Regional Oral History Office University of California The Bancroft Library Berkeley, California

IRVING S. JOHNSON, PH.D. ELI LILLY AND THE RISE OF BIOTECHNOLOGY

Interviews conducted by Sally Smith Hughes, Ph.D.

in 2004

Copyright © 2006 by The Regents of the University of California

Since 1954 the Regional Oral History Office has been interviewing leading participants in or well-placed witnesses to major events in the development of Northern California, the West, and the nation. Oral History is a method of collecting historical information through tape-recorded interviews between a narrator with firsthand knowledge of historically significant events and a well-informed interviewer, with the goal of preserving substantive additions to the historical record. The tape recording is transcribed, lightly edited for continuity and clarity, and reviewed by the interviewee. The corrected manuscript is 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 Irving S. Johnson, dated February 9, 2004. The manuscript is thereby made available for research purposes. All literary rights in the manuscript, including the right to publish, are reserved to The Bancroft Library of the University of California, Berkeley. No part of the manuscript may be quoted for publication without the written permission of the Director of The Bancroft Library of the University of California, Berkeley.

Requests for permission to quote for publication should be addressed to the Regional Oral History Office, The Bancroft Library, Mail Code 6000, University of California, Berkeley, 94720-6000, and should include identification of the specific passages to be quoted, anticipated use of the passages, and identification of the user.

It is recommended that this oral history be cited as follows:

Irving S. Johnson, “Eli Lilly & the Rise of Biotechnology,” conducted by Sally Smith Hughes, 2004, Regional Oral History Office, The Bancroft Library, University of California, Berkeley, 2006.

Copy no. ___

Irving S. Johnson

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Table of Contents—Irving S. Johnson

Biotechnology Series History vii

Series List ix

Interview History xi

Tape 1, Side A 1

Family background--Education–Employment at Eli Lilly & Company–Associations with Jonas Salk.

Tape 1, Side B 7

Searching for drugs to treat cancer–Johnson initiates Lilly’s relationships with small companies and universities–Lilly’s lab at the Scripps Institute–Learning of recombinant DNA–Lilly’s refusal to start an in-house unit–Peroxosome drugs.

Tape 2, Side A 15

Lilly’s conference on insulin, 1976—Johnson’s role in the recombinant DNA debate–10-liter limit on recombinant organism fermentations.

Tape 2, Side B 21

Johnson's service on the Recombinant DNA Advisory Committee—Human insulin Genentech’s “bugs” [bacteria]–UCSF’s complementary DNA–Walter Gilbert—Bob Swanson and the UCSF postdocs.

Tape 3, Side A 28

Lilly and the NIH guidelines—University of California, Genentech, Lilly lawsuit–More on human insulin–Harvard, UCSF, and Lilly research–Uncertified plasmid incident at UCSF–Lilly’s compliance with the NIH guidelines–Lilly’s human insulin plants Johnson’s proactive strategy with the FDA–Scale-up and the 10-liter limit–Lilly’s royalties to Genentech–FTC investigation of Lilly.

Tape 3, Side B 35

Genentech’s focus on proteins, not small-molecule drugs–Johnson rejects becoming Genentech VP of Research–More on human insulin–Lilly’s contracts with Genentech and UCSF–Proinsulin and complementary DNA approaches –Patents and patenting.

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Tape 4, Side A 43

Biotech contracts with Big Pharma—Cetus Corporation—Genentech's focus.

Tape 5, Side A 48

UCSF’s contract with Genentech–More on NIH guidelines applying to industry–Intellectual property–Dearth of patent attorneys with biological knowledge–Patenting at UCSF–More on the UC, Genentech, Lilly lawsuit–Native and “met” forms of growth hormone–Potential shortage of animal insulins.

Tape 5, Side B 54

Still more on the lawsuit–More on patents and patenting–Regulating the genetic technologies.

Tape 6, Side A 60

Diamond v. Chakrabarty–Lilly’s policy for publication and presentations–More on Lilly’s relationship with UCSF–More on the recombinant DNA controversy.

Tape 6, Side B 66

Physical containment facilities abroad–Opponents to recombinant DNA–DNA synthesis at City of Hope Medical Center–Lilly’s refusal to buy Genentech.

Tape 7, Side A 73

Interactions of Lilly and Genentech scientists–Lilly scientists who worked under Johnson–Human insulin variants–Hybritech and the Lilly purchase.

Tape 7, Side B 78

Lilly’s immunology group–Johnson’s consultantships and membership on advisory boards–Athena Neurosciences–Agouron–Salk Institute–Ligand–Pharmaceutical Manufacturers Association–American Association for the Advancement of Science–Lilly’s limited interest in agriculture.

Tape 8, Side A 84

Johnson’s one regret–Summarizing Lilly’s role in biotechnology–Johnson’s failed suggestion for Lilly to spin off a company–Johnson’s greatest contributions.

Tape 8, Side B 90

Developmental genes.

Curriculum Vitae 93

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Biotechnology Series History—Sally Smith Hughes, Ph.D.

Genesis of the Program in Bioscience and Biotechnology Studies

In 1996 The Bancroft Library launched the forerunner of the Program in Bioscience and Biotechnology Studies. The Bancroft has strong holdings in the history of the physical sciences--the papers of E.O. Lawrence, Luis Alvarez, Edwin McMillan, and other campus figures in physics and chemistry, as well as a number of related oral histories. Yet, although the university is located next to the greatest concentration of biotechnology companies in the world, the Bancroft had no coordinated program to document the industry or its origins in academic biology.

When Charles Faulhaber arrived in 1995 as the Library's new director, he agreed on the need to establish a Bancroft program to capture and preserve the collective memory and papers of university and corporate scientists who created the biotechnology industry. Documenting and preserving the history of a science and industry which influences virtually every field of the life sciences and generates constant public interest and controversy is vital for a proper understanding of science and business in the late twentieth and early twenty-first centuries.

The Bancroft Library is the ideal location to carry out this historical endeavor. It offers the combination of experienced oral history and archival personnel and technical resources to execute a coordinated oral history, archival, and Internet program. It has 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 and to digitalize documents for presentation on the Web in the California Digital Library. It also has longstanding cooperative arrangements with UC San Francisco and Stanford University, the other research universities in the San Francisco Bay Area.

In April 1996, Daniel E. Koshland, Jr. provided seed money for a center at The Bancroft Library for historical research on the biological sciences and biotechnology. And then, in early 2001, the Program in Bioscience and Biotechnology Studies was given great impetus by Genentech’s major pledge to support documentation of the biotechnology industry. Thanks to these generous gifts, the Bancroft is building an integrated collection of research materials--oral history transcripts, personal papers, and archival collections--related to the history of the biological sciences and biotechnology in university and industry settings. A board composed of distinguished figures in academia and industry advises 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.

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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 2,000 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 UC Berkeley and national online library networks; and, in most cases, digital presentation at http://bancroft.berkeley.edu/ROHO/projects/biosci.

Sally Smith Hughes, Ph.D. Historian of Science

Regional Oral History Office The Bancroft Library University of California, Berkeley November 2005

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February 2006

ORAL HISTORIES ON BIOTECHNOLOGY

Program in Bioscience and Biotechnology Studies Regional Oral History Office, The Bancroft Library

University of California, Berkeley Paul Berg, Ph.D., A Stanford Professor’s Career in Biochemistry, Science Politics, and the Biotechnology Industry, 2000 Mary Betlach, Ph.D., Early Cloning and Recombinant DNA Technology at Herbert W. Boyer's UCSF Laboratory, 2002 Herbert W. Boyer, Ph.D., Recombinant DNA Science at UCSF and Its Commercialization at Genentech, 2001 Roberto Crea, Ph.D., DNA Chemistry at the Dawn of Commercial Biotechnology, 2004 David V. Goeddel, Ph.D., Scientist at Genentech, CEO at Tularik, 2003 Herbert L. Heyneker, Ph.D., Molecular Geneticist at UCSF and Genentech, Entrepreneur in Biotechnology, 2004 Irving Johnson, Ph.D., Eli Lilly and the Rise of Biotechnology, 2006 Thomas J. Kiley, Genentech Legal Counsel and Vice President, 1976-1988, and Entrepreneur, 2002 Dennis G. Kleid, Ph.D., Scientist and Patent Agent at Genentech, 2002 Arthur Kornberg, M.D., Biochemistry at Stanford, Biotechnology at DNAX, 1998 Laurence Lasky, Ph.D., Vaccine and Adhesion Molecule Research at Genentech, 2005 David Martin, M.D., UCSF Professor, Genentech Vice President of Research and Beyond, 2005 Fred A. Middleton, First Chief Financial Officer at Genentech, 1978-1984, 2002 Diane Pennica, Ph.D., t-PA and Other Research Contributions at Genentech, 2004 Thomas J. Perkins, Kleiner Perkins, Venture Capital, and the Chairmanship of Genentech, 1976-1995, 2002

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G. Kirk Raab, CEO at Genentech, 1990-1995, 2003 George B. Rathmann, Ph.D., Chairman, CEO, and President of Amgen, 1980–1988, 2004 Regional Characteristics of Biotechnology in the United States: Perspectives of Three

Industry Insiders (Hugh D’Andrade, David Holveck, and Edward Penhoet), 2001 Niels Reimers, Stanford’s Office of Technology Licensing and the Cohen/Boyer Cloning Patents, 1998 Steven Rosenberg, Ph. D.: Early Scientist at Chiron Corporation William J. Rutter, Ph.D., The Department of Biochemistry and the Molecular Approach

to Biomedicine at the University of California, San Francisco, volume I, 1998 Richard Scheller, Ph.D., Conducting Research in Academia, Directing Research at Genentech, 2002 Robert A. Swanson, Co-founder, CEO, and Chairman of Genentech, 1976-1996, 2001 Axel Ullrich, Ph. D., Molecular Biologist at UCSF and Genentech, 2006 Daniel G. Yansura, Senior Scientist at Genentech, 2002 Oral histories in process: Brook Byers Ronald Cape Stanley N. Cohen Donald Glaser James Gower William Green Keiichi Itakura Irving Johnson Daniel E. Koshland, Jr. Arthur Levinson Arthur Riggs William J. Rutter, volume II Mickey Urdea Pablo Valenzuela Keith R. Yamamoto William D. Young

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Interview History—Irving Johnson, Ph.D.

Dr. Johnson has had various professional “lives”—as a scientist, corporate consultant, public spokesman for industry, and, for 35 years, Vice President of Research at Eli Lilly & Co. It is in the latter capacity, specifically his leading role in the company’s sponsorship of research on recombinant human insulin, the first genetically engineered pharmaceutical product, that provides the emphasis of this oral history. In the interviews, he tells with the detachment of time passing, the contentious race at UCSF and at Genentech to clone and express the gene for human insulin. Intent that Lilly should not lose its dominant position in the insulin market, Johnson encouraged the company to fund two novel and differing research approaches. Largely at his behest, Lilly negotiated simultaneous contracts, one supporting DNA synthesis of the hormone at Genentech, and a second supporting UCSF biochemistry’s complementary DNA method. Collaborating scientists at Genentech and City of Hope Medical Center in Los Angeles, working feverishly to clone and express the gene, claimed the trophy in August 1977. The accomplishment, touted in the media worldwide, represented the first practical triumph of recombinant DNA in commercial application, producing a protein, which in Lilly laboratories was turned into a commercial product reaching the marketplace in 1982. With all this occurring against the backdrop of the recombinant DNA controversy, Johnson describes the company’s compliance with NIH biosafety guidelines and his subsequent service as an industry representative on the NIH Recombinant DNA Advisory Committee. Unfortunately, the scientific and commercial successes were not the end of the insulin story. Johnson discusses in partial fashion the bitter litigation involving UCSF, Lilly, and Genentech regarding human insulin and growth hormone that occurred in the 1990s. Despite this denouement, there is much of historical note in the human insulin story: it confirmed the utility of recombinant DNA as a practical industrial process; it resulted in the first recombinant human pharmaceutical to be approved by the FDA and brought to market; and it represented the first productive collaboration between a biotechnology company and a pharmaceutical corporation. In all respects, Dr. Johnson can rightfully claim to have made a marked contribution.

Three interviews were conducted in the living room of the Johnson home overlooking the shell-strewn beachfront on Sanibel Island, Florida, and the Gulf of Mexico beyond. Genial and avuncular, Johnson relaxed into the interviews, his memory for events considerably better than he anticipated after a recent serious head injury. He spoke with obvious pride of his early recognition and promotion of genetic engineering as a promising new method of pharmaceutical production. Although enjoying the slower pace of retirement at his homes in Florida and Maine, he keeps abreast of biomedical developments through wide reading and a number of corporate consultantships.

Genentech is to be commended for having the historical vision to support interviews with individuals—Arthur Riggs and Keiichi Itakura as well as Johnson—involved in major lawsuits with the company and in so doing to document the dawn of commercial biotechnology from several perspectives. By agreement with Genentech regarding the oral histories it supports, its legal department receives transcripts of all interviews to review solely for current legal issues. As in all other instances to date, no changes were requested in the transcripts.

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The Regional Oral History Office was established in 1954 to record the lives of persons who have contributed significantly to the history of California and the West. A major focus of the office since its inception has been university history. The series list of completed oral histories documenting the history of the University of California is included in this volume. The Regional Oral History Office is a division of The Bancroft Library and is under the direction of Richard Cándida Smith.

Sally Smith Hughes, Ph.D. Historian of Science Program in Bioscience and Biotechnology Studies The Bancroft Library University of California, Berkeley January 2006

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Interview #1: February 9, 2004 Tape 1, Side A

Hughes: Dr. Johnson, please tell me a little bit about your grandparents on both sides, where they came from and what they did.

Johnson: My maternal grandfather was named Tuttle, Frank Tuttle. He married a German woman, and he was a newspaperman. He set type and had a little country newspaper in Nebraska, and he eventually moved to California. But while setting type he unfortunately managed to spill some lead into his shoes, and he eventually died of lead poisoning. My mother, Frances Lucetta Tuttle, was born in Denver, Colorado. My paternal grandparents of course were named Johnson. My paternal grandmother was named Addie Woodring. The Woodrings are derived from Huguenots in Alsace-Lorraine who spelled their name Vautrin [pronounces], and they moved to Germany because of religious persecution and spelled it Wotrin. Four brothers came to the United States and anglicized to Woodring. My paternal grandfather, Guy Johnson, I don’t know that much about to be perfectly honest. He ran away from home when he was about eleven because of a stepmother he didn’t like. He lined up at the Cherokee Strip in Oklahoma, went in homesteading when he was about sixteen, and he ended up as a farmer in southeastern Nebraska. I used to go and work on the farm every summer with him.

Hughes: So you were born in Nebraska?

Johnson: I was born in Colorado. They had two sons. Both of the boys went to Peru State Teachers College in Peru, Nebraska, a small school in eastern Nebraska. My father, Walter Glenn Johnson, used to walk home by the railroad tracks and visit his parents periodically, and for whatever reason he decided he didn’t want to be a teacher. and he went to Colorado School of Mines in Golden, Colorado and was trained as a mining engineer. When he got out of school he got a job in civil engineering with the Colorado State Highway Department. He did most of the surveying for roads in western Colorado. We lived all over western Colorado. I was born near Grand Junction, lived in places like Grand Mesa, Safinero and four or five towns in western Colorado. When they were doing the surveying for the roads, it was a very pioneerish sort of thing. It was a pack train and cook tents and all that sort of thing. From beautiful Colorado, he decided there was a greater opportunity in the Kansas State Highway Department, and he moved to Kansas, and he was a resident engineer, civil engineer with the Kansas State Highway Department. The longest I ever lived in one place for more than three years was when I was in graduate school. We moved wherever the job was, and we lived all over Kansas.

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Hughes: What did that do to your education?

Johnson: Well, I was always adjusting to the new school situation, but I don’t think it harmed my education at all. I’ll tell you why in just a second.

There is an organization in Washington that was essentially interested in moving people. And they recently named two people in every state in the union that did the most in terms of transportation and were the best public officials. In Kansas, my father was one of them. He eventually became a secondary road engineer—that’s the farm-to-market roads. When he got through, Kansas had more miles of secondary roads than any state except Texas. He became chief engineer. A few years ago—he’s dead now—they tracked me down and said they had a plaque which they wanted to present to a representative of the family. I suggested that my youngest daughter Kirsten Shawn, who is a tenured faculty member at Wichita State University, represent the family because she lived in Kansas, and it would be difficult for any of the rest of us to get there. She did, and she has the plaque, but I have copies of the book that talks about his contributions.

I think my education was satisfactory, and one reason is that when World War II came along, the services conducted a series of tests on high school students. The navy one was called V-12, and there was an A-12 for the army, and there was another one for the air force, A-5 I think. It was supposed to detect the tenth of 1 percent of the brightest kids in the country. I was the only one in my high school that passed, and it was a small high school. I reported for active duty on my eighteenth birthday, and it was a curious program. I was interested in medicine and science in general, but particularly, I think as I said in my Nature paper that I have two great loves of my life. One is my wife Alwyn Neville Ginther, and we just celebrated our fifty-fifth wedding anniversary. And the other is biomedical science. But I was interested in all sorts of things in high school. I got interested in extrasensory perception. A guy at Duke developed a set of 25 cards of pluses, and circles, and minuses, and squares. I wrote to him—and his name was [J.B.] Rhine—and asked him for a deck of cards, and he sent them to me and I started testing, convincing some of my high school acquaintances to test for me. I found a girl who could sit in another room, and as I turned the cards she would write down what she thought it was. And she always got more than twenty out of twenty-five.

Hughes: Oh, my heavens!

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Johnson: I’d look at the card and think about it—and she wasn’t really all that bright [laughs] gradewise.

When I went to the V-12 program, I was sent to Westminster College, which is in Fulton Missouri, and it’s where Winston Churchill made his Iron Curtain speech. Harry Truman’s military aide was a graduate of Westminster College, and that’s how that happened. By and large it was a college where wealthier families in St. Louis sent their kids to be educated. I was in a pre-med program ,and my roommates—three of us in one room—I had two roommates—went through the whole thing and they got their M.D.s. To get it paid for by the government, they only had to agree to serve for three years as physicians in service. I had friends in high school who were in the military and were dying all over the world, and I felt like I wasn’t making a contribution. I felt guilty about it, and I asked for a transfer to a line program, and they agreed, and they sent me to midshipmen’s school at Cornell University. And midshipmen’s school was four months and was supposed to be the equivalent of four years at Annapolis—a year per month. When I graduated, I said I’d like to have submarines and PT boats or destroyers. Because I was aware of the fact that they were training a lot of people in communications, I said under no circumstances do I want to go to communications school. So that’s where I went—at Harvard. [laughs] I ended up on an escort carrier in the Pacific, but I felt better about it in terms of my service to the country. I suppose I would have been better off in a way if I’d stayed there, but I didn’t. When I got home, I had picked up enough hours at Westminster that I went to a small municipal school, Washburn University in Topeka, Kansas where my parents then lived, in the capital of the state, and my father was chief engineer.

[laughs] This will tell you how I met my wife. I took a few courses. I had about a year left to finish up. The school taught about three or four courses for a nursing program at a local hospital called Storemontvail. And I was an assistant instructor in anatomy and physiology for student nurses. In the first class I had, my [future] wife came in, and I was immediately attracted to her. I was concerned by what the university would think about me dating a student in one of my own classes. I bent over backwards being severe so I couldn’t be accused of favoritism by any of her classmates. She will say that I waited until the first test to see if I thought she was smart enough. And my response to that is, her brain was not what attracted me, [laughter] and she shouldn’t worry about that. But eventually we started dating, and while she was still in nursing training, we were married. I applied to the University of Kansas for medical school, but every veteran was applying for medical school, and I didn’t get in. So I just applied for graduate study in a zoology department in what today we call developmental biology. In those days it was just called embryology.

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Hughes: Why did you choose that field?

Johnson: Well, I could see a relationship to medicine because you knew how all the organs developed, the tissues evolved. I found it fascinating. My thesis was rather fundamental in nature, as I mentioned in that nature article.

It was the molecular basis of the first heart beat. I developed a method of culturing chick embryos in a petri dish from a primitive streak stage through a stage of a beating heart, which is about a seventy-two-hour embryo. And what I did was I fractionated adult chicken hearts into all the proteins I could possibly find. I produced antibodies to all of them in rabbits. I would incorporate the antibodies in the culture medium, and if that protein was necessary to be present for the first heartbeat, the antibody to that protein would stop it. And that was essentially my thesis.

Hughes: Where had you learned that technology? That sounds like rather complicated biochemistry or molecular biology.

Johnson: Yes, well, I took a lot of my courses in the medical school, because I couldn’t get them in the zoo[logy] department. Biochemistry was in the medical school. The first three semesters of medical school were still on campus, and the rest of them were in Kansas City, Missouri where there’s a larger population. It’s all in Kansas City now. I took histology in the medical school because it was a seven-hour course, and it was only a two-hour course in zoo[logy], and I took biochemistry because that’s the only place biochemistry was taught and that sort of thing. I had a biochemistry teacher, one of several—they would rotate people in for lectures. He would lecture and write with his right hand and erase it with his left hand, so you had to pay attention! I found that there were many things that were attractive to me, and I still had this feeling that I’d like to be associated with the biomedical sciences in some way. I graduated [1953] and I applied for several jobs. Salaries at that time in the universities for teaching were pretty low—four or five thousand a year.

Hughes: Was your wife working?

Johnson: She actually never graduated—well, I probably shouldn’t say that—she did get her RN, but I interfered with her graduation, and we had our first child while I was in the graduate school. But where I got upset was, she had to go to St. Louis for psychiatric training in her nursing school, and I objected to that. As I matured, I think I was completely wrong. I didn’t want to be separated for six months. After we moved to Indianapolis to work for Lilly, at the age of, I think, fifty she went to the University of Indianapolis and got her RN.

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Hughes: Good for her!

Johnson: She has done volunteer nursing. She has never done nursing for money—she’s worked with Hospice, and things like that. There’s a nice children’s hospital, that you went by as you came in, and she worked there as a volunteer. She kept her interest in medicine as well. We eventually had four children. My oldest son, Bryan Glenn, works for Lilly in the CNS [central nervous system] area. He was kind of a late bloomer, and he started out in toxicology, cleaning animal cages. Eventually he got his master’s in the medical school in neuroscience, and that’s where he works. He loves the work and is very happy with it, and he’s written papers and made some very useful contributions. My youngest son, Kevin Bruce, and his wife, Dana Krempels, decided they would not have children. They thought there were too many children in the world, which I regret, but it’s their decision. She’s on the faculty of the University of Miami, and that’s where he met her when he was going to the University of Miami. He had a 100 percent scholarship there. He now works for a guy in the medical school who is interested in Islets of Langerhans transplantation, oddly enough, so we chat about diabetes and things like that on occasion. My oldest daughter is Rebecca Lyn Brown. She married a theological student and they have lived in several towns in Ohio.

I wrote to some pharmaceutical companies when I graduated and asked what kind of people they were looking for. I had a letter in response from Lilly from a physician who had been chairman of the Department of Pathology at IU medical school and now was working for Lilly and was director of what was called the biological research division.

Hughes: Now was that a common route for a graduate to take if you decided that you didn’t want an academic career?

Johnson: Well, the Lilly salary was more like $6,000, and that influenced me to some degree, but not totally. I was going to work for a pathologist, and after my job interview I was very impressed with him. I thought over the years of working with him that I learned a lot about medicine, and pathology for that matter. He’s dead now; his name was Clyde G. Culbertson, but I really enjoyed Dr. Culbertson.

Lilly had an unusual individual named George Henry Alexander Clowes who was a British citizen. He was the first man hired by Roswell Park—the man not the institute. The institute was later named after him. And he convinced the New York State Legislature, as many people have since, that if you spend enough money, you can cure cancer. He was the first scientifically trained director of all research at Lilly. He did things for the rum industry in Cuba not unlike [Louis]

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Pasteur did for the wine industry in France. When he was at Roswell Park Institute, his first child died of leukemia, and he always suspected a viral relationship. There was another pathologist, Paul Harris, in the pharmacology division who did the only cancer research at that time at Lilly. He happened to be interested in carcinogenesis—things that cause cancer—but wasn’t too interested in looking for things that would cure it or treat it. Culbertson thought that was a terrible waste of time, and he wanted to set up a cancer research program developing therapeutic drugs for the treatment of cancer.

I have always enjoyed my work at Lilly. I was hired to start this cancer program and my first Christmas Eve I was reading the [Jonas] Salk polio vaccine safety tests. I happened to be one of the few people who had experience in tissue culture, and I produced the first hundred liters of the Salk vaccine that was produced that was used in Salk’s clinical trial. Jonas went out and started vaccinating kids. He couldn’t do that now. He and I became good friends. I’m sure you know about the Salk Institute, for example. He eventually married Picasso’s last mistress. I visited him in the institute one time, and I walked in and saw all these beautiful paintings in his office, and I said, “Ah! Picassos.” And he grunted, “Hers, not his.”

Hughes: What was he like as a personality?

Johnson: He was an interesting man. But what he felt about himself and what I felt about him are quite different. He thought of himself as a sort of a Renaissance man, and when he created the institute he brought in historians and language people, not just scientists. He wanted more than that. I thought what he was was a very practical problem solver, almost an engineer. Up to that time polio virus had only been grown in brain tissue in live animals–in rabbits primarily. Weller, Enders, and Robbins (Harvard) made cultures of primate kidney cells, monkey cells, and the polio virus to grow in those cells. Jonas said, if they grow there, he ought to be able to make a vaccine, and that’s what he did. He was hoping before he died that he could develop an HIV vaccine—that’s what he wanted to go out on—and he came to Lilly for help. I looked at the work, and I advised the company not to help him. I didn’t think it would work.

Hughes: He was using his old killed-virus technique, wasn’t he?

Johnson: Well, in my view there’s a terrible tragedy in the public disagreement between him and Albert Sabin. Kids would rather take a spoonful of syrup than get a needle. So when Sabin developed his live attenuated vaccine, it shifted. From a public health viewpoint, the rational thing to do would have been to give a shot of Salk vaccine and then the Sabin vaccine because 90 percent of the polio cases that occurred in the

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United States after the two vaccines were available were derived from the Sabin vaccine. Washington didn’t do anything about it, and the two men didn’t do anything about it—they hated each other. I thought it was a tragedy from a public health viewpoint.

I did help Jonas in some things. There’s a disease that you can induce in animals called allergic encephalomyelitis. If you immunize animals—rats or guinea pigs—with brain tissue (and actually there was a specific protein called myelin basic protein) they develop a disease which has all the histology and behavior of multiple sclerosis. What’s unique about it—and this is the problem-solving guy again—if you take the same protein that you induce the disease with—you induce the disease with an adjuvant to get more antibody formation and more severe disease. You can cure it by injecting just the protein without the adjuvant.

Tape 1, Side B

Johnson: Jonas said if you can do that—and people have been using this as a model for multiple sclerosis for fifty years—you ought to be able to cure it with injections of myelin and basic protein. Would I produce myelin basic protein so he can treat MS patients, Jonas asked me. And I said, “Yes,” and we did. The first ten or twelve patients were people who had been given up by their own physicians. They were burned-out cases. They occasionally would get corticoids to suppress a flare, but they clearly were going to die, and there was no useful treatment for them. The first ten or twelve patients that received the protein that we prepared for them came into the hospital in San Diego, so that they could talk to each other. The great Dr. Salk would come in with his white coat, and the doctors and nurses would flock around, and [the patients] thought Jonas was going to help them. And it looked like he did. They have visual problems; they can’t retain their urine; they have a lot of physical problems, and it was miraculous. People started having a normal sex life, retaining their urine, their visual acuity improved. It was just miraculous. So I said, “Jonas, now we’ve got to do a double-blind crossover study if you want this to be approved with the Food and Drug Administration.” We did that, and people did not talk to each other, they didn’t know what they were getting. It was a placebo or the myelin basic protein. They still knew that Jonas was trying to help them and that helped, but when we did the double-blind crossover, neither group was benefited at all. That’s what I call the Jonas Salk placebo effect. [laughter] It was just miraculous in those first dozen patients. I have a lot of people ask me about alternative treatments, this, that, and the other thing, in cancer particularly. If I’m convinced that it’s not going to hurt them and they think it will help, do whatever you like, feel free.

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Hughes: Aside from working with Salk, what you were really there to do—

Johnson: Was to develop drugs to treat cancer.

Hughes: What was the research?

Johnson: Well, we wanted to develop drugs for the treatment of cancer. It was during the Nixon administration. Besides other things that he did, he declared war on cancer. I was actually a consultant of the National Cancer Institute on that war. As we discussed the intent of the program, which was under an organization they called CCNSC—the Cancer Chemotherapy National Service Center—they took what I thought was a wrong approach to looking for drugs. There were a few drugs that seemed to have some benefit-—methotrexate was one. I knew Sidney Farber, and the first leukemic child to respond to methotrexate was the fourteenth one, but he kept on trying. They took the handful of drugs that had some effect on human malignancy, and they looked for a single tumor system that would detect the largest number of them.

There was a single murine leukemia, lymphocytic leukemia, that would detect the highest percentage of them. So they asked all of the pharmaceutical firms in the country to submit organic compounds, fermentation products, anything, to be run by the CCNSC through this single lymphocytic leukemia system. I advised the company not to do it. I said, “It’s ridiculous to assume that a single murine lymphocytic leukemia would predict and detect drugs for cancer of the prostate, the breast, the colon, etc.” That’s my old training as an embryologist showing. I said, “I would like to set up a screen with at least five different histological types of tumors, and I’ll rotate new ones in periodically. I would offer to the national cancer program anything of interest that we find, for them to do as they see fit. But let’s not screen through them; we’ll screen my way. And Lilly agreed to that.

Hughes: Was it characteristic of the thinking about cancer then, that it was essentially one disease, and you would find one therapeutic if you were lucky?

Johnson: No, I don’t think so because the handful of drugs that had some modest effect were not effective with all types of cancer.

Hughes: So people should have known.

Johnson: I think they should have. You know more now about oncogenes and things of that sort, which are really almost developmental genes. It’s really not a big jump from embryology to oncology. I decided it was a totally mistaken view, and the company agreed with me. We set up a building, and we screened five thousand things a year. I had my own

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fermentation set-up for [beers], and synthetic chemists would submit compounds to me. We had an animal tumor group where we kept rotating tumors in and out. And we had a cell-culture group where we looked for novel means of detecting anti-tumor agents at the cellular level. There was a small group of chemists in the company who were interested in what they called phytochemistry—drugs derived from plants. There’s a basis for that—reserpine, and digitalis.

One of these guys, his name was Gordon Suoboda, got a plant which you find in many parts of the world called a periwinkle. You find it in Florida. It grows wild. The plant that we got happened to be shipped in from Madagascar. Mistakenly, it has been thought that we were destroying the tropical forests. It’s not a tropical forest plant; it’s a ubiquitous plant that grows any place it’s warm enough. So Gordon submitted extracts of the plant. I had to actually talk him into submitting it for the cancer program. He had come across a reference, maybe it was in the Philippines: if you had diabetes you’d make a tea out of this plant for treatment. So he was hoping to find a diabetic agent. He eventually did but it turned out not to be useful. But he submitted extracts to us.

To my chagrin, in a way, I had a different lymphocytic leukemia in my five-panel screen, but it wasn’t murine lymphocytic leukemia. The government used the one called the L1210. I used one called the P1534. They were both mouse-strain-specific leukemias. But I detected activity, and Gordon went through an exhaustive isolation program. This plant has almost ninety very large indole-dihydroindole alkaloids. And the isolation was a terrible chore, but I detected activity, and Gordon pursued it, and we found four alkaloids were active in the P1534. They’ve changed their names to indicate the plant origin. They first called it leurocristine; they called it vincristine eventually, and the trade name was Oncovin vincristine Lilly. We found four alkaloids. Vincristine was one; the second one was velban. It was vincaleukablastine. One called leurosidine and one called leurocine. These were the four active ones. We accumulated enough of each one to do exhaustive studies. We found out that we actually could cure animals with vincristine and also the one called leurosidine.

The leurosidine was there in very small quantities. They all were there in small quantities. It took a ton of dry leaves to get an ounce of active drug (vincristine). That’s an isolation problem that was pretty insurmountable. I [inaudible] just out of curiosity and tested the vinca alkaloids on the L1210 leukemia, and it would not respond to them. So in the government CCNSC program they would have been missed. I published the data, and the National Cancer Institute got all excited. Two gentlemen, Emil Freireich and Emil Frei —Freireich they called “J” because his middle initial was J—and Emil Frei they called Tom to

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distinguish the two. They worked under a guy named Gordon Zubrod at NCI. They were very interested in vincristine. They discovered at the NCI with the material that we supplied to them that if you gave acute lymphocytic leukemic kids vincristine plus cortisone you’d get 100 percent bone marrow remission. One hundred percent! Those two gentlemen—“J” went to M.D. Anderson [Medical Center], Tom went to Harvard. Jim Holland, who was a later president of the American Association for Cancer Research, and a guy at St. Jude’s Hospital collaborated and developed protocols for combination chemotherapies for these kids that by five-year survival standards could cure 80 percent of leukemic kids. They’re well known for that and deserve to be. All of them would say that if they had not had vincristine, they could not have developed that combination protocol. It was vincristine that tipped the balance in our favor.

Hughes: When was this research happening?

Johnson: It started in the ‘60s. I was in molecular biology by the ‘70s. [laughs]

Hughes: Were you involved in the patenting of some of these cancer therapeutics?

Johnson: In the pharmaceutical industry, at least in those days—I think it’s still pretty true—it’s the chemist who gets the patents, not the biologist. He detects the activity. That’s the way it was done. I’ve always thought that was a mistaken philosophy, but that’s the way it was done. So I didn’t hold any patents on the vinca alkaloids. It was because of the biological activity that we got patents.

Actually, the alkaloid that always most interested me was the one called leurosidine. It was the least toxic of the alkaloids, and we could get cures. But it was there in such small quantities that you couldn’t make it available commercially. There wasn’t enough there. These alkaloids are so complex they’ve never been totally synthesized. There are two massive chunks of alkaloids that are joined together, and no one has been able to completely synthesize the whole molecule, at least on a commercial scale. That was a tremendous experience for me. My kicks in life were not just the science, which I loved. But my kicks in what I did was that what I worked on helped people. Maybe it was a frustrated physician, but that’s where I got my kicks.

Hughes: Was one of the motivators at Lilly, we’re producing drugs that will help people?

Johnson: To a large degree. I mentioned Clowes. He was the one who brought animal insulin into Lilly and into the market. Diabetics died. [Frederick G.] Banning and [Charles H.] Best and a couple of other Canadians were interested in it and depancreatized dogs and

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discovered they got diabetes and made pancreatic extracts and could treat them. Clowes went to a meeting where this was first described, in the twenties I think, came back and convinced the Lilly family that ran the company that this was something that Lilly should do. And they did. We and eventually other companies made beef and porcine insulin, which differ in amino acid sequence a little bit—porcine only by a single amino acid, but beef by about three or four. Because of his contribution to the company, when Clowes retired they gave him an emeritus position in the research area of the company. He had a lab and was publishing in his eighties when he died. He would take his lab and move it to Woods Hole, Massachusetts in the summertime! [laughs] So I think, in answer to your question—yes, to a considerable degree that was true. I think the Lilly family felt that way, and I won’t say that everyone in the company felt that way.

When I first came to Lilly it was the first time that a non-Lilly family member was president of the company. His name was Eugene Beesley, and he was a marketing individual by training, but he established this emeritus position for Clowes. He also made the decision to help Salk. Lilly made 90 percent of the Salk vaccine. Clowes used to call me down about once a week to his office and ask, “Well, young man, what have you been doing?” With a severe implication that I should have been curing cancer since the last time we talked. I enjoyed talking with him and he was a really interesting individual.

Hughes: Was most of the research in house? Not through collaborations?

Johnson: Yes. I think I could say very easily that the idea of striking up relations with small companies and universities was one that I started at Lilly. I felt I had to because I understood and knew what we wanted to do in terms of producing human insulin. I could not hire enough people of appropriate backgrounds, in some cases even finding the people with the right backgrounds to bring in, to make that kind of an effort entirely internally. I convinced the company that we would have to work with other people. I thought of Wally Gilbert and then decided not to, and Bill Rutter and we decided we would work with them, and was approached by Genentech when they started making news in that direction [human insulin] and agreed to work with them. But that concept was not a normal concept at Lilly. You did everything inside internally.

Hughes: Did it take a lot of arguing to convince your superiors?

Johnson: It took far more than I think it should have, I guess. But I didn’t run into stone walls, resistance to it. To bring in the number of people that I thought would be necessary was a large group of people, and I could understand their reluctance to adding that on to the expenses of the

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company. But if they wanted to be the first ones to market human insulin that’s what we had to do.

The reason I ended up on boards of directors out in California is I was convinced there was a corridor of scientific excellence out there from San Diego to Seattle. There were little regional discussions which didn’t appear in print for a year and a half or two years later, and unless you were out there and you went to the meetings, you never heard them or too late. So I convinced the company that we needed to have a laboratory on the West Coast. And we ended up at Scripps Institute, not Salk. Frank Dixon, who was running Scripps Institute—he was a pathologist and a physician—was an immunologist, and that’s what Scripps was at that time, an immunopathology group. I had a lab and an office out there. Beesley had been long gone, and the company agreed to my proposition of a lab out there. They asked me to do it. I went into the guy who was then president and CEO/chairman—his name was Richard Wood, Dick Wood, and I said, “Dick, my wife has just gone back to nursing school. This is not a convenient time for me to do this, and I’d rather not.” He said, “You’re the only one we have—have a good time there. We have to do that; I want you to do it; take your wife with you for a vacation.”

Hughes: Wasn’t this after the Genentech relationship?

Johnson: It was before our relationship with Genentech. I could see this, the commercial potential of recombinant DNA, coming. Anyone who followed the literature, you could see it coming. The people at Arthur Riggs’s lab were synthesizing DNA. Gobind Khorana had synthesized an entire gene. Developments were happening in terms of nucleotide chemistry that you could synthesize almost any gene. You could play it like a piano, type it in, and it would come off the resin.

Hughes: So this lab that you were starting at Scripps was to take on these new genetic technologies?

Johnson: I had tried to convince the company that there were two or three areas of biology that were going to be the future of the pharmaceutical industry. One was molecular biology; one was immunology. The third was brain research. Those were the two reasons I wanted to have labs out there, where I and people who were working with me could go to these local little meetings, hear things. Wood took the position that there wasn’t anyone else that they wanted to send out there, and I had to do it. They would rent a place for me—they rented a condo in Del Mar, actually. I left clothes out there, and the corporate plane would occasionally take me out. Other times I’d travel commercially. I did my own laundry, my own cooking when I was out there.

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Hughes: So your wife did not go?

Johnson: Yes, she did; she would go with me for occasional short trips. But I didn’t live out there all of the time; I had to come back part of the time.

Hughes: And what actually were you doing?

Johnson: Well, at Scripps I was really learning more about where immunology was going. That’s how we got into Hybritech, in ’81, I guess. Dixon was a very interesting guy. I mentioned he was an M.D. and a pathologist. If you called him a physician he would get angry—“I’m a mouse doctor!” He did his work in mice. Frank was at the cutting edge of a great deal of what was happening in the world in immunology. We didn’t have any immunologists at Lilly at that time. None. And among other things I was hoping I could find postdocs at Scripps and things like that. We had a five-year contract with Scripps for a paltry amount of money nowadays. Half a million dollars a year, I think. And I had the rights of first refusal of everything that was going on at Scripps. So I would circulate in all of Scripps laboratories—“What are you working on. Oh, that’s interesting. Have you thought of this or that?”

Lilly is now touting a drug for the treatment of sepsis. It’s the only drug approved by the FDA for the treatment of sepsis. And it’s a large protein called activated protein C. It’s nature’s own anticoagulant. And one of the problems in sepsis is you have multiple organ failure, because of microcoagulopathies that occur in the tissues. In one of my excursions I came across a young man, John Griffin, who was a postdoc who devoted his life—

Tape 2, Side A

Johnson: —to research on activated protein C deficiency. We had a rough idea of what the function of activated protein C was of course. So that was one of the projects I chose. We made the gene that coded for activated protein C. It could not be grown in bacteria. It had to be grown in human cells because it had to be glycosolated, and then it had to go through some other post-translational modification which didn’t occur in bacteria. Yeast will glycosolate, but not always in the right spot. By laborious efforts we accumulated enough, and we tested it in sepsis in baboons, and it worked.

Hughes: You were getting enough because you were using recombinant DNA and cloning?

Johnson: No. We had to use human kidney cells to produce it. We got enough to do the baboon work. We could not make enough to do a clinical trial.

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Thirty years later, a group of biochemists and cell culture people that I had hired kept working—almost surreptitiously if you want.

Hughes: At Lilly.

Johnson: Yes. And got to a level where they could make enough to do a clinical trial. And they did the clinical trial. If we could have done that at the beginning, they would have had this drug thirty years earlier. This is thirty years later that they finally could make it in large enough amounts.

Hughes: Were they at Salk or Lilly?

Johnson: Oh, they were at Lilly.

Hughes: So you started something.

Johnson: This was after I retired! [laughs] That’s why it was partially surreptitious. I’d talk to these people on the phone.

Hughes: What were the years you were at Scripps? Would that be in your CV?

Johnson: I don’t think so, because it was a Lilly assignment, and I thought of it as a Lilly job. I’ll try and give some thought so that I can get you that information, but I can’t tell you precisely.

Hughes: But you think it was before you became involved with Genentech and UCSF?

Johnson: Oh, it was after that. It was in the seventies.

Hughes: Do you remember when you first began to hear about recombinant DNA?

Johnson: Well, as I indicated in my article, I was aware of the Watson-Crick paper fifty years ago. I’d followed other people’s publications. [Marshall] Nirenberg. The chemical synthesis of genetic material and was aware of the moratorium that was requested by the Gordon conference people.

Hughes: Did you specifically know of the Cohen-Boyer work?

Johnson: Oh, yes!

Hughes: Do you remember when you first heard of that?

Johnson: I read it in the literature but I don’t remember what year that was. I didn’t know Boyer at that time.

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Hughes: Well, those papers were published in 1973, 1974.

Johnson: Yes, it was early seventies.

Hughes: You weren’t in touch with those people?

Johnson: Well, I followed it scientifically. I’m a terrible browser. I don’t have a library facility since I retired. I take a humongous number of journals, I like to browse in journals. But you could see this coming, and I attended Gordon conferences, and you could see it coming there. I asked to go to the Asilomar conference and they wouldn’t let me because I was not an academic. They wouldn’t let me in. My feeling was the recombinant guidelines, the NIH guidelines, served a useful purpose, which is largely like my feeling of responsibility to talk to anyone who wanted to discuss it to learn what it was. I think one of the things I do best—I think I can see these things coming. If you can do that, you ought to be able to do this. It’s like Salk. If you can grow polio in primate kidney cells instead of rabbit brains you should be able to grow buckets of polio virus, kill it and make a vaccine. There were publications from the City of Hope and from Genentech and from UCSF and from Wally Gilbert; you could tell that it was coming. They were cloning proteins. Insulin is a protein. We knew a lot about how to hook chains together because we took animal insulins and took them apart and put them back together. We knew how to do that. And I was sure we could do it if we had the right number of people and the right kind of people. There wasn’t any question in my mind. But the company would not let me bring that kind of an effort inside the company; I had to go outside. That’s very common nowadays, but it wasn’t when I started.

Hughes: Do you think if the first potential product had not been insulin that you would have had a harder time convincing Lilly to take on recombinant DNA?

Johnson: Well, the first one I remember was somatostatin.

Hughes: Yes, but Lilly didn’t have any connection with that, did it?

Johnson: No, they did not. That was proof of principle. It was a small peptide.

Hughes: And that must have meant something to you, didn’t it? That maybe there was a commercial application?

Johnson: Oh, yes. No question in my mind.

Hughes: The question I’m asking—when you were trying to convince your bosses that Lilly needed to take up this new technology, it seems to me it would have been a much harder sell if the product you were hoping

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to make had not been insulin. If you just wanted to introduce recombinant DNA—

Johnson: I think you’re right. Lilly was a major producer of insulin in the world, eventually not the only one, but the major one. Certainly the major one in the U.S. And they were the first ones to bring it to the market. What’s curious to me, and I think I refer to that in the Nature paper, is this huge increase in the number of diabetics in the world was partially responsible for the fact that insulin was brought to the market. Because these people now led, not only productive lives but reproductive lives. You’re treating a disease that’s a geneticist’s nightmare, but it’s passed on. To me, that increases the responsibility to develop the best therapy, which is the natural human insulin.

Now, with the advances in molecular biology, we were finding lots of genes are involved in diabetes and lipid metabolism and a variety of things that are associated with diabetes. And we have this epidemic of obesity in the United States and elsewhere. One of the curious things is the first really good anti-asthma drug was a leucotriene antagonist, and a number of companies were working on leucotriene antagonists which is part of the anti-inflammatory prostaglandin pathway. Lilly developed the first B4 antagonist for leucotriene B4. We were in the clinic the first time. In the tox[icology] studies it turned out that it was a peroxisome proliferator. The FDA took the position that anything that was a peroxisome proliferator was probably going to cause liver cancer. They just stopped the trial and stopped that effort.

Now we look for things that tickle some of the peroxisome genes, and those things will help actually in the treatment of diabetes. They work in animal models of diabetes. In clinical trials they are working. The beauty of this technology is that you don’t have to do everything to a nuclear receptor. You can just specifically modulate some aspects of the receptor. Take an estrogen receptor—you need not have any effects of estrogen on breasts or uterus but have the effects on bone. Again, you can play that like a piano almost. So lots of people, lots of companies, lots of Big Pharma companies, they’re working on peroxisome drugs now.

The other thing that came along, of course, were the drugs that— Diabetics—particularly maturity-onset diabetics—it’s not that they don’t make a lot of insulin. They make lots of insulin, but they’re not sensitive to it. So people kept taking more insulin to get the insulin reaction. Drugs which push the sensitivity button [becoming] sensitizers to insulin were very useful, and they came along. All these things fall into place if you’re following the literature; you can see what’s going to happen. One of the companies whose board I’m on has a relationship with Lilly in the diabetes, adipose, and cardiovascular

17

areas, and we are developing drugs like that, and some are in clinical trial. I won’t give you any results about it but I’m very encouraged.

Hughes: Good! Well, fairly early on in the recombinant DNA story, namely in the spring of 1976, Lilly sponsored a conference on insulin in Indianapolis. Do you remember that?

Johnson: Yes.

Hughes: Were you one of the organizers?

Johnson: The people who organized the program reported to me directly, so I was associated with it. But the people who organized it were the people who worked in diabetes, and I thought that was what they should do. I couldn’t know everything, so it was always the people who worked in the area who developed the agendas of those conferences.

Hughes: Do you remember if recombinant DNA was one of the themes in that conference?

Johnson: Yes.

Hughes: Was this pretty much an in-house group? Or were there outside speakers?

Johnson: It was both.

Hughes: Do you remember if there were any names that later became famous in genetic engineering?

Johnson: My memory isn’t as good as it used to be. I think the answer to that is probably yes, but I’m not sure I can tell you who they were. We reported some of the work that we were doing with our collaborators on the outside, and I think Wally Gilbert was invited to that if I remember rightly. There were people both inside and outside that were involved in that type of work that were invited to the conference. That was published either in the Journal of Diabetes or the Journal of Biochemistry.

Hughes: I have a quote that certainly indicates that you were very enthusiastic about recombinant DNA—

Johnson: I get enthusiastic about a lot of things.

Hughes: [laughs] But do you agree that you were enthusiastic about recombinant DNA?

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Johnson: Yes, absolutely.

Hughes: In U.S. News and World Report, a December 1979 article, you were quoted as saying, “Potential applications of recombinant DNA are limited only by the imaginations of the people using them.” Was that pretty true of the way you looked at it?

Johnson: Yes. I used to say that we were going to understand what the switches are to turn these genes on and off, and we’re going to put those switches in bottles and call them drugs. I still feel pretty much that way. Some of the things you just have intense gut feelings with what’s happening, what’s going to happen. I think you have to have a little vision. You have to be able to think prospectively. In my usual modesty, that’s one of the things I think I do well, but it’s because I enjoy it.

I started to talk about the Asilomar conference and the NIH guidelines. I think that served a useful purpose in the sense that the NIH held public meetings. The RAC [Recombinant DNA Advisory Committee] meetings were public meetings, and people who were interested and wanted to go and listen could do so. They could hear the ethicists and the philosophers and ask key questions and hear the scientific answers to those questions. I think to a large degree it helped keep the public informed. I think the guidelines were a hindrance to how rapid progress was because you were limited in what you could do in terms of facilities and size of fermentations and things like that. In the United States under the original guidelines you had to have a P4 laboratory facility to work with human DNA which was so com[plicated]—it was like Fort Detrick. You had to be able to process your own sewage and all that sort of thing, and wear space suits. But the rules were different in different parts of the world. In Switzerland all you had to do was register that you were doing that kind of work. And the concept was if something bad happened, they’d know if you were registered, they’d know who to go after. France, you could work with human DNA in a P2 facility, which is essentially an ordinary lab with some positive pressure added to it. Of course, under the NIH guidelines you couldn’t work anything in larger than ten liters. I was the first one to ask for more than that, and they didn’t want to go to 40,000, but they allowed me to go to 200, I think. You couldn’t do anything on a commercial scale.

Hughes: Why do you think the United States was more stringent than the European countries?

Johnson: That’s a good question. I’m not sure I know the answer to that. There was this public concern about safety and the Congressmen responded to that concern. I spoke to committees in both houses of Congress. I

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remember the senior senator from Arkansas, Dale Bumpers, who later was Clinton’s primary defense counsel in his impeachment, although he was not in the Congress at that time. The senior senator at that time from Arkansas said, “I don’t know what recombinant DNA is. I never heard of it until yesterday. But by God we’ve got to control it!” That’s what you were faced with. I felt you could sit down and talk to these people and explain what it was—and I wasn’t the only one doing this, there were many scientists doing this—but the feeling was very intense. I spoke at the first National Academy of Sciences meeting on genetic engineering.

Hughes: Was that the one in Washington in March 1977?

Johnson: Yes. They called it an open forum, which was so people could come and listen. I was the only representative from industry. I elected to discuss that the increasing incidence of diabetes was such a problem that we were concerned about being able to produce enough insulin to treat all the diabetics. At that time it was communist China under Mao. Even if we could collect all of the pancreases from all the pigs in China, you couldn’t produce enough insulin to treat all of the people diabetics in the world. And there were some people that were in academia concerned that were just as concerned as some of the less informed members of Congress. At this open forum the meeting was physically interrupted and taken over by protesters, while I was speaking, actually [laughs]. They were carrying banners and accusing me of being like Hitler, and all sorts of erroneous stuff.

Hughes: Was it just coincidence that they interrupted you?

Johnson: I don’t think so; it was the fact that I represented an industrial participant. But that’s a feeling. I don’t have any proof of that. I never knew who these people were, actually. I knew people like Jeremy Rifkin, I knew who he was.

Hughes: How did you feel about the interruption?

Johnson: Well, I was shocked. I didn’t expect anything like that. I knew there was concern but I didn’t expect it to be like that. They got order restored, and those people removed. Then I finished my presentation that one of our concerns was a matter of being able to supply insulin diabetics and not have them revert to the 1920s when they would die. I remember a Harvard academic when it was opened to questions. He wanted to know when was I going to quit lobbying to prevent legislative control of recombinant DNA. I can give you his name if you want it.

Hughes: Is that George Wald?

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Johnson: No, it was not. It was Sheldon Krimsky. I said, “I am not lobbying against legislative control of recombinant DNA. I am not in favor of it but I am not doing any lobbying. I don’t favor legislative control of freedom of scientific inquiry. I object to that. The one thing I would lobby for though, if it comes to that, is that it applies to everyone—academia as well as industry, so there’s a completely level playing field. We in industry are used to having government people standing behind us and looking at what we’re doing. You’re not, and I don’t think you’re going to like it.”

Hughes: Did you get any response to that?

Johnson: A few industry people applauded. [laughter]

Hughes: Well, another thing that I know happened, is you gave an interview which was published in Lilly News, the Lilly company newsletter, and then that article was submitted in full to a congressional hearing. Do you remember that?

Johnson: No, actually I don’t.

Hughes: I wondered if you had given the interview knowing that eventually it was going to end up as one of the factors in this controversy.

Johnson: I don’t know how to answer that. As I told you, I would talk to anyone who had an interest in trying to learn what [recombinant DNA?] was, and I viewed that as a personal responsibility as a scientist, not necessarily representing Lilly. Everyone knew where I worked and who I worked for, and I feel that’s a responsibility all scientists should have. If the public has concerns about the experiments you’re doing, you should explain to them what you’re doing and why you’re doing it and respond to any of their concerns. I think that scientists have that responsibility, and it has to be done in terms, in language that is easily understood by lay people so that they understand what you mean. I think that can be done with almost anything. I may be wrong but that’s the way I feel about it. Lilly never attempted to control me on that sort of thing as some companies would and do. In my discussion in state legislature committees and in the Senate and the House, Lilly didn’t do anything particularly to help me, but they didn’t try and keep me from doing it, and I appreciated that.

Hughes: Do you think that they recognized that in the end it was helpful to their cause as well? That if you had a public that was more understanding of this new science, it was going to help Lilly.

Johnson: Yes, I do think so. I think they understood that. Not necessarily everyone but enough of them. [laughs]

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Hughes: Anyway, you weren’t stopped.

Johnson: I was never stopped.

Tape 2, Side B

Johnson: Then I received a letter from the secretary of HHS [Health and Human Services] asking me if I would serve on the RAC, and then I responded to her, yes I would. I sent copies of my letter to some of my superiors, and one of them was a vice-president, Cornelius W. Pettinga, of the company. He said, “Irv, why were you so quick to accept that appointment?” And I said because I wanted to do it. The implication was, I think, that he thought I should have asked him was that all right. I didn’t feel like I had to do that. There was a group of meetings in Colorado called the Keystone conferences. (I was actually on the board of that group at one time, helped to organize those meetings.) That’s a place that you could find Congressional staffers going to learn about the people they were trying to control. One staffer was complaining in one of our discussion sessions about the lack of public representation on the RAC. I said, “I represent the public on the RAC but that probably doesn’t give you a lot of comfort, does it?” “No!” [laughter] “But the public is represented, the majority of the people are not scientists, they are public people concerned about ethics and the philosophy, and they are representing the public interest and you may not believe it but so am I.”

Hughes: Well, that is a stretch, don’t you think? Here you were employed by a company—

Johnson: Because I was from industry?

Hughes: Yes.

Johnson: Well, I’m sure that’s what he thought, and many other people would. I didn’t look at it that way. I felt I was representing the public, not just industry. I was representing the public and science in my view; that’s what I was doing.

Hughes: Well, aside from the public being concerned about the biohazard issue, there were people concerned about the commercialization of academic research.

Johnson: Yes.

Hughes: And here you were dealing with UCSF and maybe with Harvard, although you rejected that option. Lilly was one of the first companies to become interested in recombinant DNA. Irving Johnson, vice-

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president of research at Lilly—he’s the enemy. He’s pushing the commercialization of this science. I’m playing devil’s advocate here.

Johnson: No, I understand what you’re saying. I’m sure there were people who felt that way. And I could understand why they felt that way. But I object to the concept that because you’re an industrial employee, the only group that you can represent is industry. I was a scientist, and I felt I was also representing science. As I said, my concern about legislative control was freedom of scientific inquiry. People like the senior senator from Arkansas who never heard of recombinant DNA until yesterday and didn’t know what it was but he wanted to control it. Why didn’t he want to know what it was? Why didn’t he want to find out what it was and whether it was dangerous or not. Or was it something that man had been doing ever since he’d been on the biosphere but he didn’t know what he was doing? As opposed to the preciseness of this technology where you knew exactly what you were doing. I felt that if he was representing the public he should want to know that.

I understand what you’re saying, and I know there are people who felt that way. I don’t know they agreed with it, didn’t agree with it and that’s just the way I felt about it. I felt I was a scientist and I had the right to speak and represent other scientists and to represent the public. Right or wrong that’s the way I looked at it.

Hughes: Do you remember having discussions about the guidelines per se? Well, I know when you were on RAC you obviously did.

Johnson: No, they were formulated and put in place before I got on the RAC. They were almost continuously being modified. They weren’t as open as things are today, or as they were in France or in Switzerland. It took years for some of those things to happen, to get over the ten-liter limit, for example, that sort of thing. The chairman of the RAC when I first asked for an approval to go above ten liters wanted to know if I would present a seminar to the RAC. She was a woman from Brookhaven [Laboratories], and I’m sorry but I can’t remember her name. Would I present a seminar on large-scale fermentation to the RAC? I said with a couple of caveats, we will present a seminar. I probably will not do it myself because I’m not a complete technical expert in that area, but I have people who are. We will be happy to do it if it can be done publicly so there is nothing secret about it—no closed meetings but everyone can hear what we say. She agreed, and we did. A gentleman named David Dennen, who was in one of the large-scale fermentation areas, presented the seminar.

I had the distinct impression, right or wrong, that there were people who realized for the first time we were talking— One reason she asked

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me would I do it, she said they were thinking about building dikes around fermentators that could contain the entire contents if one broke. I said yes we’d do it but with these caveats. There were people there, I felt certainly in the audience but even on the RAC who realized for the first time we were not talking about huge Erlenmeyer glass flasks on some massive shaker but stainless steel tanks that you could push a button and inactivate them. They didn’t realize that.

One reason I was concerned about the original Asilomar conference was that I didn’t think they had enough people in that meeting who were experts in infectious disease and pathogenesis and that sort of thing. We were going to do experiments where we fed genetically engineered [organisms] producing the insulin into animals and see how long they lived. If you look at some of the publications in this area, E. coli-producing insulin has these huge, dense bodies. They are sick bacteria. They don’t grow well. They don’t live in a gut very long. They disappear. That has a tremendous advantage in terms of economic advantages in that 1 percent of the pancreas are islets. A few cells in the islets are the beta cells. 99.9 percent you’ve got to get rid of to get the protein you want. In this case [insulin-producing bacteria], 100 percent of the bugs are producing exactly the protein you want, and that’s it.

Hughes: Your point also was, was it not, that these are sick organisms. If they escape, they’re not going to survive very long.

Johnson: There was a publication in Science, of all things in Science, by a Harvard academic, it may have been Jonathan King, who suggested that if Lilly was allowed to do this that children in the area of our production facilities would become infected by these bacteria and die of hypoglycemia. That’s hogwash! Just hogwash! I debated him several times. I remember one time the United Press had brought in a bunch of foreign correspondents, and they’d asked the two of us to discuss, what if you had engineered bacteria that would eat oil and then got loose, would it destroy the oil preserves of the country? And this guy—and I can give you his name too, but I won’t unless you are comfortable with it—looked at me before we went up on the podium, and he said, “You think we ought to get actor equity cards, Irv?” [laughter] He later won a Lilly prize in microbiology [American Society of Microbiology]. We funded several prizes in the AACR [American Association for Cancer Research]. We funded the Clowes lecture, because Henry Alexander Clowes was one of the thirteen founding members of the American Association for Cancer Research. And I thought when he died we should do something about that. Anyway, I questioned the guy’s seriousness when he made this actor equity sort of comment. But he was a good microbiologist; I have no question about his ability. I think he was bright enough to know that

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what he was arguing was wrong, but I didn’t have any control over that.

Hughes: You spoke earlier of the difficulty of finding people who had this expertise.

Johnson: Yes, there were several kinds of expertise.

Hughes: Yes, but also the problem of convincing your bosses that yes, indeed they should fund a recombinant DNA effort in-house. But Lilly did eventually, right? There was a recombinant DNA group at Lilly and when did that happen? And was it because they were going to be the development arm for human insulin that Genentech had produced?

Johnson: The best way I can respond to that is that the first bugs that we got from Genentech were a dual fermentation. One fermentation produced A-chain, and one fermentation produced B-chain. And because we knew how to combine chains or take them apart, we could do that, but it was not a cost-effective way of doing it. We always wanted to produce proinsulin and convert it to insulin, as we did when we extracted it from glands.

Hughes: Was that just a simple excision? You just clipped off the amino acids that were the proinsulin?

Johnson: It was enzymatically clipped off.

Hughes: And was that a relatively easy procedure?

Johnson: At the scale you wanted to do it, no. At a laboratory scale, yes.

Hughes: And that of course was one of the reasons that Lilly kept supporting UCSF because—

Johnson: I’m sorry, what?

Hughes: Even after Lilly contracted with Genentech, you continued to give money and have a contract with UCSF.

Johnson: Yes.

Hughes: UCSF had the proinsulin, working with a natural gene, cDNA approach.

Johnson: Which is the approach I preferred, of course.

Hughes: Did you see early on that that was the way Lilly would eventually go?

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Johnson: Oh, absolutely. This gets into this kind of touchy area in a way. I don’t know how your response to this is: I felt that some of the things that Bob Swanson wanted to do were immoral. One of the things was, here were these postdocs in Bill Rutter’s department, which oddly enough included Herb Boyer. And Swanson made standing offers of employment to them if they would bring their cultures with them.

Hughes: He didn’t want just them; he wanted them and the cultures.

Johnson: Absolutely. I would discuss this with him and I’d say, “Bob, you should not do that; I think that’s immoral.” And he said, “It’s common for postdocs to bring cultures with them.” And I said, “For research purposes, that may be. That’s not what you have in mind, and that’s immoral. Commercialization from it is immoral.” This was an argument I had with Lilly attorneys. When Genentech and UCSF got into litigation over who owned what cultures—people like Peter Seeburg was happy to do that.

Hughes: What do you mean, happy to—

Johnson: Lilly attorneys took a position that these things [cultures] were the property of UCSF, which they were. We had paid for their development, which I thought gave us some rights. The principal Lilly lawyer, Walter Buting, involved in recombinant DNA took a position we [Lilly] could only be friends of the court because they were UCSF property, and for the litigation between UCSF and Genentech, we could only be friendly observers. I said, “But I paid for the development of these cultures, and had right of first refusal to them. Why aren’t we as interested as UCSF?” This same individual eventually became a Genentech employee. He’s dead now too, both he and Swanson. I don’t like to do anything to hurt their families or anything of that sort, but it was a moral issue to me, it really was.

This one Lilly attorney was open about his interests in Genentech, and we were good friends. He would come over and say, “I’m thinking of retiring, Irv, and Genentech is making me an offer—what do you think about it?” I said, “ I think that’s a decision you have to make on your own, it’s not one I can make for you. It’s your life and it’s your decision.” And I told him how I felt about Genentech, how I felt that they had some superb scientists. I didn’t think that the future of molecular biology in the pharmaceutical industry was entirely related to proteins. In cloning drug targets, eventually we would be making drugs based on the genetic backgrounds of the patients we were treating. But I said, “I like Bob Swanson as a person, I’ve played tennis with him. But I disagree with him philosophically about some of the things he’s doing.” He could have a Friday afternoon session with

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his employees and appear in a tutu, and that’s great. But that doesn’t have anything to do with morality. I was disturbed at some of that.

Hughes: Because the Lilly attorney had designated the company as a friend of the court, did that mean that you couldn’t testify? Did you testify in that Genentech-UCSF case?

Johnson: No, we did not. As I understood it, on his recommendation we could not. We met with UCSF attorneys, and I talked to them about how I felt about it.

Hughes: Along the vein of what you just told me?

Johnson: Absolutely, yes. But I couldn’t give legal advice. I’m not an attorney. I felt that was wrong, but legally maybe it wasn’t, I don’t know. [tape interruption] I was deposed several times by attorneys from both parties.

Johnson: I was invited to give a talk at the National Academy of Sciences center on the West Coast, which is at Irvine and was built by some philanthropists—Arnold Beckman, I think. My wife, Alwyn, was with me. This was the meeting where I was asked in the audience, “Couldn’t you have done that with animal insulins?” I said, “Yes, but why in heck would I want to?” We got out of our car to walk into the Beckman Center there, the National Academy center, and there was a man walking in front of us. He turned around and looked at me and he said, “Are you Irving Johnson?” And I said, “Yes.” And he said, “I’m Steve Hall.” I said, “I know who Steve Hall is; I’m glad to meet you.” And that’s the first time I ever met Steve. We talked some there, but his book was already out so none of our conversations were in the book except those that were on the telephone.

Hughes: You mentioned earlier Wally Gilbert and the fact that you did not contract with the Harvard group.I was wondering what they were doing that was different and why you didn’t contract with them.

Johnson: I felt my responsibility was to make sure that Lilly was the first company to have human insulin. My assessment of what Wally was doing compared to what Genentech was doing—even though they had to go to City of Hope for nucleotide synthesis—and what Bill Rutter’s group was doing was superior to Wally. Now, I can’t tell you in any quantitative reason why I felt like that, but one thing I thought Wally was going to have trouble with—he wanted to maintain his post at Harvard and still be President and CEO of Biogen—and I said, “They won’t let him do that, and he’ll have to make a choice.” My responsibility was to make sure that we were first, and we were. What he wants to do, even though he might be able to do it physically and mentally, they’re not going to let him, and I think that will be a

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hindrance. So I decided not to work with him. He and I frequently appeared on the hustings, and people wanted to talk about their concerns and that sort of thing together. I like Wally, and I think he’s a superb scientist, but I thought he was going to have problems with Harvard. I didn’t want to have to worry about those problems, compared to these other opportunities where I didn’t think I’d have any problems of that sort at least. That’s the main reason.

Hughes: He was using the cDNA approach as was the Rutter group?

Johnson: If I remember rightly, he had a relationship with Khorana as well. So he had access to nucleotide synthesis. I’m not completely sure of that, but that’s the way I remember it—I could be mistaken.

Hughes: The Rutter group did not have DNA-synthesis capability.

Johnson: No, they did not. So I was hedging my bets a little bit.

Hughes: Didn’t the Gilbert group have— I remember reading something about a secretion method.

Johnson: The answer to that is yes. That’s not difficult in the case of yeast, but it is difficult in the case of bacteria. But he did engineer a system in bacteria—in E. coli—in which they would spit it out. My feeling, although I can’t confirm that in any mathematical way, is that it was not as efficient to be secreted. It sounded like it would be handier, easier—you don’t have to break up all these cells and all that sort of thing. But I didn’t think that was a major problem, and I’d rather have a more highly efficient system than the secretory system.

Hughes: So that came to naught.

Johnson: It came to naught. But it wasn’t because I had any real problem with Gilbert’s ability as a scientist. I thought he was a very good scientist. I had my thing that I felt it was my responsibility to do, and I liked to do it the way that I did because I thought I’d win one way or the other, and Wally would slow me down.

Hughes: Switching to the UCSF story, do you remember when you first contact them? And was it Rutter that you contacted?

Johnson: Yes, it was Rutter.

Hughes: Do you remember the circumstances?

Johnson: I had slowly built up a small group of molecular biologists at Lilly, and we would meet periodically and brainstorm and that sort of thing.

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Hughes: The Lilly group was working on insulin as well?

Johnson: Well, we’d worked out a way to go from hamster insulin to human insulin. We were doing mega-hamster kills. We could do that chemically, but that in my mind was not a manufacturing process. You couldn’t make tons of insulin that way. I didn’t want to be limited by doing it that way, and that’s just because I didn’t have access to some other types of molecular biologists and molecular biochemists. At one of our brainstorming sessions, to go back to your question—we’d brainstorm about what group was doing some of the most interesting wor