University of California • Berkeley

Regional Oral History Office University of California

The Bancroft Library Berkeley, California

Program in the History of the Biosciences and Biotechnology

Arthur Kornberg, M.D. BIOCHEMISTRY AT STANFORD, BIOTECHNOLOGY AT DNAX

With an Introduction by Joshua Lederberg

Interviews Conducted by

Sally Smith Hughes, Ph.D.

in 1997

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.

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All uses of this manuscript are covered by a legal agreement between The Regents of the University of California and Arthur Kornberg, M.D., dated June 18, 1997. 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, 486 Library, University of California, Berkeley 94720, 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 Arthur Kornberg, M.D., 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:

Arthur Kornberg, M.D. , "Biochemistry at Stanford, Biotechnology at DNAX," an oral history conducted in 1997 by Sally Smith Hughes, Ph.D., Regional Oral History Office, The Bancroft Library, University of California, Berkeley, 1998.

Copy no.

Arthur Kornberg, ca. 1987,

Cataloguing information

Arthur Kornberg, M.D. (b. 1918) Biochemist

Biochemistry at Stanford and Biotechnology at DNAX. 1998, xiv, 268pp.

Early career at National Institutes of Health: nutrition research, mentored by Severo Ochoa and Carl Cori; chairman, microbiology, Washington University, St. Louis: C.B. van Niel's microbiology course, faculty, Erwin Chargaff, nucleotide chain synthesis research, DNA as genetic material; chairman, biochemistry, Stanford University: renovation of Stanford Medical School, founding and staffing of biochemistry department, interaction of basic and clinical sciences, departmental operational style, new biochemistry curriculum, industry ties, Industrial Affiliates Program; research programs: DNA polymerase, DNA replication, viral synthesis, polyphosphate, Nobel prize; recombinant DNA: Senate testimony, 1968, patenting in biotechnology, controversy, Stanford biochemistry contributions to/failure to recognize commercial potential of, Peter Lobban's research on; ALZA Corporation; DNAX: foundation, funding, and staffing, purchase by interactions with Schering-Plough, antibody and interleukin research; anti-Semitism; Paul Berg; Dale Kaiser.

Introduction by Joshua Lederberg, Ph.D., Rockefeller University, New York.

Interviewed 1997 by Sally Smith Hughes for the Program in the History of the Biosciences and Biotechnology, Regional Oral History Office, The Bancroft Library, University of California, Berkeley.

TABLE OF CONTENTS --Arthur Kornberg, M.D.

PREFACE i

INTRODUCTION by Joshua Lederberg vi

INTERVIEW HISTORY x

BIOGRAPHICAL INFORMATION xiv

I EARLY CAREER AT THE NATIONAL INSTITUTES OF HEALTH 1 Research in Nutrition 1 Mentors 2

II CHAIRMAN, DEPARTMENT OF MICROBIOLOGY, WASHINGTON UNIVERSITY

SCHOOL OF MEDICINE, ST. LOUIS, 1953-1959 5

Decision to Leave the National Institutes of Health [NIH] 5

Cornelius B. van Niel's Course in General Microbiology 6

Teaching Microbiology to Medical Students 7

Members of the Department 9

Erwin Chargaff and Base Pairing 12

Early Work on Nucleotide Chain Synthesis 13

DNA as the Genetic Material 14

Jacques Monod and DNA Polymerase 16

Obtaining Diverse Scientific Expertise 16

III CHAIRMAN, DEPARTMENT OF BIOCHEMISTRY, STANFORD MEDICAL SCHOOL, 1959-1969 18 Renovation of Stanford Medical School 18

The University Administration 18

Creation of the Biochemistry Department 18

Offer of the Chairmanship, 1957 19

Recruiting Other Major Scientists 20

Reluctance to Establish Joint Appointments 22

Relations with Clinical Scientists 23

Financial Aspects 25

Tensions 26

The New Department of Biochemistry 27

Choosing Faculty Members 27

Leaving St. Louis 29

Melvin Cohn 30 Relations with the Two Biochemists in the Chemistry

Department 32

Communal Structure 32

Later Changes in Departmental Faculty 34

Interaction Between the Basic and Clinical Sciences at Stanford 37

Limited Success 37

The Beckman Center for Molecular and Genetic Medicine 37

Clinicians as Basic Scientists 38

Bridging the Basic Sciencies 40

The Medical Center as an Intrusion 40

The Basic Science Environment, circa 1959 41

Later Efforts to Strengthen Basic Science at Stanford 42

Joshua Lederberg 43

More on the Department of Biochemistry at Stanford 44

Intellectual Focus on DNA 44

Joint Appointments 45

Broadening the Focus on DNA 45

The DNA Club 46

The Chairmanship 46

More on the Department's Distinctive Operational System 49

The Biochemistry Curriculum 51

The Laboratory for Medical Students, 1959-1965 51

The Medical Science Training Program 52

The Department's Relations with Industry 53

Industry Relations in Academic Science 53 Genesis of Biochemistry's Industrial Affiliates Program

[IAP] 55 The Chemistry Department's Industrial Affiliates Program 56

Biochemistry's Industry Affiliates Program 57

Current Attitudes About Industrial Affiliations 59

Proposing a Scientists' Lobby 60

More on Viral DNA Synthesis 103

Use of the Term "Genetic Engineering" 103

Trying to Produce a Biologically Active Molecule 104

Early Concerns About Genetic Engineering 106

Senate Testimony, March 1968 106

Critics of Genetic Engineering 107

Benefits and Dangers 108

The Nobel Prize 110

Stardom 110

Mistakes of Commission and Omission 111

Factors in the Nobel Committee's Decision 111

Drawbacks 113

Professional and University Service 114

Scientific Repercussions 115

RECOMBINANT DNA AND BIOTECHNOLOGY 117

Patenting in Biotechnology 117

Negative Influence on Academic Science 117

Secrecy in Industry 118

Decisions Regarding Product Development 119

Secrecy in Academia 120

Commercial Applications of Biology 120

Recombinant DNA Research 122

Concerns in the 1960s 122 Asilomar and the NIH Guidelines for Research on

Recombinant DNA 124

Scientists Opposing Recombinant DNA Research 125

Concern about the A-T Polymer 126 Conference on Biohazards in Cancer Research, Asilomar,

January 1973 127

The Moratorium 128

Potential for Scientific Research 128

An Interview with Dr. Kornberg in 1975 130

Controlling and Monitoring Research , 131

Potential Legislation 133

The Public's Role 135

The Department's Scientific Contributions 136

Dispersion of the Technology 137

Failure to Anticipate Commercial Applications 138

Industry Skepticism about Recombinant Products 139

Missing the Significance of the Lobban-Kaiser and Berg

Research on Recombinant DNA 140

Peter Lobban's Research 140

Cohen and Boyer's Research 142

Mort Handel's Technique 143

Bestowing Credit on Lobban 144

Janet Mertz 145

Summary 146

Rewards and Omissions 147

The Pajaro Dunes Conference on Biotechnology, March 1982 148

Participants 148

Engenics 149

ALZA Corporation 150

DNAX Institute of Molecular and Cellular Biology as a

Free-standing Company

Foreseeing Commercial Applications of Molecular Biology 152

Foundation 153

Goals and Policy 154

Attempts to Raise Funds 154

Recruiting Staff 155

Initial Focus on Antibodies 157

DNAX and Schering-Plough 159

Marketing Issues 159

Schering-Plough' s Previous Ventures in Biotechnology 160

Debate over the Commercial Viability of Biotechnology 161

Problems with Middle Management 162

Expression Cloning 166

Interleukins 167

Ken-ichi and Naoko Arai 168

Biochemistry Department Reaction to DNAX 169

Debating the Association with Schering-Plough 170

Milestones 171

Reconciling Interests within DNAX 173

The Postdoctoral Program 175

The Scientific and Policy Advisory Boards 177

Restrictions and Patents 179

Anti-Semitism 181

Greatest Contribution 183

SAMPLE EDITED PAGES 184

APPENDIX

A Arthur Kornberg curriculum vitae 186

B Arthur Kornberg publications, 1941-1997 190 C Basis for a conference call of March 28, 1997 regarding

increasing funding for basic research, to the National

Association to Promote Basic Science 231 D "Centenary of the Birth of Modern Biochemistry," keynote

lecture to the ASBMB, San Francisco, August 24, 1997 236 E "Centenary of the Birth of Modern Biochemistry," an

essay for TIBS, ca. June, 1997 249 F E-mail from Joshua Kornberg regarding "Kornberg oral

history—some contemporary clips," April 18, 1998 255

INDEX 261

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BIOTECHNOLOGY SERIES HISTORY--Sally Smith Hughes, Ph.D.

Genesis of the Program in the History of the Biological Sciences and Biotechnology

In 1996, a long-held dream of The Bancroft Library came true with the launching of its Program in the History of the Biological Sciences and Biotechnology. For years, Bancroft had wished to document the history of the biological sciences on the Berkeley campus, particularly its contributions to the development of molecular biology. Bancroft has strong holdings in the history of the physical sciences—the papers of E.G. Lawrence, Luis Alvarez, Edwin McMillan, and other campus figures in physics and chemistry, as well as a number of related oral histories. These materials support Berkeley's History of Science faculty, as well as scholars from across the country and around the world.

Although Berkeley is located next to the greatest concentration of biotechnology companies in the world, Bancroft had no coordinated program to document the industry nor its origins in academic biology. For a decade, the staff of the Regional Oral History Office had sought without success to raise funds for an oral history program to record the development of the industry in the San Francisco Bay Area. When Charles Faulhaber arrived in 1995 as Bancroft's new director, he immediately understood the importance of establishing a Bancroft program to capture and preserve the collective memory and papers of university and corporate scientists and the pioneers who created the biotechnology industry. He too saw the importance of documenting the history of a science and industry which influence virtually every field of the life sciences, generate constant public interest and controversy, and raise serious questions of public policy. Preservation of this history was obviously vital for a proper understanding of science and business in the late 20th century.

Bancroft was the ideal location to launch such an historical endeavor. It offered the combination of experienced oral history and archival personnel, and technical resources to execute a coordinated oral history and archival program. It had an established oral history series in the biological sciences, an archival division called the History of Science and Technology Program, and the expertise to develop comprehensive records management plans to safeguard the archives of individuals and businesses making significant contributions to molecular biology and biotechnology. All that was needed was funding.

In April 1996, the dream became reality. An anonymous donor provided seed money for a center at the Bancroft Library for historical research on the biological sciences and biotechnology. Thanks to this generous gift, Bancroft has begun to build an integrated collection of

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research materials—primarily oral history transcripts, personal papers, and archival collections — related to the history of the biological sciences and biotechnology in university and industry settings. One of the first steps was to create a board composed of distinguished figures in academia and industry who advise on the direction of the oral history and archival components. The Program's initial concentration is on the San Francisco Bay Area and northern California. But its ultimate aim is to document the growth of molecular biology as an independent field of the life sciences, and the subsequent revolution which established biotechnology as a key contribution of American science and industry.

UCSF Library, with its strong holdings in the biomedical sciences, is a collaborator on the archival portion of the Program. David Farrell, Bancroft's new curator of the History of Science and Technology, serves as liaison. In February 1998, Robin Chandler, head of UCSF Archives and Special Collections, completed a survey of corporate archives at local biotechnology companies and document collections of Berkeley and UCSF faculty in the biomolecular sciences. The ultimate aim is to ensure that personal papers and business archives are collected, cataloged, and made available for scholarly research.

Project Structure

With the board's advice, Sally Hughes, a science historian at the Regional Oral History Office, began lengthy interviews with Robert Swanson, a co-founder and former CEO of Genentech in South San Francisco; Arthur Kornberg, a Nobel laureate at Stanford; and Paul Berg, also a Stanford Nobel laureate. A short interview was conducted with Niels Reimers of the Stanford and UCSF technology licensing offices. These oral histories build upon ones conducted in the early 1990s, under UCSF or Stanford auspices, with scientists at these two universitites . ' The oral histories offer a factual, contextual, and vivid personal history that enriches the archival collection, adding information that is not usually present in written documents. In turn, the archival collections support and provide depth to the oral history narrations.

Primary and Secondary Sources

This oral history program both supports and is supported by the written documentary record. Primary and secondary source materials

1 Hughes conducted oral histories with Herbert Boyer, William Rutter, and Keith Yamamoto of UCSF, and with Stanley Cohen of Stanford. The first volume of the oral history with Dr. Rutter is available at the Bancroft and UCSF libraries; transcripts of the other interviews are currently under review by the interviewees.

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provide necessary information for conducting the interviews and also serve as essential resources for researchers using the oral histories. They also orient scholars unfamiliar with the field or the scientist to key issues and participants. Such orientation is particularly useful to a researcher faced with voluminous, scattered, and unorganized primary sources. This two-way "dialogue" between the documents and the oral histories is essential for valid historical interpretation.

Beginning with the first interviews in 1992, the interviewer has conducted extensive documentary research in both primary and secondary materials. She gratefully acknowledges the generosity of the scientists who have made their personal records available to her: Paul Berg, Stanley Cohen, Arthur Kornberg, William Rutter, Keith Yamamoto. She also thanks the archivists at Bancroft, UCSF, and Stanford libraries, and personnel at Chiron, Genentech, and Stanford's Office of Technology Licensing, for assistance in using archival collections.

Oral History Process

The oral history methodology used in this program is that of the Regional Oral History office, founded in 1954 and producer of over 1,600 oral histories. The method consists of research in primary and secondary sources; systematic recorded interviews; transcription, light editing by the interviewer, and review and approval by the interviewee; library deposition of bound volumes of transcripts with table of contents, introduction, interview history, and index; cataloging in national on-line library networks (MELVYL, RLIN, and OCLC) ; and publicity through ROHO news releases and announcements in scientific, medical, and historical journals and newsletters and via the ROHO and UCSF Library web pages.

Oral history as an historical technique has been faulted for its reliance on the vagaries of memory, its distance from the events discussed, and its subjectivity. All three criticisms are valid; hence the necessity for using oral history documents in conjunction with other sources in order to reach a reasonable historical interpretation.1 Yet these acknowledged weaknesses of oral history, particularly its subjectivity, are also its strength. Often individual perspectives provide information unobtainable through more traditional sources. Oral history in skillful hands provides the context in which events occur-- the social, political, economic, and institutional forces which shape the course of events. It also places a personal face on history which not only enlivens past events but also helps to explain how individuals affect historical developments.

1 The three criticisms leveled at oral history also apply in many cases to other types of documentary sources.

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An advantage of a series of oral histories on a given topic, in this case molecular biology and biotechnology, is that the information each contains is cumulative and interactive. Through individual accounts, a series can present the complexities and interconnections of the larger picture. Thus the whole (the series) is greater than the sum of its parts (the individual oral histories), and should be considered as a totality.

Emerging Themes

Although the oral history program is still in its infancy, several themes are emerging. One is "technology transfer," the complicated process by which scientific discovery moves from the university laboratory to industry where it contributes to the manufacture of commercial products. The oral histories show that this trajectory is seldom a linear process, but rather is influenced by institutional and personal relationships, financial and political climate, and so on.

Another theme is the importance of personality in the conduct of science and industry. These oral histories testify to the fact that who you are, what you have and have not achieved, whom you know, and how you relate has repercussions for the success or failure of an enterprise, whether scientific or commercial. Oral history is probably better than any other methodology for documenting these personal dimensions of history. Its vivid descriptions of personalitites and events not only make history vital and engaging, but also contribute to an understanding of why circumstances occurred in the manner they did.

Molecular biology and biotechnology are fields with high scientific and commercial stakes. As one might expect, the oral histories reveal the complex interweaving of scientific, business, social, and personal factors shaping these fields. The expectation is that the oral histories will serve as fertile ground for research by present and future scholars interested in any number of different aspects of this rich and fascinating history.

Location of the Oral Histories

Copies of the oral histories are available at the Bancroft, UCSF, and UCLA libraries. They also may be purchased at cost through ROHO.

Sally Smith Hughes, Ph.D. Research Historian

Regional Oral History Office April 1998

V

Oral Histories on Molecular Biology and Biotechnology

Arthur Kornberg, M.D., Biochemistry at Stanford, Biotechnology at DNAX, 1998

William J. Rutter, Ph.D., The Department of Biochemistry and the Molecular

Approach to Biomedicine at the University of California, San Francisco, 1998

Paul Berg, Ph.D.

Herbert W. Boyer, Ph.D,

Niels Reimers

Robert Swanson

Keith R. Yamamoto, Ph.D.

In Process

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INTRODUCTION by Joshua Lederberg, Ph.D.1

For the Love of Enzymes; The Odyssey of a Biochemist is not the book that Arthur Kornberg originally intended. His first drafts were focussed on an exposition of the facts of biochemistry he felt should be more widely learned by the general public. His friends and admirers sought to persuade him of the legitimate interest in a biography of a science, in its day-to-day challenges, in the development and personal character of its practitioners, in the interplay of innate and environmental influences that may lead to extraordinary accomplishment. Gradually, almost grudgingly, the successive drafts of his manuscript have responded to that appeal: we now have a work that combines scientific exposition with autobiographical memoir. Kornberg has played such a commanding role in the biochemistry of the gene: it is impossible to tell its history and exclude the personality that brought so much of it about. The subject is at the very center of public expectations for the application of science to human understanding and benefit.

His story has no simple lessons. Its drama has little of the spice of interpersonal conflict, of any "race for the gold." His rivalry is with a reluctant Nature who demands ingenuity and perseverance before delivering the real prize, the secrets of how the world and its life are contrived.

My scientific acquaintances are almost evenly divided between those who were born with a passion for science, have been driven by an inner vocation, and those who came to it as a later discovery, perhaps even an accident. Kornberg belongs to the second category; it may be associated with the unflagging and methodical way in which he has pursued one accomplishment after another for four decades, and with more yet to come. He has always been deeply devoted to his family, with no noticeable decrement to his scientific productivity, and with a yield of

'At Dr. Kornberg 's suggestion, the interviewer asked Dr. Lederberg if we could reprint for this oral history volume his introduction to Dr. Kornberg's autobiography, For the Love of Enzymes. When Dr. -Lederberg kindly agreed, the interviewer asked him to write additional comments on the interactions of the Stanford Department of Genetics, which Dr. Lederberg was recruited to chair in 1958, and the Department of Biochemistry, which Dr. Kornberg was brought in to head the following year. Again, Dr. Lederberg agreed, and also added a concluding paragraph on the biotechnology industry. Because the sections which were not updated differ from the foreword published in the Kornberg autobiography, this present introduction contains substantially new information. We are grateful to Dr. Lederberg for his time and effort.

— o.o.n.

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companionship and laboratory collaboration with a gifted wife (the late Sylvie Kornberg) and three sons already exhibiting extraordinary scientific and professional achievement. That balance and moderation has characterized his administrative accomplishment in building a department of biochemistry whose productivity is unmatched, and one which gives the lie to the proposition that science today is achievable only with immense groups and huge machines, or that it demands a renunciation of other human values.

Kornberg 's early life typifies a generation (like my own) of second generation immigrant Jews in New York City, the parents making great sacrifices to ensure an education for their children. Nothing in his home background pointed to science except the encouragement to study and to excel. The public schools reinforced that acculturation, the ideal that academic achievement would be a unique opportunity for social and economic mobility out of the sweatshops. City College in New York has nurtured a lion's pride of Nobel Prize winners; but it offered very little in the actual content of undergraduate scientific education (and in those days, none whatever at the graduate level). It did offer a talented, ambitious and competitive peer group that helped to sharpen the aspirations of its students, and a faculty that, whatever else, fed the sense of individual worth of each of them, notwithstanding attributes of race, color or economic class. The external world was not so receptive; there were few opportunities open to Jews in academic or industrial science. The professions such as medicine (however the medical schools might ration their admissions) at least offered a prospect that individual careers might depend on skill rather than belonging to the right clubs.

A decade later, it was the mobilization of the universities for training in the skills to be recruited for World War II that finally cracked those barriers (as shaped my own experience). Indirectly, the same process had opened up the National Institute of Health, and gave Kornberg (now a medical graduate and a naval ship's doctor) his first research opportunities. His interests meandered from jaundice to nutrition (as studied in rats) to what was his predestination, the isolation of enzymes. This foreword should not take the place of his text; and indeed better that it be read afterwards as well.

I first met Arthur thirty-five years ago, at the summer course given by van Niel where he "learned microbiology" in preparation for his taking that chair at Washington University. That was a fateful meeting, eventually leading to my joining him at Stanford five years afterwards.

I would indeed have preferred joining his new biochemistry department; but we have differences in how (or whether) we voice a philosophy of science, that he may have been wise to foresee from the point of our first meeting. It fell to me to join a fraternal order of basic science departments: Arthur's vision of how to maintain some

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balance in the politics of the medical school executive committee, between the ideals of the sciences and of the clinical services, the latter also leveraged by their being the fount of much greater cash flows in one or the other direction. In its research programs, Genetics was hard to distinguish from Biochemistry. Indeed, as molecular biology attained its ascendancy, this became true as well of Pharmacology, Microbiology, even Anatomy (under the rubric of Structural Biology), Developmental Biology, and so forth. In its teaching, Genetics had the special role of fomenting an interest in populations, and how they evolve. That is, we sought to enlighten our understanding not just of how some biological system worked, but also how it had come about. This entailed a focus on mutation, how mutations affect development and phenotype, and the dynamics of selective forces that eventuate in evolutionary change. Recruiting Luca Cavalli-Sforza was to be the keystone of providing that intellectual oversight, joined for a time by Walter Bodmer, until he was lured by an Oxford professorship. Yet both of these giants have also spent much of their careers in a similar application of DNA analyses. Arthur and his group were to play a major role in providing the principal tools for that new molecular genetics.

Arthur's manifest approach to the choice of scientific problems is to focus on the small particular, to eschew large social or scientific goals, to set aside grand design and theoretical synthesis. He says "I have never met a dull enzyme." Less certain is whether this is good advice for anyone but an Arthur Kornberg, which is to ask whether he has truly followed it himself. If not by design, then by intuition, he has always managed to sight the central targets of biological enquiry in his " enzyme -hunt ing ;" and his method has always embraced far broader issues than the mechanical steps of purification and isolation. He may be right that these are daunting to many impatient youngsters, and that enzymology is lamentably being bypassed by the more facile doctrines of gene-hunting. I agree with him that the thousand and odd enzymes involved in intermediary metabolism and nucleic acid and protein synthesis are the indispensable periodic table of biology. As with the chemical atoms in Mendeleev's time, only a small proportion of the enzymes we can infer have actually been isolated—and this is an arduous and indispensable task that must not be overlooked as the real work of mapping the human genome. But besides Kornberg 's technical skills, we also need his taste in selecting those targets that warrant first priority. As he has always practiced, despite his preachments, we need to embed that knowledge of enzymes in a broader panoply of their functional relationships in the cell. This will require a host of other skills, like electron microscopy, NMR spectroscopy and X-ray diffraction, not to mention genetic analysis. Explanation in contemporary biology is chemistry; we need the purified components to reconstruct the cell as the final test of our analytical models. The essential prerequisite for all of this is his puritanical prescription: "isolate it!"

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As the practical applications of molecular genetics became more evident, starting around 1970, Arthur was at first reluctant to play any part in the Biotechnology startups. He has written how his friendship and burgeoning business relationships with Alex Zaffaroni led to the most constructive of partnerships. The private sector could bring enormously more capital to bear, and could focus on achieving material results for public benefit — and when this happened to add pecuniary to psychic composition for the time spent. Biotechnology Alley had been an extrapolation from Silicon Valley, the consummation of Provost Fred Terman's dreams that the basic ideas from Stanford's physical and engineering sciences could fertilize brand new industries as important as Intel and Hewlett-Packard have become in the U.S. economy. The conjunction of intellectuals and entrepreneurs in the San Francisco Bay Area is unmatched anywhere, and was nucleated by the early emergence of forms like Syntex, Alza, Genentech, Cetus, now followed by an almost endless list. California's climate and natural beauty enhanced the attraction; and for a while there was enough vacant land to provide a garden for the startups at modest cost.

The modern era of DNA research began in 1944 with the discovery by Avery et al. that pneumococcal DNA could transmit heritable characters from one cell to another. For years, until about 1980, I was bemused with the question: given such a revolutionary discovery, how long will it take to reach practical medical benefit? The flowering of the biotechnology garden makes such questions foolish today, and are all indebted to Dr. Arthur Kornberg for achieving some of the most important insights that have led to that eventuality.

Joshua Lederberg, Ph.D. Rockefeller University

July 1998 New York

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INTERVIEW HISTORY- -Arthur Kornberg, M.D.

This oral history with the Stanford biochemist and Nobel laureate Arthur Kornberg is one of a series tracing basic biomolecular science in northern California and its association with the rise of the biotechnology industry. Professor Kornberg himself has a foot in each camp. A steadfast advocate of biochemistry as the path to understanding fundamental biological processes, he could, despite his medical degree, be taken as the quintessential basic scientist. As any biochemist can tell you, his name is linked with early work on DNA replication, for which he was awarded the Nobel Prize in 1959. Eight years later, in 1967, he and his laboratory were first to achieve the artificial synthesis of viral DNA--"creation of life in a test tube", as the journalists to his displeasure headlined it. In short, he is a basic scientist of world stature.

Yet Dr. Kornberg, like so many of his colleagues in contemporary biology, has strong ties with industry. Most if not all of his associations were instigated by his friend Alejandro Zaffaroni, chemist, entrepreneur, and founder of several companies based on technologies first developed in academic biology. One of the first of these was ALZA--Zaf f aroni ' s company in name as well as actuality—for which Professor Kornberg became a scientific consultant in 1968. He recounts in the oral history how this introduction to industry led to deeper commercial involvement in 1980. In that year, Zaffaroni persuaded Dr. Kornberg, who in turn persuaded his Stanford colleagues Paul Berg and Charles Yanofsky, to join him in founding DNAX, a biotechnology company located in Palo Alto, adjoining the Stanford campus. Dr. Kornberg currently is a member of the scientific advisory board of this and several other companies. At eighty, having outlived two accomplished wives, he continues to keep a regular schedule in his Stanford laboratory where he and his students pursue research on the enzyme polyphosphate . Thus in effect he is a man of both the academic and commercial worlds.

Dr. Kornberg has published an autobiography, For the Love of Enzymes, and The Golden Helix, his history of DNAX.1 There is also a 36-carton collection of his personal papers in Stanford's Green Library. With extensive information available, one might well ask, why the need for an oral history? The answer is that the three types of documents--

1 For the Love of Enzymes; The Odyssey of a Biochemist, Cambridge: Harvard University Press, 1989; The Golden Helix; Inside Biotech Ventures, Sausalito, California: University Science Books, 1995. Although the latter gives brief treatment to Genentech, Amgen, Chiron, and Regeneron, the major focus is DNAX.

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the books, the papers, and the oral history- -are complementary, yet distinct, differing in both substance and tenor. Dr. Kornberg's two fine books tell a story deliberately limited to his endeavors in science and business; he writes a little about personality, less about context. Like his approach to scientific research, his style is focused and spare. His correspondence in the Stanford archives is that of a scientist deeply engaged in his work, reluctant to write more than necessary to get the point across. He does not make letters occasions for digression into personality, politics, and the circumstances surrounding his science. Therefore, an oral history capturing a more informal and discursive Professor Kornberg and his institutional context, particularly that of Stanford University and the Department of Biochemistry, was well warranted.

It was for the purpose of forming and directing a new department of biochemistry that Dr. Kornberg came to Stanford in 1959, the year that its medical school was moved from San Francisco to the Palo Alto campus. The idea was not only to unite all aspects of the medical curriculum (the first two years had been taught in Palo Alto and the two clinical years, in San Francisco) but also to encourage interchange between the basic and clinical sciences. Kornberg and the Department of Biochemistry were key ingredients in this program, all the more so when Kornberg was awarded the Nobel Prize a few months after his arrival.

There is much in the oral history about the department's organization, earliest faculty (which came almost to a man--and one woman—from Kornberg's lab at Washington University, St. Louis), and characteristics — small size, insularity, and communal social and financial structure. There is also discussion of wider contextual issues, notably the recombinant DNA debate of the 1970s and the subsequent commercial application of the recombinant DNA and cloning science to which Stanford scientists made seminal contributions. Of particular interest is Arthur's commentary on the controversy surrounding DNA polymerase I research of the 1950s, for which he received the Nobel Prize. Also significant is his adamant opinion that the biochemistry department provided the building blocks for recombinant DNA science and yet largely missed its potential for practical application. Instead of Stanley Cohen in Genetics at Stanford and Herbert Boyer at UCSF, he credits Peter Lobban, a Stanford graduate student in biochemistry in the late 1960s and early 1970s, for recognizing the commercial potential of recombinant DNA technology: "I believe, without historical research on this, that he [Lobban] was the first and clearest exponent of this technology and its applicability."

The discussion of DNAX reflects Kornberg's selective enthusiasm for the commercialization of biology that the biotechnology industry represents. He speaks with respect of the corporate executives of Schering-Plough, the American pharmaceutical company that bought DNAX in 1982. But he also provides insights into tensions and resolutions at

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several levels—between scientific research and commercial production; between DNAX scientists and advisors, and Schering-Plough management; between DNAX and competing biotech companies; between molecular biologists and biochemists within DNAX.

The oral history also describes a scientific style that places enzymes — clean enzymes and clean substrates — at the center of laboratory endeavor in biomedicine. "It was the classical tradition of enzymology , " Dr. Kornberg remarked, "that led me to DNA polymerase and DNA ligase and the other reagents without which there would be no recombinant DNA." The interviews suggest that his exacting standards for science might possibly spill over into lifestyle. He comments, for example, on his preoccupation with the efficient use of time, and reluctance, until recently, to leave the laboratory in order to travel and give talks. One watches between the lines of the oral history an individual living up to his own high standards— in science and every other aspect of life.

The oral history is organized around three themes: the Department of Biochemistry, Dr. Kornberg1 s research at Stanford, and DNAX. He describes the department's transformation from a pure basic science enterprise into one with increasing ties with industry, through its Industrial Affiliates Program, consultantships, and faculty member equity in corporate concerns. The department's history reflects the gradual commercialization of biology, a process now pervasive in American universities.

The Oral History Process

At an initial meeting on January 7, 1997, Professor Kornberg and I discussed how best to orient the interviews around pre-existing material, particularly the two books mentioned above. Because For the Love of Enzymes provides a full account of his upbringing and education, we decided to begin the interviews with an overview of his work at Washington University in order to provide the context for his move to Stanford in 1959 and his continuing research on DNA replication. The reader seeking full treatment of this earlier history will wish to refer to these published sources and to Dr. Kornberg 's collected papers.

The six interviews conducted between March and May, 1997, are based on the interviewer's extensive research in Dr. Kornberg 's papers in Stanford's Green Library as well as those on DNAX, stored in his laboratory, which he kindly made available to me. Although some duplication of existing accounts was inevitable, this oral history provides substantial new information and a more spontaneous and expansive historical view. A cordial but careful informant who chooses words carefully, Dr. Kornberg wanned to the interview process, eventually allowing himself digressions and personal asides. I suspect

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he was pleased and somewhat surprised to learn that I had found his personal papers to be a rich historical source. Fit and youthful for his near-eighty years, he was a joy to work with, supplying documents-- and on one occasion a hand-packed lunch--to support the interviews and interviewer.

The edited transcripts were mailed to Professor Kornberg for his review; he made careful additions but did not substantially change the tenor or content. Characteristic of his efficiency, he returned the transcripts before my deadline. The oral history stands as testimony to one man's vision of the ideal institutional base for biochemical research—the Stanford Department of Biochemistry, single-minded dedication to science, and to the fruitful alliance that can—and has- been forged between academia and industry.

I wish to thank John Wilson, M.D., who is writing a history of Stanford Medical School and who supplied background information on the school; Margaret Kimball and Heidi Heilemann, archivists at Stanford Libraries, for providing access to and assistance with, respectively, Green Library and Lane Medical Library archives; and to Beverly Forsyth, Dr. Kornberg 's devoted assistant, who supplied documents and conveyed messages .

The Regional Oral History Office was established in 1954 to augment through tape-recorded memoirs the Library's materials on the history of California and the West. Copies of all interviews are available for research use in The Bancroft Library and in the UCLA Department of Special Collections. The office is under the direction of Willa K. Baum, Division Head, and the administrative direction of Charles B. Faulhaber, James D. Hart Director of The Bancroft Library, University of California, Berkeley.

Sally Smith Hughes, PhD

Research Historian/Senior Interviewer

April 1998 Berkeley, California

XIV

-

Regional Oral History Office Room 486 The Bancroft Library

University of California Berkeley, California 94720

BIOGRAPHICAL INFORMATION (Please write clearly. Use black ink.) Your full name Arthur Kornberg

Date of birth March 3, 1918

Birthplace Brooklyn, New York

Father's full name Joseph Kornberg

Occupation Merchant

Birthplace Poland

Mother's full name

Occupation Housewife

Your spouse

Lena Kornberg

Birthplace Poland

Widowed

Occupation

Birthplace

Your children R°9er '

- Kenneth

Where did you grow up? Brooklyn, New York

Present community Portola Valley, California

Education B.S. - City College of New York

M.D. - University of Rochester

Occupation(s) Professor, Department of Biochemistry Stanford University School of Medicine

Areas of expertise Biochemistry

Other interests or activities Writing, Lecturing, Travel

Organizations in which you are active

-

I EARLY CAREER AT THE NATIONAL INSTITUTES OF HEALTH1

Research in Nutrition

Hughes: Dr. Kornberg, because you have so fully covered your upbringing and education in your autobiography,2 we are not going to focus here on those aspects of your life. But I would like to hear a little about your early career. Your early research fell under the rubric of biochemistry, did it not?

Kornberg: Well, not in my first three years [1942-1945] as a nutritionist at NIH. As you know, I never earned a Ph.D. in biochemistry.

Hughes: But you were doing biochemical research, right?

Kornberg: Well, it would have been regarded as biochemical in some

contexts of nutrition. The group at the NIH was not at the vanguard of the new nutrition, that is, working with microorganisms rather than rats.

When I went to work with Severo Ochoa in 1946, enzymology was utterly new to me. That was my introduction to genuine biochemistry and enzymology, and from then on that was all I was interested in and wanted to do.

Hughes: Is that when you really got hooked?

Kornberg: Yes, it is fair to say that. I was already uneasy with

nutritional research in '45, getting bored with feeding rats and not understanding what was going on inside the rat. At the

1 To achieve better chronology, the transcripts as they appear in this volume do not always follow the order in which the discussion was recorded.

2 Arthur Kornberg. For the Love of Enzymes: The Odyssey of a Biochemist. Cambridge, Mass.: Harvard University Press, 1989. Hereafter, Enzymes .

end of the war—that was the summer of '45--Bernard Horecker, who was a good friend, returned to biochemistry in which he had taken his degree. So I apprenticed myself to him, and he taught me how to make some enzyme preparations and so forth. We began planning where I would go if I could persuade the authorities at NIH to let me go somewhere to learn the new biochemistry.

Hughes: Was that what people called it, the new biochemistry?

Kornberg: It was certainly new to me because I hadn't learned it in medical school. It was certainly new to my advisors in nutrition, but not new to people who came from Europe, and to people who were trained in a few laboratories, such as [Carl] Cori's laboratory at Washington University in St. Louis or [Hans T.] Clarke's at Columbia or Harland Wood's, not yet at Western Reserve University. There were pockets of people doing enzymology or dynamic biochemistry, for example, at Wisconsin. A textbook of the time, Dynamic Aspects of Biochemistry, by Ernest Baldwin,1 described the state of the science.

Hughes: Nothing had come out of the Cambridge School?

Kornberg: Baldwin was from the Cambridge School, but all was destroyed during the war.

When I convinced NIH to sponsor my trip to a laboratory, I thought first of David Keilin's. But I was told that his lab really wasn't functioning well as an aftermath of the war. One of the American refugees from Cambridge, David Green, invited me to his lab, but I had friends who said David was a difficult character.

Mentors

Kornberg: There was a young Spaniard, Severe Ochoa, working at New York University Medical School. Actually, he was a guest in the Biochemistry Department; he was doing some interesting work. Bernie Horecker and I read his papers and found that he was doing the kind of enzymology we'd love to do. So I applied to work with him. He had nobody else so he took me. I was still in uniform.

New York: Macmillan Co., 1948.

There was no housing in New York. My wife Sylvy and I had to move from one hotel to another every few days, until we found an apartment saved for us by Herman Kalckar. Those were such eventful, exciting years; I learned something new every day. I wasn't doing anything important experimentally, but I was acquiring scientific language and attitudes. Ochoa was a very impressive person, with his enthusiasm, optimism, and his breadth of vision. You may know that in later years he was among the most celebrated people in Spain. Don Severe and King Carlos; Juan Carlos and Severo--they were actually good friends .

That year with Ochoa was absolutely great; every day mattered. Ever since, I've told my students and people working with me, "Hey, you wasted an afternoon; it will never come back." I have always been preoccupied with time. Time mattered. Every hour mattered. There was an exhilaration with discovery. I could get a fact, or fail to find a fact, in a matter of minutes or hours, rather than waiting for months as in research with rats, or in humans to sort out a very muddled set of circumstances presented by a patient.

Hughes: So it was precision as well as time saved which appealed to you?

Kornberg: Control. I had the authority to impose certain conditions that were well enough controlled that I could decide I'd either learned something or didn't.

And then things did go well. There was so little known at the time that no matter what you did, you'd discover something exciting. Or so it seemed.

Hughes: Did you feel that you were on the crest of a new wave?

Kornberg: I had confidence that my association with Ochoa gave me access to, familiarity with, those who were identified as being at the forefront of biochemistry. I felt that I knew what they were doing and that I was capable of doing something along- those lines. I was confident that, if I worked hard and did things carefully, I would find something worthwhile. When we come to discuss, as I think I frankly did in my book,1 how we discovered this utterly novel enzyme DNA polymerase I that is the basis for heredity, it was not done with a vision that I would discover such a key enzyme. It was more my love of enzymes and

1 Enzymes .

always wanting to tackle something at a point of difficulty beyond what I had done before.

Hughes: So you were pushing yourself a little each time as a scientist.

Kornberg: Always, always — looking for trouble. [laughs] I think the

essence of science is that you don't sit back and say how great this finding is. You say, "Gee, this tells me I don't understand this." Or, there is another opportunity. "Can we use our methods and ingenuity and drive to find the enzyme that does something that hasn't been done before?"

Hughes: Are there people besides Ochoa that you consider to be mentors?

Kornberg: There are those I knew personally and others I admired from the literature.

Ochoa gave me the opportunity to learn about enzymes. I was impressed by him; he had endured so much. He had been through wars and revolutions in Spain and Germany and England. And in New York he was in the most tenuous of positions. There was a sublime air about him—intense interest in the science, not seeming to worry about what would happen the next day, an enthusiasm for the results, even if they weren't that interesting.

Did I learn that from him; I don't know. I have a similar attitude. Could I have learned something like that? I don't think so. I haven't been able to teach it to anybody. So you can say that you're born with it or you have it, and then you are reinforced by seeing it practiced by somebody whom you admire. The other thing I learned was that I didn't think Ochoa was that much smarter than I was . I thought I could achieve what he had.

Cori was something else again. Cori had extraordinary intellect and breadth of knowledge and was awesome that way. And yet he was so supportive of what I was doing that I was encouraged by his respect and confidence in me. So in that sense he was also a mentor.

There are giants in the literature, like Otto Warburg and others... You learn from everybody; you learn from your students and colleagues all the time. I can't believe the patience that my students have. They should be discouraged by repeated failures and the arduous nature of experiments and yet they go on. That's great.

II CHAIRMAN, DEPARTMENT OF MICROBIOLOGY, WASHINGTON UNIVERSITY SCHOOL OF MEDICINE, ST. LOUIS, 1953-1959

Decision to Leave the National Institutes of Health [NIH]

Hughes: Dr. Kornberg, I want to go back to 1959 or perhaps even earlier to establish the context for Stanford's overtures to you to become chairman of the newly created Department of Biochemistry.

Kornberg: Yes, we should go back well before 1959. The department as it was constituted at Stanford in 1959 was really assembled at Washington University in St. Louis beginning in 1953. It might be appropriate to start there.

In 1952, I was at the NIH, very comfortable, and my work was going exceedingly well, or at least I thought so. Then I was approached by some very eminent people, Carl Cori and Oliver Lowry, at the Washington University School of Medicine to consider the chairmanship of the Department of Bacteriology and Immunology, renamed Microbiology. There were two elements that led me to accept their offer. I was becoming disillusioned with the less-than-inspiring administration of the NIH, and I was at the level where I had to intersect with them. Secondly, the NIH was building its Clinical Center and I thought that this was ominous because the basic science that was dominant at the NIH would now become very clinically and practically oriented.

I was attracted by the flattering invitation from Washington University and the association that I would have with some of the great scientists in medical science—Carl and Gerti Cori, and others. And so in mid- 1952 I decided to accept their offer and appeared in St. Louis in January of 1953. As events turned out I had misjudged the situation. I inherited dismal, medieval laboratories which became my responsibility to rehabilitate. As a member of the executive committee, I looked

forward to the opportunity to discuss science and education. Rather, there were debates about nurses' salaries and things like that. It was no more inspiring administratively than it had been at the NIH.

Then something occurred I hadn't counted on. In 1952, I had four applications for postdoctoral work from people who later became eminent in science, but were reluctant to go to St. Louis. Their interest in me was genuine, but they were also interested in being at the NIH. So three of them found alternative sponsors at the NIH. They were Bruce Ames, Ed Korn, and Gordon Tomkins, who before his premature death [1975] in a surgical procedure, was one of the people who rejuvenated the UC San Francisco Department of Biochemistry.1 The fourth was Paul Berg, and I'll come back to him in a moment.

I often wondered in the succeeding years whether I had made a great blunder in moving from the NIH, where I was so comfortable, had such excellent facilities and things were going so well; the academic heaven in St. Louis never materialized. Nevertheless in 1953, I became chairman of a department dealing with subjects in which I had no special knowledge. I was not a microbiologist or a bacteriologist or an immunologist .

Cornelius B. van Niel's Course in General Microbiology

Kornberg: That summer I arranged to come to California to take a course that became legendary. It was a course given to twelve people every summer at Stanford's Hopkins Marine Station. The alumni of that course became a who's who in science, including chemists as well as biologists.

Van Niel was an extraordinary figure and a teacher of the kind that one never finds anymore. He could lecture for eight hours a day and enthrall you with accounts of heroes and villains in science; the Dutch microbiologists were always the heroes. He wouldn't mention any pathogenic organism or the host's immune system. The course in general microbiology was

1 For more on Tomkins and the rejuvenation of UCSF biochemistry, see the oral histories with Herbert W. Boyer, William J. Rutter, and Keith R. Yamamoto in the UCSF Biotechnology Oral History Series. Hereafter, UCSF Biotechnology Series.

inspiring and enlightening but not suitable to teach medical students I would face in September.

Hughes: He was teaching people who were then going to apply the information in basic research—was that the idea?

Kornberg: Yes, I would think so. He was on the Stanford faculty, and the Hopkins Marine Station still is a branch of the biological sciences department.

Teaching Microbiology to Medical Students

Kornberg: In September of 1953, we were confronted with teaching

bacteriology to 120 medical students in their second year. The remnants of the previous department, two or three people, taught old-fashioned bacteriology in which you carry out certain procedures to determine the bacterium by staining or some other means. The focus was on the pathogenesis of the disease for which the particular bacillus or coccus is responsible. When I listened to a few of the lectures, it was apparent how inappropriate it was to teach microbiology in these very narrow practical ways. I was accustomed to the old orientation from having been a medical student, but that was fifteen years earlier and I was now imbued with biochemistry and genetics.

Hughes: And you had been exposed to van Kiel's approach--

Kornberg: --as a general microbiologist. He was neither a biochemist nor a geneticist, but a good general microbiologist. My recruiting of new faculty was in the direction of introducing the modern aspects of biochemistry and genetics into microbiology.

Hughes: Had you been recruited with that understanding?

Kornberg: No, but there was no deception. My patrons there and

particularly Carl Cori, the most distinguished member of the faculty, knew that I was a biochemist and what I wanted to do in research. As far as teaching was concerned, well, it would take care of itself.

After a year or two of teaching, the students, who had taken biochemistry in their first year, dubbed our course Biochemistry II. It was not well received. A fifth column of several people left over from the old department would tell the students that they weren't learning medical bacteriology and

8

were being deprived of exposure to information about syphilis and other diseases that would be crucial to becoming legitimate M.D.'s. [chuckles]

I might say as a postscript that in subsequent years the students we had those years, either practicing M.D.'s or in academic medicine, would refer to that course as the most memorable and enlightening course that they had had. That was due not only to the curriculum, but also to the spirit of the young people who were teaching the course. They were teaching subjects that they hadn't known anything about, but were learning it with novel insights.

Hughes: Did you have a model for the curriculum?

Kornberg: That's the point; there was no model; we had was no textbook. The famous textbook by [Bernard] Davis and co-authors came out only years later. We had no book the students could consult to capture this new attitude about the importance of biochemistry and genetics for learning about microbes, whether they were "good" or "bad" microbes.

Hughes: Didn't student attitude run counter to the basic science tenor you were trying to establish in the department?

Kornberg: Yes, and it's still true. Medical students by and large want to learn what they need to know to practice medicine, and they are not disposed to learn about photosynthesis or the scientific method. They don't want to spend time unnecessarily on subjects that aren't going to be tested on the national medical specialty boards. Medical students are not graduate students in the sense of wanting to increase their fund of knowledge and expertise and basic techniques. It is common now to introduce them to clinical applications of biochemistry. Things were even worse at that time.

Hughes: On the other hand, you shared medical experience with them; you are a physician who has turned to basic science.1

Kornberg: Yes, but reactionaries can be less tolerant than other people, once having seen the light. I could see the importance of basic science, but couldn't convey it.

In fact, after two or three years in St. Louis, I wrote a memo to the dean of the medical school—it could have been Carl

1 Dr. Kornberg received an M.D. degree from the University of Rochester in 1941.

Moore--proposing that instead of having students who wanted to be sports medicine doctors and private practitioners, we should appeal to those who want a school to prepare them for a career in academic and research medicine, without diminishing their capacity to practice medicine. My memo was ignored. It was considered almost suicidal that a school distinguish itself by focusing on the science in medicine. I think that would be true even today.

Now of course we have NIH medical scientist training programs. The NIH demands that students in the program be candidates for the Ph.D. as well as the M.D. Stanford prides itself on the fact that there are many research opportunities for all medical students. Perhaps two-thirds or three-quarters of them take advantage of these opportunities, some for financial reasons (because they get stipends for it), and others because the experience looks good in their curriculum vitae.

Members of the Department

Kornberg: The first person to join the department at St. Louis, who came with me from NIH, was a postdoc, Osamu Hayaishi. He was my first appointment as an assistant professor. After a couple of years he went back to the NIH in a scientist position, and a few years later became professor of biochemistry at Kyoto. He is the doyen of biochemistry in Japan, invited repeatedly by the emperor for his wisdom in science. He is both a great scientist and great statesman, and for many years the most eminent biomedical scientist in Japan. Osamu, before joining me, was very much involved in enrichment culture work, discovering soil bacteria with specialized metabolic capacities .

Also joining me later in 1953 was Paul Berg. He told his mentor, Harland Wood, at Western Reserve University that he did not want to work with Carl Cori, because he didn't want to go to St. Louis. His first postdoctoral year [1952] was with Herman Kalckar in Copenhagen. When he got my letter saying that I was moving to St. Louis, he agreed to come there. That was a momentous choice, because we've been close colleagues and friends ever since. He is not only bright and inventive, but also a very good citizen, a "boy scout."

As a young postdoc, Paul was willing to do some of the teaching in microbiology. We divided up the pertinent

10

subjects. He took some pathogenic bacteria and I took bacteriophages (bacterial viruses), about which I also knew nothing. Teaching that course proved to be instrumental in my later discovery of DNA polymerase. I became curious about the growth of the phages and how they replicated their DNA.

My next appointment was Melvin Cohn, who later became a founding member of the Salk Institute. Mel had been in Paris with [Jacques] Monod and [Francois] Jacob and was highly regarded by them. He was recommended to me as an exceedingly bright and effervescent person who knew microbiology.

In 1955, a postdoc, Robert Lehman, came. We became closely attached. I'm mentioning the people who would eventually become part of the faculty of the Stanford biochemistry department. Bob was one of the major figures in the purification of the system that revealed DNA polymerase, an enzyme unlike any other because it took directions from a template. No enzyme was known which could make a product with instructions from its substrate. Bob was exceedingly important in all that early work. He too lectured in the microbiology course .

The two or three people who had been in the department before I came left. None of them had held appointments with tenure. It was clear that that department had been languishing for a number of years. Appointments were reserved so that a new chairman could come in and fill the slots with freedom to develop a truly new department.

Then we recruited David Hogness. (He has just won a major prize, a consolation for not having gotten the Nobel Prize last year, something he richly deserved.) Dave had been with Mel Cohn, Jacques Monod and Francois Jacob in Paris, and before that at Caltech both as an undergraduate and graduate student. He was an outstanding student, working on bacterial metabolism, genetics, and biochemistry. After Paris, he had taken a job with Bernard Davis at New York University, but was unhappy there for various reasons. With Mel Cohn's advice and my choice, he came to St. Louis. His share in the teaching was microbial metabolism with proper attention to the pathogenic microbes.

We needed virology, and recruited Robert DeMars, who is now at the University of Wisconsin. When he left to fulfill his military service, we got Dale Kaiser, once again a postdoc in the Monod- Jacob group in Paris. At that time the Paris group was the world's most eminent in microbial genetics. Both Monod and Jacob, and to some extent [Andre] Lwoff, their mentor, were

11

recognized as the most brilliant in aspects of microbiology that would become molecular biology. So, we had three people who had come directly from that mecca of science.

Hughes: Why did they want to come to Washington University? Kornberg: I can't be sure.

There was one person we tried to recruit but failed. Peter Geiduschek. He has since become an outstanding scientist at UCSD [University of California, San Diego]. He is a physical chemist. I was attracted to him because he would bring physical chemistry to the department. But he declined and later confided that he regretted not joining us.

Before inviting Dale Kaiser, I had invited Gordon Lark, but he said it would be another year before he could come. I felt we couldn't afford to wait, so we went to Kaiser. I have gathered from Gordon that he too was sorry not to have become part of a congenial and productive group. Then a very brilliant scientist, Jerard Hurwitz, joined my group as an instructor or assistant professor.

Hughes: Had the medical school at Washington University decided that its effort should take on a more basic science orientation?

Kornberg: There was a strong legacy of basic science at the group. Carl Cori, Joseph Erlanger, and Herbert Gasser, and many others in the medical school, were distinguished in the basic biomedical sciences. Washington University at that time was arguably one of the top medical school in basic science. To this day, it remains one of the top medical schools. It has suffered from the fact that it is named Washington University, confused with George Washington University and the University of Washington.

Hughes: How did you think of yourself in St. Louis?

Kornberg: Oh, as a misfit. [laughter] I had no credentials in microbiology or being a Midwesterner.

Hughes: So you weren't yet thinking of yourself as a biochemist?

Kornberg: I did. I wanted to explain why biochemistry was essential for the teaching and practice of microbiology. But as I said, there was no textbook at the time that validated that approach. The students were very unhappy because ours was a novel, unorthodox, and possibly wrong approach to medical microbiology. We had no textbook, no tradition, no precedent.

12

One of the reasons I was happy to move to Stanford was to teach biochemistry rather than microbiology.

Hughes: Did the focus of the department at St. Louis gradually broaden?

Kornberg: No, it actually narrowed to DNA and nucleic acids. People

joined the department who had really never heard of DNA. DNA was quite novel then. In the late 1940s and early 1950s, geneticists had not accepted that DNA is the genetic material. They didn't trust the work of [Oswald] Avery, who had shown that genes are DNA, and prominent people refuted it. Most thought that proteins had to be the genetic material.

Erwin Chargaff and Base Pairing

Kornberg: As late as 1956, three years after the Watson-Crick publication on DNA structure, which had credibility and celebrity everywhere, Chargaff, an eminent biochemist, presented a paper at a major symposium in Baltimore on the chemical basis of heredity. He ridiculed the double helical structure and stated it had no significance. Ten years earlier, he used the newly found paper chromatography technique to show the equivalence in DNA of A [adenine] to T [thymine] and G [guanine] to C [cytosine] .

Yet in 1956, he still didn't accept the fact that there is base pairing, the lock and key relationships of A and T and of G and C. Later, when it became so commonplace that it was newspaper text, he claimed to have discovered base pairing. He never did. Some people deplore the fact that Chargaff never got a Nobel Prize for his discovery. But he rejected the significance of base pairing long after it was accepted by everyone else.

Hughes: So Chargaff originally talked about the equivalence--

Kornberg: He talked about the equivalences. It was a phenomenon but not understood. In all DNAs , A's equal the T's and the G's equal the C's. He also pointed out that in different species, the number of A-T pairs versus G-C pairs can vary from a ratio of 0.5 to 2.

Hughes: He didn't suggest the concept of base pairing?

Kornberg: He rejected it, three years after the base-paired structure of DNA had been proposed and accepted by everyone else.

13

Hughes: In the paper published before 1953?

Kornberg: He simply described base-pairing as an interesting feature of DNA. He didn't know its structural significance and certainly didn't understand its biological significance, that base- pairing is the basis for replication.

Early Work On Nucleotide Chain Synthesis

Hughes: Were you originally taken in by the protein hypothesis concerning gene structure?

Kornberg: No, I was quite remote from it. I freely admit that when the Watson-Crick paper came out, I was not electrified by it, as I should have been.

Hughes: Why weren't you?

Kornberg: I was so focused on enzymology, on how enzymes work, that to this day I joke about it. I was ambitious enough to want to know more about the enzymology of nucleic acids from the bottom up; how each building block is made. I spent five years trying to determine the true building blocks and how they are made. Then, how are they assembled into DNA? I shouldn't say I'm proud--but I am appreciative that my contribution, along with those of others, defined the pathways of how you make the building blocks. Virtually all drugs used in the treatment of cancer, AIDS, herpes, autoimmune diseases, are designed to interrupt those pathways. Our basic studies proved to have great practical value--but I didn't know that then or anticipate it.

I was inspired by the work of Carl and Gerty Cori on glycogen and starch, polymers of glucose units. I hoped that I could do the modest thing of extending chains of nucleotides as we find them in RNA or DNA. The first work I did was on RNA. We made an important discovery that we didn't fully understand, and then we blew it.1 [interruption]

That is another story but not irrelevant because it wasn't

DNA that I was after as much as knowing how a chain of

nucleotides is made. Actually, I approached the problem in a

roundabout way. The phosphodiester linkage found in RNA and

See Enzymes , pp. 148-151.

DNA is also found in another class of compounds, the phospholipids. I studied them because I thought that if I could understand how that linkage is made in a simpler and more accessible molecule, then I might understand how it is made in the chains of DNA and RNA.

My interest in nucleic acids goes back to 1950. Yet when the DNA structure was announced, it interested me but didn't alter my research or give me new vistas. When I was disappointed that my discoveries with RNA had been preempted by Ochoa, I said, Well, I've made some observations about the synthesis of DNA; let's go back to DNA. But I have to admit it wasn't because DNA is the central molecule in heredity. I appreciated that it was, but what inspired me was the enzymology of lengthening chains of preexisting DNA.

DNA as the Genetic Material

Hughes: Had you been convinced before [James] Watson and [Francis] Crick that DNA was the prime molecule in heredity?

Kornberg: I was not involved in that debate. In defense of biochemists, I recall Gerty Cori telling me in 1947 that the Avery paper was a very important paper. Yet in the mecca of genetics at Caltech in 1952, [Max] Delbruck and others didn't appreciate its significance even eight years later.

Hughes: What was your reaction to Gerty Cori?

Kornberg: She was a very volatile and inspiring person, a fascinating person, truly a great scientist.

Hughes: Watson and Crick established the dogma that DNA was the hereditary material?

Kornberg: No. In 1952, it was a member of the [Max] Delbruck

[bacteriophage] "church", Al[fred] Hershey, who did a rather crude, but telling experiment. He showed that what was transmitted by a phage to generate its progeny was not the protein coat but rather its DNA. The interpretation of the Hershey experiment turned out to be correct.

Hughes: Why wasn't the experiment impressive?

Kornberg: It was crude; some protein was also injected into the cell, and it wasn't very quantitative. The results were predictive of

15

Hughes :

Kornberg:

Hughes : Kornberg :

Hughes: Kornberg:

more elegant experiments. I was probably aware of them but no more so than of the paper by Watson and Crick. So I can't claim to have had the inspiration from those discoveries that then led to my discovery of the enzyme that makes DNA. It was a great stroke of fortune that I did and Bob Lehman figured prominently in that research because he was the postdoc; we worked very closely together.

Could some of this be due to the division between the biochemical and biological sciences that you referred to? phage group was composed mainly of biophysicists and biologists, not biochemists.

The

You are right. There were great intellects from physics who went into biology and thought they could solve problems by the power of their intellect. I'm critical to this day of some of the physicists who entered biology to solve biological problems — some called biophysicists. I am critical of their disinterest and contempt for chemistry.

Some physicists are dismissive of chemistry as messy stuff. But unfortunately for them, life processes are chemical, [laughter] You've got to get though the chemistry. You can't do quantum mechanics in enzymology; you may not be able to for another fifty years. What someone called the mumbo- jumbo of biochemistry is at the heart of the matter.

But does the lack of communication cut both ways? You were focused on enzymological problems; you didn't have a great incentive to read the literature of the phage school.

Well, yes and no. Lehman joined me as a postdoc, and he was trained in phage biology. Dale Kaiser came and was one of the leading lights in phage biology and genetics.

So they were following phage biology.

Yes, and they were doing it. When I decided to teach an element of microbiology, I chose phages as the topic -for discussing virology with medical students. I wasn't as dumb as I make out. I was very inspired as a medical student by the spectrum of life from inorganic matter to the very simple plant viruses-- tobacco mosaic virus. It's a molecule; is it living or not? I had heard inspiring lectures that showed a continuum of life from the simple to the more complex viruses to the simple bacteria and so on. There was no division--! had a good sense of that.

16

Also, when I was in nutrition, I heard Ed Tatum give a seminar on his Neurospora work: one gene as the source of information for one enzyme. I was greatly inspired by that. It didn't affect my work, but much more than most people in nutrition I was absorbing things. But in my work I was always focused; I would say, Well, that's great to learn, but this is the next thing I have to do in my research.

Jacques Monod and DNA Polymerase

Kornberg: Jacques Monod, who is one of the great luminaries in the modern science which was to become molecular biology--a very imposing figure and a great intellect — came to Stanford to visit Mel Cohn, one of his postdoc students. As I mentioned, three of the key people who came to the department were trained at the Pasteur Institute for their postdoctoral work: Mel Cohn, Hogness, and Kaiser. So we were sort of an outpost or a remote colony in St. Louis of the Pasteur Institute.

In 1956, it was apparent that we needed all four building blocks to get the DNA chain to progress. I would have had to have been pretty stupid not to realize that this is what an enzyme has to do to make DNA, and we were lucky enough to have stumbled on the enzyme that does it. Monod said, "Arthur, do you appreciate the significance of this enzyme?" His comment is telling; he thought that I lacked appreciation of what that enzyme accomplished, an enzyme unique in enzymology. No other enzyme had ever been described that took its instructions from the substance it was working on. An enzyme converts A to B; it doesn't convert A prime to B prime.

Obtaining Diverse Scientific Expertise

Hughes: What was your strategy when you found that you needed expertise that was not available in the department of microbiology?

Kornberg: We were designated, and accepted the responsibility, to teach what had been bacteriology and immunology, and which I renamed microbiology, to medical students and an occasional graduate student. When some of the older members of the department who had this expertise departed, we were left without the credentials for, the experience of, teaching various aspects of

17

bacteriology and immunology. So I tried to learn some bacteriology and virology, and we brought in people to the department who would fill those gaps.

Kaiser came because he was a virologist. Now, he wasn't a legitimate medical virologist; he worked with [bacterio]phages, which was really uncommon in any medical microbiology department. Mel Cohn brought in immunology. We shopped for a parasitologist when the old-line person was about to leave. Fortunately, we couldn't get the person that we wanted otherwise the biochemistry department would have been saddled with a parasitologist.

Hughes: You needed a parasitologist to fulfill your teaching obligations?

Kornberg: Yes, exactly.

Hughes: Parasitology doesn't seem to relate to your DNA interests.

Kornberg: The DNA emphasis gradually emerged. The emphasis grew largely around my work, and the natural interest of someone who is doing genetics to appreciate DNA, which was already clearly the genetic material, and to use it that way. Fortunately, the initial appointments to flesh out a proper modern microbiology department included genetics and biochemistry. So we could be transplanted to a new or different discipline called biochemistry. Now, for some of us, biochemistry was reasonably natural. I had learned it; Lehman had a degree that included virology and biochemistry; Paul Berg got his Ph.D. in biochemistry; Mel Cohn I think got his Ph.D. in biochemistry; Hogness also; Kaiser has a Ph.D. in genetics but, as I said earlier, thinks biochemically very comfortably.

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III CHAIRMAN, DEPARTMENT OF BIOCHEMISTRY, STANFORD MEDICAL SCHOOL, 1959-1969

Renovation of Stanford Medical School

The University Administration

Kornberg: In 1955 or thereabouts, the president of Stanford, Wallace Sterling, with proper advice and so forth, decided that the medical school should be moved from San Francisco to Palo Alto. Up until that time, just the first year of courses- biochemistry, anatomy, and a few others—had been taught here on the Stanford campus; the last three years were spent in San Francisco. Several years later Sterling told me people were calling the move "Wally's folly."

We had an impressive administration here at the time. Wallace Sterling had lofty goals and his provost, Fred Terman, was a no-nonsense, uncharismatic, but very effective person. Fred Terman is responsible for Silicon Valley. He and Wally Sterling were a great team; they complemented each other beautifully.

Creation of the Biochemistry Department

Kornberg: Sometime in early 1957 or possibly even 1956 the faculty of

this new medical school here in Palo Alto was being assembled. The job of being chairman of the biochemistry department, a department which didn't exist because biochemistry was taught by the chemistry department, was created. But now in the new medical school there would be a proper biochemistry department, and the chairmanship was offered to Ed Tatum who was in the biology department here at Stanford.

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It was assumed—this might have to be documented—that the two people, Hubert Loring and Murray Luck, who had been teaching biochemistry in the chemistry department, would then join Tatum. Hubert Loring had once been a brilliant young biochemist but I think some of that luster had disappeared. Murray Luck was a rather versatile person, did a lot of interesting things, and was working on compounds, called histones, that at that time were considered too difficult or unimportant to study. These now of course are crucial proteins. It was assumed that Hubert Loring and Murray Luck and Tatum would be the nucleus of the new department.

So if it was an embryonic department of biochemistry, it was aborted.

Offer of the Chairmanship, 1957

Kornberg: A very important person was Henry Kaplan, who was radically different from other radiologists in that he was both biochemically oriented and very skilled clinically. We had known each other at the NIH. I don't think we overlapped, but there were a number of personal interactions and friendships. He approached me in the spring of 1957, mentioning the rather amorphous situation in biochemistry and asked whether I would be interested. I said I might be; I'd been in St. Louis four years, a long time for St. Louis. I had come to California several summers to get away from St. Louis.

That was, I think, March or April 1957, and in June, I'd heard nothing further. I had mentioned it to nobody, and it was with some relief that I didn't hear anything further because I was busy with my work and things were going well. Then there was an invitation to come out to look at the job. I might even have said, I'm not interested in looking; are you people serious? They said, Yes, they were very serious.

My group was very close in age and everybody knew what everybody else was doing; it was very much a family affair. I told them in 1957: Don't worry, I'm not going to take this job; I just feel obligated out of friendship to look.

I came out here and, well: Not only do we want you, but you're not being looked at; you're looking at us. What can we do to interest you? And yes, you can bring your whole group to Stanford. You don't have to go through months and years of

20

search committees and all kinds of bureaucracy. Terman simply said, Okay, bring your group and we'd love to have you.

Hughes: Without examining individual credentials?

Kornberg: Yes, but I think they already knew that this was a stellar group of young people at Washington University. And there would be a new building. Just plan the space. We'll send the architects out to St. Louis; you can design what you want. It was a lovely June day, and they said, "Look, weather has nothing to do with it. Discount that." Very slick salesmanship. I said, "Well the chemistry department isn't that strong." "Well, we're going to replace the chemistry department. We want you on the scene to help us do that." So there was a spirit of rejuvenating both chemistry and biology, and the medical school. I would become one of the senior people .

Recruiting Other Major Scientists

Kornberg: As it turned out, my decision to move here was instrumental in bringing two major stars to Stanford. One was [Joshua] Lederberg, who had been sought after by every other university and had agreed to come because we were moving, and Charles Yanofsky, who was then at Western Reserve.

Hughes: Did they come with the idea of collaborating with you?

Kornberg: Who knows? I think they had confidence in me, yes. There was also the overt movement by the university to support a group like this, and maybe they thought that I would have some influence in its further development. I don't know.

Lederberg really wanted to join my department. I knew him; he's a genius, but he'd be unable to focus and to operate within a small family group like ours, and so, I was- instrumental in establishing a department of genetics of which he would be chairman.

Hughes: Which was one of the few departments of genetics in a medical school?

Kornberg: Could be, Sally, I don't know.

Hughes: I found what I think is quite an interesting letter that

Lederberg wrote to you in February 1959, when he was already at

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Stanford.1 Stanford apparently approached you first, but Lederberg arrived on the scene before you, which wasn't until that summer. [Pause while Dr. Kornberg reads letter]

Kornberg: I don't know the details. We were coming with a rather large group and there was simply no space here. And I couldn't reasonably take people who were doing really very active and exciting work and ask them to sit here on their hands while Stanford readied space for us. So we were necessarily lame ducks for two years in St. Louis. Lederberg had just his wife and himself and maybe nobody else.

Hughes: One measure of the degree to which Stanford wanted you is that the letter shows that even before you arrived, you were involved in recruitment in several other departments.

Kornberg: Yes, that's probably true.

Hughes: Stanford was creating a new enterprise.2

Kornberg: Yes, that was attractive.

Hughes: But it also gave you opportunities that I presume you wouldn't have had if you had moved to an established school, regardless of who you were.

Kornberg: The most critical thing is how rarely one can create a new

department. In most situations, you inherit a lot of people whom you haven't selected. Some of them fare well, others not, and you live with them. So we could introduce a novel way of housekeeping and other things one couldn't impose on an existing department.

Hughes: That must have had a tremendous appeal.

Kornberg: I never thought it through. As I say, these things evolve.

1 Joshua Lederberg to Arthur Kornberg, February 23, 1959. (Arthur Kornberg papers, Archives and Special Collections, Green Library, Stanford University, SC 369, box 25, folder: 1959. Hereafter, Kornberg papers.)

In 1959, the clinical programs of the medical school were relocated in Palo Alto where the preclinical sciences had always been taught. For a history of the relocation, see various recollections, including Kornberg' s, in a 1984 publication, "Stanford University Medical Center: 25 Years," of the Office of Public Events, Stanford University Medical Center. For a description of the new medical curriculum, see: L.M. Stowe, "The Stanford Plan," Journal of Medical Education. November 1959, 1059-1069.

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^>

Reluctance to Establish Joint Apppointments

Hughes: I'd like to quote from Lederberg's letter:

[Irving] London says one of his chief motivations [in coming to Stanford] is the chance to develop academic medicine, which includes research training for some of his internists in the basic sciences. I suspect that he is rather concerned that your own perfectionism and aversion from clinical investigation might limit the advantages that such a superb Biochemistry Department might offer as part of the context for his interests. I think he does need assurance as to the extent of your own interest in his program."1

Kornberg: It is an interesting point, and there is some truth in it. My first paper was on clinical research2 and I trained in medicine. I was a happy medical student; I intended to be a practitioner. I was raised in this clinical family and then I rejected it by turning to basic science. [pause]

Clinical medicine to this very day constantly has to make adjustments that I would find distasteful in science. You deal with an individual, uncontrolled; you apply something, and you don't know whether it has been useful or not. I'm very respectful of clinical medicine because I'm a patient; my family members have been patients, and I'm curious about and interested in clinical medicine. But would I take a group of people from the department of medicine and include them as full and active members of the biochemistry department? In some cases, yes, but in a blanket way, no. And so the department of biochemistry here has had the reputation of being very exclusive, elitist, and we have not had the kind of joint appointments that are common in other institutions.

On the other hand, I've been willing to have someone called a professor of biochemistry and pediatrics so that he can

1 Lederberg to Kornberg, February 23, 1959, Kornberg papers.

2 A. Kornberg. Latent liver disease in persons recovered from catarrhal jaundice and in otherwise normal medical students as revealed by the bilirubin excretion test. Journal of Clinical Investigation 1942, 21:299.

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Hughes : Kornberg: Hughes : Kornberg:

maintain his identity with his Ph.D. in biochemistry. But I don't want him as a member of the biochemistry department. So his official attachments are with another department. He can come to our seminars; we're eager to have him use our apparatus.

Stanley Cohen, when he came to Stanford in 1968, used our centrifuges and our apparatus freely; all his early work with plasmids was done with our apparatus.1 He was really housed in this department. Lederberg says it is about perfectionism; let's say standards — and attitudes and demands we make of ourselves and our students.

When I was a clinician, the patient was paramount; that eclipsed any other consideration I had. It's not like a culture of E. coli; you throw it out if it doesn't work. So doing clinical medicine and doing research are really contradictory. And it is very rare — there are exceptions — that someone can do both well. It's extraordinarily difficult.

I knew Irv London very well at the time. Could we have reached a modus Vivendi in which I could keep him and his people happy and maintain our scientific standards? I don't know; perhaps we could have.

You don't remember compromising.

I'm saying we never compromised by offering joint appointments.

Was that what Lederberg was asking?

I don't know. London, who pictured himself as a biochemist and did some biochemistry, might have wanted some privileges or appointments or whatnot that I might have been reluctant to give. I don't know. But I've had the reputation of being less tolerant.

Relations with Clinical Scientists

Kornberg: Let me say this: my colleagues in the department, all of whom until recently are Ph.D.s, suffer from an inferiority complex because of not having any medical training. They assume when

1 An oral history is in progress with Stanley N. Cohen, eventually to be available for research at Stanford and UC Berkeley.

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Hughes :

Kornberg: Hughes :

Hughes:

Kornberg: Hughes :

Kornberg:

you get a medical degree that you acquire a capacity that they simply couldn't get in a Ph.D. program. So, data on animals are more important than on bacteria; data on humans more important than on dogs. There's an exaggeration of the importance of clinical medicine, I think.

I haven't suffered from that belief. When my clinical colleagues on the executive committee or elsewhere tell me this or that is so, I can say, "How do you know it's so?" Whereas my colleagues might be reluctant to challenge a professor of surgery or pediatrics or medicine. I can say the emperor has no clothes. Prove to me he has. Whereas someone with a Ph.D. might think, Maybe he knows what he's talking about.

I think that's an advantage. But it hasn't endeared me to my clinical colleagues. It has given people the impression that I am anti-medicine, anti-clinical science. I don't think that's fair. The clinical science building was built largely through my efforts and those of a group including Lederberg and [Norman] Kretchmer, and a few others'. The dean, Robert Alway, was exhausted. The clinical departments had no research space. We worked evenings, week in, week out to get together the resources to build that building. I was never invited to the dedication of the building. Well, those things happen.

You describe a self-sufficient group. Some of it comes, I presume, from the nature of the research itself.

You are very perceptive, Sally; that is so.

But it also comes from other factors, which you've been outlining. [telephone interruption]

I'm saying that the department has an internal cohesion, but there also seems to be an external exclusion which was thought through.

I think you're right.

What about the history of free-standing biochemistry departments?

That was well established.

So it was an anomalous situation to have biochemistry within the Department of Chemistry?

I don't know. Where the campuses were split, that might have been the mechanism in those instances. There were quite a few

25

institutions where the hospital and the medical or clinical group was in one place and the undergraduate in another.

Hughes: Berkeley would be another example.

Kornberg: The Department of Biochemistry at UCSF really was not distinguished and sort of struggling for a long time.

Financial Aspects

Hughes: Did you consider what the neighboring institutions would have to offer?

Kornberg: Not really. Decisions like this are so emotional. With me they are, and with many others. I didn't calculate all the aspects: f inancial--it didn't matter, even though it was favorable.

My move from NIH to Washington University was unfavorable. I was very naive about that. I never bargained for salary and retirement and moving expenses. I'm not boasting but that is the truth. With my department I've never discussed salary. Isn't that interesting? No one has asked me for an increase in salary.

Hughes: Ever?

Kornberg: Ever. I always felt that I should get the highest salary that was possible within the framework of the institution. In fact, when I invited Esther Sherberg, a secretary at Washington University in St. Louis, to come to Stanford and be our departmental secretary in 1959, she asked for a certain salary and I submitted that and they said: "Well, you can't have that because the president doesn't pay his secretary that much." And I said, "Well, you ought to increase her salary." [laughter]

Hughes: And what happened? Kornberg: She got the salary, [telephone interruption]

Kornberg: Henry Kaplan was still in San Francisco because the medical

school hadn't moved. He was influential not only in clinical

Kornberg;

Hughes : Kornberg:

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and scientific circles but also was recognized as a major figure in the medical school and the university.

Then another figure: Avram Goldstein. He was head of pharmacology, very astute, and had been instrumental in unseating the previous dean, Windsor Cutting. So there was a new dean now; his name was Robert Alway, head of pediatrics.1 He was one of the people that I had to deal with when I came out for the interviews, and I liked him very much. It was evident that there would be a very supportive, congenial group, and many appointments were yet to be made.

The fact that Lederberg would join the faculty gave Stanford instant visibility, even more so when I got the Nobel Prize a few months after I arrived [1959]. [laughter] Terman, I was told in talking to groups around the country, boasted of this coup in which he had captured a whole department and now with its increasing celebrity was something in which the university took great pride.

Tensions

It had a downside, because in moving from San Francisco to Palo Alto, some of the fine clinicians chose not to move their practice, and the clinicians in Palo Alto felt very threatened. For many years, even to this day, Stanford was and is seen as a medical school of scientific eminence and clinical inadequacy. I'm sure that's exaggerated on both sides. So there was some resentment then I'm sure and has been to this day.

In the discussions that must have gone on, was there talk about the new medical curriculum?

Yes, everything would be new. There was going to be a new medical curriculum, not so much by my doing; I neither encouraged it or acquiesced to it. But Goldstein and other young Turks here were pushing it.

Hughes: And Alway.

1 For more on Alway, see: The Alway Years, 1957-1964. Stanford University School of Medicine, (brochure, n.d.). The brochure, prepared for Alway 's retirement from the deanship and hence presumably written circa 1964, traces accomplishments in the preclinical and clinical sciences under Alway 's deanship.

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Kornberg: Yes. Alway was supportive--a very decent man, who then became the victim of impatience and attacks by Kaplan and Goldstein.

Hughes: Why?

Kornberg: I don't know. At Washington University where I was a junior person on the executive committee, the meetings were very orderly, maybe even perfunctory, and the decorum was intact. Here, everyone was squabbling and calling each other names. I couldn't believe it! Poor Alway was actually taken ill as a result of all this and was exhausted after a couple of years.

The estimates for the cost of this medical center were wildly inadequate. Had the real costs been known, it never would have been built. The medical center went into a partnership with Palo Alto which in significant ways limited the autonomy that the medical school would have, having to share authority with physicians in Palo Alto.

Hughes: Was the partnership agreed to largely because of the financial advantages?

Kornberg: I think so. Or maybe there were some diplomatic reasons.

Whatever it was, it complicated matters here for a long time.

The New Department of Biochemistry

Choosing Faculty Members

Kornberg: When I decided to move, I invited some people whose names I've mentioned, and disinvited others. Bob DeMars was still in the army, and I didn't invite him to come to Stanford because he was a little bit of a maverick and I had Dale Kaiser. I thought in a small department there wasn't room for an additional appointment in the area of virology.

Hughes: Their science was similar, DeMars' and Kaiser's?

Kornberg: Reasonably so. Science, if it is good, keeps diverging and changing within a few years. I felt we needed a physical chemist in the biochemistry department. Peter Geiduschek, whom I mentioned earlier, had turned us down. Buzz [Robert] Baldwin, identified as a young man of great promise and already considerable achievement, was at Wisconsin. He had been a

28

Rhodes scholar and gotten a degree at Oxford, and to my surprise was eager to come. He was not yet thirty.

Hughes: Why were you surprised?

Kornberg: Well, because there was no one in the department doing that

kind of work. Physical biochemistry was embryonic; it didn't really exist.

Hughes: You mentioned Jerry Hurwitz, whom I believe did not come.

Kornberg: Yes, and that was very traumatic. Jerry and Paul [Berg] grew up together as students. Jerry is more combative and blunt, and was doing very similar things to what Paul and I were doing. It was really sort of a good-natured competition. I had to choose between him and Paul, and I chose Paul. That precipitated a "nervous breakdown", as we called it then. Jerry was just utterly shattered by that, and I've had that on my conscience. But we're very good friends now and have been for many, many years.

Hughes: I know from Love of Enzymes that you were later involved in another competitive situation.1

Kornberg: Jerry is very competitive. It is characteristic of his work that he does many things at once and wants to push ahead in every one of them. In the case that you allude to, he barged into an area that I was already developing, and I felt that was inappropriate. I wouldn't have done that. If there's an area that intersects with yours and further progress requires that you move into that area, okay. But if you see something attractive but it is somewhat tangential and you move into that area--I didn't think that was very tasteful, especially by someone who is a friend and a previous colleague. So there were ruffled feelings for a while, but that's gone.

Hughes: A member of your lab relayed research results to Hurwitz 's lab.2

Kornberg: Yes, Bill Wickner kept talking to his sister-in-law Sue Wickner over the phone. But fortunately, with all those brushes, I don't think there is any residual ill feeling. People go their ways .

'

1 Enzymes, pp. 235-236.

2 Ibid.

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If we take the roll, I think we have covered all the people who moved en masse to Stanford. Six are still together forty years later. They have all been invited to take prestigious jobs and have elected not to leave. The impression is that we've remained intact; nobody has left, and that somehow I've been so shrewd and brilliant in choice of people that there have been no defections. I'll have to correct that, because there have been.

Leaving St. Louis

Kornberg: We were going to be lame ducks in St. Louis for two years. That was not good. When we left St. Louis there was a fair amount of ill feeling. At first, there was the pleasure and pride of having a bright young group like ours and suddenly it was gone. And Kornberg took it with him.

In my defense, all the people that came to St. Louis were recruited by me; they didn't come to St. Louis to be part of the university. Secondly, we left the department in far better fiscal shape than when we came. It was now up to date. We left lots of equipment. We left a legacy in science and in teaching that was then taken intact by my successor, Herman Eisen, who became and has remained a very close friend. He later left St. Louis to go to MIT. So when the dust settled, I think there was very little hostility.

In the summer of 1957, I had to tell Carl Cori that I was going to leave. Well, I hated anticipating this moment but it had to be done, the sooner the better. I approach him and sure enough, Gerty Cori, a member of one of the legendary scientist teams in history, was there. I was delighted she was there when I walked into Carl's open office. He said: "Well, what have you decided to do?" And I said, "I've decided I'm going to go to Stanford. "Ach!" It was the only time in our long association that he was irritated, angered. He sputtered and said: "Well, where will you go on vacation?" [laughter] Gerty immediately calmed him down and said, "Carly, we should have gone to Berkeley when we were offered the opportunity."

Hughes: Had you thought through what you wanted to create when you got to St. Louis?

Kornberg: Number one, the teaching of bacteriology and immunology was not comfortable. This was not my center of interest, and the

30

reception of it in St. Louis was not all that cordial, even after four years.

Hughes: You mean reception by the medical students?

Kornberg: Yes. The faculty tolerated it; I wasn't being applauded for doing anything novel. Although as soon as this became apparent, I was told by the dean that when Cori retired I would become professor of biochemistry. That was very unofficial. So there were efforts to persuade me, and efforts to persuade some of my people, to stay- -Berg and Cohn and others.

Hughes: Was Cori going to be retiring within a few years?

Kornberg: Yes. In 1957, he would have been sixty-one. Retirement at sixty-five was pretty mandatory.

It is important to mention that in 1957 the architects came to St. Louis and we laid out the plans, and everybody was now involved in planning to go to Stanford. In the period in which we were examining the blueprints, we determined what we'd need in terms of apparatus and began to make applications for research grants. Especially in the last year, 1958-59, we spent a fair amount of effort on the logistics of this move: how we would move perishable materials, where they would go, the furniture and whatnot.

Melvin Cohn

Kornberg: During that interval, Mel Cohn had a collaborator, Ed Lennox,

who had been trained in physics. Ed later went with Mel to the Salk Institute and stayed for many years; he is now a rather prominent entrepreneur in biotech. He and Mel were working intensely on a basic question in immunology: whether one cell could make two different kinds of antibodies. Mel was singularly disinterested and uninvolved in the preparations we were all making to move to Stanford. He was just too busy doing his most important experiment.

When we got to Stanford, there were many things to do of a custodial nature in getting settled. Again Mel was singularly uninterested. [long pause] I think in a way he felt above it all. As the chairman, I laid out the various responsibilities for the people in the group, with a generous amount being taken by myself. On that list were some assignments to Mel, and he said, "You know, I don't want to do that." I said, "Well,

31

someone's got to do it." He said, "Well, if I have to do all this crap, I'd be chairman." "Well, you're not chairman and this is what you need to do."

Some months later, shortly after the Nobel Prize, our relations still remained cordial. On one occasion, he said, "Arthur, I've had this offer from Harvard." I said, "Well maybe you ought to take it." That was absolutely shattering. And so, when the Salk Institute was being organized and he was one of the organizers of it, he took the Salk Institute position and immediately took a sabbatical. He was bitter and angry and wrote a very nasty letter which I never saw because it was intercepted by Esther Sherberg. She was a very skillful, wise, and also officious. In fact, she signed my name for the Nobel Prize memoir. [laughter] So it's not my signature.

Hughes: How do you feel about that?

Kornberg: Oh, I don't care. Mel was a major defection.

Hughes: What role had you expected him to have in your Stanford group?

Kornberg: Well, by then he was very much involved in immunology. And

while immunology was still not very biochemical, one could see that it would become biochemical. So it was very reasonable that he would lecture on hormones, proteins, and immunoglobulins as biochemical entities. I learned secondhand that the immunology department here resented the fact that the biochemistry department was teaching immunoglobulins, but nothing was ever said overtly.

With a catalytic mind and personality, Mel was brilliant and engaging and intellectually involved. He was a very important person in St. Louis and could have been here as well, but there was a certain aloofness and maybe even contempt for some things that were going on that I found incompatible. His leaving was certainly disappointing to Paul Berg, Dave Hogness, and others, although I never heard from them. They may have even tried to persuade him to stay.

So, his departure, and the two others that I mentioned, document the fact that people left the department as well as stayed.

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Relations with the Two Biochemists in the Chemistry Department

Hughes: How did you handle the two biochemists, Murray Luck and Hubert Loring, who were in the Department of Chemistry when you arrived at Stanford?

Kornberg: Not well, not well. I'm sorry that I was not more diplomatic. The chemistry department, as it was being reorganized, wanted desperately to unload these two people on the Department of Biochemistry. Before I got here, Terman broached that to me. I said, no. They were so much older than we were and doing research that was different from what we were doing. I couldn't possibly forego two appointments; it was going to be a small department of seven or eight people. Terman agreed.

I could have found ways in which to involve Luck and Loring more than I did, and I'm sorry I didn't. But I was absolutely right in not including them in the department. No question about that.

Hughes: Did they remain in Chemistry?

Kornberg: Yes. The chemists found things for them to do that were maybe even distasteful to them—teaching elementary chemistry or something else. They didn't want to teach biochemistry anymore .

Communal Structure

Hughes: Your plan for the shape of the new department had larger

parameters than just simply the science. It was not just a matter of needing certain people to do certain kinds of science; it was also how they were going to mesh productively.

Kornberg: People have said that this group of people was intellectually very outstanding; it did something very unusual. And I think they did. It is not true anymore because for many years now we are not distinguishable from a dozen other departments. But it was crucial for organization of the department, and my being happy in it, to have this be a family rather than a department of the conventional kind. We are communal in our sharing of all resources—money, space, everything else. And that precipitated the departure of two key people.

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Hughes: The communal idea evolved over time or did you come with that philosophy?

Kornberg: 1 didn't shape it as an idea or a pattern; it just evolved. I think this department is unique in that while there is proper accounting and auditing of grants that are obtained by each of us, unlike virtually every other department in the country or the world, there's no space assigned to a specific person. The result is that each lab has associations with students and fellows from three or four different groups.

Students and postdocs who have left have invariably said that this arrangement was one of the most enriching things that they've had in their experience. They learned not only from what their own group was doing--a group is, on the average, ten people—but they interacted with or were aware of what three or four other groups were doing. And it gave them more friends and contacts with more alumni.

When you share space, that means equipment, supplies, caretakers. The bookkeeping of who takes what, uses what, and so on would be impossible. So we share all our resources. Does each faculty member have a secretary? That would be foolish. A secretary can share the work of two of three professors or contribute when someone's ill or on vacation. So we also pool our secretarial staff.

Some reagents are expensive. There is no point in everybody having expensive radioactive reagents, especially early on when we were all doing very similar experiments. So we go back and forth to our refrigerators and share reagents.

We've had a reputation of being well-heeled, but that's not true. I as chairman or my successors would say: there's a moratorium; you can't buy any more equipment, and you have to go slow on supplies until the next funding interval. Someone uses animals which are expensive; someone uses more expensive equipment. It was crucial that those of us who were in positive balance would say, Well, my colleagues are doing work similar to what I'm doing; we're sharing ideas and reagents and results. Okay, so right now I'm being more generous. That attitude has prevailed

Young faculty members who came into the department were immediately full partners in the whole enterprise. They could take as many students and postdocs and reagents as anybody else, even though their funds were grossly inadequate for that. So there was a legacy of that kind of indebtedness and ultimately responsibility and sharing.

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Now, things used to be much better because we were a small group confined to a narrow space and knew what everyone else was doing. You could ask, How did that experiment go, and they'd say, It went well, or it didn't. That is not true anymore. The science has gotten so huge and the forces that take people away are so great.

Hughes: That growth occurred before the department moved to the Beckman Center in 1989?

Kornberg: Oh yes. The phenomenon is worldwide. It isn't unique to us. Even people of not great seniority are constantly being asked to give seminars, to join this or that visiting committee or grants committee. That was not true thirty years ago.

Later Changes in Departmental Faculty

Kornberg: Let me finish with two items that I want to be sure we include in the history of the department. In 1963, we had an appointment that we wanted to make and there was someone that we thought was very attractive. We were six or seven at the time, and three of us thought he was someone we wanted, and the other three were uncertain. He turned out later to be an outstanding person, so we would have done very well to get him --but that's beside the point. Even though I had all the authority as chairman and was in the group that wanted him very much, I deferred to those who had some doubts. That's clear evidence of the democratic nature of the most crucial decisions that one can make, appointing people to the department.

Then we identified two young people who were very attractive and we couldn't decide between them, so we got special permission to hire them both. One was Lubert Stryer and the other was George Stark. Lubert Stryer is an eminent person, who has written the most popular textbook of biochemistry; he's a professor in structural biology, now. My son Roger was chairman of that department for a number of years; Jim Spudich, a student of mine, was also chairman of that department.

Lubert Stryer was a very ambitious, brilliant, and mercurial person. His work was going exceedingly well. At one point, I didn't allow him to apply for a grant because he didn't have the space with which to use that extra money. He represented the bulk of my worries and time spent in departmental affairs. He was very good, but very restless. At

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Hughes : Kornberg:

one point, we were confronted by his demand to have a wing of the department assigned to him for his exclusive use. He said, "If I don't have it, I'm going to leave." I consulted with each of the people in the department. We didn't have a formal meeting. I said, "Lubert, we're not going to change the philosophy of the department, so if you really want to leave to get this kind of authority and freedom, that's your choice." He left for Yale, where he had his own very generous space, but not long after he was fishing for ways to come back. That's another story.

George Stark was a gem and was in the department for twenty years. He also loved London where he'd been on sabbatical visits several times. He had turned fifty, may have had disaf fections with something here and felt attractions in London. He enjoyed ten years of research at the ICRF [International Cancer Research Fund] laboratory and living in London. Now he's back as head of the Cleveland Clinic research department. I've always regretted his leaving, both scientifically and personally. I would say George is the only one who left despite our entreaties to have him stay.

Another who defected is Jim Rothman, who is very prominent in science today, rather ego driven and scientifically gifted, truly a robust personality. Someone said to me when we were recruiting him as an assistant professor, "You know, Arthur, he's not in your style." I said, "Yes, but he loves science and he's so good at it. Maybe he'll adapt to our style."

You mean the cooperative family style.

Jim always lived beyond his means. He attracted many students and postdocs and expanded his base. Eventually it was clear that even though he knew and we knew that he was living beyond his means year after year, something had to give, and he left for Princeton. He since moved to become the deputy director at Sloan-Kettering. His work is going well, and he is an international figure. So you see, some people have left us.

Yes, I see that.

The image people have is that our group in biochemistry has remained intact for forty years. That is largely true. Hogness, Kaiser, Berg, Lehman, Baldwin, myself have remained together for forty years.

Hughes: Does any other group have that record?

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Kornberg: I don't know of any other We are all members of the National

Academy of Sciences, and two people have received Nobel Prizes. Paul has been offered the presidency of prestigious institutes, universities, and others have too. People [in the department] have never come to me with competitive offers from elsewhere. I learned about them only later and indirectly.

I gave up the chairmanship in 1969. Even before that, I had shared decision-making about appointments and so forth. Since 1969, I've remained closely involved in the administration of the department. I don't think I've been intrusive. Rather I've kept concerned and aware of the problems. I give advice if asked. Scientists are like everybody else; they have all the common attributes- Hughes: I hope so. .. [laughter]

Kornberg: Selfishness, greed, egotism. They do not always have the greatest wisdom as to how to get along. It has been the essence of this department that your self-interest is best served by being generous and thoughtful. Generosity is its own reward.

Hughes: One could argue that with such a stable group there is a lack of innovation because there is not much new blood coming into the department. What are the downsides?

Kornberg: In recent years, we have brought in new people—six in all. They chose our department because they were attracted to its small size, cohesiveness , and the attitudes that I've mentioned. Rapport between the senior and junior people is very good; our relations are most cordial. This is so, even though the seniors are physiologically aberrant in being active beyond their years. The seniors are respected for what they continue to do, and very much admire the work the young people are doing.

One downside is a perception that the department is very old. Would I as a young person go to work with an older person like me? I guess I wouldn't. I'd want to work with a young person. I'd want him to be here nights and weekends, be ambitious, and be around long enough to recommend me and push me.

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Interaction Between the Basic and Clinical Sciences at Stanford

Limited Success

Hughes: As I understand it, one of the purposes for moving the medical school to the Palo Alto campus was to encourage interaction between the basic and clinical sciences. What is your opinion of the success of that endeavor?

Kornberg: Not as successful as you might have hoped- -anywhere. Clearly, something had to be done if clinical medicine were to make use of advances in science in an optimal way, for teaching and research and eventually practice. That point can be evaluated differently by different people.

It would be hoped that the preclinical and clinical departments would work more closely together. Was it simply fashionable to do so, or are there more substantial reasons?

The Beckman Center for Molecular and Genetic Medicine

Kornberg: We can digress about the Beckman Center. It was clear as time went on that we needed more space and resources for developing areas of preclinical science — developmental biology, molecular physiology, other burgeoning areas of science. So there were very good and strong reasons for requiring additional space resources to expand and strengthen the preclinical sciences. The problem was not land, because Stanford was very rich in that, but money.

I with others approached Arnold Beckman, who, unlike most rich people, was eager to give his money away, but he wanted to do it in a very meaningful way, which he has done to his great credit. I recall an occasion when he was here and being presented with a proposal to build a center that would house these new departments. The dean at the time, who will be nameless, made a rather inadequate, I would say foolish, presentation. I knew Dr. Beckman and told him very seriously what we intended. He said, "Will you be doing anything really new?" I said, "Not in the sense of starting something utterly novel. What we'll do is provide resources for young and older people to be creative and to work at the forefront of genetics and biochemistry and molecular biological sciences." Dr. Beckman listened and was unimpressed.

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A couple of years later when Paul Berg took over the leadership of this new project, the three of us-- [President Donald] Kennedy, Berg, and myself--went to interview Dr. Beckman in his home near Irvine and instantly got his approval. But the ground had been laid to nucleate the fund that would build this building. It would be called, maybe at that time it was already known as, the Center for Molecular and Genetic Medicine .

Clinicians as Basic Scientists

Kornberg: I pointed out to Beckman that this center would form a very clear bridge between the preclinical and clinical sciences. We'd bring discoveries to the bedside more meaningfully and more quickly than otherwise could be done. "Well, that's a great idea; we should do that," Beckman responded. Has that been done? Not really.

Hughes: Why not?

Kornberg: Well, because it is rare that you can do both. People who look after patients are consumed with that activity, and they should be. You are consumed with the individual, the uniqueness of that illness, the family, and all the other aspects. You develop some very special skills and a certain kind of routine to respond to an illness by naming it and determining what is to be done or what others should do, and go on to the next patient, and so forth. Of course you're carrying on research and you have a lab. You go there occasionally, and you observe what students and technicians are doing; you write grants and appear at meetings and give papers. But at best you're doing some of both and are not competitive with the best clinicians and certainly not with the basic scientists who have made a choice to do research full time.

Hughes: Kornberg:

Let's take Stan Cohen or Hugh McDevitt or any of- the other people here who have appointments in both clinical and basic science departments: when their research is going well and is well received, and they have many applications from students and postdocs, and they get grants, they have to leave the clinical departments.

Did those two do that?

Oh yes. I mention them; I could name others. There are instances when there has been defection from basic science to

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clinical medicine. Those people generally just do clinical medicine. One of my very best postdocs, who had an early impressive career in science, gave it up, disillusioned with certain circumstances, and he simply went into private practice, with no attachment whatever to science research.

It is very tough to do both. The research that is done in clinical departments generally is a little of this and that, rather than focused on one topic. I'm overgeneralizing, but it often happens. So the considerable stimulation of trying to understand illness is difficult to pursue, because you don't have twenty to a hundred examples of exactly the same genetic background that you can then decide to do thus and so with half of them. Clinical research is tough.

Human nutrition will remain a very ambiguous area for a long time. We understand rat nutrition reasonably well, but human nutrition, which is very similar to that of the rat, is beset by so many problems unique to that individual. You're treating an individual; you are not treating a population of rats. So that tells you why it is difficult to form an effective bridge between clinical medicine and basic research.

Now is it of any value to have the preclinical and clinical sciences at one location? Yes, it is of value because people can go back and forth, and I think the transmission of knowledge, concepts, techniques, does occur. And it wouldn't occur if the clinical people were in San Francisco and we were here, except through the literature.

Hughes: Was moving the clinical sciences to Palo Alto supposed to heal the schism with the basic sciences?

Kornberg: I don't know; I was not here at the time. But I can imagine that some might have pointed out the value to the campus, to the biology department, to the chemistry department, of having some of these clinical disciplines within easy reach. It has turned out that the influence of the medical school on a number of departments in humanities and sciences and engineering has been very considerable. Biology here has been enormously enriched by the variety of biological sciences done here of a very high caliber. I'd say more so in the direction of the clinical sciences helping the humanities and basic sciences than the reverse.

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Bridging the Basic Sciences

Hughes: We've been talking about the bridge between the basic sciences and the clinical sciences, but there is also a potential bridge between the basic sciences. You write about what you see as the division between biology and chemistry.1

Kornberg: Chemistry should have been bridged better than it has been, and I've talked about that. It is frustrating that there has been so little acceptance by the classical chemists of biochemistry. [Instead,] it has been: We know it is important, but we would rather others did it; we want to teach true chemistry. Molecules as bizarre as proteins and nucleic acids and phospholipids--now that's religion; don't bother us with that. That attitude still exists, although there are numerous exceptions now, and I'm sure that most people in chemistry would protest that this represents their thinking. So in that sense there has been progress.

The Medical Center as an Intrusion

Kornberg: The invasion of the campus by the medical school has been

regarded comparable to that of the Stanford shopping center. Critics said that the medical school was an intrusion; it would bring nothing but noise and grief and drain resources. In practical terms, if you were to go to donors who contribute to Stanford, clearly those projects with a medical implication would have much greater clout than others. To this day, there is an undercurrent that occasionally bubbles up with fear and resentment of the medical school.

The hospital is an enormous operation that dwarfs the budget of the rest of the campus. It is an intrusion, with all of its commercial activities, a cutthroat industry unlike any other departments in the school. The engineering department doesn't do engineering; the law department doesn't do legal work; so the medical school is unique that way, unfortunately.

Hughes: How did the basic sciences that were already in place in Palo Alto feel about the influx of the medical school?

1 See, for example: "The two cultures: chemistry and biology." (Draft, courtesy of Dr. Kornberg, of presentation at Harvard University, May 28, 1991.)

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Kornberg: It must have varied. You should talk to Avram Goldstein, who has now retired, but is very knowledgeable and articulate and perhaps has written about it.

The Basic Science Environment, circa 1959

Kornberg: At that time, there was also a new medical curriculum that was to be put in place with the new organization of the medical school.1 I told you how the chemistry department felt; they would now get rid of the two biochemists who were teaching biochemistry and, with great relief, have two slots available. It was with great despair that they found that they still couldn't dispose of these people.

The biology department might have had a more sanguine view. Yanofsky was a great addition. He came largely because I was coming to Stanford in biochemistry, and so there would be resources and strength in biochemistry which would be very helpful to him. And then others came. You'd find that there was a very healthy respect for biochemistry in the biology department. The most popular course at Stanford is human biology. That course was generated by people in the medical school who then included people from sociology and psychology, as well as biology.

Hughes: In 1959?

Kornberg: The course was introduced maybe ten years later.

Hughes: Was a basic science environment conducive to interdisciplinary exchange one of the reasons you came to Stanford?

Kornberg: You may find it in my correspondence; I don't remember. I know Lederberg had a joint appointment in the Biological Sciences Department in the School of Humanities and Sciences as well as his primary appointment in Genetics in the medical school. I might have toyed with doing that too, but it doesn't work. It is enough to attend the numerous boring faculty meetings in one school. Almost invariably people hue to one department or the other.

1 See, for example: L. M. Stowe. The Stanford plan: an educational continuum for medicine. Journal of Medical Education, November 1959, 1059- 1069.

I mentioned that it was evident to me that the chemistry department here was very weak and disintegrating. The provost, Fred Terman, said it was the intention of the university not to appoint people under the current regime but to bring in a fresh cadre of people, and to appoint a new chairman. And that's what they did. It was obvious that I was concerned and hopeful that there would be good interactions with chemistry.

Kaplan in radiology was interacting with people in physics regarding the accelerator that they had built for radiation therapy. Goldstein, with his excellent memory and intimate involvement in this move and the details of what was expected, could give you more information.

Later Efforts to Strengthen Basic Science at Stanford

Hughes: Here are your notes for one of several later efforts on your part to strengthen the basic science component of the medical school.1 [Pause while Kornberg scans document.]

Kornberg: "Basic science at Stanford is a paper tiger."

Hughes: Yes, who said that?

Kornberg: I did. [He continues reading.]

Hughes: You were asking for greater integration of biochemistry--

Kornberg: Oh, it was clear [clearly needed] with chemistry; it was clear with biology. Those facts are there.

Hughes: You spoke of the drift to the clinical sciences, presumably to the disfavor of the basic sciences.

Kornberg: The clinical sciences proliferated, with all their specialties, They complained that too much money and attention was- given to basic science, which did have much greater celebrity and visibility in the world. They blamed the basic sciences for their own lack of recognition.

1 Handwritten notes titled, "Notes for Saturday, March 26, 1977, Meeting with Peter Bing, Bill Miller, Clayton Rich, Bob Lfehman], Paul B[erg], Dale K[aiser], Dave H[ogness]." (Kornberg papers, SC 359, box 5, folder: 1977.)

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Hughes: I'm trying to establish how the 1959 plan for the medical

school actually played out. One of the strands I'm interested in is biochemistry's interaction with other basic science departments. There are indications that the Department of Genetics-

Joshua Lederberg

Kornberg: Oh, the Department of Genetics was created to give Joshua Lederberg a basis for operations. He is a genius, but he couldn't pay attention for any length of time to deal with things like personnel and management of resources. His research has been characterized as being very inventive, but he didn't go on and perfect it. He saw very early that genetics was chemistry, but he wasn't prepared to change what he was doing. He thought I would do it. I invited him to do things with me, but he didn't have the stomach for it. He got interested in exobiology--space--and had a very early interest in the use of computers to do chemistry. He is involved in any number of public affairs now, such as defense policy.

Hughes: Had you hoped that there would be more scientific interaction between Biochemistry and Genetics?

Kornberg: He wanted to be in the biochemistry department at the time that he came here. I saw that--how should I put it politely?--it wouldn't be a good fit. His activities were so varied, and he was such an important personality, that I didn't think he would fit into this modest family atmosphere. I was right.

He's told me that he would have been happier had he been in the biochemistry department so he would be relieved of all of this nonsense. Yet at executive faculty meetings he was far more attentive to the housekeeping of the medical school, of the university, than I was. It was utterly boring, but he paid attention to it, at least for a brief interval. So yes, Genetics was contiguous with Biochemistry. In fact initially we gave up some of our space so that some of his people could be housed until the new clinical science building was built.

The appointments Josh made were diverse-- [Leonard A.] Herzenberg, Luca [Luigi L.] Cavalli[-Sforza] , [Ann K.] Ganesan. They were outstanding people but they had very little to do with one another, which in his defense is not atypical of departments. A biochemistry department might have a dozen people, each one specializing in some unique area. You can get

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better teaching opportunities because the faculty represents a wide range of areas.

More on the Department of Biochemistry at Stanford

Intellectual Focus on DNA

Kornberg: In contrast, this department was narrowly focused. We didn't do research in carbohydrates, lipids, vitamins, minerals, bioenergetics . Ninety-five percent of what was considered important in a biochemistry text was not pursued in this department. Our focus on nucleic acids and proteins that bound nucleic acids was less than 5 percent of the biochemical text. But my defense was, and still is, that we were approaching this rather limited topic, (which of course then got very fashionable), from the very broad standpoint of genetics, enzymology, and physical chemistry. We had Kaiser, Hogness, Berg, Lehman, myself, and then Baldwin. They talked to each other; they collaborated, and then things gelled around DNA when it got to be so meaningful and fertile for studies.

If there is one thing I could say about the intellectual aspect of this department, it was to bring different disciplines to bear on a narrow area of bioscience. We've been applauded for that. Many people have recognized retrospectively that it was really the only department that was sharply focused on DNA biochemistry. Others were doing it, but they were units within much larger departments. Even though we were a small department, collectively we had the critical mass to do the physical chemistry, the genetics, the enzymology of the nucleic acids. I'd say that was key.

Hughes: So instead of reaching outside the department for expertise--

Kornberg: We were generating it here. There were other people -who did even better DNA chemistry or DNA genetics, but within this department those fields were represented at a very respectable level. I have to admit that the enzymology of DNA was done best here. And when we talk about recombinant DNA and genetic engineering, you've heard it said many times, by others as well as myself, that we provided some of the key reagents that made that technology possible.

Hughes: You have described a very self-contained department.

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Kornberg: Hughes:

Kornberg:

Elitist.

And it was doubtless perceived that way. That perception would not be conducive to interdepartmental interchange.

I think you're right, perception.

I think we contributed to that

Joint Appointments

Kornberg: It is common among biochemistry departments in medical schools to have joint appointments with many departments. They may have forty or more. To what extent are these joint appointees active in the department? It varies. Some joint appointees may be included in departmental meetings or retreats or sharing of resources. How big can a family be? How many people can you interact with, understand, be sympathetic to, be helpful to, get help from—six, eight, nine, ten people? If they each speak a different scientific language, it is impossible.

Broadening the Focus on DNA

Hughes: I realize that there was a topical focus in the department on DNA, but as time went on, with recruitment, wasn't there an expansion of focus?

Kornberg: I said earlier that we were accused of being very narrow. Yes, there was a narrowing of interest around DNA and RNA and proteins that interacted with them. My defense against that criticism was that, unlike other departments which handle many different topics, we approach this topic from diverse disciplines, disciplines as diverse as genetics and physical chemistry. So in a sense we broadened our focus.

Buzz [Robert] Baldwin was appointed in the new department of biochemistry at Stanford to provide us with physical biochemistry, which clearly was needed for a proper department. He was a specialist on proteins and how proteins sedimented in centrifuges. When he came to Stanford, he started working on DNA, and he has since gone back to proteins. But it is a measure of how interactive we were that he then applied his skills and experience with physical chemistry to nucleic acids. He made important contributions to the literature and to us.

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The DNA Club

Kornberg: We had a DNA club which met in the other building, in my room, a room like this one. Virtually everyone in the department attended the DNA club, and for two reasons: one, it was small, and secondly, almost everybody had an interest in DNA.

Hughes: What was the format?

Kornberg: I don't remember. Also, the whole department met in my living room once a month and filled it with cigarette butts and so forth. [laughter] Those were the good old days when the group was small and speaking one language and infused with the excitement of discovery.

Hughes: Was the meeting unstructured?

Kornberg: No, people presented their work in a regular fashion. The same wasn't true of the DNA club. People tell me things about the conduct of those meetings that now seem foreign: the time of day we met, the format, my behavior, which I think has always been so benign.

Hughes: They don't see it that way?

Kornberg: I don't know; I couldn't speak for others.

The Chairmanship

Hughes: I saw a memo written in 1976 to Dean [Clayton] Rich in which you revived "an old suggestion" for rotating departmental chairmanship in the medical school.1

Kornberg: When I resigned the chairmanship in 1969, it was quite heretical to propose that there be a regular rotation.

Hughes: Rotation wasn't used at many universities?

Kornberg: Well, we used it. I felt that the chairmanship should not be a "life sentence." The letter was to suggest that it be done more widely, to get some turnover and fresh blood.

1 Kornberg to Rich, June 15, 1976. (Kornberg papers, SC 359, box 5, folder: 1976.)

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Hughes: Did you innovate that idea?

Kornberg: I don't think so. But if there is such a memo then I was

proposing it because it was not being done at this school, and still is not done in many places. I think we were probably helpful or even instrumental in this kind of practice. Also the pyramidal structure of the departments was severe at the time. It was rare to have two full professors in one department.

In Physics here, Leonard Schiff, at a very young age, was chairman of the department when some very celebrated senior people were in the department. I don't know much about that history, but it must say that one could have a chairman who is lower in rank than some of the people under his executive authority. That is a whole matter in itself. I never thought about it. Except that, I'll say again, in practice I think the rotating chairmanship was reasonable and very useful as a device to get new leadership.

Hughes: I know from reading your essays that you believe that a

scientist's first responsibility is to his science. Wasn't there also the idea that a chairman should want to get back to the bench?

Kornberg: Yes. When I first became chairman of an academic department, it was traditional that there was the secretary and the chief officer of the department, and the chairman had an adjoining office. At Harvard it would be palatial; at Washington University, it was also very large. I changed that immediately. I converted the chairman's office to a library. I had my office way down the hall so that I wouldn't be bothered or tempted to get involved in administrative affairs. I had a very small office as part of the lab, with a partition on one side.

Hughes: I would think that in establishing a new department at

Stanford, you would have needed to spend a lot of time on administration.

Kornberg: Not really. Again, I placed my office adjacent to my lab and

remote from the executive offices. No, I have rather different and I would say heretical views about administration and teaching. So much time is spent on administration that is self generated. For a large fraction of the ten years I was chairman here, one individual consumed 90 percent of my administrative time. Despite the nuisance created, I didn't spend more than 10 percent of my time on departmental affairs. Part of the reason is, I asked everyone else to do various

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things, so that I was not the custodian of all the physical and functional attributes of the department.

Hughes: I saw one of those schema outlining specific responsibilities

for departmental faculty members.1 Did you begin that system at the start of your chairmanship?

Kornberg: I don't remember. But people felt that they shared and had a responsibility for the operations of the department. In 1963, when we had a vacancy we needed to fill, we couldn't agree. I actually felt quite comfortable with the choice that I would have made, but it was then not a vote as much as my sense of who felt strongly and who much less so, and then we went on and chose two young people.

Hughes: Was 1963 the year when you began to consider new faculty appointments to be a joint decision?

Kornberg: I'm not sure. I made the decision of who would come to

Stanford and who would not. I don't know how much I agonized over it, and I think I've told you there were some serious consequences. Looking back, it was largely a good set of choices .

When we were choosing a physical chemist, we interviewed at least two people, and there was a consensus about Buzz Baldwin, the person we chose. It didn't come up again for three or four years, and then it was implicit that we would arrive at some consensus. It was quite natural too that Paul Berg would succeed me as chairman because he is an interactive person, a boy scout in attitude. He is very generous with his time and concern, bright and accomplished, and he carried on what I had been doing. I didn't feel as though I was no longer chairman. He made some innovations, and that was great. He could have made them without being chairman.

The chairman does have authority and in many instances, in this school and elsewhere, exercises that authority. Even at Berkeley, the chairman can do things without the approval of the department, or sensing that there was a clear majority.

Hughes: Why do you say "even" at Berkeley?

Kornberg: I think Berkeley has an eminent faculty in biochemistry. There are a dozen professors, and they are all very distinguished. I

1 Departmental Responsibilities, 1975-76. box 5, folder: 1974-75.)

(Kornberg papers, SC 359,

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am saying that even with a faculty of that size and eminence, the chairman still exercises authority.

More on the Department's Distinctive Operational System

Kornberg: We've discussed the distinctive intellectual features of the department; its operation was even more radical in distinguishing it from other departments within the school or elsewhere. There may be some other examples, but I haven't heard of them: a communal operation, sharing space, resources, responsibilities, and money.

Hughes: You talked about this in the first interview.

Kornberg: I may also have said: the reason people resisted the temptation to go elsewhere to more prestigious, lucrative positions, was that they were comfortable with this system. In essence, it demands that you understand your self-interest to be dictated in the very long term by being generous. It is a human trait, with the exception of a few saints, to believe that you are giving more than you are getting.

Occasionally, we got close to running out of money, so there would be a moratorium on ordering, which was an inconvenience to everybody, particularly those who felt that their budgets were more than adequate. They thought that others in the department were not getting enough grants or spending too much. But strangely enough, everyone felt that way. [laughter] I would go to people that I knew were underfunded or overspending and I'd be told, "I've got enough grants; I'm not overspending."

The reason the department didn't split apart and go to the conventional 'every tub on its bottom' is that we--and I think I clearly was in positive balance—respected what others were doing, even if they were overspending or underfunded; and they were doing great work. One could tolerate some eccentricity, or call it even lack of communal concern.

What is unique at the moment and very worrisome is that there are two professors who are at odds with each other. So we are wrestling with that. I should be out of the loop because my emeritus status makes my involvement anomalous . I am so far past the conventional retirement age. I don't want to be meddlesome. I am concerned with the potential for disruption between the younger and older faculty.

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Hughes: How do you in general handle interpersonal problems in the department?

Kornberg: This situation is novel. You try to modify people's behavior and to some extent you can, but there are people who are not going to change in any fundamental way. It leads to divorce in marriage, and it leads to disruption of groups like this. So I think you cannot afford to keep a person like that, even one with great talent, without disrupting the department.

Hughes: So you prioritize the group, rather than the individual?

Kornberg: Clearly, I do. I would not want a genius in the department who would not conform in the general and acceptable way to the behavior that we expect of someone in the group. It is as simple as that. There is enough talent, enough ingenuity in the department that we've been able to attract and keep outstanding people for a long time.

When one of these people that I've referred to came to me repeatedly with plans to get more grants, and I had the authority to sign the grant application, I did not sign it. I said, "We don't have the physical resources, and in my judgement, you don't have the capacity to do all these things." Well, he bridled and disagreed and ultimately left. Twenty plus years later, I still think I was right.

Actually, that was a collective decision. Everybody in the department reflected on it, and it was unanimous. So there was no dissension. And it happened again fifteen years later. There was another such personality: outstanding scientific talent, but again, that inability to live within the confines and the restraints of communal living. And it is a restraint for someone who is expansive and has lots of ideas.

Hughes: And he left as well?

Kornberg: Yes. He is very grateful to me for the intellectual discipline that he acquired here, the objective of 'purifying' tf system. You try to characterize a component of the system and do it well.

51 The Biochemistry Curriculum

The Laboratory for Medical Students, 1959-1965

Hughes: I read that the five-year new medical curriculum was actually not new, that the model was the curriculum already established at Western Reserve University.1 Do you know if Stanford adopted the curriculum lock, stock and barrel?

Kornberg: I don't remember. At that time I probably not only accepted

but maybe strongly promoted that curriculum. I have become so disillusioned with curricula. Let me give you one example; I could give you many more. We were practicing this new medical curriculum--! think it was a five-year plan—and I'll describe the biochemistry curriculum. We took our lectures very seriously, to the point where we attended each other's lectures.

We introduced a laboratory, which was not traditional. Instead of teaching the procedures of biochemistry, how to analyze this or that, we did something that I think was utterly novel. We asked the students to design the experiments they wanted to do. There were only ten weeks, divided into two five- week periods. One assignment was to isolate DNA from some novel source and characterize it; a second experiment was to take an enzyme and demonstrate its catalytic function and supply information that was not available in the literature.

Most remarkably, everyone on the faculty was involved in the laboratory, including our postdocs and graduate students, so there was a faculty-medical student ratio of perhaps one-to- two. The students were very responsive; they would come in evenings and weekends. It sounds so free and open; of course we tried to restrain our reagents in a skillful way. The laboratory was exceedingly popular with the students as shown by the fact that with few exceptions it was done with such enthusiasm. The faculty were also very involved and cheerful about it .

I recall clearly that at the beginning of each session I would tell the students that it was a very different kind of laboratory. The purpose was not to teach biochemistry, but rather to teach how information is acquired and evaluated, the

1 S. Andreopoulos. A novel curriculum at center stage. Stanford University Medical Center: 25 Years, [n.d.], p. IV-V.

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meaning of a control, trust in an observation. Some students might even make some very novel observations. As a faculty we put in more time into this laboratory than into our lectures. But we believed that training a physician in acquiring and evaluating data is an important part of that person's education and training.

We had students in those years, 1959 through 1965, who are today very well-known scientists, and they talk about those days in the biochemistry lab. It really was a remarkable lab.

In 1965, there were some departments that were really inadequate, and yet they were giving lecture courses and laboratories, and there were a lot of complaints about them. I was one of the exponents for a change in the curriculum: a free market — the students could choose the courses they wanted. They had to take a certain number of hours of anatomy, or this or that, but otherwise, there was a lot of latitude. Among the choices they could make was not to take the laboratory because it really wasn't essential for passing the national boards in medicine or anything else.

The ye.ar the change was made, 1966, all but four out of eighty-six students elected not to take the laboratory. There were three reasons given: first, it was well known that the lab didn't teach them what they needed to know on the exams. Secondly, it had nothing to do with clinical medicine. Finally, skipping the lab made it easier to graduate in four years instead of five, with significant financial and other implications. In as much as we couldn't provide a lab course for four people, we took them into our own labs, where they were given the exposure of a rotating graduate student. The next year there were no applicants — the end of the biochemistry lab.

The Medical Science Training Program

Hughes: Is integration of medical students into the departmental graduate program a different issue?

Kornberg: It is entirely different. I was talking about how to provide a small number of medical students with an intensive and sustained research experience.

We have the MSTP (Medical Science Training Program) . The sponsors of the program, the NIH, insisted that the student

53

complete both the Ph.D. and M.D. programs. I was opposed to that, largely from my own experience. I thought one degree was enough. The opportunity to do creative research in either program mattered most. A graduate student or a medical student could choose a curriculum focused on genetics, chemistry, whatever, and thereby have the opportunity to do something creative in research. But I was overruled; and yet we have had some outstanding MSTP students.

MSTP was very attractive because it provided tuition, a generous stipend, and an opportunity to get both degrees. You also had the insurance that if you didn't succeed in science, you had an M.D. to fall back on. The credentials and prestige of a Ph.D. might also be helpful. There were obvious practical advantages. The MSTP is still going strong.

Hughes: Why did the five-year M.D. program end?

Kornberg: The five-year program required an extra year of schooling,

expense and time. With few exceptions, medical students are there to learn a trade or craft or profession. That mentality maintains to this very day. After four years of college and many years of schooling before that, they decide to become doctors. They want to get on with it and learn what a doctor needs to know.

Just this last semester, the medical students in the biochemistry course were unhappy that it was populated by undergraduates. Imagine the indignity of going to medical school and finding that your near neighbors and competitors in exams were juniors and seniors in college! And by virtue of that you were all being taught things that were not as focused and relevant to becoming a doctor.

The Department's Relations with Industry

Industry Relations in Academic Science

Hughes: In the late 1970s, there was a shift in the tradition that

commercial ties in academic biology were not respectable. I've seen some traces in your correspondence that the department had links to industry before that time. For example, I saw a

-

54

letter from Du Pont, dated the late 1960s, which proposed a financial connection.1

Kornberg: A fellowship. Hughes: Do you have comments?

Kornberg: Let me expand upon this point. First of all, chemistry

departments traditionally were tightly linked with industry. Their Ph.D. and M.S. graduates invariably went into industry. Very few went into academia. They were producing them by the dozens; there weren't that many academic jobs. Chemistry departments were tightly linked with industry; they consulted with industry. That goes way back. Stanford, when I got here in 1959, had as one of its guidelines that faculty members could spend one day a week outside the university in some other activity. One day a week!

But in biology it was utterly unknown. That's where the revolution was. So I'd be specific that in the late 1970s this became an accepted and even respected kind of association in bioscience. It was completely novel. No one expected the extent of it.

I had avoided consultantships or any dealings with the pharmaceutical industry. I found my occasional consulting visits disillusioning and disappointing with nothing there that I felt attracted to. It wasn't all that lucrative either, so I wasn't tempted by enormous financial fees.

As described in some of my papers, my virginity ended when [Alejandro] Zaffaroni started ALZA [1968]. I liked him so much and he was so inspiring as a colleague that when he started this new venture and asked me to join his advisory board, I was interested and felt flattered. I didn't know that I could contribute much, and I don't think I did. I served on that board for twelve years and I learned a lot about applied science and business—production, chemical trials, regulatory approval, and marketing.

I learned how difficult it is to translate a good discovery to a point where it is a marketable, profitable product. Without that you're out of business. For example, growing polio virus in a kidney cell in a test tube was an important

1 Burt C. Pratt, Executive Secretary, Committee on Educational Aid, Du Pont, to Kornberg, October 11, 1967. (Kornberg papers, SC 359, box 26, folder: 1967 A-L.)

55

feat and earned John Enders and colleagues a Nobel prize. But until it was put into children in a reliable, acceptable, marketable form and proved its utility, the job was not finished.

Yet for one of our graduates to enter industry would have been regarded a disaster, comparable perhaps to the marriage of an orthodox Jew to an orthodox Gentile.

Hughes: Why?

Kornberg: It was not acceptable to degrade and prostitute yourself by engaging in activity that was done under such nonscientif ic, unproductive, intellectual circumstances. The thinking was that people in the pharmaceutical industry, even if they started off bright, became drudges. Their function was to find ways to avoid an existing patent or to get some new patent based on a trivial thing. Occasionally there were genuine discoveries in industry, but they were relatively rare.

Now it is radically different. Biotechnology ventures and pharmaceutical industry are reasonable career alternatives to academia. There are also attractions to enter law, and start a business—what a revolutionary change in attitude!

Genesis of Biochemistry's Industrial Affiliates Program [IAP]

Kornberg: Now, the Industrial Affiliates Program—do you have the date?

Hughes: As far as I can tell from going through your papers, the

Biochemistry Industrial Affiliates Program was first considered in 1979. You mention it in this memo.1

Kornberg: [scans memo] Yes, that makes sense because this is the time of the Genentech success; and Biogen and Cetus were also getting into the act. Paul and I and others were being approached to start a venture. Having been the source of the knowledge and people doing recombinant DNA work, it was quite natural that

1 Memo, Kornberg to Dale Kaiser, September 9, 1979. (Kornberg papers, SC 359, box 5, folder: 1979.) An "Industrial Associates Program" is one of several ideas Dr. Kornberg offers as strategies for future funding of the department. The memo is also instructive regarding departmental organization and financial strains.

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*

the department would be seen as an attractive place for a pharmaceutical company or biotech venture to get access to recruit these people and be introduced to the new knowledge that was still unpublished.

Hughes: Who originated the idea of an industrial affiliates program?

Kornberg: I don't know. I'm amazed that I would write this lengthy a memo.

Hughes: You mentioned that Paul had already discussed the idea and that if the department was going to launch an industrial affiliates program, it should do so soon because "[w]e're already a little late in getting into this kind of venture and it may soon become too competitive to make it attractive."1

Kornberg: Talk to Paul about that. It may have been that he initiated the idea. But it was in the air that our advice and services were being sought, and that we were perceived to be at the forefront of this new technology.

Hughes: There is a precedent for an industrial affiliates program right here on campus .

Kornberg: Oh yes.

The Chemistry Department's Industrial Affiliates Program

Hughes: The chemistry department had an industrial affiliates program in 1970, perhaps earlier.2

Kornberg: Oh yes. It goes back maybe a century that chemists trained their students for industry. But that was not true for biologists. The chemical industry is huge, and it relied on the chemistry departments for its personnel. I would guess that 80 percent of chemistry graduates, even from elite institutions, went into industry, whereas less than 5 percent of biology graduates did so. And engineering, of course, was very intimately allied with industry. Silicon Valley was started by engineering graduates from Stanford.

1 Ibid.

2 Carl Djerassi to Kornberg, July 29, 1970. box 27, folder: 1970(A-E).)

(Kornberg papers, SC 359,

57

Hughes: I have here a letter from Carl Djerassi to you dated July 1970 in which he mentions the department's industrial affiliates program.1 Was your program modeled after the chemistry department ' s?

Kornberg: [looks at memo] Well, you are finding more information here than I remember. Archives do make up for bad memories.

Hughes: You're not expected to remember a letter from 1970.

Kornberg: That is fortunate, isn't it? Well, Gobind Khorana happens to have total recall. He not only remembers a paper in detail, but he knows the page of the journal.

Hughes: He has a photographic memory?

Kornberg: Well, it is more than that because he understands what he has read.

At one time I had a good photographic memory because I was under great constraint when I was in college, competing with top students and not having much time--I worked every evening. Before an exam, I almost mentally photographed page after page including footnotes. And that was necessary to compete in City College [of New York] .

Hughes: And you could call it forth?

Kornberg: Including poetry that I memorized and knew exactly where it

stood on the page. But the half life of that was very brief. Khorana remembers these things for countless years.

Biochemistry's Industry Affiliates Program

Hughes: Do you want to comment on the success or otherwise of Biochemistry's Industrial Affiliates Program?

Kornberg: It was very successful for a while and it is floundering near extinction now. The reasons are several, but largely because we don't have a unique product to offer, and we don't have any super salesmen for what we've got.

Ibid.

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Also, our industrial affiliates have become so huge and bureaucratic that when we try to provide them with some perk or privilege — attending our retreats, or presenting some of their work, or meeting with them--our invitation doesn't reach the right people in time for them to participate.

We still have a top flight group of students and postdocs, and industry needs to recruit talent all the time. And our retreats are good scientific meetings and interesting information is presented in a very nice atmosphere. People who might want to attend from Bristol-Myers or Monsanto never see these notices in time to attend because of the time required for notices to filter through their bureaucracy. They are lost on some manager's desk. That's part of the problem.

The main problem, however, is that we don't have an attractive and unique product to sell, and we don't have the salesmen to do it. Some of us were eager salesmen; we'd give seminars at these companies; we'd know the people involved and have some personal interaction.

Hughes: Were you one of those people?

Kornberg: Oh, sure.

Hughes: I know of your association with ALZA and DNAX. . .

Kornberg: Bristol-Myers, Monsanto, Abbott, and some others. There were several of us who really went out of our way to do this.

Hughes: What was your prime motive?

Kornberg: I think that it had several advantages. It gave us money that was not earmarked; it was money which we then could use for a rainy day. There were threats, some which would have interrupted our graduate program. We could provide stipends to foreign students that weren't otherwise available; we could provide increments to salaries when they were necessary; we could conduct retreats and other activities that might not be appropriate to assign to an NIH grant.

We built up a kitty that was close to a million dollars. Then our chairman was so non-combative that he let the dean consume it. The administration was pressed for money, so they weren't going to give us any to run the department because we had this extra money. Intolerable; I never would have allowed that. It was just not fair.

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The affiliates program represented a very good quid pro quo in that we provided access to students and postdocs who were increasingly available to take jobs in industry. They in turn could meet these people in a very nice setting to persuade them or inform them of the virtues of jobs in industry. Early on, representatives from competitive companies had a playing field in which they could interact, and there were some collaborative projects between companies which were generated in this atmosphere.

Finally, I think the program had an educational advantage. We were giving information that would be useful in developing products, and in turn we got some sense of where things were moving in the biotechnology field. It was very useful.

Current Attitudes About Industrial Affiliations

Hughes: What were some of the factors that turned attitudes around about students and faculty having industrial affiliations?

Kornberg: The factors were: when jobs got tighter in academia after the explosive growth in the fifties and sixties, there was a big lag in which all of the full-time equivalent positions were filled. Industry provided another source of jobs.

Secondly, many of the biotech ventures were attractive scientifically, and they in turn influenced the pharmaceutical companies which became increasingly supportive of good science. So the jobs were more numerous and the opportunities to do science were better. They were lucrative. You got a better salary; you got a piece of the company, and people became rich rather quickly. It was also perceived to be the wave of the future. And some people were genuinely interested in applications of knowledge beyond what would be possible in an academic environment. Students saw their faculty involved in some of these ventures and heard how their experiences were worthwhile and intellectually enriching.

The revolution in which biologists became entrepreneurs is as drastic as any other thing that has happened in postwar science. But, to an excess. Discoveries are commonly made that twenty years ago would have been pursued in greater depth in terms of their chemical basis and biological significance to other species, which now become part of a new business. The discovery is immediately translated into a new venture to produce a product that will make money.

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-

Hughes: And what are the effects--

Kornberg: The effects are disastrous. Science isn't being pursued to a depth and a breadth that enriches our knowledge. Discoveries should be developed, but not to the exclusion of the extension of basic knowledge. Then again, the illusion is generally created that these kinds of ventures are not only desirable but imperative, so that the university will make money from its share in the invention; that the scientific fraternity will be seen as part of the mainstream of American life and capitalism; that the country will get rich from the economic advantage of application and discovery; and that industry of this kind can replace the tax dollars that are now being spent to support federal grants. It is like cutting down a forest for the immediate use of the lumber, without having any concern about replacing it. It is very spendthrift and foolish.

Proposing a Scientists' Lobby

Hughes: Do you see ways of halting these trends?

Kornberg: Yes, I'm very much involved in that today. In brief, I'm

proposing a lobby of scientists of a magnitude that has not been envisioned, which will then have some voice in Washington. This is a lobby in the best sense of the term; it will inform Congress of the value of biomedical discoveries. That information will then be transferred to every community, where scientists will be available to meet with lay groups and explain why work on, lets say, the pathway of making building blocks of DNA will lead to better drugs and better devices.

One aim will be to dispel the illusion that basic research of any quantity and quality will be done in other than an academic setting. Ninety-five percent of the information that is going to be used in a fundamental way is not obtained in an industrial setting.

Let me make it clear that all of the biotechnology that we have been talking about was done in laboratories that were built and supported by the NIH. It was not done in any commercial laboratory. All the ventures, people and ideas, came from these academic groups. That is still largely true.

Hughes: If the money and the technology to do the science are now more heavily concentrated in industry, aren't young bright minds going to move from academia into industry?

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Kornberg: Yes, especially if they observe that grants from the NIH are so difficult to get that established investigators—their research advisors, their role models — can1 1 get grants and quit.

Hughes: That is happening.

Kornberg: It is happening. Or, almost as bad, that the research projects now being proposed for funding are safe, not courageous. In fact, the best projects are those that are already underway, that is, best from the standpoint of getting funded.

More on the Department's Program

Kornberg: When did we start our industrial affiliates program? Hughes: Nineteen eighty.

Kornberg: By that time, this department had been so innovative in

recombinant DNA that pharmaceutical companies were beginning to be interested in it. The department was a very special place of attraction so that we could select a limited number of companies that we would accept as participants in this program. Now everyone is scrounging to find some company to be affiliated with.

It was not only the unrestricted money that the companies would provide; we felt that we would learn something from these biotechnology efforts, and that our students and postdocs might become interested in those opportunities. And that is of course what has happened. But in 1968 when I joined the ALZA board of advisors, it was the first time that I felt I could in good conscience and comfortably be affiliated with a commercial enterprise.

Hughes: As I said, it really took off in 1980, but there was

discussion, not surprisingly, in 1979. The first seminar, at Asilomar, was not until early 1981, but companies became affiliated with the department in 1980. ' What was the impetus for considering such a program?

1 By July 1980, fifteen companies were reported to be members of the department's Industrial Affiliates Program. (Minutes, Faculty Meeting, July 8 [1980]. (Kornberg papers, SC 359, box 5, folder: 1980.)

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Kornberg: I'm going to guess that we were a resource that was relatively unique. As you saw in that letter to Bert Zerner, we did have a focus and an expertise here in recombinant DNA technology and its applications. And so we had a product to sell. There may also have been overtures from various pharmaceutical groups.

What was attractive is that we would get maybe ten thousand dollars a year from each of a dozen affiliates, and that as a budgetary component that was not allocated—had no strings attached—was very attractive in management of the department. As examples, we could supplement salaries of graduate students and postdocs; we could offer stipends to foreign students and postdocs who otherwise were not eligible for scholarships; we could help in getting new faculty members started and do a variety of things that might have been difficult to do with government grants.

Secondly, we were making a contribution to biotech firms by affording them access to technologies and new developments that were ongoing in the department. At these Asilomar conferences [for our industrial affiliates], we could expose our students and postdocs to representatives of the biotech firms or pharmaceutical companies; we were interested in both. And they in turn could recruit or educate them. It used to be unacceptable that any of our graduates would gain employment with pharmaceutical companies. But by that time, some of that stigma had been reduced. It was seen by both sides as an attractive kind of quid pro quo where we were offering something that was valuable and getting compensated for it financially and academically. I would say with regard to DNAX, we were heavily recruiting our postdocs and excellent academic people.

More on the Chemistry Department's Program

Hughes: In a memo on departmental finances, you wrote in 1979 that the issue of an industrial affiliates program was under discussion in the department, and stated: "I think we should consider this a top priority item and do it soon if we do it at all. We're already a little late in getting into this kind of venture, and it may soon be too competitive to make it attractive."1 You apparently knew that programs of this nature already existed.

1 Kornberg memo to Dale Kaiser, September 10, 1979. (Kornberg papers, SC 359, box 5, folder: 1979.)

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Kornberg:

Hughes: Kornberg:

Hughes:

Well, in the chemistry department they had been doing it for many years. There were very few departments like ours that had such a strong focus on recombinant DNA, but there were others

that were getting into the act. which they were.

I can't think specifically

Biological sciences departments as a rule did not have industrial affiliations.

That's true. Even if I sensed we might be a little late, we were certainly among the very first in biology, began to copy our moves in this direction.

Then others

You're quite right that the Department of Chemistry here had a program, and I can't tell you exactly when it began. But I know it was at least as old as 1970, because in 1970, Djerassi wrote to you, inviting you to be a speaker in the program.1 [tape interruption] .

Kornberg: Djerassi might have been the architect of that because he had such intimate connections with industry. But, as I've mentioned, chemistry in general was very tightly linked with industry, and some of the most illustrious academic figures in chemistry were known to have very strong industrial ties.

Hughes: So there was no stigma in chemistry. Kornberg: Not at all.

Current Status of Biochemistry's ZAP

Hughes: Did you see any disadvantages to the Industrial Affiliates Program?

Kornberg: It has been a concern of late because the program has dwindled and is almost moribund. Were we spending a lot of energy chasing a buck? If we expended a similar amount of energy getting another grant from the NIH, we'd be better off. Also it was evident that in the 1990s we were not offering a unique product. Companies were dropping out and it was difficult to recruit new ones. So, somewhere along the line, we wondered whether it was a good business to be promoting.

1 Carl Djerassi to Kornberg, July 29 box 27, folder: 1970 A-E.)

1970. (Kornberg papers, SC 359,

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Hughes: Since most pharmaceutical houses did not immediately jump onto the biotechnology bandwagon, did they look upon a program such as this as an excuse to be in touch with this technology, but without having to make a big investment?

Kornberg: Well, that is some of it. The program has become less

attractive to companies for several reasons. One, they already have in-house much of what we were offering them.

Hughes: But they didn't in 1980, did they?

Kornberg: Not in 1980.

Hughes: I'm asking about 1980.

Kornberg: Yes, I think that was the attraction; that we could expose them to this new technology. We also offered to come and give a seminar once a year without expense to them. But you know they were such large bureaucracies that the source of the money or the contact was remote from the people who would make use of it. So within a company like Bristol-Myers Squibb, one part of the company never knew that they were affiliates of the Stanford biochemistry program. And when invitations went out to come to the Asilomar meeting, they often didn't reach the people who might have wanted to come. And that's partly our fault because we didn't have an organized, aggressive person or group within the department to correct for this lack of communication. I think the program has had its day.

Hughes: At one point you actually had a non-faculty member in charge.

Kornberg: That was someone [Elizabeth Kirk-Fulton] in the department

office, and they were not fully directed to that. It was one of their duties in addition to secretarial or some other duties.

Hughes: That implies how the department weighted the importance of this program.

Kornberg: We were very eager to maintain and extend that program, and I think it was successful for at least a dozen years. And maybe that is the lifetime of any enterprise like that.

It was disillusioning too with Genentech. After all, Genentech existed because of the technologies we'd introduced; some of their scientists came from Stanford; and after one year they opted out of the affiliates program. At that time, it was ten or twelve thousand dollars a year; it was a trivial amount even for companies that weren't making any profit. Some of the

65

biotech ventures were involved briefly and had very tight budgets .

The large companies used their research budget, rather than some other budget, to pay for the affiliation, and so corporate research people there would say, well, this affiliation is worth half a postdoc or half an assistant. Surprising how narrowly some of these multi-billion dollar companies could look upon collaborative arrangements that could be helpful.

Smith Kline & French1

Hughes: I saw some minutes of a faculty meeting in late 1981 about

Smith Kline.2 Apparently there was consideration of the company underwriting a postdoctoral training program in the department.

Kornberg: Smith Kline at that time had a middle manager involved in

university relations—wish I could remember his name; a very nice person- -and I think they did underwrite a fellowship for a few years. [pause]

Hughes: George Poste.

Kornberg: Yes, Poste was in charge. [pause while looking over minutes] Who wrote up these minutes?

Hughes: It varied from meeting to meeting.

Kornberg: I don't remember exactly what became of this.

1 Now, SmithKline Beecham.

2 Minutes of Faculty Meeting, November 16, 1981, 359, box 5, folder: 1981.)

(Kornberg papers, SC

66

Potential Conflicts of Interest

Hughes: I'm interested in the basis for one opposing view, which came from Brutlag.1 Apparently the faculty was concerned about a departmental relationship with a specific company.

Kornberg: Yes, that is always a very serious matter. We were steadfast in not wanting to have an exclusive relationship with one company. Scripps has been very successful—Richard Lerner, the director, has been the architect — in such exclusive arrangements .

Hughes: Brutlag 's point of opposition was not so much the exclusivity of a relationship with Smith Kline, but rather that having a relationship with Smith Kline might interfere with his relationships with other corporations. I thought that was an interesting twist. [laughs]

Kornberg: That of course affects people who already have an industrial relationship.

At an early stage, I was approached by another biotech venture, and I consulted with Schering-Plough, which a few years earlier had bought DNAX, and they felt very strongly that I shouldn't be involved with another venture. Later on, that changed; there were pros and cons. One is a direct conflict of interest — and that was not true in this case— where you have a competing firm and then unconsciously divulge information to a competitor. Schering Plough's argument was more that I was a commodity that would be reduced by being shared with other companies .

That has changed now; it can be seen as an advantage that in knowing and being involved with another company or venture I could catalyze contacts between them and be more broadly informed so that I could be a better consultant.

Kornberg 's Relationships with Industry

Kornberg: Over the years I've been involved with a half-dozen different companies. On the whole, it was worthwhile. The financial

1 Douglas Brutlag memo to Dale Kaiser, November 30, 1981. (Kornberg papers, SC 359, box 5, folder: 1981.)

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rewards have been significant; they've not been overwhelming. I've enjoyed meeting people from another walk of life. These are lawyers, accountants, investment people, marketing people, and I do appreciate the problems they have to solve; they are genuine problems; they are not fictitious in any way. And I appreciate the expertise they bring to bear and their outlook on life. Maybe I am lucky or overly impressionable, but I found them attractive people for the most part.

Hughes: Are you a bit surprised? Kornberg: I am surprised, yes.

Hughes: Did these connections with industry present a new vision in respect to your own science?

Kornberg: Not in respect to science; just to people who create ventures in society. I've not been involved with philanthropies; these are business ventures. On the whole, I found them honorable, bright, and creative people. Their integrity matches anything I encounter in academia. Also, I've dealt with a few patent lawyers, and I like them. I wouldn't want to do what they do, God forbid, but given the society we have and the opportunities for people to do a variety of things, yes, I find them bright and engaging. That's of course the patent attorneys on my side. On the other side, they are just villains. [laughter]

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IV RESEARCH PROGRAMS

DNA as the Genetic Material

Hughes: Dr. Kornberg, can you pinpoint when you became aware that DNA was the genetic material?

Kornberg: As I mentioned earlier, I confess to not having as a focus of my attention the chemical basis of heredity. But I was not inattentive to discoveries that were relevant to it. I think I might have appreciated that DNA is the genetic material even earlier than geneticists who were focusing on that question because I was aware of the Avery paper which used deoxyribonuclease to identify the transforming factor as DNA in the Pneumococcus ; I trusted that enzyme.

Others for theoretical reasons decided DNA would not be complex enough to carry that much information. The knowledge of DNA chemistry was primitive enough that they couldn't be satisfied and believed that there might be a protein that carried hereditary information. The geneticists, who were in most cases above the "mumbo jumbo" of biochemistry, really didn't care that much. So it was not until a rather inexact and I'm going to say primitive experiment by Hershey, the Hershey-Chase experiment, showed that the genetic information from the bacterial virus resided in its DNA content rather than in its protein coat. Only then, the phage fraternity— -because one of the members of that church had done the experiment- - decided that, yes, Avery eight years earlier was probably right, the genetic material was DNA.

Then there was great impetus from the Watson-Crick model, that not only reconciled the physical facts about DNA in terms of the double-helical structure but was also the means to understand its replication by base-pairing--copying of each of the parental strands.

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Hughes: Was the significance of Avery's experiment generally

appreciated before it became clear that DNA was the genetic substance?

Kornberg: Avery--and [Colin M.] MacLeod and [Maclyn] McCarty who were his younger associates — clearly appreciated that, and in his very modest way, Avery understood its implications. As I say, a key element in that proof was that an enzyme had been purified that was specific for degrading DNA. It was not a protease. It destroyed the transforming factor principle, as they called it at that time.

You could argue that the DNA was a scaffold or a protective device that kept the true genetic material, protein, in an active state. Some people did; they actually challenged the assertion that DNA was the genetic material, including Alfred Mirsky, who was a very prominent biologist at the very same institution, the Rockefeller [Institute for Medical Research] . So the assertion was controversial.

DNA also wasn't the center of attention in biochemistry or biology that it later became. I've said several times already that the geneticists at Caltech, who were the outstanding group in 1952, gave it very little attention before the Hershey-Chase experiment. You'd have to do research to find out how widespread was its acceptance or its rejection, but I would say it was not the focus of attention, and it was not widely accepted.

Research on DNA and RNA Polymerase

Hughes: Why did you become interested in the synthesis of DNA?

Kornberg: To repeat, I was interested in how enzymes function, and

specifically in how enzymes might lead to the production from simple materials of the building blocks of DNA and RNA. And thereafter, knowing what the building blocks were- -namely the nucleotides of a certain structure and composition--! wanted to learn how they might be added to an existing chain of DNA.

Then, as is well known, from the studies we did and later others did, we discovered an enzyme, which we named DNA polymerase, that does more than simply add a building block to a preexisting chain. This enzyme, wherever you find it--and it is found everywhere where DNA is made — takes instructions from preexisting DNA and therefore replicates the genetic material.

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Hughes :

Kornberg:

It was not lost on me that this enzyme with these very impressive properties of copying a template was of direct importance in the replication process. But I can't say honestly that I sought that enzyme to solve a biological problem.

I do want to emphasize that it has been my conviction, and it's the basis of the books I have written on DNA replication,1 that you have to know the actors in order to understand the plot. And the actors are the enzymes. They are the mini- chemists, the devices by which a biological phenomenon takes place, whether it is the legendary question of alcohol fermentation- -how the juice of a grape generates a fine wine or champagne- -that bedeviled people for over a century, or how a firefly comes to luminesce. Applying that same reductive approach to replication and to other phenomena, I believe we can get to the core of biologic questions and phenomena—by finding the actors, and the actors are the enzymes.

So in this case we were rewarded by seeking out an enzyme that does something as simple as adding one building block to an existing chain, and finding that this event required that for building a chain you have all the components that enable the actor, DNA polymerase, to do its job.

Am I right that your interest in the synthesis of DNA was not so much because it happened to be the genetic material but because it was a logical extension of your previous work?

That's absolutely true. And I believe I've said so in my book and to you a few times. It's an admission, but yet in being as honest as I can be, it proves my point that a focus on enzymes can lead you to the solution of biologic questions that you don't anticipate. It may take time; it may be roundabout. I'm emphasizing that because this faith--this dogma—is hardly practiced now at all. Apparently there is such an emphasis on genetics to solve problems, and its offshoots in cellular biology, that enzymologists are a highly endangered species. Enzymology is practiced now by chemists who are curious about the intimate catalytic mechanisms in the structures of the enzyme rather than their biologic functions. And because of this division of cultures between biology and chemistry, the enzymology that falls in between is very much neglected.

1 A. Kornberg, DNA Synthesis. San Francisco: Freeman, 1974. A. Kornberg and T. A. Baker. DNA Replication, 2nd ed., San Francisco: Freeman, 1992.

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Joseph Fruton's Reaction to DNA Polymerase

Kornberg: I knew Joseph Fruton at Yale pretty well, and he was my host at Yale in 1958. After I had presented my work, which was by then almost iron clad, he said, "You know, Arthur, I can't believe that an enzyme would take instructions from its template. No enzyme has been known to do that." My response was, "Well, Joe, how else can you interpret these data? What's more, isn't this an unusual situation for which you would need an unusual enzyme to do the biologic job that has to be done?"

Hughes: Why is it unusual?

Kornberg: Well, as I've said, Fruton says an enzyme is designed to do a job and doesn't take instructions from a substrate. So how does the enzyme know to put a T next to an A or a G next to a C? How does it select the A, T, G, and C on instruction from what is in the preexisting DNA? Well, once you accept that, you can imagine how such structures could be oriented on the surface of an enzyme to do that.

Hughes: It was shocking to you, too, wasn't it, when you first discovered it?

Kornberg: Yes. But that was three years earlier. And we had lived with it. And maybe I wasn't as steeped in the history of enzymology as Fruton was. He had written the most authoritative textbook, and was a very estimable scholar of enzymology, biochemistry, and history.

Hughes: But pursuing the research on DNA synthesis as you had, wasn't the conclusion inescapable?

Kornberg: It was inescapable. I'm saying that someone as experienced and erudite as Joe Fruton, two years later couldn't quite accept it; I mean, it went against the grain.

He wrote an autobiography on his eightieth birthday which came out two or three years ago. It was circulated to a limited number of people and he sent me a copy. He asserts in the preface the standards of historical narrative that he follows, and said that he wouldn't do anything as irregular as what Kornberg did in his book, which was to quote somebody without having the exact quotation available. He went back to his notes for that day, and found no notation of his having been engaged in that conversation with me. Number one, does he have in his daily notes a complete transcription of everything that happened that day? Number two, isn't it obvious that

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thirty years later when I quote a conversation that I'm not using the text? I'm using it to convey the spirit of the exchange .

Then, I think in a footnote- -this is where my memory fails me--he states that the enzyme that I described at the time wasn't the true replicative enzyme. [laughs] Which is utterly ridiculous, because all replicative enzymes have the property that was confounding him. The fact that there are other DNA polymerases which have different functions doesn't alter the fact that they all carry out the very same basic catalytic activity of matching a template with a nucleotide. So he made the ridiculous accusation that I didn't quote him correctly, and then compounded it by still being confused thirty years later about the very nature of DNA polymerase.

E. coli Mutants Without Polymerase

Hughes: The episode reminds me of the controversy about the E. coli mutant that appeared to do without polymerase. Is that pertinent?

Kornberg: Exactly. Nature New Biology' went a step beyond that in saying that the mechanisms that we worked out so painstakingly for some fifteen years might not apply to the true replicative enzymes that were operating in this mutant. You know, the pendulum swings. True enough, we thought that this DNA polymerase was adequate and could perform in the cell the replicative functions which we observed in the test tube. And it wasn't until that mutant was discovered that the strong possibility was raised that other DNA polymerases were operative.

About that time, Crick was angered almost to the point of fury that reverse transcriptase, which copies RNA back into DNA, had violated his dogma of DNA to RNA to proteins- had been upset, and it was headline news. He was very angry about that. He said that he didn't regard it as contrary to his dogma that nucleic acids might be interconnected, but that nucleic acids did dictate the structure of proteins. That was his dogma.

In 1970, I was sharing an office with Crick in Cambridge, at the time of this vendetta by Nature New Biology against my

1 Nature New Biology 1971, 229: 65-66; 230: 258; 233: 97-98.

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DNA polymerase. He said, "Oh, forget it. It's like trypsin and chymotrypsin; they have essentially the same function but they are designed a little differently. When they find this new polymerase, it will be much like what you've described." And he was absolutely right.

Then a year or two later when reverse transcriptase was discovered, and the excitement was that the Crick dogma had been upset, he was furious [laughter], and wasn't all that impervious to the noise and excitement about his being attacked for his dogma.

Hughes: In the end, did the Nature New BioloRy editorials provoke a discovery?

Kornberg: I don't know if the editorials did. Hughes: The thinking that they represented?

Kornberg: Obviously, the Cairns mutant was very provocative because the

genetics of E. coli, beyond that mutant, established that there were additional genes that were needed for replication and were numerous enough to imply that they encoded novel factors without which coli couldn't replicate. Among them was one that dictated a new DNA polymerase. There were still others. So it was obvious that we didn't have the whole story, that replication was enzymologically much more complex than this one enzyme could explain.

Also, we hadn't answered several critical questions. We didn't know at that time how a chain got started; we didn't know what the controls were for starting a whole cycle of replication, for starting a chromosome- -many questions. In lectures, just to be amusing, I show the picture of the replication fork with its fork covered discretely by a fig leaf. [laughter]

A person I thought was a friend mine, Noboru Sueoka, a pretty knowledgeable person, gave a talk at Stanford on some aspect of replication and started off by saying--with me in the audience and the host — that the replication process is utterly obscure. I was irritated because he could have said, "We've learned a great deal about replication but there is so much more to know." That would have been not only diplomatic, but I think more accurate. The questions about replication are far more numerous than the things we can cite that we know clearly. The machine that does the replicating is awesome. How it is assembled and exactly how it functions are still major questions .

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Tom Kornberg's Contributions

Hughes: Do you want to talk about Tom Kornberg's role in working out some of these problems?

Kornberg: Well, it has been recited in my book. Hughes: You could say how you felt about his work.

Kornberg: It is difficult to relate honestly how my feelings were, unless there is a written record, and I don't have one. It was a very mixed set of emotions. Here is your child who loved the cello, who was devoted to it without any parental pressure, who would spend many hours in the day—four, five, six hours—practicing a few notes to get them right. Tom was very driven and motivated, and gifted enough so that he was accepted by the premier cellist in the country, Leonard Rose, as a student, and at Juilliard [School of Music]. He was doing very well and had the mental stamina to cope with Yo-Yo Ma, who was his classmate .

Then he developed a lesion in his left index finger, which was like a major athlete losing his arm or leg and being unable to function. It was very painful, and he simply couldn't use his finger—very traumatic. It looked like the termination of his musical career at which he had labored more than ten years. And to this day, he is a very fine cellist and loves music. That's one side of it.

The other is that unlike Roger, his older brother, or Ken, his younger brother, Tom was so devoted to music that he hadn't had any lab experience. In the place of music, he was going to try to do what Bob Lehman, Charles Richardson, and others who were very practiced at research on DNA replication and [DNA] polymerase were unable to do. I thought he'd waste his time, get frustrated further. So my advice was, "Tom, these people have tried to find the other enzyme in the Cairns mutant; they haven't been able to do it." So yes, I discouraged him.

Then he went to work in a lab at Columbia where he was also a student, and where Malcolm Gefter gave him lab space and— I don't know the details- -modest encouragement. Within weeks, he had manipulated cells and extracts, and demonstrated that, yes, in these mutants there is another activity. Then months later, he found that he could detect still a third activity which proved to be the ultimate polymerase. I know that Jerry Hurwitz, who can be a very accomplished and decent person but can also be carping and critical, ridiculed the data on which

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Hughes: Kornberg:

Tom was basing the claim that there was a third polymerase. Tom turned out to be right .

There was an international conference in Switzerland, and Sol Spiegelman, who was a major actor on the scene, very bright and accomplished--! think maybe to show me up—featured Tom's presentation at a major symposium at this international meeting, just a few months after Tom had first entered a lab.

What are my feelings? Certainly pride. And why did Tom do it? I think he did it out of loyalty. He wanted to show that his father, unlike what was being said in lectures and hallways, was not misleading the world as Nature New Biology was claiming, but that there was a likelihood that for some reason in this mutant, my DNA polymerase was being masked or somehow inhibited. Years later it was shown that many mutations of this enzyme were lethal because of its other functions: its capacity to engage in the removal of the primer RNA is essential, also its capacity to fill the gaps created by removing the priming RNA. But clearly the major discovery was that there is another far more complicated DNA polymerase.

Gefter got a prize for that discovery, and didn't deserve it; it was Tom's work, which Gefter then expanded; he was instrumental in the genetics that established that this new polymerase was a truly novel protein encoded by a different gene.

Why was your earlier work on polymerase I considered misleading?

Well, for no good reason. There were people who were eager to make news and jump on some Achilles heel of a person or an institution. It is newsworthy that some leading figure or some leading idea is vulnerable or can be discarded. In the current New Yorker, it is [Bruno] Bettelheim, the psychologist, who is being dismembered by biographers. I'm sure that there is a disproportionate eagerness to consume the target.

Severe Ochoa's Research on RNA Polymerase

Kornberg: Let me give you an example: A postdoc in Ochoa's group, Marianne Grunberg-Manago, and Ochoa believed they had discovered RNA polymerase. It was their evidence at the time that led me to abandon early experiments that were leading us to RNA polymerase. That was a classic example of where a

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plausible interpretation needn't necessarily be correct. We were misled by that, and it was one of the significant mistakes among others that I've made. Having discovered an enzyme that could make something that resembled RNA, they then concluded that they had discovered the enzyme that made RNA. That was wrong .

It was on the strength of that work that Ochoa got the Nobel Prize. He deserved it amply for many other discoveries that he had made that were germinal and significant, but that wasn't the one. The enzyme later was shown to be a scavenger, an RNA disposal recycling mechanism, that has nothing to do with RNA synthesis.

In fact, Fruton whispered to me at some point before or after 1958, "I think you've got an enzyme that makes DNA, but I don't think Severe has it [RNA polymerase]." And Fruton was right; many of us were convinced of that.

Hughes: But you must have initially thought that Ochoa had found RNA polymerase, otherwise you wouldn't have abandoned your own research.

Kornberg: Yes, I'm saying it was a mistake. But a year later, their work began to be more tenuous, and two years later, even more so, so that people were whispering, "Hey, this enzyme doesn't behave like an RNA polymerase."

But looking back on it, if we had stuck to our guns and pursued the assay we had in hand and had discovered RNA polymerase, that would not have been a trivial discovery. To my great disappointment--! was hurt by it—when Ochoa became aware of the work we were doing on DNA synthesis, he was about to plunge in and work on that as well. I thought that was, to put it mildly, improper, maybe unethical. But in some instances there are people like that who say that this is everybody's territory; why can't I work on it?

Hughes: And indeed he did?

Kornberg: No, he didn't. I think our progress was so rapid and the work went so well that nobody could catch up.

Hughes: Did Ochoa consider taking up research on DNA polymerase after the news that his RNA polymerase was not the right one?

Kornberg: I can't remember.

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Kornberg's Research on DNA Synthesis

Hughes: Well, I want to quote you from a 1984 lecture: "My own attempts at synthesizing DNA with enzymes in a test tube were regarded by some as audacious."1 Why?

Kornberg: Anyone at that time who understood the nature of a substance

complicated enough to give genetic information would have been quite awed and discouraged that you could find a purified entity that would do such an unprecedented job. As I've been saying, Fruton, confronted several years later with the evidence, was still finding it hard to swallow. He was certainly in the minority. But remember, he was a thoughtful and accomplished scholar in biochemistry and various aspects of the history of biochemistry. So yes, it was audacious.

I was inspired by something far more trivial, which was the building of a glycogen chain. Not trivial to me--I thought it was magnif icent--but something like that is all I'd hoped to accomplish. So even I thought it was audacious. But I never stopped to think that I couldn't try something in my work, and as I said time and again, it worked even beyond my dreams.

Hughes: Was there a certain aura around the nucleic acids?

Kornberg: There was a bad aroma. [laughter] They were messy. Remember that nucleic acids just a few years earlier had been thought to be a monotonous succession of tetranucleotides ; a few years earlier, just a little molecule of four nucleotides. And then their polymeric nature was discovered; their complexity; the Chargaff rules; they became more and more complex. How do you isolate a nucleic acid? No one knew how to do that. Proteins were being isolated as homogeneous entities from a morass of proteins, but not nucleic acids. There was no entity that you described with a formula. It was a mess. Serious biochemists weren't working with nucleic acids.

Hughes: Did those obstacles ever give you pause?

Kornberg: Not really. [chuckles] I just didn't know enough to be discouraged. I was not that astute.

1 A. Kornberg. Understanding life as chemistry. In: Medicine. Science, and Society: Symposium Celebrating the Harvard Medical School Bicentennial. K.J. Isselbacher, ed., N.Y.: John Wiley & Sons, 1984, pp

1 / •

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In 1970-71, three or fours years after we'd "created life in the test tube"1 and had used a homogeneous DNA, the circular DNA of a virus, as our template, we still didn't know how to start a DNA chain. After faltering and frustrating experiments for four or five years, I then learned the importance of one of the Ten Commandments of DNA enzymology. We had certainly observed the commandment: Don't waste clean thinking on dirty enzymes. But not the next commandment: Don't waste clean enzymes on dirty substrates.

I make the point that there was no dirtier substrate than DNA. When you get it out, it is fragmented, frayed, all messed up, because it is a large molecule, and sheared, broken up, and degraded by enzymes. That truth finally dawned on me. It was at that time [1971] I said, "Well, if we want to find out how to start a DNA chain, we'd better work with an intact DNA molecule. And that could be furnished by a virus, a bacteriophage, in which we could actually see that the DNA circle was intact, both chemically and under the microscope.

You are aware of that controversy about accepting our papers on DNA polymerase by JBC [Journal of Biological Chemistry] . Ten different people were involved in an extensive review and initially rejected the paper, because we called it DNA. They were willing for us to call it

polydeoxyribonucleotide. According to some of the reviewers, the authorities in the field, DNA implied genetic material, and we hadn't proved that the product of DNA polymerase action was a genetically active, biologically active product. My contention was that I didn't want to diminish the significance of the title by calling it something as nondescript as a polydeoxyribonucleotide, when it was DNA by a definition that had been used by that journal in 98 percent of its papers.

Hughes: So why were they singling out your work?

Kornberg: I think a reluctance to have any implication that we were advanced enough to synthesize "real" DNA.

1 A phrase used by the media, including Stanford's news bureau. See Stanford's news release on the Kornberg group's synthesis of viral DNA. (Stanford University School of Medicine, News Bureau, December 14, 1967. Kornberg papers, SC 369, box 18, folder: press conference December 14, 1967.)

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Synthesis of Viral DNA. 1967

Scientific and Popular Responses

Hughes: Kornberg:

Was what you had achieved with the synthesis of a biologically active virus appreciated for what it meant for science?

The popular response to it as I told you was excessive. It was over appreciated in terms of what it actually represented. It was something like Dolly [the cloned sheep]. It was on front pages that we had created life in the test tube, just as it's a front page story in the [San Francisco] Chronicle that an artificial human chromosome had been created. As I mentioned in my book, Max Perutz, the venerable scientist in Cambridge, England, wrote a rather caustic letter to the London Times saying, in effect, "What is all this hoopla about? Kornberg 's doing things that were scientifically anticipated. It isn't all that novel."

I think that both responses, awe on the one hand and deprecation on the other, were inadequate or improper. First, the public perception that I'd made a virus, one of these big ugly things more complicated than the bacterium in that it makes you sick--was not a proper understanding of what had been done. And Perutz 's appraisal--to pick on him because his criticism was public—was not adequate either, because we did show that we could synthesize an infectious molecule, meaning that it has 5376 nucleotides probably in the correct order. That hadn't been done before. Our enzyme had that much accuracy and fidelity.

Second, we used synthetic nucleotides, proving there were no novel nucleotides in an infectious DNA. That had never been known before. Yes, it is as simple as A's, T's, G's, and C's. And then we pointed out in the paper that this could be used for site-directed mutagenesis, for which a Nobel Prize was given some years later. We could do so by introducing a novel nucleotide that would be the source of a mutation. We pointed out that we could put in analogous nucleotides that were foreign and therefore the source of mutations. That was not fully appreciated.

Hughes: Why wasn't it?

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Kornberg: Well, Lobban's work in recombinant DNA didn't get its full or adequate appreciation in 1974. J That was seven years later. And frankly, if we thought this ability to cause mutations was important, why didn't we exploit it? The same thing is true of PCR [polymerase chain reaction) . Why did [Kary] Mullis get a Nobel Prize for it fifteen years after all the elements of PCR had been demonstrated? Well, it just wasn't exploited. Why wasn't it exploited?

You could ask that question from now to eternity. Why at a given time were people not as impressed as they might have been? Or why is Jules Verne now venerated for all of the seemingly absurd predictions that later turned out to be genuine? I think it's just a reflection on how inadequate our perceptions are, not of the possibilities, but of the time scale. If we talk about biotechnology and its pros and cons, it is something like [Gordon] Moore's law for transistors and silicon chips: a doubling in capacity every eighteen months. The chips now carry information that was absolutely unanticipated, undreamed of ten years before.

Technology builds on technology; ingenuity then builds on advances and exceeds the time scale. And sometimes it lags far behind. The World's Fair of 1939 made all kinds of predictions of what society would be like. People would be flying around from one place to another like birds. Some things happen; some things don't. Okay?

Hughes: Okay. You mentioned the press response and I know from having looked through your papers that it was tremendous. It seemed to have been covered in virtually every paper of any size in the country.

Kornberg: In the world.

Hughes: How did you feel about that?

Kornberg: Bewildered. The best account was by Alistair Cooke, a

television personality with Masterpiece Theater. I've been a great admirer of his since, because I really didn't know much about him before. Bruce Blevin I think was the editor of a major magazine, New Republic or The Nation or something. He was very well known in literary circles. His daughter, Naomi Blevin, is a regular book reviewer for the New Yorker.

Peter Lobban's work is discussed below.

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Alistair Cooke was a friend of the Blevins whom I met through my son, Ken, who lived in the same apartment building while he was at Stanford. Cooke was correspondent for the Manchester Guardian and his account of viral DNA synthesis was so sharp and clear that I quoted it in my book. He was also very flattering; that mattered too.

So where does life begin? At what point do we socially accept its sanctity; its inviolability? It is in the succession of molecules that in becoming more and more complicated get to be self sufficient. There is no question that E. coli is living. It has personality; it has locomotion; it has a nervous system; it endures. Is a complicated virus living that needs only a little bit of cellular equipment? Well, maybe. But it does depend on another cell for its procreation. Anyway, I don't have to instruct you, but people simply don't know that.

And so that audience of reporters and other media people didn't know what a virus was or what the genome of a virus is; why it can be infectious. Thirty years later it might still invoke the same kind of uninformed, maybe even incredulous reaction.

Hughes: Did the virus synthesis work mark your first encounter with the press?

Kornberg: On that scale, yes. With the Nobel Prize in 1959 there were all kinds of reporters here and in Stockholm.

Now DNA is known to people. It used to be that DNA in most people's minds stood for an item in motel guides: No Dogs Allowed. Today, with all the attention to DNA, you can go around your community of informed people, highly intelligent people, people who read the Tuesday section on science in the New York Times . Could they give me a clear statement of what DNA does? If one out of ten did I would be very impressed.

Science and the Public

Publicist of Science

Hughes: Have you considered it important to maintain an association with the press in order to keep the public scientifically informed?

'

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Kornberg: I think we should keep trying, even though I think it is almost hopeless. I have attempted to explain what DNA does, what it is, and above that the importance of gaining basic knowledge to solve very practical problems in society, such as health and sanitation and environment. Does the public know that it is a good investment to support the whimsy of people who are curious about facts in nature? If you ask people, would they provide their tax dollars for medical research, 75 or 80 percent say yes. Frame the question a little differently: Major medical discoveries have been derived from the pursuit of curiosity of physicists, chemists, and biologists. Would you provide tax dollars for them to pursue their curiosity about facts in nature? They've not asked that question. Maybe 10 or 20 percent would say yes.

My mission has been to cite chapter and verse as to how the drugs they are taking, the procedures they use — the MRI [magnetic resonance