Klaus Buchholz, John Collins Concepts in Biotechnology History, Science and Business Klaus Buchholz and John Collins Concepts in Biotechnology Related Titles Nicolaou, K. C., Montagnon, T. Molecules that Changed the World 385 pages 2008 Hardcover ISBN: 978-3-527-30983-2 Sneader, W. Drug Discovery A History 472 pages Softcover ISBN: 978-0-471-89980-8 Ho, R. J. Y., Gibaldi, M. Biotechnology and Biopharmaceuticals Transforming Proteins and Genes into Drugs 576 pages 2003 Softcover ISBN: 978-0-471-20690-3 Greenberg, A. The Art of Chemistry Myths, Medicines, and Materials 384 pages 2003 Hardcover ISBN: 978-0-471-07180-8 Sapienza, A. M., Stork, D. Leading Biotechnology Alliances Right from the Start 216 pages 2001 Hardcover ISBN: 978-0-471-18248-1 Klaus Buchholz and John Collins Concepts in Biotechnology History, Science and Business The Authors All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and Prof. em. Dr. Klaus Buchholz publisher do not warrant the information contained Technical University Braunschschweig in these books, including this book, to be free of Institute for Chemical Engineering errors. Readers are advised to keep in mind that Hans-Sommer-Str. 10 statements, data, illustrations, procedural details or 38106 Braunschweig other items may inadvertently be inaccurate. Germany Library of Congress Card No.: applied for Prof. em. Dr. John Collins British Library Cataloguing-in-Publication Data Technical University Braunschschweig A catalogue record for this book is available from the Life Sciences Faculty British Library. c/o Helmholtz Centre for Infection Research – HZI AG Directed Evolution Bibliographic information published by Inhoffenstr. 7 the Deutsche Nationalbibliothek 38124 Braunschweig The Deutsche Nationalbibliothek lists this fi Germany publication in the Deutsche Nationalbibliogra e; detailed bibliographic data are available on the Internet at http://dnb.d-nb.de. # 2010 WILEY-VCH Verlag & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Cover Illustration: Production fermenters with kind permission by Roche Penzberg, Germany Cover Adam Design, Weinheim Typesetting Thomson Digital, Noida, India Printing and Binding betz-druck GmbH, Darmstadt Printed in the Federal Republic of Germany Printed on acid-free paper ISBN: 978-3-527-31766-0 For Diana and Marie-Christiane VII Contents Preface XVII Abbreviations and Glossary XXI Part One History 1 1 Introduction 3 2 The Early Period to 1850 5 2.1 Introduction 5 2.2 Experimental Scientific Findings 8 2.2.1 Alcoholic Fermentation 8 2.2.2 Unformed, Unorganized Ferments 11 2.3 Application 12 2.3.1 Education 15 2.4 Theoretical Approaches 16 2.4.1 The School of Vitalism 17 2.4.2 The Chemical School 20 2.4.3 History of Science Approaches: Preparadigmatic Research; Fermentation – An Epistemic Thing 21 References 24 3 The Period from 1850 to 1890 27 3.1 Introduction 27 3.2 Experimental Findings 27 3.2.1 Fermentation – Definite Results by Pasteur 27 3.2.2 Unformed, Soluble Ferments – Enzymatic Reactions 35 3.3 Practical Application, Technical Progress and Institutional Development 35 3.3.1 Products and Progress in Processes 35 3.3.2 Application Research, Bacteriology, and New Institutions 40 3.4 Theoretical Approaches 41 3.4.1 Fermentation Theory, an Epistemic Thing 41 Concepts in Biotechnology: History, Science and Business. Klaus Buchholz and John Collins Copyright Ó 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-31766-0 VIII Contents 3.4.2 Pasteur Establishes a New Paradigm 42 3.4.3 The Question of Living and Unformed Ferments (Enzymes), and Explanatory Concepts 45 References 47 4 The Period from 1890 to 1950 51 4.1 Introduction 51 4.2 Research – Advances in the Basics of Biotechnology: Experimental Findings 51 4.2.1 Biochemistry 51 4.2.2 Microbiology 59 4.2.3 The Case of Penicillin – the Beginning of the Antibiotics Era 62 4.3 Technological Development, Progress and Application 64 4.3.1 Expanding Enzyme Technology 64 4.3.2 Wartime Production, First World War: Acetone, Butanol, Glycerol 65 4.3.3 New Fermentation Products: Citric Acid, Fermented Food, Enzymes; Waste Water Treatment 68 4.3.4 War Requirements of the Second World War: Penicillin Production – A New Quality of Technology 70 4.4 Theoretical Approaches 76 4.4.1 The Biochemical Paradigm, and the New Discipline of Biochemistry 76 4.4.2 Microbiology – Normal, Postparadigmatic Science 81 4.4.3 Influences External to Science: War Requirements – the Case of Penicillin 83 References 84 5 Outlook, from 1950 Onwards: Biotechnology – Science or What? 89 5.1 Introduction 89 5.2 Traditional Biotechnology and the Dechema Report 90 5.2.1 Traditional Products 90 5.2.2 Political Initiatives: The Dechema Report 90 5.2.3 The Scientific Status of Biotechnology up to the 1970s 92 5.3 The Changing Focus in BT in the USA in the Early 1980s 93 5.3.1 The Role of Politics in the USA: The OTA Study, Promoting New BT 93 5.3.2 New Products and Companies 95 5.4 Conclusions 97 References 98 Part Two The New Paradigm Based on Molecular Biology and Genetics 101 6 Broadening of Biotechnology through Understanding Life, Genetics and Evolution 103 References 105 Contents IX 7 The Beginnings of the New Biotechnology 107 7.1 Introduction 107 7.2 The Beginnings of Evolution Theory and Genetics 109 7.2.1 Robust Cultures barely Addressed in Biotechnology 111 7.3 The Origin of Recombinant DNA Technology 113 7.3.1 The Cradle of Gene Cloning: Bacterial and Bacteriophage Genetics 113 7.3.2 Antibiotic Resistance in Hospitals: Genetic Flux in Plasmids 114 7.3.3 Restriction and Modification: Finding the Enzymatic Tools for DNA Recombination 115 7.3.4 Gel Electrophoresis for DNA Analysis and Isolation of Specific Fragments 116 7.3.5 Handling DNA 118 7.3.6 New Tools to Study Single Molecules 119 7.3.7 The First Recombinant DNA Experiments 120 7.3.8 DNA Sequence and Recognizing Genes and Gene Function 122 7.3.9 Cloning Larger DNA Fragments 122 7.3.10 Further Tools for the Assembly of Physical Genome Maps 123 7.3.11 Uniting Fragment, Sequence and Chromosome Maps 124 7.3.12 Understanding Gene Regulation in Eukaryotes: A Branch of Reverse Genetics 127 7.4 Oligonucleotide Synthesis Leads to Protein Engineering 127 7.4.1 Chemical Synthesis of Macromolecules: Peptides and Oligonucleotides 130 7.4.2 Combining Chemistry and Biology to Develop Novel Pharmaceuticals 133 7.4.3 Biotechnologys Competitor: Cheaper Chemical Synthesis 133 7.4.4 Muteins and the Beginning of Protein Engineering 134 7.5 Synthetic DNA, Reverse Transcriptase: Isolating Genes 136 7.5.1 Reverse Genetics: Providing Cheap Renewable Resources for Germ-Free Products 139 7.5.2 Gene Cloning contributes to the Discovery of and Characterization of New Viral Pathogens: Risk Prevention for Biotechnological Products 141 7.5.3 1979–1990: A Rapid Advance in Characterizing Viral Agents 141 7.5.4 Sera and Antivirals: Biotechnological Products in their Own Right 142 7.5.5 Gene Cloning and Production of Pure Material to Characterize Activity: second Generation Products 143 7.5.6 Enzymes for Replacement Therapy 144 7.5.7 The Emergence of the New Biotech Industry 145 7.5.8 Third Generation Products and the Post-Gene Cloning Era 146 7.6 Biodiversity and Gene Mining 147 7.6.1 Recognizing Groups within Biological Diversity 147 7.6.2 Knowledge of Microbial Diversity was Limited by the Lack of Pure Cultures 147 7.6.3 How Much Diversity is There? 148 X Contents 7.6.4 Genetic Diversity can be studied by Sequencing Microbial, Organelle and Viral Genomes 148 7.6.5 Microbial Genome Analysis and Bioinformatics to Identify Druggable Targets 150 7.6.6 Recognizing and Utilizing Useful Functional Diversity 150 7.6.7 Functional Screening of Shotgun and Metagenomic Libraries 153 7.6.8 Entire Genome Sequence of Microbes of Special Interest 155 7.6.9 Gene Mining Commercialization and Terminology 156 7.6.10 Dealing with the Data Flux 158 7.7 Creating New Diversity by Design or Empirically 160 7.7.1 Limitations in Predicting Protein Structure and Function 160 7.7.2 Genetic Recombination to Create New Assortments of Gene Fragments: PCR 161 7.8 Genetic Fingerprinting 161 7.9 Inherited Predisposition to Disease 164 7.9.1 Heritable Factors Affecting Probabilities of Developing Disease: Predisposition 165 7.9.2 Services for Genome Analysis as Part of Personal Medicine 166 References 166 8 Ethical Aspects Related to Genome Research, and Reproductive Medicine 171 8.1 Negative Public Reaction to Gene Technology 171 8.1.1 Initial Lack of Acceptance for Gene Technology in Europe 173 8.1.2 International Scientists Concerns Led to Guidelines for Gene Cloning 174 8.1.3 Towards a Solution: Increase Scientists Involvement in Technology Assessment 176 8.2 Ethical Aspects: Animal Cloning and Fertility Research 177 8.2.1 The Origin of Cloning Animals 178 8.2.2 An Example of Cloning in Animal Husbandry 179 References 179 9 Elucidating Protein Structure: The Beginnings of Rational Protein Design 181 9.1 Cambridge England, the Cradle of Structural Analysis of Macromolecules 181 9.1.1 Using Knowledge of Structure for Protein Design 182 9.2 Redesigning the Protein Core 184 9.3 Redesigning the Protein