malmö [46, 47]. A second family with Hemoglobin Malmö was later identified in Stockholm. A point mutation in the same position resulted in a CAC→CAA shift at codon 97, whereas the Malmö family had CAC→CAG shift. Both mutations resulted in the His→Gln change of the hemoglobin molecule conferring identical higher oxygen affinity [48]. Even in his late 80s, JW was excited when Berglund told him of the new discovery. JW was also involved in discussions about the cause of erythrocytosis in members of a third family living in Southern Sweden. The members of this family had normal blood oxygen affinity and low blood erythropoietin levels and in this respect were similar to members of a Finnish family studied by Albert de la Chapelle (1933–2020) in Helsingfors. He found that their erythrocytosis was caused by an erythropoietin receptor, EPOR, mutation. This was also present in the Swedish family members with erythrocytosis, although they had a different mutation. Functional studies confirming the mechanism were carried out in the U.S. with the help of colleagues from Germany. The results were later published in Blood [49]. JW followed the developments with interest (Fig. 22.13). Bengt Hamrin (1913–1976) from Smolandia spent three years in the department in the 1950’s participating in limited clinical research projects, but as he wrote in the introduction of his thesis: “I had the pleasure of working under professor J Waldenström in the department of internal medicine, a stronghold of resistance to

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Fig. 22.13 Stig Berglund 1980s. Öppet bildarkiv, Sydsvenska Medicinhistoriska Sällskapet. © Lars Stavenow 131120-002Copp.jpg. http:// www.medicinhistoriskasyd. se/smhs_bilder/

all tendencies towards disintegration of internal medicine where the strategy and tactics of ordinary patient care go hand in hand with research in various sectors of the specialty, I was caught by the general interest in collagen diseases and autoimmunity at the department, and I intended to investigate the cases of temporal arteritis seen there. It so happened however, that I moved to Växjö, which temporarily thwarted my intentions.” [50]. In Växjö his encounter with a patient with new onset polymyalgia rheumatica, PMR, complicated by painful ischemia in one arm stimulated his interest in research, and he set out to work on a doctoral thesis mentored by JW. Bengt Hamrin was struck by the presence of a strong arterial murmur in the elbow region of the patient’s affected arm. Could the stethoscope be a help to detect patients with PMR? He collected more cases and started a systematic investigation examining for arterial murmurs in patients and normal subjects, both in Växjö and in Malmö. He had to devote more than 20 min with the stethoscope to perform a complete screening of the arteries of a single patient. He established collaboration with the young surgeon Torsten Landberg (1935–2015) and the Lund pathologist Nils Jonsson (1932–2016). On the assumption that similar arterial pathology could lead to both temporal arteritis and PMR a first report was published in the Lancet, suggesting the logical name “Polymyalgia arteritica”, PMA, replacing PMR [51]. Regrettably this name never was adopted by the profession (Fig. 22.14). In 1972, Hamrin successfully defended a thesis based on 92 patients and 93 controls [50]. Hamrin was correct in realizing that temporal arteritis and PMR should be regarded as different manifestations with common pathology of giant cell arteritis, GCA. This was confirmed in collaboration with the Malmö pathologist Görel Östberg (born 1932). She defended her own thesis in 1973 [53]. It was based on a comprehensive histologic examination of the arteries of consecutive unselected autopsies representing the majority of all persons dying during one year in Malmö and can therefore serve as a population based epidemiologic study. It showed that GCA was far more prevalent than previously suggested. It also documented that cases of GCA were commonly clinically silent or missed [52, 53] (Fig. 22.15).

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Fig. 22.14 Arterial murmurs in 52 patents with polymyalgia arteritica (PMR) and in 52 healthy controls. Figure 1 from reference 51 with permission

Fig. 22.15 The dissertation in the aula in Malmö in 1972. Standing to the left is the dean of the faculty Gösta Hagerman, the defendant Bengt Hamrin, the external reviewer Lars-Erik Böttiger. To the right is Karl Gydell and Jan Waldenström. Photo © Torsten Landberg Öppet bildarkiv, Sydsvenska Medicinhistoriska Sällskapet. PSMHS444_000_01Copp.jpg SMHS479_ 000_01Copp.jpg. Photo © Torsten Landberg. http://www.medicinhistoriskasyd.se/smhs_bilder/

22.3 Concluding Remarks This chapter highlights the diversity of hematological research performed in the department. All Ph.D. students shared a great respect and admiration for JW. The respect could be accompanied by anxiety for precipitating one the feared emotional outbursts, but these were not long-lasting and in the end warm affection prevailed. His

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supervision could be limited or indirect but not his interest and encouragement. Triggered by JW into research, one was rewarded by experiencing some of the pleasure it created and which was the mentor’s trademark. Physicians trained in JW’s department benefitted from an outstanding educational environment, fostering them to become both good physicians and future leaders of an impressive number of major hospitals spread over the country. There they implemented lessons from the experience in Malmö. The hospitals included a full dozen, perhaps one-third of all major hospitals at the time. The hospitals included Lund Vänweborg, Helsingborg, Kalmar, Växjö, Skövde, Jönköping, Linköping, Norrköping, Västerås, Karlstad, Säffle, Sundsvall, and Kiruna. JW and his “Malmö School” had an important and durable influence on the quality of internal medicine in Sweden. JW valued maintaining contact with his former scholars, providing them with informal and prized continued education. JW also was a model promoting the value of humanity for physicians decades before it is realized as an essential part of good medical education.

References 1. Oettgen HF, Burkitt D, Burchenal JH. Malignant lymphoma involving the jaw in African children: treatment with Methotrexate. Cancer. 1963;16:616–23. 2. Archer O, Pierce JA. Role of thymus in development of the immune response. Fed Proc. 1961;20:26. 3. Miller JF. Immunological function of the thymus. Lancet;2:748–9m. 4. Martinez C, Dalmasso AP, Good RA. Effect of thymectomy on development of immunological competence in mice. Ann N Y Acad Sci. 1964;113:933–46. 5. Milgrom F, Witebsky E. Autoantibody formations as a failure of “Self-recognition.” Proc Can Cancer Conf. 1963;5:319–36. 6. Sullivan LW, Herbert V, Castle WB. In vitro assay for human intrinsic factor. J Clin Invest. 1963;42:1443–5. 7. Sullivan LW. Suppression hematopoiesis by ethanol. J Clin Invest. 1964;43:2048–62. 8. Gahrton G. Microspectophotometric quantitation of the periodic acid-schiff (PAS) reaction in human neutrophil leucocytes. Exp Cell Res. 1964;34:488–506qa