Regional Oral History Office University of California The Bancroft Library Berkeley, California Stanley N. Cohen SCIENCE, BIOTECHNOLOGY, and RECOMBINANT DNA: A PERSONAL HISTORY With an Introduction by Stanley Falkow, Ph.D. Interviews conducted by Sally Smith Hughes, Ph.D. in 1995 Copyright © 2009 by The Regents of the University of California ii 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 and corrected by the interviewee. The corrected manuscript is 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 Stanley N. Cohen dated September 24, 2003. The manuscript is thereby made available for research purposes. All literary rights in the manuscript, including the right to publish, are reserved to 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 Director of The Bancroft Library of the University of California, Berkeley. Requests for permission to quote for publication should be addressed to the Regional Oral History Office, The Bancroft Library, Mail Code 6000, University of California, Berkeley, 94720-6000, and should include identification of the specific passages to be quoted, anticipated use of the passages, and identification of the user. It is recommended that this oral history be cited as follows: Stanley N. Cohen, M.D., “Science, Biotechnology, and Recombinant DNA: A Personal History,” an oral history conducted by Sally Smith Hughes in 1995, Regional Oral History Office, The Bancroft Library, University of California, Berkeley, 2009. iii Stanley Cohen, 1995 Photo courtesy of University of Pennsylvania iv v Table of Contents – Stanley Cohen Introduction by Stanley Falkow xi Interview History by Sally Smith Hughes xiii Curriculum Vitae xv Interview #1: January 11, 1995 1 FAMILY BACKGROUND AND EDUCATION 1 Parents 1 Childhood Interests and Activities 1 Family, and Family Religion, Politics, and Ambitions 2 Interest in Science 3 UNDERGRADUATE, RUTGERS UNIVERSITY, 1952-1956 4 Choosing Rutgers 4 Extracurricular Activities at Rutgers 5 Interest in Music 5 MEDICAL STUDENT, UNIVERSITY OF PENNSYLVANIA, 1956-1960 6 Choosing Penn 6 Research with Charles Breedis 7 Research in Peter Medawar's Laboratory, 1959 8 EARLY PROFESSIONAL CAREER 9 Decision to Go to NIH 9 Clinical Associate, National Institute of Arthritis and Metabolic Diseases, 1962- 1964 9 Research on the Interaction of Chloroquine with DNA 10 Colleagues at the NIH 10 Senior Resident in Medicine, Duke University Hospital, 1964-1965 11 POSTDOCTORAL RESEARCH FELLOW, ALBERT EINSTEIN COLLEGE OF MEDICINE, 1965-1967 12 Research on Lambda Phage Development 12 Interview #2: January 18, 1995 14 Developing an Interest in Antibiotic Resistance 14 Decision to Study Plasmids 15 Initial Postdoctoral Plans 16 Decision to Move to Stanford 17 JOINING THE STANFORD FACULTY 18 Starting a Research Program and Trying to be a Hematologist 18 Interactions with Faculty in Departments of Biochemistry and Medicine 19 Clinical versus Research Activities 20 Starting the Division of Clinical Pharmacology 21 Computer-Based Research On Drug Interactions and Antimicrobial Therapy 22 Joining the Department of Genetics 23 Congruency of Research Interests with Lederberg 24 vi Interview #3: February 1, 1995 25 EARLY LABORATORY RESEARCH AT STANFORD: SCIENTIFIC BACKGROUND AND INITIAL EXPERIMENTS 25 Plasmid History 25 Role of Plasmids in Antibiotic Resistance 27 Molecular Nature of R Factors 28 Isolation of Circular R-factor DNA and Resistance Transfer Factor (RTF) 29 Hiring Lab Personnel: Annie Chang and Chris Miller 30 Expanding the Lab Group 31 Organization of Lab Activities During the Early Years 32 RESEARCH FINDINGS BY VARIOUS LABS PRIOR TO THE INVENTION OF RECOMBINANT DNA 33 Uptake of Bacteriophage DNA by E. coli: the Work of Mandel and Higa 34 Cohen Lab’s Development of a System for Genetic Transformation for E. coli Using Plasmid DNA 34 Interview #4: February 7, 1995 36 End-to-End Joining of DNA Molecules by DNA Ligase 37 Work on DNA Joining in H. Gobind Khorana Lab 37 Work by Peter Lobban, by Jackson, Symonds, Berg, and by Jensen et al. on DNA End Joining 38 Lobban’s Priority 39 Gene Splicing versus Recombinant DNA 40 DNA CLONING: THE INVENTION OF RECOMBINANT DNA 43 Leading Up to the First Cohen-Boyer Experiment 43 The Species Barrier Issue 44 Scientific Goals in the Development of Recombinant DNA Methodology 44 Restriction Enzyme History 44 Inviting Boyer to the Honolulu, Hawaii Meeting on Plasmid Biology, November 1972 45 Work by Sgaramella and by Mertz and Davis Showing that the EcoRI Restriction Enzyme Generates Complementary DNA Termini 46 At the Honolulu Meeting: Beginning the Collaboration with Boyer 48 Caveats About the Feasibility of DNA Cloning 48 Initial DNA Cloning Results 49 pSC101: the First Vector for Recombinant DNA 50 Measuring Success in the Experiments 51 Contributions of Individual Team Members 51 Recognizing Potential Industrial Applications 53 Interview #5: March 1, 1995 53 WRITING THE FIRST COHEN-BOYER PAPER 53 Order of Authorship 54 Disclosure of Results at Gordon Conference and the Singer-Söll Letter 55 Publication Delay 56 INTERSPECIES GENE TRANSPLANTATION 57 The Staphylococcus Experiments 57 Cloning of Eukaryotic Genes: the Xenopus DNA Experiments 58 Experimental Strategy for Xenopus DNA Cloning 58 Transcription of Eukaryotic DNA in E. coli 60 vii Individual Contributions to the Xenopus Work 61 Other Research on Eukaryotic Genes Begins in the Cohen Lab 63 DNA CLONING STARTS IN OTHER LABS 64 Beginning the Distribution of the pSC101 Plasmid 64 Restrictions on Recipient Use of pSC101 67 EXPANSION OF THE BIOHAZARD CONTROVERSY 68 Raising Concern in the Draft Version of the Xenopus DNA Cloning Paper About Potential Biohazards 68 The Committee on Recombinant DNA Molecules, National Academy of Sciences— “The Berg et al.” Committee 69 Berg Expands Committee Membership 70 The Press Conference Announcing the Berg et al. Letter 71 Change in Public Perceptions After the Berg et al. Letter 72 Interview #6: March 7, 1995 73 THE PLASMID NOMENCLATURE WORKING GROUP 73 Need for a Uniform Nomenclature for Plasmids 73 Formation of the Plasmid Nomenclature Working Group 74 Devising the Nomenclature 74 A Nomenclature for Transposons 75 THE PLASMID NOMENCLATURE GROUP’S ROLE IN THE ASILOMAR CONFERENCE 76 Establishing the Plasmid Working Group for the Asilomar Conference on Recombinant DNA 76 Developing a Protocol for Defining Potential Hazards 76 Group Dynamics Among Committee Members 77 Devising a Classification for Experiments According to Perceived Potential for Hazard 78 Interview #7: March 22, 1995 79 MORE ON THE PLASMID COMMITTEE FORMED PRIOR TO THE ASILOMAR MEETING 79 Basis of Recommendations of Plasmid Committee for Asilomar 80 Use of Standard Microbiological Practices 81 Differences of Opinion Among Committee Members 82 Guidelines versus Regulations 85 Biohazard Likelihood as Viewed from Different Perspectives 86 THE ASILOMAR CONFERENCE, PACIFIC GROVE, CA, FEBRUARY 1975 88 Participants 88 Expectations for Asilomar 88 Public Nature of the Discussions 89 Fearfulness at Asilomar 90 Opposition to the Consensus Statement 90 Interview #8: March 29, 1995 92 THE BIOHAZARD CONTROVERSY POST-ASILOMAR 92 Early Days of the RAC 92 Biological Containment for Recombinant DNA 94 Doomsday Scenarios Involving Conjectural Biohazards 95 The RAC in Operation: Getting Permission for Production of a Functional Mammalian Protein in E. Coli 97 viii FEDERAL AND STATE LEGISLATION AIMED AT REGULATION OF RECOMBINANT DNA RESEARCH 98 Views of Stanford Faculty and Administration 98 Lobbying in the U.S. House of Representatives 100 Scientists and Others Supporting Control of Recombinant DNA Research 102 Erwin Chargaff 104 Opponents to Legislation Restricting Recombinant DNA Research 105 Explaining the Berg et al. Letter Retrospectively 106 Early Interactions with Larry Horowitz and Senator Edward Kennedy 107 The U.S. Senate Hearing 108 Interview #9: April 5, 1995 109 FURTHER DISCUSSION OF THE PERIOD FROM 1975 THROUGH 1985 109 Effects of the NIH Guidelines on Research in the Cohen Lab 109 Consulting for Cetus 110 Cetus’ Missed Opportunity 112 On Consulting Relationships With Industry 113 The NAS Forum, Washington, D.C., March 1977 114 On the Responsibilities of Scientists Doing Basic Research 116 Role in the Withdrawal of Proposed Legislation by Senator Kennedy 117 Change in Public Perceptions about Recombinant DNA Research 120 The Issue of Public