'Berkeley University o'f California Regional Oral History Office UCSF Oral History Program The Bancroft Library Department of the History of Health Sciences University of California, Berkeley University of California, San Francisco The UCSF Oral History Program and The Program in the History of the Biological Sciences and Biotechnology William J. Rutter, Ph.D. THE DEPARTMENT OF BIOCHEMISTRY AND THE MOLECULAR APPROACH TO BIOMEDICINE AT THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO VOLUME I With an Introduction by Lloyd H. Smith, Jr., M.D. Interviews by Sally Smith Hughes, Ph.D. in 1992 Copyright O 1998 by the Regents of the University of California Since 1954 the Regional Oral History Office has been interviewing leading participants in or well-placed witnesses to major events in the development of Northern California, the West, and the Nation. Oral history is a method of collecting historical information through tape-recorded interviews between a narrator with firsthand knowledge of historically significant events and a well- informed interviewer, with the goal of preserving substantive additions to the historical record. The tape recording is transcribed, lightly edited for continuity and clarity, and reviewed by the interviewee. The corrected manuscript is indexed, bound with photographs and illustrative materials, and placed in The Bancroft Library at the University of California, Berkeley, and in other research collections for scholarly use. Because it is primary material, oral history is not intended to present the final, verified, or complete narrative of events. It is a spoken account, offered by the interviewee in response to questioning, and as such it is reflective, partisan, deeply involved, and irreplaceable. ************************************ All uses of this manuscript are covered by a legal agreement between the Regents of the University of California and William J. Rutter, dated November 8, 1992. The manuscript is thereby made available for research purposes. All literary rights in the manuscript, including the right to publish, are reserved to the UCSF Library and Center for Knowledge Management, and The Bancroft Library of the University of California, Berkeley. No part of the manuscript may be quoted for publication without the written permission of the Head, Archives and Special Collections, UCSF Library and Center for Knowledge Management or the Director, The Bancroft Library. Requests for permission to quote for publication should be addressed to the Head, Archives and Special Collections, UCSF Library and Center for Knowledge Management, or the Director, The Bancroft Library, and should include identification of the specific passages to be quoted, anticipated use of the passages, and identification of the user. The legal agreement with William J. Rutter requires that he be notified of the request and allowed thirty days in which to respond. It is recommended that this oral history be cited as follows: William J. Rutter, Ph.D., "The Department of Biochemistry and the Molecular Approach to Biomedicine at the University of California, San Francisco," Volume I, an oral history conducted in 1992 by Sally Smith Hughes, Ph.D., Regional Oral History Office, The Bancroft Library, University of California, Berkeley, 1998. Copy no. \ - William J. Rutter. Cataloguing information RUTTER, William J. (b. 1928) Biochemist-biotechnologist The Department of Biochemistry and the Molecular Approach to Biomedicine at the University of California. San Francisco. Volume I of II, 1998, vi, 237 pp. Education; early career at universities of Illinois, Stanford, and Washington; research on galactosemia, aldolase, RNA polymerase, pancreatic differentiation; Department of Biochemistry and Biophysics, University of California, San Francisco [UCSF] : recruitment, development of department, introducing molecular approach, administrative and science strategy, collaboration and competition; director, Hormone Research Institute, UCSF; UCSF role in early biotechnology industry; Genentech; rat and human insulin gene projects; recombinant DNA controversy; biosafety; pBR322 plasmid episode; hepatitis B vaccine; commercialization of basic academic sciences; intellectual property; Gordon Tomkins; Howard Goodman; Axel Ullrich. Introduction by Lloyd H. Smith, Jr., M.D., Associate Dean, UCSF School of Medicine. Interviewed 1992 by Sally Smith Hughes for the UCSF Oral History Program, Department of the History of Health Sciences, University of California, San Francisco, and the Program in the History of the Biological Sciences and Biotechnology, Regional Oral History Office, The Bancroft Library, University of California, Berkeley. TABLE OF CONTENTS--William J. Rutter - PREFACE i INTRODUCTION by Lloyd H. Smith, Jr., M.D. ii INTERVIEW HISTORY vi BIOGRAPHICAL INFORMATION x I EDUCATION AND EARLY CAREER 1 Early Education 1 Doctoral Student, University of Illinois 3 The Decision to Study Biochemistry 3 Postdoctoral Fellow, University of Wisconsin Institute of Enzyme Research, 1952-1954 4 Postdoctoral Fellow, Biochemistry Department, Nobel Institute, Stockholm, 1954-1955 6 Assistant Professor to Professor, University of Illinois, Urbana, Division of Biochemistry, Department of Chemistry, 1955-1963 7 Return to Illinois 7 Structure-Function Studies of Protein Families 7 Research on Aldolase 8 Early Studies of RNA Transcription Regulation 9 Guggenheim Fellow, Stanford University, 1962-1963 11 Professor, Departments of Biochemistry and Genetics University of Washington, 1965-1969 12 II CHAIRMAN, DEPARTMENT OF BIOCHEMISTRY AND BIOPHYSICS, UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, 1968-1982 15 Dr. Rutter 's Recruitment 15 Basic Science at UCSF 19 Before Dr. Rutter 's Arrival 19 Recognizing the Need for a Molecular Approach 20 The Department of Biochemistry and Biophysics 21 Impediments to Recruiting a Chairman 21 Opportunities to Develop the Department 23 Previously Appointed Faculty Members 25 Hiring New Faculty Members 26 Negotiating for Contiguous Space 27 Faculty Recruitment 28 Policy Regarding Joint Appointments 30 A Molecular Approach 31 The Basic Science Departments: Collective Action 32 Consolidating the Department 33 Biomathematics and Crystallography 35 Recruitment 38 Strategic Sense and "Taste" in Science 39 The Department's Collaborative Approach 41 Choh Hao Li and the Hormone Research Laboratory 43 Characteristics of the Laboratory 43 Li as a Personality 44 More on X-ray Crystallography 46 Genetics in the Department and at Berkeley 46 Yeast, Drosophila. and Nematode Genetics 49 The Influence of European Molecular Biology Laboratories 51 European Models for the Department 53 The Biotechnology Industry 54 Intellectual Property and Venture Capital 54 European Models of Funding Science 55 Biological Information Becomes Applicable 58 Framing Biological Questions in Mechanistic Terms 60 Teaching 61 Initial Subordinant Role in the Department 61 W. J. Rutter as Teacher 62 Using Research Labs as Teaching Labs 63 Teaching Medical Students 64 The Graduate Curriculum at UCSF 65 The Department's Enterprise System 67 More on the Department 70 A Cooperative, Interactive Approach 71 The Importance of Contiguous Space 73 Fostering the Biological Sciences in the School of Medicine 74 Money, Space and Growth Problems at UCSF 77 Efforts to Develop the Basic Sciences: PIBS and the "Fifth School" 81 III RESEARCH IN THE MOLECULAR SCIENCES 84 Fundamental Scientific and Technology Developments in Genetics 84 Bacteriophage 84 Restriction Enzymes 85 Recombinant DNA Technology 86 Networking in Science 88 Sequencing Techniques 89 Hybridization Techniques 90 Research in the Rutter Laboratory in the 1970s 91 Transcription Enzymes and Pancreatic Differentiation 91 Cloning Methodologies 92 The Cohen-Boyer Experiments 92 Decision to Clone the Rat Gene for Insulin 94 Gordon M. Tomkins 95 Illness and Death 97 The Asilomar Conference on Recombinant DNA, February 1975 99 The Birth of the Biotechnology Industry 101 Genentech 101 Problems at UCSF Associated with Commercialization 102 Dealing as Chairman with Departmental Issues 106 The Safety Issue 10 7 The Rat Insulin Gene Project 108 Strategy and Goals 108 Dr. Rutter 's Background in Developmental Mechanisms 109 Strategy for Obtaining Islet Cells HO Competition 111 The Players at UCSF 113 More on the Problem of Obtaining Islet Cells 115 A Method for Controlling RNase Activity 117 The Ingredients of Success 118 Genentech's Approach to the Insulin Gene 120 The NIH Guidelines for Recombinant DNA Research 120 The Rat Insulin Gene Project (cont'd.) 121 Studies of Pancreatic Differentiation 121 Key Laboratory Personnel 123 Individual and Laboratory Styles 124 Vectorology 126 The P3 Laboratory 128 Repeating the Gene Cloning 132 Destruction of the Insulin Clones 133 Seeking a Source of Insulin 134 Isolating the Insulin Message 135 Howard Goodman and His Laboratory 137 Controversy over the Use of pBR322 138 The Press Conference at UCSF, May 23, 1977 143 Commercial Prospects 143 Targeting Human Insulin 144 Debate about Regulation of Recombinant DNA Research 145 Senate Hearing on Recombinant DNA Technology, November 1977 146 The Cloning Race 148 The Smithsonian Article and the NIH Guidelines 150 Weighing the Scientific Rewards 152 More on the Senate Hearing 154 Translational Fidelity, Risk/Benefit, and Recombinant DNA Vaccines 158 Hepatitis B Vaccine 159 The Rat Insulin Gene Project: Context 161 Constructing Safe Vectors 161 Departmental Tensions 162 Genentech at UCSF 163 Transference of Intellectual Property Rights to Genentech 164 More