Program in the History of the Biological Sciences and Biotechnology, The Bancroft Library, University of California, BerkeleyScientist At Genentech, CEO At TularikDavid V. Goeddel, Ph.D.With an Introduction by
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Introductory Materials
Legal Information
Since 1954 the Regional Oral History Office has been interviewing leading participants in or well-placed witnesses to major events in the development of northern California, the West, and the nation. Oral history is a method of collecting historical information through tape-recorded interviews between a narrator with firsthand knowledge of historically significant events and a well-informed interviewer, with the goal of preserving substantive additions to the historical record. The tape recording is transcribed, lightly edited for continuity and clarity, and reviewed by the interviewee. The corrected manuscript is indexed, bound with photographs and illustrative materials, and placed in The Bancroft Library at the University of California, Berkeley, and in other research collections for scholarly use. Because it is primary material, oral history is not intended to present the final, verified, or complete narrative of events. It is a spoken account, offered by the interviewee in response to questioning, and as such it is reflective, partisan, deeply involved, and irreplaceable.
All uses of this manuscript are covered by a legal agreement between The Regents of the University of California and David V. Goeddel dated February 14, 2002. 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 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:
David V. Goeddel, Ph.D., "Scientist at Genentech, CEO at Tularik," an oral history conducted in 2001 and 2002 by Sally Smith Hughes for the Regional Oral History Office, The Bancroft Library, University of California, Berkeley, 2003.
Biotechnology Series History
Sally Smith Hughes, Ph.D.Genesis of the Program in the History of the Biological Sciences and Biotechnology
In 1996 The Bancroft Library launched the Program in the History of the Biological Sciences and Biotechnology. 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, Bancroft had no coordinated program to document the industry or its origins in academic biology.
When Charles Faulhaber arrived in 1995 as Bancroft's 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 and the pioneers 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 and archival 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 plans to safeguard the archives of individuals and businesses making significant contributions to molecular biology and biotechnology. 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 the History of the Biological Sciences and Biotechnology was given great impetus by Genentech's generous pledge to support documentation of the biotechnology industry.
Thanks to these generous gifts, Bancroft has been 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.
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 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 a 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] The three criticisms leveled at oral history also apply in many cases to other types of documentary sources. 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.
Emerging Themes
Although the oral history program is still in its initial phase, 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 business. 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 have 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 personalities 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 the Regional Oral History Office. Some of the oral histories, with more to come, are available on The Bancroft Library's History of the Biological Sciences and Biotechnology Website: http://bancroft.berkeley.edu/Biotech/.
Historian of Science
Regional Oral History Office
The Bancroft Library
University of California, Berkeley
Oral Histories On Biotechnology
Program in the History of the Biological Sciences and Biotechnology
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
David V. Goeddel, Ph.D., "Scientist at Genentech, CEO at Tularik," 2003
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
Fred A. Middleton, "First Chief Financial Officer at Genentech, 1978-1984," 2002
Thomas J. Perkins, "Kleiner Perkins, Venture Capital, and the Chairmanship of Genentech, 1976-1995," 2002
"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
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
Daniel G. Yansura, "Senior Scientist at Genentech," 2002
Oral histories in process:Brook Byers
Stanley N. Cohen
Chiron Corporation
Roberto Crea
Herbert Heyneker
Irving Johnson
Arthur Levinson
G. Kirk Raab
William J. Rutter, Volume II
Axel Ullrich
Keith R. Yamamoto
Introduction
by Herbert Boyer
I am honored to write the introduction to Dave Goeddel's oral history for The Bancroft Library. Introductions to these oral histories are traditionally personal and not necessarily focused on the science of the individual. Dave's history documents his scientific accomplishments, as the reader will soon discover. So I will begin my introduction with an account of how I first became aware of Dave Goeddel.
On a cold and damp evening in late 1977, Bob Swanson and I stood outside a small, trendy restaurant in San Francisco. It was located on Clement Street where about a year earlier Bob Swanson and I had mapped out the beginning of Genentech. We had recently returned from a visit to the University of Leiden where we successfully recruited a former postdoctoral fellow of mine, Herb Heyneker. Herb had just taken a faculty position at the university but agreed to join Genentech the following fall. We were to have dinner with Dennis Kleid as a possible recruit for Genentech's scientific team.
While we waited for Dennis to arrive we discussed one of the major concerns I had about Genentech's startup, namely the recruitment of bright, young scientists. Bob had arranged the dinner meeting to try and recruit Dennis to Genentech's embryonic research team. Dennis had just arrived at the Stanford Research Institute in Palo Alto and was in the process of starting a new department of molecular biology. Dennis's scientific interests were congruous with Genentech's application of synthetic DNA to molecular biology. After a dinner of French food and wine we left the restaurant with Dennis's assurance that he would seriously consider joining Genentech with one proviso, namely, that Dave Goeddel, a newly recruited postdoctoral fellow in his lab, would be hired as well. I soon met Dave for the first time at our pro forma interview. I immediately called Bob to tell him that Dave was exactly the type of scientist that we wanted at Genentech and that he would be a great complement to Herb Heyneker. My reservations about recruiting bright, young scientists to Genentech were diminishing.
Upon arrival at Genentech, Dave and Dennis were assigned to provide support for the human insulin project, which had been delegated to Art Riggs's laboratory at the City of Hope Hospital in Duarte, California. After a series of frustrating experimental failures at the City of Hope, Bob sent Dave to the Duarte labs with the charge to "get it done."
Get it done he did, with a vengeance. In a heated race with two premier scientific teams, one at UCSF and one at Harvard, Dave was the man of the hour with the successful development of a microorganism that would produce human insulin. His eclipse of the academic labs is thoroughly documented in Stephen Hall's book, Invisible Frontiers.
The next major research project at Genentech was the development of a genetically engineered microbial source for human growth hormone. Herb Heyneker, Dave, and Dennis Kleid were the principal scientists assigned to this effort. Herb Heyneker had arrived by this time and quickly became a close friend and scientific collaborator of Dave's. This was a period during which I got to know more about Dave and which was also the beginning of a lasting friendship. Tall, wiry, and bespectacled, what impressed me at the time was Dave's ability to focus on what had to be done and how to do it. I found this to be his modus operandi in everything he undertook. Although he claims in the oral history that he had been a "lazy student," I never saw this trait in his personality. With an impressive steel-trap mind (Dave's recall of sports statistics and records won numerous wagers for him), dedication (during one project he slept for six weeks in a sleeping bag in the lab), and sheer will (clearly entrenched in his demeanor through his notable rock-climbing talents and accomplishments), he led his research teams through one success after another. During his career Dave has been involved with the development of more biotech drugs than any other scientist in the field.
To think that Dave is all work and no play would be a serious misjudgment of his character. First of all, Dave was the number one practical joker at Genentech--and he had some serious competition. Dave recalls in his history that these were the early, wild days at Genentech. New recruits in his lab were encouraged to participate in a dexterity test in order to assess their laboratory skills. Balancing a nickel on their foreheads, they were instructed to drop it into a funnel inserted in the belt of their trousers. Suitably distracted by this time, one of Dave's conspirators would dispense a liter of ice water into the funnel. Others soon learned that they would lose a few dollars on a contest to outlast Dave at hanging by their fingers from the doorsill in the lab, not realizing this was a standard training exercise for rock climbers. These antics and numerous others were incorporated into the legendary Genentech ho-hos held on Friday evenings to balance the hard work and dedication. Hard work and hard play were to become part of the Genentech culture and Dave was the general.
One of Dave's passions is fly fishing, which is a passion we share and has resulted in our joint purchases of two fly fishing retreats. During breaks in the laboratory routine Dave would fish for striped bass in the waters of San Francisco Bay on the doorstep of Genentech's lab. On one occasion he cajoled Dennis Kleid to accompany him, and as a novice, of course, Dennis managed to catch a thirty-five pound striper. I remember the next day Dave excitedly taking me to the cold room to show me the prize catch, all the while Dennis displayed a neutral demeanor.
Our first of many fishing trips together was in 1982 when along with Tom Kiley we spent a week in Alaska. This became an annual excursion for the next ten-plus years, always with Tom and other scientists and friends. Dave was just as dedicated on the stream as in the lab, and he would have us fishing twelve or more hours a day in the prolonged days of those northern latitudes. It was always a challenge to try and keep pace with Dave on these excursions. One year Dave and I decided to spend the night in a collapsible tent beside one of our favorite Alaskan rivers, the lower Tularik. In order to be the first to fish early in the morning, with a few tins of sausages, water, and a .44-Magnum pistol to deter the ever-present grizzly bears, we crawled into our sleeping bags. No bears appeared, but a storm with 40 M.P.H. winds kept collapsing the tent on us, and I did not sleep one minute that night. In the morning I asked Dave if he got any sleep. He said no, and then reminded me that the miserable experience would result in us being the first to wet our lines in the lower Tularik that morning. Unfortunately the fishing was lousy that day.
Dave continually found new, interesting, and sometimes exotic fishing trips for our itinerary. On one disastrous fishing trip to the Yukon (we fished in a blizzard for two days), Genentech's stock price rose nine dollars and Dave mused that this was a reason to do more fishing. Ever competitive, Dave challenged me to see how long we could stand in the icy (four degrees centigrade) water of the Yukon River. While I managed fifteen minutes, Dave would last for sixteen.
In the early nineties, Dave and a fellow fishing enthusiast, Bob Tjian at the University of California at Berkeley, would name their new pharmaceutical company after our favorite river in Alaska, the lower Tularik. As Dave became more recognized for his accomplishments at Genentech as well as externally, Bob Swanson would encourage him to take on more managerial duties. And Dave consistently resisted these requests. So I was quite surprised when Dave confided in me that he was going to leave Genentech and start a new company with Bob Tjian. Dave explained that he wanted to take on the challenge and with success we would be able to spend more time fishing. I thought the latter to be an excellent reason for his new enterprise. Alas, our fishing has become more sparse as of this writing because of his new responsibility. But knowing Dave, it is just a matter of time. I confidently predict that sometime in the future Dave will have to bring his oral history up to date. I do find it amusing that Dave and Art Levinson evolved to the poisition of CEO, Dave at Tularik and Art at Genentech, two exceptions to the rule that scientists don't make good CEOS. The reader should keep this in mind when they read Dave's account of their assessment of management at Genentech; i.e., we could cut the number of employees by one half and double the output. [1] See page 141 of the oral history.
Dave Goeddel is a scientist's scientist. He was the role model for many of Genentech's scientists as well as non-scientists. His dedication and professionalism were directly responsible for the early success of Genentech. We can thank him for that.
Emeritus Professor of Biochemistry
University of California, San Francisco
and Co-founder of Genentech
Interview History
David Goeddel was selected for interviews in the history of biotechnology series because of seminal contributions to Genentech from the time that he arrived early in 1978 as one of the first scientists employed to work at the company's new facility in South San Francisco. In the company's previous two years of existence, its research had been contracted out to scientists at other institutions.
Goeddel, a boyish-looking twenty-six year old at the time he was hired, was not the initial target of Bob Swanson's effort to recruit a permanent scientific team for Genentech. Herb Heyneker, one of the contract scientists and soon to join Genentech's permanent staff, had suggested that Swanson contact Dennis Kleid, Goeddel's boss at Stanford Research Institute [SRI]. Goeddel had arrived there as a postdoctoral fellow in 1977, fresh out of graduate school and attracted as much by SRI's proximity to Yosemite where he could pursue his passion for mountain climbing as by his interest in applying the new genetic technologies. Kleid hemmed and hawed over Swanson's job offer, leery of leaving a secure position at SRI to join a risky new enterprise. If he decided to go, Kleid told Swanson, it would only be if Goeddel went with him. At that point only an add-on in Swanson's scheme, Goeddel leapt at the opportunity to apply recombinant DNA technologies for commercial purposes and immediately decided to join Genentech. In hindsight, his fast reaction and willingness to take risks can be seen to predict the tenor of his future course. Pulled along by his postdoc's decision, Kleid agreed to join Genentech.
With this introduction, the reader is now left to follow in Goeddel's own words what happened over his ensuing years at Genentech. Suffice it to say that Goeddel in short order became the cloner with the golden hands, at a time when the cloning of any gene was cause for celebration--and at Genentech the impetus for a publicity announcement. By 1980, Goeddel had become director of the company's molecular biology department, but not without stepping on a few toes in his precipitous rise. In 1993 he left Genentech to form Tularik with two other scientists. Within three years he was CEO. He explains in the oral history how his observations at Genentech have shaped his style as a chief executive. The Genentech influence was reenforced when he recruited Bob Swanson to chair Tularik's executive board. Not every Genentech spinoff enjoys such a close relationship with the parent company.
Oral History Process
Four interviews, each two hours in length, were taped in Goeddel's office at Tularik in South San Francisco. His remarkable memory was much in evidence throughout the interviews as he recalled names, dates, and events with seldom a pause. He returned the transcripts with slight editing. According to an agreement with Genentech, its legal department received transcripts of these interviews to review solely for current legal issues. As in all other instances to date, no changes were requested.
This oral history is a record of a scientist caught up in the process of "doing science," willing to give everything to reach a goal, and attempting to drive those around him to similar focused activity. His achievements at Genentech are already legend in the industry; evaluation of his achievements at Tularik in the business realm are a work in progress.
Historian of Science
Regional Oral History Office
The Bancroft Library
University of California, Berkeley
I Family Background, Education, and Early Career
[Interview 1: August 1, 2001] ## [1] ## This symbol indicates that a tape or tape segment has begun or ended. A guide to the tapes follows the transcript.
Focus on Sports
HughesPlease tell me about your family and your educational background.
Goeddel
My father is a physical chemist. I was born in 1951 and early on had an interest in science, and math in particular. That was probably partially influenced by my father. I was generally quite a lazy student. Science and math were easiest, so I gravitated toward them. My real interest was in sports. I just wasn't good enough to make it in sports. I would have much preferred to have been a baseball player or something. As a teenager, most of my time was spent playing tennis and mountain climbing.
Hughes
Where was this happening?
Goeddel
I grew up in San Diego County, in a small town called Poway. It used to be a small town; it's a little bigger now. I grew up on a small avocado orchard. Besides playing tennis, when I had free time, I tried to go to the mountains, the Sierras usually, and climb. It was more of an outcast-type sport than popular, as it is now. I assumed I was going to end up being a full-time climber or climbing bum or climbing guide, something like that.
Choosing a Major
HughesWhat changed?
Goeddel
Well, I went off to a local college, University of California at San Diego. The single main reason for going there was I could still live at home, save money, and then climb on weekends, breaks, and during the summers. My major kept changing. I was math first, and then physics, and then earth sciences, and ended up with a chemistry major.
Hughes
Why all those switches?
Well, math was easiest, so I decided to be a math major first. But after a year of it, I couldn't imagine, if I did end up with a job, being a mathematician. I just thought that would be a little too boring or unconnected to real life. Physics was the closest science to math. I had that for a year, and I had too much trouble with relativity.
Hughes
[laughs] You mean in a mathematical sense or in a conceptual?
Goeddel
Conceptual, yes. I wasn't smart enough to be a physicist is the main thing to say. Earth sciences--geology--I thought might be interesting.
Hughes
Tied in with your climbing?
Goeddel
But you had to take chemistry courses, and I took chemistry and ended up enjoying that well enough. So during my last year at UCSD, I said, "Well, maybe I should go to graduate school. I don't really know what else to do now. I don't really want to get a job."
Family Dynamics
HughesBefore we talk about graduate school, let's go back to your family. Are there brothers and sisters?
Goeddel
Yes, I have two younger brothers and one younger sister.
Hughes
What were the family dynamics?
Goeddel
My brother Peter is a year and a half younger than me, and he and I really did quite different things--had our own friends and everything. My sister Cindy is eight or nine years younger, and the other brother Mitch twelve years younger. I think what I had in common with them is they both loved sports just like I did. They had different athletic events, and as an older brother I would go to theirs, and then they would come to mine. It was a very competitive family in that there was always some sort of competitive activity going on in the family.
Hughes
Who generated the competition?
Goeddel
I think the competitive nature probably comes more from my mom [Barbara Goeddel], more than anyone else. We'd go on family vacations--who could spot the most animals out the window in the next two hours, or something. There was always some kind of competition. I grew up with it and didn't realize it until I would have friends over and they would always say, "Does everything have to be a competition here? Who can eat their dinner the fastest, who can do--?" It was only later that I realized, yes, I guess that's how I grew up--everything was a competition.
Hughes
Were you competitive when you were mountain climbing?
Goeddel
In some ways climbing is competitive. You want to get better. If it's a first ascent, you want to do it before somebody else. If a climb has already been done, you might want to do it in a
Hughes
Is there anything as competitive?
Goeddel
I think sports are--real sports, head-to-head competitions. Climbing doesn't quite fall into that.
Hughes
What about discipline in the family?
Goeddel
My dad was pretty tough. Things were reasonably strict, not outrageously so. I don't think we had any criminal activity in the family, or didn't get in trouble too many times for wild things that kids do growing up. I got arrested once for fishing where I wasn't supposed to--for crawling over some fences into areas that were clearly posted. But I enjoyed fishing so much that-- But getting arrested there and taken home and told how you can't do that, I was certainly scared enough that I didn't try it anymore.
Hughes
You mean you were told by your parents not to go there again?
Goeddel
Well, I think they were actually pretty easy on me. But just the way I had been raised, I knew that being arrested was not something they would like, and when I was being driven home in the police car I was terrified of my parents more than anything else. It almost would have been better to go to jail than to have to go see my parents.
Hughes
And yet their response wasn't too outrageous?
Goeddel
No, I had overestimated completely how they were going to respond. I think they actually probably thought it was funny and didn't tell me that at the time. They said, "Okay, you probably shouldn't do that anymore." But I had no further discipline.
Hughes
Did your interest in science create a special bond with your father?
Goeddel
I think not, because the types of science we were in were different enough. The special bond was more that he first introduced me to the mountains through backpacking trips. Later I became very interested in rock climbing, mountaineering, ice climbing, and so on. But it was having been introduced to going to the mountains and living there a week or two at a time that got me into it.
Hughes
So your father didn't have an expectation that one of his children, particularly his oldest son, was going to follow in his footsteps?
Goeddel
No, I wasn't pushed at all into science. Probably the only time ever he encouraged me was in the seventh or eighth grade when our school had a science fair and he said, "Well, are you going to do a project?" And I said I hadn't really thought about it. He said, "Well, I think you ought to do one." But if I had said no, I don't think he would have pushed too hard. And so I did a project.
I really think I got into science just because it was the easiest thing for me to do. I was a very lazy student, and I could get by with the least amount of work.
Hughes
Were there academic expectations of the children?
My mom, more so. I remember I got an A on a report card and I got a quarter. She was always reminding us of that.
Hughes
Was that an incentive?
Goeddel
Well, it was nice to get. When you got eight A's and you would get two dollars, that was pretty good. But I don't think that ever made me study or put more effort into it. It was nice to get, but it wasn't enough incentive to do the extra work to get the grade. I think it was pretty clear that good grades were expected.
Hughes
Did your siblings meet that expectation?
Goeddel
Over time in the family there maybe wasn't the same amount of pressure as there was on me. I know my youngest brother didn't get very good grades, and he has never said he was given a bad time for that. It may have been, when you're raising your fourth kid, you're not going to put as much effort into saying, "Hey, how are your grades?"
I did skip a grade; I never went to third grade; I went from second to fourth.
Hughes
Which meant, of course, that you were a little young for your class. Did that have any influence socially?
Goeddel
Yes, I think it did. I went from being the star of the class, both academically or intellectually and athletically, to-- The first few years, I was still the smartest in math-related things. In sports, which were very important to me, I was now average for a couple of years. That probably changed how I saw myself. I couldn't go out and dominate on the playground. I actually worked much harder at that, and it took a few years to catch up. At the time and the place, how good you were in sports had a lot to do with your social standing. It wasn't until later in high school that I was the best tennis player. We won two league championships.
Mountain Climbing
HughesWere you popular?
Goeddel
I wasn't one of the real popular ones. I wouldn't go to the dances or things like that. I would spend all the money I would save on climbing equipment. Weekends, Friday evenings, as soon as I was old enough to drive, or had a friend that could drive, we would leave to go mountain climbing somewhere.
Hughes
Your parents were comfortable with you being out in the wild?
Goeddel
My dad liked that I was doing it, extending what he had done in the mountains to a little more dramatic level. I think my mom was quite scared about the technical climbing. The one thing they did was insist that I buy and wear a climbing helmet. Now all climbers wear helmets. It's almost natural, like motorcyclists or something. But at that time, you were considered a sissy if you wore a helmet, even climbing. So I bought the helmet, would carry it off climbing
Hughes
How old were you when you began those technical climbs?
Goeddel
I had just turned fourteen when I started, but I couldn't get off and do much then, so it was mainly practicing on big boulders in San Diego County. But once in a while I would get invited with older kids who were sixteen and could drive. And my parents would let me go. If I got invited to go down to Mexico to surf for a weekend, they wouldn't let me go. Then I felt I was under restrictions. But anytime I was to go to the mountains to climb, that was okay.
Hughes
Did girls figure in your life then?
Goeddel
No, not at all. I guess I had one or two dates in high school, that was it, and that wasn't until my senior year. I was sixteen most of my senior year in high school.
Hughes
Yes, you were pretty young. You weren't a nerd?
Goeddel
No, I didn't fall into the nerd class or the very popular one. I had a lot of friends, was on a very good tennis team, and had good climbing partners, some of whom are still my friends. That's the kind of bond you develop climbing.
Undergraduate, University of California, San Diego, 1968-1972
Bruno Zimm's Laboratory
HughesNow, please go on about school.
Goeddel
I went to UCSD, and I spent a lot of my time there climbing and surfing. It was very convenient for surfing. I got by fine in school, didn't do great, but did okay. At the end of my time there, a very important thing was deciding to work for a quarter or two in the lab of a professor. I ended up in Bruno Zimm's lab. He's quite a famous physical chemist who had gone into biochemistry late in his career. Working in his lab, doing some research, I became much more interested in science. He encouraged me, gave me a list of graduate schools, and at the same time I was thinking, "What am I going to do? Maybe I should go to graduate school."
Hughes
Had you thought of graduate school before Zimm brought it up?
Goeddel
I had thought about it. I don't know if I ever would have applied. I think I applied late; it wasn't on the normal application timeline. But Bruno Zimm was quite helpful. He had gone through a list with me. I decided to head more toward biochemistry, and that was partially his influence. He was really doing physical biochemistry at that point.
Hughes
What were you doing in Zimm's lab?
He had built this device called a viscoelastometer that measured some of the physical properties of long DNA molecules. I had a project to try to work on this instrument that he was building to solve one of the problems. It was run by magnets, and this magnet-type device sat in the middle of this solution. It would turn slowly, and it could get off center. So my job was to try to figure out a way to keep it centered.
Hughes
The problem doesn't sound very biochemical.
Goeddel
Correct. It was measuring a biological molecule, DNA, and so it was an instrument to allow you to determine some of the features of DNA. Rather than learning something in a book, the idea was you were doing an experiment, trying to solve the problem.
Hughes
Did you like that?
Goeddel
Yes. I actually became much more interested in science then.
Graduate School, University of Colorado, Boulder, 1973-1977
Selecting Boulder
GoeddelSo when Zimm had given me this list, and I had thought about it, I looked on the list and right away there was one college, and I said, "Okay, I'm going there." It was University of Colorado in Boulder. The reason I chose it was that Boulder is one of the great climbing centers of the world.
Hughes
I knew it was coming.
Goeddel
So that's how I selected my graduate school. There's a lot of serendipity where your career ends up.
Hughes
You didn't know anything about specific laboratories at Boulder?
Goeddel
No. Zimm told me,"There's a couple of good people there," and he gave the names. I applied and I got in. I applied a few other places, but I had ordered them based on access to good rock climbing or mountain climbing. I got into all of them, so Colorado was my top choice and that's where I decided to go.
Marvin Caruthers's Laboratory
GoeddelI got there and I decided to go into the lab of a new professor who had just arrived that year. So Zimm hadn't even know about him in suggesting I go there.
Hughes
Who was that?
That was Marvin Caruthers.
Hughes
Why did you choose his lab?
Goeddel
I went around and talked to a few people. The fact that he was new and didn't have anyone in his lab yet made me think that I would get a little more attention early on than going into a large, established lab. Since I had worked so little in a lab before, I didn't feel real comfortable that I could just go in on my own and do something. He made it sound that I was going to get to do a lot of things, including physical biochemistry, which was kind of my interest then. By the time I got done, that was no longer really an interest at all--it was molecular biology. When I originally talked to Caruthers there was no discussion of molecular biology at that time.
Hughes
What was his background?
Goeddel
Caruthers was trained as an organic chemist at two famous nucleic acid labs: Robert Letsinger's at Northwestern and Gobind Khorana's, Nobel laureate at Wisconsin. Caruthers was with Khorana at Wisconsin and then moved with Khorana to MIT. So Caruthers's background was DNA synthesis. What he wanted to do in his lab was synthesize some important regions of DNA, in particular the lac operator, and study its physical interactions with the lac repressor protein. So that was the project, and I said, "That sounds good to me."
Hughes
Had you had any particular interest in DNA before meeting Caruthers?
Goeddel
No. I didn't take any classes in molecular biology until then. I was a chemistry major. I had taken Zimm's graduate physical biochemistry, but there were a lot of basics of biochemistry and molecular biology that I didn't know.
Hughes
You hadn't had any molecular biology, had you?
Goeddel
I took classes right away at Colorado. In the chemistry department I took biochemistry. In their molecular, cellular, and developmental biology department, I took a molecular biology class, right when I got there.
Hughes
Was that a good basis for what you went on to do?
Goeddel
Yes, very good.
Hughes
Do you remember who taught it?
Goeddel
Molecular biology was Larry Gold, who has since started a couple of biotech companies and remains a very good friend of mine. He taught my first molecular biology course.
Introduction to New Genetic Technologies
HughesWhat was the general state of molecular biology at that time? Let's see, when were you there?
This would have been the fall of '73. Molecular biology was just reaching the stage when it really became a major science. When I arrived at graduate school is probably when Boyer and Cohen were just starting their experiments.
Hughes
Was that work trickling into your consciousness?
Goeddel
Not at that time. I don't think it did until late '74. Then at some point it became clear that maybe some of this DNA I was synthesizing could be put to use in cloning experiments. The project I happened to have, which was ideally suited for applying recombinant DNA techniques, just happened to end up in a position near the end of my graduate time that I could jump into all aspects of recombinant DNA. I had had some training with Caruthers in the enzymology that was needed for isolating the kinases and the ligases and so on that were needed to assemble small pieces of DNA. We were using them to put our small pieces of DNA together, but those enzymes were also very useful tools for cloning. So my experience with DNA synthesis and enzymology, and this cloning technology especially helped at Genentech early on.
Hughes
How established were these techniques that you've mentioned? Were you following a recipe book, or were you creating as you went along?
Goeddel
You could probably say it was pretty much a recipe book, in retrospect. At the time, when you're a grad student, you think you're really doing things.
Hughes
Where was this technology coming from?
Goeddel
There were a number of enzymology groups, whether it was Arthur Kornberg or Bruce Alberts or someone else at that point that had methods for isolating the enzymes you needed. I think the chemistry came largely from Khorana.
Hughes
Through Caruthers, right?
Goeddel
Through Caruthers.
Caruthers's Working Style
GoeddelCaruthers had been at Khorana's lab for five years, and one of the major people there. So he knew how to do a lot of these things. He would come in the lab on Saturdays, work with us and show us things, and we would work all week, and if we had problems-- That first year, Caruthers had a lot of time to show us various techniques in the lab. After the first year we were pretty much on our own.
Hughes
Because he got busy?
Goeddel
He got busier, and we knew what we were doing. We had then moved beyond the stage where he was experienced in the lab. We were better able to access the scientific literature and bring those techniques into the lab. But the first year he was very--.
Hughes
He was very accessible. Were you having conceptual conversations as well as technological?
Yes, a lot of those.
Hughes
Give me a flavor of what went on.
Goeddel
He was always thinking big on what we were going to get done in the future. So that was fun, throwing out ideas. A lot of the things we never ended up doing.
Hughes
Was Caruthers thinking in basic science terms, or was he thinking of practical application, or both?
Goeddel
I think purely basic science, at that point.
Hughes
Can you remember some of the ideas that he was tossing around?
Goeddel
The biggest one was, we're going to understand how DNA is regulated by proteins. Gene regulation is still a big topic now, but in the '70s that was what everyone was interested in--how are genes turned on and off? The lac system in bacteria was reasonably well understood genetically, but his big ambition was to isolate enough lac operator DNA and enough lac repressor protein, co-crystalize those, and determine the three-dimensional structure to understand exactly how this functioned. Twenty-five years later it wasn't done. We did a lot of pieces of it, but the actual crystal structure, no. My first year as a naive grad student, I figured by the time I was done in four years, I was going to have the crystal structure solved. He had me believing that--thinking big.
Hughes
Was his lab set up for that?
Goeddel
No. He was setting up his lab from scratch. He was in a university with a lot of expertise and places to collaborate. He was clearly thinking bigger than the capabilities of the lab at that time and the number of people. He didn't have a lot of postdocs. He had none the first year, and then he got one the second year who was really lousy because Marv hadn't established himself yet. So he had to build his lab with students.
Hughes
You said, "We did a lot of pieces of it--" Who was "we"?
Goeddel
There was a group of three or four of us that first year. I was the only one in the first group who got a Ph.D. Daniel Yansura, who's still at Genentech, got a master's degree. I worked with him for four years there, and after I came to Genentech I hired him within a few months.
DNA Synthesis
HughesWere you working together on similar projects?
Goeddel
We were collaborating on the lac program. It was a big enough thing. Probably 90 percent of what he and I did in graduate school we did collaboratively.
Hughes
Describe that project.
Starting with monomeric building blocks, we would synthesize DNA fragments anywhere from six to thirteen nucleotides long, which is as big as we could synthesize chemically.
Hughes
You? Or anybody?
Goeddel
Well, anyone from Caruthers's lab. At that time anything bigger you would have such a small amount as you increased the size that the yield would be so low that you would almost have nothing to work with. Since you couldn't clone them and make more, I think thirteen to fourteen-mers was the practical limit chemically. But then you can assemble those pieces enzymatically to make longer pieces. You would add a fourteen plus a six, and you could make twenty enzymatically. But adding them chemically, you would just take too big of a hit in your yield.
Hughes
Why does the yield drop?
Goeddel
Just the amount of material you can work with. Each coupling, maybe you get a 20 percent yield chemically. And then you'd have to purify it, so you maybe lose 50 percent. So overall, every time you do a coupling, you only got 10 percent of what you started with. In our case we would almost run out of material by the time we reached thirteen or fourteen.
##
Hughes
Were you focusing on what was going on elsewhere in your field?
Goeddel
Not very well. I was really focused on what we had to get done. For about a year and a half it was mainly nucleic acid organic chemistry--trying to make the lac operator. The lac operator is twenty-six base pairs, which means fifty-two nucleotides of DNA. It took Dan Yansura and myself about a year and a half to make that fragment of DNA and assemble it. Then we could start doing experiments--testing how it interacted with lac repressor protein that we had isolated.
Hughes
So it wasn't enough in those days to have built the lac operator?
Goeddel
No, I think at that point, enough DNA chemistry had been done in Khorana's lab that we probably could have gotten a master's degree for doing that, but not a Ph.D.
Hughes
It was sort of the way cloning was at one point; you could write a paper on cloning a gene and get it published.
Goeddel
Just clone something, right.
Hughes
Who else was working in the area of DNA synthesis, aside from Khorana?
Goeddel
There was Saran Narang who worked with Ray Wu at Cornell. Narang had been trained by Khorana. And then out of his lab was Keiichi Itakura, who really made some major breakthroughs in changing some of the chemistry and making it cleaner.
Hughes
Were you aware of these people?
Goeddel
I was aware of Narang. Probably it was '75 or '76 I became aware of Itakura when he went to City of Hope. I guess Art Riggs had helped recruit him there.
Why did you become aware of Riggs?
Goeddel
Riggs was a big name in the lac operator field, and so I was familiar with all of his work. Caruthers had made it clear to us that we were competing with Narang, and Wu perhaps, on trying to do some of the same projects. I don't remember the exact time I first heard of Itakura. But it was clear there was some person with Narang who was good at improving the chemistry so that the triester chemistry was becoming competitive with the diester chemistry that we were doing. Maybe it was in '76 I went to a meeting at Cold Spring Harbor on the lac system. Maybe Itakura was there. That may have been where I met him. But Riggs I knew from the literature even before the meeting.
Hughes
So you were reading the literature?
Goeddel
Yes, things directly relating to my work. I wasn't the type of person that would read Science or Nature, all the articles, and know what was going on.
Hughes
Is that still true?
Goeddel
I read a lot of abstracts now. It's impossible to keep up. I think the early '80s, late '70s, was probably the easiest time to keep up with the literature because a lot of people were doing cloning, so there were a lot of articles on that. I was familiar with the field so I could easily read and keep up. I think now there are just so many journals and so much stuff that--
Hughes
No one person can absorb it all, right?
Is the competitive theme that seems to be running through your early life carrying over into the Caruthers lab? Did he set up a competitive environment?
Goeddel
As a scientist, I didn't see him as being especially competitive, compared to others I have seen. He's just a real nice guy; here's a good project; "Let's do it." Sure he wanted to win, but he would never be obviously competitive. But I tried to get everything done as fast as I could. I wanted to graduate as fast as I could.
Hughes
Why?
Goeddel
I don't know; I think I was different. Some of the students there were like, "This is a great life, just being a student." I think partially I wanted to get back to California to be near Yosemite. There was still some climbing in Yosemite that I wanted to do.
Hughes
So it was still not science that motivated you?
Goeddel
Right. But I do have to say that, especially the last two years in Colorado, I did a lot fewer climbs than I expected. I was more interested and dedicated in the lab, and it cut into the climbing time a lot. So there were a lot of things in climbing that I wanted to do in Boulder that I never got done.
Hughes
Anything more to be said about that Colorado period?
No, I think that I just happened to get there at the perfect time and get in the perfect lab. So for me, ending up at Genentech when I did, the training probably couldn't have been better than what I had.
Becoming Aware of Recombinant DNA
HughesTalk about how you became aware of the Boyer-Cohen work and what the implications were for basic science.
Goeddel
I think Marv came in one day when I was doing a chemical reaction and was explaining something to me and how exciting it was. I don't know if he had just read a paper or been at a meeting or seminar. It was about the Boyer-Cohen work. He explained it, and I really didn't understand it. I got parts of it and not the others. I was busy doing an experiment and couldn't go to a board like I usually like to. It is much easier for me to visualize things if someone can draw them.
Hughes
When would that have been?
Goeddel
[pause] Seventy-four, maybe.
Hughes
The three papers on cloning came out in '73 and '74.
Goeddel
It wouldn't have been '73. So it would have been '74. Caruthers had an idea of how we could apply this to what we were doing.
Hughes
Which was what? How did he explain it?
Goeddel
Well, I didn't understand. There wasn't one point when, ahhh, it all clicked in. And then it was students' talk, and then you see the paper. I think it never hit me instantly like, "Oh, this is going to revolutionize science." It was more of a gradual thing over a few months, where I went from not understanding much at all the first time Marv had told me, to all of a sudden, "Oh yes, I know this [recombinant technology] is going to be very important." It wasn't like other things in science, where you go from not knowing anything at all to, "Oh great!" This just didn't happen like that. It may have been that I was still more focused on chemistry and not biology.
I do remember at a later point talking with Larry Gold who taught that molecular biology course and explaining to him a cloning experiment that I wanted to do with the lac system. I thought it was pretty funny because he said, "That cloning is just going to be fad. It will go away." So even some professors who ended up doing a lot of cloning still didn't have a complete understanding. It wasn't that everyone saw, hey, this [recombinant technology] is going to revolutionize science.
Hughes
It sounded to me from what you said that Caruthers got pretty quickly how recombinant DNA could feed into what presumably was his primary interest of DNA synthesis.
Goeddel
Well, his interest wasn't DNA. He'd been a chemist, synthesizing DNA. But it was clear when he came to Colorado that he just wanted to use that as a tool to answer biological
Hughes
Do you think Caruthers was ahead of the game in terms of biologists in general?
Goeddel
I don't know if I would say that. Anything new, he was the type that would come in the lab and talk and try to get you excited. "Hey, why don't you guys think about doing this?" He would never say you have to; it was always just throwing out the ideas for the students. Which was very nice. We could decide what we wanted to do, but he would generate new ideas.
Caruthers had another characteristic I really liked: he didn't worry about dumb ideas. He would come in and tell you a lot of the times just stupid ideas. He would throw them out--"How about this? How about that?" He didn't tell you how to do it. Some of them you would say, "That's a good idea. Maybe I'll go try it."
Hughes
So it was a freewheeling setup?
Goeddel
Yes.
Hughes
Were you also tossing ideas around with this small group that you were working with?
Goeddel
Mainly with Dan Yansura. Dan and I were in the same small lab. There were other people over the years who joined the lab group, but they were in different physical laboratories. We did a lot of things with them, too. It could be practical jokes or our intramural sports teams or whatever. The lab got along very well. But regarding science, it was usually Dan and me who were always working together on the same project and who thought a lot alike who interacted.
Postdoctoral Fellow, Stanford Research Institute, 1977-1978
A Missed Opportunity with Tom Maniatis
HughesThe next step, I believe is Stanford Research Institute.
Goeddel
During my last six months at Colorado, when it was clear that I was going to start writing my thesis and get out, I decided to apply for jobs. I wanted to be in California because of Yosemite. I looked around for ads in Science and Chemical and Engineering News and other places, and there really wasn't much for people with my training. At that point, most academic people did a postdoc. I felt I had learned enough how to do science that I really didn't need a postdoc. And Marv didn't try to say, "No, you have to do a postdoc."
Hughes
Why do you think he was loose about that?
Goeddel
Maybe he just knew I wanted to go get a job and--.
Get on with it.
Goeddel
Yes. However, there was one scientist who came through Colorado and gave seminars two different times. I really liked his work. He was young, he was starting out, and I did want to postdoc with him. So I applied to do one postdoc, and that was with Tom Maniatis, who was at that point coming from Cold Spring Harbor to Caltech. I didn't get accepted. That's one place I would have done a postdoc.
Hughes
Was it Maniatis who attracted you, or what he was interested in, or both?
Goeddel
Just his approach to science. He tackled very interesting problems, I thought, and did them in a very logical, intelligent way. I just said, "I could learn something being there." A lot of people would come and give talks and I would say, "Why would I need to go and get trained to do that? I could figure out how to do that." I was very disappointed when he didn't respond to my applications. He told me a few times years later that his biggest recruiting mistake ever was not taking me into his lab.
Hughes
I wonder how your life would have been different.
Goeddel
He claims I would have gone to Genetics Institute, which he founded, instead of Genentech. And Genetics Institute would be in a different position right now.
Hughes
[pause] That's interesting to think about, isn't it?
Goeddel
Yes. Well, he told me, "I only had a small lab. I could only take a few people, and I got two applicants from Colorado." The other one was Dick Lawn who ended up at Genentech later. But Lawn came out of a more famous lab than I did, so Maniatis took him.
Hughes
And what lab was that?
Goeddel
David Hirsch in the biology department. See, I was in the chemistry department which was probably less interesting to Maniatis.
Hughes
What was Maniatis doing at that point?
Goeddel
Well, he made the first human genomic DNA libraries for screening. He was studying globin gene regulation. He'd been a postdoc with Mark Ptashne at Harvard. They worked on the lambda bacteriophage regulatory system--lambda operator, lambda repressor--which was similar to our lac. They had done very good work. He had moved to Cold Spring Harbor and performed the first cDNA cloning experiment. Some people say Winston Salzer did; some say Maniatis. But one of the first, which was cloning human globin cDNA.
Hughes
And all this had happened--?
Goeddel
The globin cDNA cloning happened in '76, I guess. Maniatis was going to start working on a human genomic library. I would have done something like that as a postdoc there. It sounded very interesting and breakthrough science, so I would have done that.
An Offer from Dennis Kleid
GoeddelBut I ended up applying to a number of places and got a call from Dennis Kleid at SRI [Stanford Research Institute], who had just started a molecular biology lab there.
Hughes
Whom you hadn't met before?
Goeddel
I had not met him but Marv knew him because they had overlapped. Marv was at MIT one year when Kleid was at Harvard, and they met each other for some reason.
Kleid said, "We're setting up a molecular biology lab at SRI." Even though it was a postdoc position he made it sound like it wasn't. He said, "I've got money; I can hire somebody." Marv must have told him on the phone when Dennis called for a reference that I didn't want to do a postdoc. Kleid said, "You can get your own grant money and run your own lab. I'll start you in mine; you can work on some of my projects."
Kleid was very good in that way. Recruited me, made me feel like I wasn't a postdoc, that I was partner with him. That was kind of his style. I went in and early on started working on his project and did write a grant, with his help, that was submitted probably in December. Then I met Swanson in January and got hired at Genentech in February.
Hughes
So December of '77?
Goeddel
Yes, I think I started at SRI in July of '77 and started working on a couple of Kleid's projects.
Hughes
What were they?
Goeddel
He was interested in studying DNA repair. We started out with some synthetic DNA cloning.
Hughes
Was he interested in you because you knew--?
Goeddel
I think he was interested in getting anyone in his lab to get started. And when my application came through to SRI it looked pretty--
Hughes
Right on.
Goeddel
Yes, it would fit right in with what he wanted to do. So I went out there and interviewed, and he offered me the job right away.
Hughes
What convinced you that SRI was the place to be?
Goeddel
It was the only place I got an offer.
Hughes
Oh. [laughs]
Goeddel
But it sounded good. I liked Menlo Park, when I went to see him. It was close to Yosemite. And it was starting up a new lab that was small. He was hiring one other guy, John Little. There were just three of us in the beginning. And we could build it if we wanted. I think Kleid's approach to not making me feel like a postdoc but more of a partner was very good. Of course I didn't stay there very long.
Why did SRI want a molecular biology lab?
Goeddel
Kleid told me the story, but I don't recall how he ended up getting there and getting that started. He was from Napa, and he wanted to come back to this area after being on the East Coast. He convinced SRI to do this and wrote a grant and got it funded. SRI was pretty much a place that if you had grant money coming in and paid the overhead, they gave you the lab space.
A Project to Clone Synthetic Genes
HughesSRI is not a basic science institution, is it? Isn't there a more practical orientation?
Goeddel
Right. I'm not sure how Dennis made that point with his DNA repair. The grant I wrote was actually very similar to the work I ended up doing at Genentech, which was cloning synthetic genes to make peptide hormones. So what we decided to do was pretty much the application of recombinant DNA technology. It was submitted in December. We probably wouldn't have heard for at least six months. In January I met with Swanson; February accepted a job at Genentech and withdrew the grant. It maybe would have been turned down, but it never got that far.
Thoughts on Leaving Academia
HughesWere you thinking about the fact that you were moving away from academic basic science?
Goeddel
That didn't bother me at all.
Hughes
Why?
Goeddel
I thought you could do just as exciting science outside academia, and here was a lab I could do the same sort of thing I could do at a university. I wouldn't have to teach and be on committees. If I could get the grant money, I could spend all my time doing research, build a lab with a few people. I know Kleid thought SRI could be a good place to pursue a scientific career, and I was convinced of the same. The fact that I was twenty-six then and able to write a grant, and if I got funding, they were going to give me lab space--it was going to be my program--was pretty attractive.
Hughes
Was anybody telling you that you were crazy to give up the possibility of an academic position?
Goeddel
No. If I had been at Stanford or UCSF or Harvard or MIT, then maybe they would have. But I wasn't really in the mainstream of the two coasts where I had come from [Colorado].
II Genentech, Inc.
Goeddel and Kleid Join Genentech
HughesTell me how you heard about this new company, Genentech?
Goeddel
I think it was through Dennis Kleid. He had a party at his apartment, and I met a guy there named Herb Heyneker, who I'm not clear how Dennis had originally met. I talked to Herb, and he had been working on the somatostatin cloning in Boyer's lab. It was then through Heyneker that I heard about this guy Swanson who was going to start a company. Herb had said he maybe would come to it if Swanson wanted him; maybe he wouldn't. But I got interested: Ah, someone's going to form a company around this technology and try to make drugs. That might have been October, November of '77, something like that.
Later Dennis, I believe, got a call from Herb Boyer, and Boyer had gotten Kleid's name from Heyneker. He asked Dennis, would he be interested in joining this company that had been just an entity funding work before but now was really going to exist as a place? So Kleid went out to dinner with Swanson and Boyer. When he got back that evening he was really excited and called me up in the evening to tell me about this dinner. "These guys really believe they can put a company together and get drugs like insulin." And I said, "Boy, it sounds great." We talked quite a while. Maybe that was Friday night or something, so maybe it was the next week at work, or maybe the next day, we talked about it some more. I was really interested in the idea of taking this new technology and doing things that couldn't be done otherwise that had practical value. Kleid over time seemed to get less interested. He was excited after the dinner, but then it would kind of wear off. "It's risky," and so on.
Hughes
His fear was that the science was not going to pan out commercially?
Goeddel
Well, here he is at SRI; maybe he's got it made if he can just write his grants. And he's going to risk that to go to a company trying to start a new industry?
Hughes
It was a little risky, wasn't it?
Goeddel
Yes. I said, "I think you ought to get back to them." He said, "Okay, I'll talk to them again." So he talked to them and came back to me and said, "I told them about you and that if I was going to go I would want you to go too. So Swanson wants to come meet you." So Swanson came to SRI--I don't know if it was December or January--and had lunch with me. I really hit
Hughes
What did you tell Swanson?
Goeddel
It was just a general conversation, like what did I want to do in science, and what would I think about these things that they were going to try to do. At the end of lunch he says, "Well, I would really like for you to come to work for Genentech."
Hughes
Did he have an understanding about how your expertise would fit into his program?
Goeddel
I really don't think so. Kleid had been recommended by Heyneker. Boyer really trusted Heyneker, who had done work for him. Kleid was telling Swanson I was a great scientist, and he should hire me. Bob said, "I really want to hire you, but I want you to meet Herb Boyer, my partner." That was probably the scientific check.
So I went up to UCSF and spent a half hour, hour, with Herb. Herb was very low key, so there wasn't any grilling: "Do you know how to do this or this?" I think partially it was that Kleid had recommended me, and partially that some of the guys [Boyer and Swanson] wanted to get they hadn't been able to get to commit yet. They couldn't get any of the more famous UCSF postdocs signed up yet.
Hughes
Why?
Goeddel
That was related to what you asked earlier: Weren't you wrecking your career by going into industry? Yes, that was the feeling. I didn't worry about that at all. I thought this was the most exciting thing possible, and I couldn't wait to get an offer. Swanson said, "I'll get you an offer letter." Then each day I would look in the mail, and I didn't get anything.
Then I went off with Kleid to a scientific meeting on DNA repair in Colorado at Keystone, and when we came back we both had an offer letter. I looked at mine and I said, "I'm going," and Dennis really couldn't decide. He had a hard time. He almost said, "Why don't you decide for both of us," even though I was his postdoc. He said, "If you go, I guess I'll go." But it wasn't nearly as easy for him to make the decision as it was for me. In fact, I went as soon as possible and started work at Genentech a month earlier than Dennis.
Hughes
When would that have been?
Goeddel
I think I started March 1st and he started April 1st of '78. If I had been hesitant at all I think he would have stayed at SRI. I was the guy in his lab, and I said, "I'm going," so he had no one left in his lab. I think he just decided to come along.
Continuing Associations with SRI
HughesWas that the end of molecular biology at SRI?
No, because then real quickly other people applied there. Dennis hired and brought in two guys, put them on the grant, and we had an overlap period where we would sometimes go back for a few hours a day during March, April, probably even May. We would use some reagents there. I remember we would fill up our distilled water jugs there, as Dennis transferred his grants. But it was kind of the end of it because they weren't the same quality people as he was. I never kept up with what happened at SRI after that.
Hughes
You were getting distilled water because you didn't have any yet at Genentech?
Goeddel
Yes. Well when we started there, the glassware washer came in and we had to work with a plumber to assemble it. We had to pick up dry ice somewhere else in South San Francisco to take to work. Bring in distilled water from SRI. Certain experiments were still performed at SRI during our time there.
The Early Days of Genentech in South San Francisco
##
Brian Sheehan and Sharon Carlock
GoeddelFurthest away from the Bay was the Genentech building. There were, I think, just three offices: Swanson had one and there were two others that the early scientists would share. One lab was being built.
Hughes
Who was there?
Goeddel
My first day of work there was Bob Swanson. He'd hired a guy named Brian Sheehan who was in charge of manufacturing. That's pretty funny because we didn't manufacture anything for years and years. But it sounded good. He was vice president of manufacturing. I think it was part of the financing side of things, to make it sound like we had products. Sheehan came from the pharmaceutical industry. And then there was Bob's secretary, and that was it. So I was the first scientist. When Kleid arrived, April 1st, he was the second.
Hughes
Bob's secretary had to be let go because she was rude to the scientists?
Goeddel
Yes. Sharon Carlock. Dennis Kleid always called her Sharon "Carload." Dennis was terrified of her, and she knew it. She tried to boss everyone around; she tried to run the company. And if someone was tough and would just give it right back to her, like me, she'd leave you alone. But Dennis was easy to intimidate. He and I carpooled together from Menlo Park. I would have to drive my car around in the back and pick him up going out the back delivery side of the warehouse so he wouldn't have to walk by her if she was still there, he was so afraid of her. She was always yelling and screaming at him. It was so ridiculous. She'd come in and tell us we couldn't put up posters on the wall. Or, "Dennis, why didn't you interview this person when you were supposed to?" It was very strange. She was giving him a bad time all the time.
Hughes
How was she with Bob?
She got stuff done, so Bob thought she was okay. I think the main thing was, Bob wanted us to be one happy family. Early on, he hadn't managed people, and instead of seeing someone was causing problems and just getting rid of them, he tried to ignore it and make them work together.
After Herb Heyneker came in September--it was about a month later--Heyneker, who had known Bob a lot longer, went into his office and said, "Bob, she's got to go. It's either her or me. I'm going back to Holland." Herb told us, "Bob's going in, don't worry Dennis, I'm taking care of this. I'm telling Bob I'm moving back to Holland if he doesn't fire her." Herb came back into the lab, and Dennis said, "Did you do it? Did you do it?" And he goes, "Well, you can't believe it. Bob convinced me that I have to go out to lunch with her and work out our differences." Then Bob called me into his office, and he asked me to go as the mediator to lunch with them, "to make sure they didn't kill each other." They had a nice lunch and talked it over. The lunch went fine. Two days later they were screaming at each other again. Eventually--and I don't know when; it seemed like it took a long time--Bob let her go.
Bob Swanson: Impressions and Interactions
HughesWhat were your first impressions of Bob Swanson?
Goeddel
This guy had a vision of what he wanted to create, and he was going to do it. I liked his confidence, his enthusiasm, and then early on when I was working there, the way he would show so much interest in what you were doing, even if he didn't completely understand coming into the lab and making you feel like what you were doing really was important. He was counting on you and everyone else.
Maybe some people would say that he would pressure you because it was always, "How much longer is this [experiment] going to take? And this?" That had the effect of making me work harder and harder. "Is that result good or is it bad?" And if it's good, great, he was so excited. And if you said, "This one is bad; I'm going to have to redo it," I could see it was tougher on him than it was on me, because as a scientist you have a feel for it. With him it was more, "Is it a 'yes' or a 'no'?" And if it was a "no" you could just see how that depressed him. He's worried; so I'd better go fix it fast. I got along great with him and really liked that style he had of being interested and when you feel your own work's important.
Hughes
Was his a genuine interest in how the science was progressing, or was it, "Oh my god, if this experiment fails, what's the future of my company?"
Goeddel
I think it was probably the latter. Well, he was interested and it was competition. Again, it was pressure that I liked. "We have to get this done; we have to get it done fast or we're going to run out of money." Okay.
Hughes
Was Bob competitive in the same way you were?
Goeddel
In a different way, but he clearly wanted to win. He was competitive.
Hughes
How was it expressed?
Just the fact that he would be in the lab everyday wondering, "How is it going? When are you going to get the next result? How long is this going to take?" For a few years he was like that.
Hughes
Were there people in the early days who collapsed under that approach? Or was it self-selective?
Goeddel
I think it was self-selective, and the important things ended up in the hands of people that could handle it. Bob had a good way of doing that that I didn't really see at first. Even though I was the youngest of all the scientists of the first group he hired over the first couple years, by September of '80 he had me directing that whole group. Before that, every time there was an important project, whatever he ranked the highest in his mind, ended up being my project. Somehow he got it there without too many other people upset that I got the best projects each time. So I think he was competitive and wanted stuff done and didn't give people who would wilt under pressure the high-pressure projects. He had a way of getting [the projects] to the right places.
Hughes
So he was a good reader of people?
Goeddel
Yes, I think so.
First Impressions of Herb Boyer
HughesWhat about Herb Boyer? What do you remember of that first meeting?
Goeddel
Herb was much lower key than I had expected him to be, knowing of his work. I think that really helped Genentech early on too. He wasn't the type of guy to use his fame and come in and try to say, "I'm running the science here, even though I'm a professor." The stories of some of the other people at that time with other companies were that they tried to still be the big-shot professor and tell the companies how to run. Herb didn't do that at all. Bob would try to get him to come around, and I don't think Herb came as often as Bob wanted him there. But when he would come, Herb would come around and say, "Do you have problems or issues? What are you working on?" And he'd try to give advice. Other things he would say, "That's up to you. I can't help you on that. You're better at that than I am." He said, "This is your project; you're going to get credit." He wasn't putting his name on the papers. I think his approach of letting the young scientists do the work really paid off well.
Hughes
Did you have the feeling that he was engaged in what you were doing? That he was interested in the science?
Goeddel
Oh, yes. He was very interested. What I realized early on--I didn't realize it instantly, but I did fairly soon--was the history of cloning was very short. These new things we were doing, trying to express [proteins], he had no experience in. So he really couldn't help us. We were the ones doing it. He would say, "Hey, you guys have to figure it out. That's your work." He would push it right back to us. So it didn't take too long to realize, yes, he's not going to be that helpful on how we do the experiments. He can be more helpful on big picture items.
Hughes
How did you feel about that?
It was great. It made it so exciting every day to go to work. Scientifically, '78 to '83 was the most exciting time of my career because every day we were doing something new, trying to do things that hadn't been done. When you accomplished them, you could see that this could become a new medicine. It was very exciting. I would call those five years the golden days of recombinant DNA technology.
Herb Heyneker
GoeddelThen, there was the quality of people we had there to work with--sharing a bench with Herb Heyneker who in my view is one of the best scientists I've ever worked with. He didn't get recognition for that because he never finished any projects, or hardly ever did.
Hughes
Why?
Goeddel
He was more of a tinkerer, working out a little technique for this or that to help you out. So having him on the same bench, he taught me a lot of things, helped me do things faster, was always willing to help out. But you couldn't give him a major cloning project and say, "Start to finish, this is yours," or, "Finish it off." He would do some of the interesting things, then he would get interested in something else. But it certainly helped me to have people like that right there working with me.
Hughes
Heyneker, of course, had come from Boyer's lab. Was he more interested in working things out so that eventually there would be a product, rather than in the basic science aspects of recombinant DNA?
Goeddel
I think Heyneker was interested in all science. What he liked to do was what we came to call "Heyneker experiments," meaning they were short. You could, start to finish, work out something in a day or a week or two weeks. So projects like cloning interferons, starting at the beginning, that is going to take you a year, two years, five years--who knows? Those weren't suited to Heyneker. That was the type I would like. Someone tell me where is the endpoint I have to get to and I want to get there first. And by any means, I am going to get there first.
Devising Procedures for Speed and Efficiency
HughesWhat was Heyneker's reaction?
Goeddel
He loved that I would work on that, but he would say, "Hey, this step you're doing here, let's speed it up. We can make this faster. I'm going to work out a technique that will allow you to do things way faster. Not only will you be able to do it on your project, this other guy will too." So little tricks, from improving expression to running your gel electrophoresis in one hour instead of two hours. When I worked with him sometimes he would say, "This is taking too long. Let's figure out a way so we can get the result in one hour."
Hughes
Which fit right in with what you were trying to do.
Yes. You save that hour every day for a year, and all of a sudden you would have saved a month of time. Or, "Let's figure out a way to lay out all our tubes for our experiment. We're not going to take time writing the numbers on them. We're just going to keep them in this order, load the centrifuge this way." Just little tricks, all the time.
Hughes
You were interested in speed, weren't you?
Goeddel
Oh, yes. I loved the ideas Herb had, and I would instantly put them to use. We would have competitions. He and I would set up gels and say, "Let's see who can load all of their samples the fastest, run the gel, and get the result." There would be a day when we would have a really boring set of experiments that would take all day, and by turning the day into a competition all of a sudden we would save two hours there, because we wouldn't take any breaks, no talking. He was really fun to work with.
Hughes
You wouldn't on your own have taken the time to develop these shortcuts?
Goeddel
Some of them I would have, but not nearly to the extent that Herb did. So he was a perfect guy to share that lab bench with.
Hughes
I've recently received the transcripts of your testimony in the Genentech-UC case. The point was made that a certain technique would take a day, let's say. And you said, "Oh no, that can be done in four to six hours." I implied from your remark that other people might be satisfied with doing things in the old tried-and-true manner, but people at Genentech were always looking for faster ways. [1] Goeddel testimony, Regents of the University of California v. Genentech, Inc, no. C 90-2232 CAL, United States District Court, Northern District of California, May 4-5, 1999.
Goeddel
We were always trying to speed things up. Always.
Hughes
Did that ever lead to disaster?
Goeddel
The technology was so new that there would be experiments that would fail, but in the end that approach always paid off in the long run. Everything we did, every new project, we could improve how it was done. I think part of the evolution of Genentech was having so many good people trying to do things better all the time.
Hughes
I imagine you were not taking time to publish these shortcuts. Did they become trade secrets, proprietary information?
Goeddel
I think over time they became standard. We weren't trying to keep little tricks secret, and they would leak out. We would have visitors come in; there would be collaborators. People from Boyer's lab would come by, and they would go off to another university. I'm sure a lot of the things we thought we were inventing--these new quick techniques, or how to make plasmids by eliminating a number of steps, whatever it was--were being done independently in other places and eventually published in methods books.
Interactions with UCSF
HughesHow much interaction was there with the Boyer laboratory and other laboratories at UCSF?
Goeddel
I don't think there was a huge amount. Maybe socially, people who had known each other. I think collaboratively, after '78, almost none. In '78 Keith Bachman, who was in Boyer's lab, spent some time doing experiments for a few weeks at Genentech. And I think it was '78 or '79, Dan Vapnek did a sabbatical with Herb, and then he came by Genentech for a while. He ended up running all the research at Amgen for at least ten years. He was a professor, then, who had done a sabbatical with Herb, and after being there and seeing Genentech I think he got interested in the biotech industry.
As far as straight collaborations, I think in those early days there weren't many. Bob probably would not have liked it then, although scientists went to meetings and talked about their work. I'm trying to think when the first collaborations came up, but I can't remember that.
Hughes
Why wouldn't he have liked it?
Goeddel
Bob was always a little more worried than Herb about publications and other people knowing what we were doing. There was probably a healthy tension--Bob at one end, Herb at the other. And somewhere in the middle was how the company worked.
Hughes
Can that difference in attitude in part be explained by a combination of background and personality?
Goeddel
Yes, right.
Plasmid Development, DNA Sequencing, and DNA Synthesis
HughesYou mentioned plasmids. People like Mary Betlach and Paco Bolivar and others were developing new and better plasmids. Were you paying attention to that work?
Goeddel
Yes. Heyneker had been a part of that when he was in Boyer's lab, And Pat Green was in the lab too. Paco worked on some of the projects with us. He was part way in Herb's lab and part way in Genentech. In fact, we thought we had him hired for a while, and then he went back to Mexico. But he would occasionally come up and come by. He would be on vacation from Mexico, and he would come by. To him, vacation might be working a week in a lab, helping us out, and doing some DNA sequencing with us.
Hughes
At what stage was DNA sequencing by the time you got to Genentech?
Goeddel
It was the early days of the Maxam-Gilbert technique. It was pretty laborious.
Hughes
Who was doing it?
Kleid, Heyneker, and I. Paco did some early on. After we hired Dan Yansura in June 1978, Dan was doing more of it than anyone else. But pretty much all of us had to do some.
Hughes
Why?
Goeddel
I think it wasn't until 1980 or late '79, Axel Ullrich suggested to all of us, "Why is everyone doing their own DNA sequencing? Genentech could be more powerful if we had one lab that did DNA sequencing for all of us, had a support facility for us."
Hughes
The same thing with DNA synthesis, right?
Goeddel
Well, with DNA synthesis we had started out that way from the beginning because chemists did that--Roberto Crea who had been trained by Itakura. But DNA sequencing was a molecular biology thing that molecular biologists did. To set up a service function there was different. I don't remember exactly when we did it, if it was '79 or '80, but it was Axel Ullrich suggesting it and everyone saying, "Yes, that's a good idea; let's do it."
Hughes
Ideas like that were coming from the scientists, not Bob saying, "Well, my business school training says that we should organize this company into functional divisions?" He was pretty much letting you scientists decide how to organize the science?
Goeddel
I remember from what must have been his business school training that he believed the more people you can put together in one lab, the more interactions there are and more gets done. He kind of carried that to an extreme sometimes, how crowded he wanted us to be.
What were some other ones? Always, when you came to talk about your experiment, and you were telling what you were doing, he said, "What happens if it doesn't work?" You said, "Well, we'll worry about that then." He goes, "No, no, you have to have a backup plan. Next time I come by I want to hear what your backup plan is." So those were the two things: the density of scientists/scientific interaction and the backup plan.
The Early Scientists' Daily Routine
HughesPlease describe a day that might have occurred in those early years, beginning with how you got to Genentech from Menlo Park with Dennis Kleid.
Goeddel
We probably carpooled for close to a year. I would usually drive. I had a VW Bug. I would pick him up pretty early. We would argue about that. I like to start as early as possible, and Dennis had been more of a late arriver when we worked at SRI. But with the insulin project, he got into the work pretty much too. I would pick him up on an average day at 6:30 or 7:00 in the morning. He would be pretty sound asleep, kind of sleeping in the car on the way to work. Then we would get there and get to work right away. There was a lot of stuff to get done.
Dennis and I shared an office, and when Heyneker joined in September he shared the same office with us, and it was right next to the one little lab. We would be in and out of the lab, into the office, always writing ideas on the white board--drawing plasmids, cloning strategies, talking about not just what we were doing now but what we might do as the next
Hughes
You would both come in if something needed to be done. You wouldn't say, "Oh, Dennis, you were here last Saturday, you stay home this Saturday."
Goeddel
Not much.
Hughes
All the scientists were there?
Goeddel
Yes, most people worked pretty hard. I may have put in a few more hours. It wasn't that it was assigned; I was anxious to get the next experiment going. So even some days when I hadn't planned to work all day on a Sunday, I couldn't stand it. I would say, "Oh, if I went in and did this I could save eight hours for tomorrow." That was the attitude I had.
There were a couple of times when I worked with Heyneker at City of Hope where he and I would do experiments together and set them up so they could continue for twenty-four hours. He might be the person who had to go do the experiment at 2:00 a.m., and I would go back at 4:00. We would organize it that way so that when we did travel to City of Hope we would be there the least amount of time possible. We would be as efficient as possible and do something in three days that maybe normally would take two weeks, just by working very efficiently together, starting a lot of things and doing them in the fastest possible time. It didn't matter what time of the day that was, we would be there to do the next step.
Hughes
Did all of you have families at that point?
Goeddel
I didn't have any kids at that point. I was married. Kleid had one young son, Jonathan, maybe two years old. Heyneker maybe had two little boys. Several of the other people that joined through '78 and '79 were single, didn't have families. Maybe Heyneker and Kleid were the only ones with kids in the first year.
Hughes
How did you negotiate this routine?
Goeddel
I don't think it was really negotiated. Here was an opportunity, here was an exciting thing, we were going to do insulin. There were other people trying to do it too, and it was not going to pay to come in second. You either came in first or you might as well be last.
Hughes
Was Swanson working similar hours?
Goeddel
No. He was always more balanced. But there wasn't that much he could do. It wasn't like he was in the lab doing experiments. He would come in at 9:00 and go home at 7:00, something like that. I think he always kept pretty similar hours, even as the company got big and there was a lot of business to be done. His mind was always occupied with the company, what needed to be done. He was very disciplined in not overworking himself, like a lot of people do. I used to wonder how he could do that.
Thoughts on Being a Scientist Versus CEO
HughesDo you have problems maintaining that discipline?
Goeddel
No, I learned a lot from Swanson. In the kind of job I'm in now, who would want to be a CEO if you had to work eighteen hours a day with the type of work you have to do as a CEO? Eighteen hours a day as a scientist is very different; I think easier. You don't have to talk to anybody; you don't have to interact; you don't have to say the right things on the phone or call the right people. It's your experiment, and you can have your mind focused only on that. There was no email then to distract you, not all the other mail to have to read. You could throw everything away and be a scientist, and if you didn't respond to a letter no one thought anything about it. If you're a CEO and you ignore all that stuff--
Hughes
You're in trouble.
Goeddel
They're just very different kinds of jobs.
Goeddel
My feeling is, it's much easier to work, mentally, a hundred hours a week as a scientist if it's your experiments, than sixty as a CEO, taking care of all the things you have to worry about in the company.
Hughes
Are you doing any bench science at the moment?
Goeddel
No.
Hughes
Do you miss it?
Goeddel
Yes. But it would be impossible to do now. There are so many distractions and things happening. You need to be at a point in your career, if you want to do great science at the bench, where that's the only thing you have to worry about. Every distraction just makes it harder to do science.
Working with Kleid and Heyneker
##
HughesYou gave me an idea of how Heyneker worked, but I don't have a feel about how Dennis Kleid worked, how he approached science, and how the three of you were getting these projects done.
Goeddel
I always looked at Kleid as the person that wanted to help out. I think he felt that I was more talented at getting the things done at the bench. It was a strange situation. I had reported to him; he had hired me; I was in a way his postdoc at SRI. Now we came, both working side by side, to Genentech. Usually we would get to work, and Dennis said, "What are you going to do today and how can I help you? What do you want me to do?" So he was deferring to me to decide what needed to get done. He would do the junk work. He would call them the backup experiments. He would say, "Oh, well, I'll be taking care of these other things in case what you're doing doesn't work." But I think he was very happy doing that. Maybe he didn't want to feel the pressure of having to do the experiment.
It was perfect for me. I loved it that way. I didn't like other people deciding what I would do. I loved it when he would say, "What do you want me to do to help you out?" So the three of us, the different styles, worked out extremely well.
Hughes
Was Herb deferring to you in terms of overall direction?
Goeddel
No. He was interacting more as an equal. He had more experience than me. But I think he could tell I had more energy and could put in more hours each day. We would discuss, and then, "Okay, this is what we are going to do." We would work together for a while, and maybe he would be distracted by something, and I would keep going. It was good that he could jump back in at any point.
Then there were certain stages of every project where I think I got so deep into it and was working so hard that at that point usually Heyneker would just step aside and start playing around with more Heyneker experiments. There would be a certain point in each project where I pretty much got to carry it. We weren't working as equals at that point. But that typically worked out naturally too. There wasn't a time where I would say, "Okay, I'm taking over. You go do something else." It was just the natural way it worked.
Hughes
So you never felt that there was any tension about who was doing what?
Goeddel
Not in the first couple years. There maybe was a little with the tPA [tissue plasminogen activator] project at a couple points where things weren't working. That was several years later. That was the time when Bob would come and ask me as director of the molecular biology division, "Why don't you take that project and do it yourself?" And I said, "Well, Heyneker's doing that now. I'm not going to do that to him." In the end, Herb took it pretty well when I had to do the project. But maybe he wouldn't have if I had taken it at the point that--
Hughes
Bob wanted you to.
Goeddel
But by that point we had expanded enough; each of us had a lab; it was different. Early on, we were in one physical laboratory together, working on the same projects. We wanted the company to make it, and there really wasn't any arguing, who's going to do what. Whoever can do it fastest and I think best, everyone was all for that. If Heyneker was better than me and willing to work all night to get it done, I would have said, "Great, you do it. Then when I get back the next morning we'll just be further along."
Stock Options
HughesI've read about junior stock. What was it?
Goeddel
I don't even remember the name. That was just a way to get cheap stock. It is what has now become stock options. When we joined we got stock, but we weren't a public company then. So I think they could set any old price. Then after we became a public company, and there weren't stock options, yes, we were able to get junior stock. Say Genentech was trading at $25 per share, they'd say well, "We'll give you these other shares at $2.50 per share, but it's
Hughes
The way I heard it, and it may have been from Tom Kiley, there was a certain amount of stock that was reserved to reward people for reaching certain milestones.
Goeddel
Yes. So early on we did get stock each year. When I joined I got stock. That is an interesting story in that there were a certain number of shares, and it was going to cost $500, and I had to pay $500 to buy this stock. I didn't have $500, and I was so excited with the salary I was offered, that I thought, "Why should I want to pay money for stock?" I went and talked to Bob and I said, "Do I have to buy this stock?" And he said, "Trust me, you'll want this stock some day. If you don't have the $500, we'll loan you the $500." I went out and I got the $500 somewhere. And yes, that $500 worth of stock became worth a few million dollars.
Hughes
What did you think of owning stock at the time?
Goeddel
I didn't think anything of it, really. When Bob said that this could be worth a lot some day, I said, "Well, he's a business man." I believed it. So that was the instant my thinking changed. "Yes, okay, I better buy this. It might be worth--." And "might be" was maybe it would be worth $100,000 some day.
Hughes
Was money at all a factor in your being interested in joining Genentech?
Goeddel
Not originally going in. The idea of being able to clone insulin and get the first drug out of this industry was all the excitement. But then after Bob explained the stock-- Kleid was always talking about money like, "If we get insulin and we sell it, look at this, we'll do this." He had done some calculations in his head and had decided we were going to get a royalty or a dividend on the stock, and we were all going to make a million dollars every year, just on dividends. I would say, "How did you figure that out?" But Dennis was more into--
Hughes
That kind of thing.
Goeddel
Yes.
Policy on Publication and Presentations
HughesYou said something earlier about Swanson being concerned about information leaking out. That led me to think about publication and scientific talks and all that. Was there a policy?
Goeddel
I think Boyer pretty much told Swanson, "If we're going to have a company, we're going to publish. That's how we'll continue to have good scientists." So Boyer took the brunt of the conflicts there and I think had convinced Swanson that if he was going to have a top company people were going to publish and go to scientific meetings. So Bob had agreed to that.
There would be certain times-- Maybe the first one was tPA. We had cloned tPA, were going to publish. Bob wanted to have a meeting and said, "Okay, I'm not going to tell you you can't publish. But does anyone else have tPA cloned?" And we said, "No, no one else." "Then why do you need to publish it now?" "Well, we want to publish it first." "Okay, let's
Hughes
What was the procedure that employees had to go through to publish in a scientific journal?
Goeddel
It changed over time, but there was a form. You would write the paper, you would have a form, and it would need to be signed by the department director and the legal person--Tom Kiley at that point. We wouldn't publish unless a patent had been filed if it was about something patentable. If it wasn't, then sure it could be published.
I think the feeling was the discovery needed to be important to warrant publication. These little technique things would have been a waste of time to write up, publish, and patent, when we had more important things to do. Those became almost just internal techniques we had, that if you were at a university probably would have been published to get the credit.
Hughes
You didn't care about the number of publications each scientist had?
Goeddel
I think here people would have said, "That's a waste of our time to be writing that." It takes time to write a paper and get it published.
Hughes
Did the patenting process ever slow down publication?
Goeddel
No. Kiley, early on, and other guys later, were fairly fast. I think they had been told that they shouldn't be holding up the scientists. It might be a day or two, but it wasn't weeks. In fact, I think the patent lawyers could always write a patent faster than the scientists could write the scientific paper.
The Interferons
[Interview 2: August 23, 2001] ##
The Ultimate Project
HughesAs I have heard it, one of Genentech's targets from the very beginning was interferon. Did you think at the start that interferon was singular as opposed to the many that we now know to exist?
Goeddel
In the earliest discussions that I remember at Genentech, it was viewed as kind of a magical substance. I think there was ever skepticism: was there an interferon? Did it exist? It wasn't going to be the first thing that we'd do with recombinant DNA; it would come at some later point. I think most cloners at that time viewed interferon as the ultimate project, the ultimate protein, to be able to clone the gene for.
Hughes
Why was that?
Rumors of it curing cancer, which is a little more attractive to be involved in than finding out a new way to make insulin or growth hormone, for example, that were already known to work. Here you could potentially produce something that wasn't available otherwise that would cure disease. But there was so little of it naturally, and it was somewhat controversial in terms of how pure it was. What did it consist of? Nobody ever had a pure piece of the protein to analyze. The cloning technology was ideal for doing it, for sorting this out. The question early on was: Did you have something to get a handle on, to go after and do it? And when would it be possible? That was in the startup time frame which was early to mid-'78.
We started our first experiments at Genentech related to interferon cloning in December of 1978. Even though we initially thought the science would have to mature awhile, it was pretty soon, only a few months later, we were trying to work on it.
Hughes
What was the difficulty?
Goeddel
It was viewed as the "sexiest" project possible for cloning, and I'm sure from a commercial point of view the one with the largest potential pay off.
Hughes
Then why not go for it first?
Goeddel
If we had started it in the spring of '78 we wouldn't have even known what to do; science was moving so fast. You do something of one degree of difficulty and then say, okay maybe I can do the next and next. Even then we were pushing it, starting interferon when we did.
Hughes
But other companies had started on interferon, Biogen for example.
Goeddel
I'm not sure when they started.
Hughes
Biogen was founded in February '78. Interferon was immediately on their agenda; that's what they were going for.
Goeddel
It was on ours; it was just a question of when do we start. So we started on it about the same time as growth hormone, with growth hormone being an obvious and easier one to go after.
Kari Cantell
HughesThe Finn Kari Cantell had some interferon; I don't know which kind. I don't know if he knew which kind he had.
Goeddel
He called it, I think, leukocyte interferon, so it was probably mainly a mixture of a number of alpha interferons, but likely had some beta interferon in it also. But it was not pure enough to characterize in terms of getting protein sequence. His interferon had been used to treat some patients.
Hughes
He wasn't molecularly oriented, as I got from Charles Weissmann's article. [1] C. Weissmann, "The Cloning of Interferon and Other Mistakes," Interferon 1981, 3:101-34.
No, not at all.
Collaborating with Hoffmann-La Roche
GoeddelWe needed a collaborator who had a source of the protein. Based on cloning techniques at that time, that's what we thought: we would need some protein. Swanson went around talking to various pharmaceutical companies. In '78 it was decided sometime late in the year that we were probably going to work with Roche. I'm not sure when the deal was signed, but I think there was maybe a letter of intent or something. It was clear we were going to go with Roche, and that was the point in December of '78 that we did the very first experiments.
Hughes
Using Roche material?
Goeddel
Yes. Roche provided us with some cells from patients with some form of leukemia, and those cells had been induced with virus and made some interferon activity. I think what they sent us first was some cells. Then we made RNA and a cDNA library. I think it was myself, Herb Heyneker, and Giuseppe Miozzari who were working together at the very beginning on that. We made some libraries; they weren't that good. It started off fairly slow. I was working on growth hormone at the same time, so I would move back and forth--growth hormone, interferon. On certain days I would only do experiments on one, other times be carrying out both. Most of 1979 I worked very hard on interferon. I definitely spent more time on interferon than growth hormone that year.
Hughes
Why?
Goeddel
Well, we got growth hormone done some point at the end of May. But even during that time I probably put just as much time in on interferon when I was working on growth hormone. I don't recall the exact mix.
Hughes
Was that a plus or a minus for you, moving back and forth between the projects?
Goeddel
The way we had worked things out initially is I was going to be committed to interferons. At some point, when growth hormone wasn't going like it should, I was asked to help there too. But I got really into the growth hormone project at the same time. I really didn't mind having two of them to do. As soon as we finished growth hormone, I was right back full time on interferon.
Difficult Science
GoeddelThe big majority of the experiments never worked, or didn't work right, or the result we got wasn't what we hoped for. It was a tough project. We tried lots of different methods to identify interferon clones. In retrospect, I see huge amounts of time wasted; but I didn't know the best way to do it then, so a lot of the things were a huge waste of time.
You devised ways of isolating interferon, or picked them up from the literature, or what?
Goeddel
We made cDNA libraries that contained these individual clones. I think the view of the scientific community was that the frequency of an interferon clone was going to be extremely rare; I don't know if it was 1 in 100,000, 1 in 1,000,000. And how do you find the clone that has interferon? So we devised different ways to go about that, some taking variations of methods in the literature, others devising new things. At the end, when it was all done, the clones were much more abundant than we thought, and so there could have been much simpler ways to find them than to try to devise methods to find something that's 1 in 1,000,000, when it's maybe 1 in 100.
All you had to do was take 100 individual clones and look at each of them very carefully. Even if you spent a day on each, doing everything very thoroughly, in three months you would have found your clone. If you think you have to go through 1,000,000, you're always devising all these methods to look at everything fast and find the one. Most of those methods didn't work or had artifacts or gave you false results; you would chase down something else. I think '79 was pretty frustrating, but I always had a view, "The next experiment will work. It will be the one." It allows you to keep working hard because you keep thinking the very next thing is going to get you there.
Hughes
Were you mislead by the myth--or maybe it wasn't a myth, it was the actuality--of the rarity of this substance?
Goeddel
There was just so little known about it that everyone formulated their own views of what they had to do. I was leading the science on the program so a lot of what got done was what I decided to do, so the mistakes were mine. It was still a very fun, challenging time. No one had it yet, so you were willing to work really hard. If the experiment didn't work, even if it was the very end of the day, I couldn't stand to go home and quit; I would start the next one, try to save a little time.
Competition from Biogen
GoeddelIt wasn't until early '80 when we heard that Biogen or Weissmann had a clone of leukocyte interferon. All that time--I would say the end of '79, early '80--we thought we were close, real close, but we just didn't quite have it. When the word went around Genentech, there were a lot of people who were real disappointed, especially a lot who thought that it would really be tough on me because I worked the hardest on it. I don't think it bothered me much; I figured someone was going to get it. I worked as hard as I could. I would have maybe felt bad if I had goofed around a lot and wasted time, but I had done it as hard as I could, and Weissmann got the clone first.
Hughes
He didn't get it by much. Biogen made an announcement in January 1980 and Genentech made an announcement in April.
Goeddel
By April not only did we have it but we had leap-frogged them in the overall project because they still hadn't figured out how to make decent amounts of authentic interferon; they made a fusion protein. They got to the first milestone before us. Then we got to the second one, and I thought we were way ahead. But then they entered the clinic at the same time, collaborating
Hughes
Who did they have working on expression?
Goeddel
I don't know. They did a lot of the work in university labs, so they had Weissmann's lab and Walter Fiers's lab in Belgium. A lot of the expression stuff doesn't get published, so you don't really know exactly. One of the key differences there, and why we got expression so much faster, was our ability to utilize synthetic DNA and the method that we developed around growth hormone. We could use that right away on interferon. It didn't take long at all. Our initial clone we converted into an expression vector in probably in a week. I think anywhere else except Genentech it would take months and months at that point to try to do the same thing.
Hughes
Because the others were using natural DNA?
Goeddel
Yes, but not only that--there were very few people that combined the ability to work with synthetic DNA and cDNA.
Hughes
Already your experience at Genentech was paying off.
Goeddel
I think it was real helpful for the first two or three years, until other people got the same experience.
More on the Collaboration with Roche
HughesWhat was Roche doing other than supplying the cells?
Goeddel
We had a collaboration with Roche through a laboratory of theirs at the Roche Institute in Nutley, New Jersey. Roche Institute no longer exists. It was essentially a research lab they funded with a lot of good people. One of the labs was Sid[ney] Pestka's. He had worked on interferon for years, so we were collaborating with him.
Hughes
How did that work?
Goeddel
Very poorly. It's probably the worst collaboration that I've ever been involved in. I think part of it was he didn't really want to collaborate with Genentech, and Roche made him.
Hughes
Pestka didn't want to collaborate with Genentech or he didn't want to collaborate?
Goeddel
He didn't want to collaborate with Genentech. He was very good at collaborating with other people over time, but he always did it in a way where he could recognize something as being important, set up the collaboration, and kind of get credit for it himself. Then that collaborator, I would guess, typically didn't collaborate with him again. They probably didn't like it.
Hughes
Because he took over?
Well, I think more on the credit side of things. So we had some difficulties collaborating with him, not being sure we were getting the right materials. Because the way the project was divided up and it worked out is: early on he kind of insisted that the interferon assay was very difficult so he should do all of those. So we didn't develop it for a long time, until we heard from other people it isn't that difficult. We didn't want to rely on him for all the assays. He wanted to produce the cell lines; he was going to make the RNA.
The postdocs in his lab were easy to collaborate with, easy to communicate with. I got a call from one of them who said, "Some of the stuff we've sent you hasn't been the best material, like we're supposed to send. So you've been making libraries out of poor material. But don't tell Sid we told you that; we could get fired." That really infuriated me. I called Pestka's bosses and it infuriated him. What I liked is, they must have known something about this sort of thing going on because they didn't say, "Are you sure? He would never do that." They said, "Don't worry. We'll take care of it."
Hughes
And did they?
Goeddel
From then on the stuff started arriving better and his postdocs said it was better quality.
I think one of the possible reasons we didn't get the clones first could have been the way the collaboration went all of 1979. Maybe we weren't getting good material or getting assays done on time. Pestka had an effort in his own lab to do the cloning, so he probably saw us as a competitor. In the end the first clone that was identified and thought to be an interferon clone come out of his lab. But then we got that and were able to use it to get a full-length clone and express it. He contributed to the project; he knew the interferon field; he just wasn't the kind of collaborator you like to have, especially if the two companies are in it together trying to do something.
I always thought Roche management was quite good. I was young; I was still in my twenties; and they let me run the combined project. It was me; it wasn't Sid. He was an established scientist. Usually the company paying the money makes all the decisions. Roche was very good at letting us make a lot of decisions, having our input in the meetings, and deciding how the joint project would move next--almost better than you could imagine. But part of that might have been making up for this other stuff; I don't know.
Hughes
Was Pestka approaching the project in a similar way in terms of molecular biology?
Goeddel
No. He had one approach that I think he was largely doing, and he spent most of the year on it. That was the one that eventually got him the clone. He was a very good scientist.
Hughes
Were you talking back and forth?
Goeddel
We would talk maybe once a week on the phone. But then after a while I couldn't handle it. So I would say, "For the next few weeks, Herb Heyneker, why don't you be the guy that does the updates with him?" I think Herb could stand it even less well than me.
Hughes
What was the problem?
Goeddel
You knew you weren't getting the straight story of what was going on. We were supposed to be collaborating but we really weren't. We had to duplicate a lot of things. The deal was we
Hughes
Why was Roche interested in collaborating with Genentech? They already had this scientist familiar with the interferon field. Why not put money, people, and emphasis on the program they already had?
Goeddel
We had way better molecular biologists than they did. We had just done insulin, done the deal with Lilly. I'm sure Swanson went around to a lot of companies and said, "Look, we have the best cloners in the world; we can express stuff, and if you don't go with us we'll go with some other company and make interferons." I don't know how the deal went, but I can easily see why Roche would do that. Pestka had never cloned anything. I can't see them having confidence to say, "Okay, we'll just give you the money, Sid; you go do it." He was in the institute, and Roche was the company making the decisions.
Hughes
The company being in--?
Goeddel
In New Jersey. A guy named Irwin Lerner was the president then. Head of research there was John Burns. They're the ones that wanted to do the deal.
Hughes
Cloning insulin made a big difference in many ways to Genentech, didn't it? It was a scientific achievement, but it was also a business validation that Swanson then ran with.
Goeddel
Yes. He was out all the time trying to do deals and bring in funding. It seemed like a long time apart but it really wasn't because insulin was done the end of August [1978], and by December we were already doing our first experiments with Roche material.
Different Interferons
HughesThat was alpha interferon?
Goeddel
Yes. The deal with Roche was to do leukocyte interferon and fibroblast interferon. Those were thought to be two different types, based on the types of cells that produce them. It turns out leukocytes can actually make some fibroblast interferon, and fibroblasts can actually make some leukocyte interferon, so they got renamed after they were cloned. Leukocyte interferon became interferon alpha, a whole class of proteins. The main component of fibroblast interferon, became interferon beta. Then there was this other class that used to be called immune interferon and became known as interferon gamma.
Our deal with Roche was on fibroblast and leukocyte, and excluded immune. That latter one was the even more magical, harder one, greater unknown. After we did alpha, and we found a whole family of those, and did beta and expressed them, they all appeared to have similar activity. We picked one alpha to move ahead to the clinic and never did beta. Beta has now turned out to be a big drug for multiple sclerosis. Something probably should have been done with that.
Hughes
Why did you decide on alpha to develop?
The activities against cancer cells and anti-viral activity were all pretty similar. I think it was more, "We can only develop one now; let's do the first one. If it's a big drug we'll follow it up with another one."
Hughes
How different are the alphas and the betas and the gammas?
Goeddel
All the alphas are anywhere from maybe 70-95 percent identical to each other.
Hughes
Does that mean functionally as well?
Goeddel
They have similarities but some differences. It still isn't completely understood molecularly why some have a little different activity than others. It's getting understood more and more. They're easily recognizable as closely related by sequence; just by primary sequence they're 70-95 percent identical. Then there's beta that falls off by itself. It's about 30 percent identical to all the alphas, but it's so much different that it's clear it falls into a different class. There's only one beta, except in some other species, like the pig might have three betas or something. But in humans there's only one beta. Same in mice, there's only one beta. Gamma or immune is completely different, unrecognizable. It just shares an activity of having anti-viral activity.
Hughes
You mean it's a completely different molecule?
Goeddel
Yes. It's used more by the immune system. It shares a receptor component, but it's not recognizable by its sequence. It's a main regulator of the immune system so it has a different function in the body too. It was actually good that we had separated that from the Roche deal.
After we did alpha and beta, there was some discussion about working with Roche, expanding the deal. The scientists, including me, just did not want to work with them. We saw no reason to collaborate with them. We ended up with some Japanese partners, and Boehringer Ingelheim as a European partner on that.
Hughes
Yes, Boehringer was certainly a partner.
The Gamma Interferon Project
GoeddelGamma was an even more difficult project than alpha and beta because there really was essentially no protein available. By then it was probably more competitive because every cloning lab around wanted to get gamma interferon, whether companies or universities.
Hughes
What was the source?
Goeddel
We used peripheral blood leukocytes from volunteers at Genentech. They would go in and get their blood drawn. It would be then be induced with various inducing agents, mainly chemicals. We would measure the anti-viral activity and then make RNA. It was a similar approach to the other interferons, but there was even less known about gamma. That followed immediately. As soon as we did alpha and beta--got those cloned by the summer of '80--we were starting to work on gamma. At the same time alpha and beta projects got continued on
Hughes
You wanted to win on gamma because it was going to be important?
Goeddel
Yes. We worked hard and devised a way to go about doing it that turned out to be the right way. When I was doing alpha and beta, I tried a lot of different ways and eventually got something; but a lot of ways did not work. For gamma, I decided, based on a number of scientific reasons, these other ways probably wouldn't be good. Let's take a method that we called induced versus uninduced as a way to screen the clones and see if that works; and it worked perfectly.
Hughes
Please explain.
Goeddel
For the source of RNA for cloning, we took RNA from induced leucocytes that gave the highest level of interferon. We had a bunch of different donors and we would say, "Who's cells made the most interferon?" Then we would get that person to keep donating so we could get more cells from him. Then we would fractionate the RNA using a gel method to spread out the RNA by all its sizes. Then we could take each size fraction and inject it into frog eggs and let the eggs make interferon activity. And then we could identify what size the active RNA was and that way get an enriched fraction of RNA for cloning.
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Goeddel
Now, to screen the library, to try to find clones, this RNA should be present only in cells that were induced, not ones that weren't induced. So we would take and make RNA from that same person's cells that weren't induced, take the same size fraction. Now we could probe our colonies with probes made from the induced and the uninduced RNA. Something should be positive only with the induced, not with the uninduced probe. The vast majority of clones are positive with both; they came out of that size fraction; these RNAs are made all the time. So you could eliminate 99 percent of the clones. This small fraction that was left, let's look at those. So we sequenced a few of the cDNAs and looked at their ability to make an activity that looked like interferon. This very complicated project turned out in the end to be pretty straight-forward cloning.
I think it was probably around July or August of '81 we thought we had an interferon clone. We expressed it in E. coli and mammalian cells and yeast, using all the Genentech expression systems that were working very well then. We made the protein, verified we had it, did a lot of experiments with it, and then wrote up a paper. The paper was published in February of '82 in Nature. The thing about that was how completely extensively we had done everything, and the competition was nowhere. Not only did we identify the first clone, but before we even published it we had done so much that when others saw that first paper it had to be pretty demoralizing to anyone thinking they could catch up in this area. It was, I think, one of Genentech's two biggest wipe-outs in terms of where the scientific competition stood at the time.
The Interferons: Not Wonder Drugs
HughesThe interferons, as you know, didn't turn out to be the wonder drugs that people had hoped. How did you feel about that?
Goeddel
I had always hoped they would be huge drugs, but it didn't change the excitement of the science. We always had new projects. I think it would have been tougher if I had been someone like Pestka who worked only on interferon their whole career. I looked at myself as someone that worked on biotechnology drugs, and there's always more to be done. In the end alpha interferon became a pretty big product; it's just it wasn't a big product for Genentech because Roche was selling it and the royalties were small, and Roche got beat by Schering on the marketing side. Alpha interferon's a very large market now, and beta interferon turned into a huge market. It's the one that was surprising because everyone thought the most valuable one was going to be gamma, and that's been by far the worst product.
Hughes
And yet that's a Genentech product, right?
Goeddel
Yes.
Genentech's Advantage: Streamlined Technology
HughesI was just re-reading transcripts of an interview with William Rutter, and he tried in the late seventies to establish an institute at UCSF that would do some of the things that you're describing. He couldn't get the university administration to back it, to fund it. He said something along the lines of, "And that's what Genentech did." Genentech developed and streamlined the technology.
Goeddel
The day that I thought we had the interferon gamma clone I could walk down the hall to Art Levinson's lab and say, "Let's figure out how to make this in mammalian cells." He was the guy developing that new [culture] system that no one else had. Right next to him was Ron Hitzeman's yeast expression systems. We did E. coli in my own lab. So simultaneously we could verify what we had to see, could this gene go into all these different cell types and make a protein that had the right activity, that was neutralized by the antibody? Then we had three choices for production systems. That's just an example of having everything together in one place that you can utilize.
Hughes
How soon did you have all those options? And was it because of interferon?
Goeddel
We had done some stuff a little earlier in yeast. I think it was perfect timing for interferon; that was the first time we could slam through every expression system at once--when gamma interferon was ready to do.
Hughes
That was 1982?
Goeddel
Summer of '81. Very exciting times. Now we had another interferon to work on. We were still working on alpha and beta, and now we had gamma. I'm not sure when we got the
More on the Competition with Biogen
HughesWeissmann talks about Tadatsugu Taniguchi working on beta interferon because Weissmann asked him not to work on alpha, right?
Goeddel
Right.
Hughes
Did you have any interaction with Taniguchi?
Goeddel
Taniguchi is a very good friend of mine. I met him in 1980 after a meeting in Japan, I guess. I also met Shigekazu Nagata at the same time. Nagata is the guy in Weissmann's lab that did most of the work on the alpha cloning. Taniguchi, I think, got his beta clone in December of '79. If I recall, I think Weissmann wasn't sure when Taniguchi announced it if he had really proven he had one. But he was right in the end.
Hughes
Yes, Weissmann questioned it.
Goeddel
It took Taniguchi a long time to get expression. I think in 1980 he came to the U.S. and went to Mark Ptashne's lab to work on expression. They eventually published a paper on expressing beta interferon. So Taniguchi got the first clone; Walter Fiers's lab got the second clone--a guy named Rick Derynck working in Fiers's lab. Derynck later came to my lab at Genentech. We were probably the third with a beta interferon clone. But again we got it expressed and produced faster than anybody. Then all these labs tried to do gamma--Fiers, Taniguchi, Weissmann. That was the one that really had the competition of everyone wanting to get it.
Hughes
Were you paying attention to where other labs were?
Goeddel
You can't really. I never could. I was in the lab all the time, so how did I know all these labs were working? Somehow you know. These were the big cloning labs; interferon gamma or immune interferon was the prize. So it made sense every lab was working on it.
Genentech Presentations on Interferon in 1980
HughesYou say you couldn't have heard. Does that mean that you weren't taking time to go to meetings?
Goeddel
I went to one or two meetings in 1980. I went to the interferon meeting in Washington D.C. at the end of 1980, in November, and gave talks on our alpha stuff. Everyone was saying, "How are you doing on immune interferon?" "Okay. How are you doing?" "Okay." You never knew what experiments or what approach or how anyone was doing things.
How did people react to your talks on alpha?
Goeddel
I think a pretty good response. We had been very quiet until that meeting, and then we presented a lot of data. I think people had assumed Fiers and Weissmann would have the majority of the data there, and I think I presented at least as much as they did, maybe even more.
Hughes
Did your silence have anything to do with the patenting issue?
Goeddel
No. I just wanted to keep working. Our two papers had come out right before that. That was really the first word on it.
There was a meeting in the summer of 1980 at NIH on interferon, where a lot of cloners showed up. Genentech got invited and Swanson wanted me to go. We hadn't published a paper yet, and I didn't want to give a talk. Then there was some legal stuff on how much we could present based on our patents. I said, "I'm not going to go to a meeting like that." Swanson wasn't so happy with that response. Eventually Herb Heyneker went and gave a general little talk about how we were doing. It was always my preference to get a main paper published and talk about it then. If you were going to give a talk at a scientific meeting you gave the whole story, not just little pieces.
Hughes
Swanson was a little leery?
Goeddel
Swanson at that point wanted us at NIH so that Genentech could get some credit for what we had done. And he said I should get credit for what I had done. He really believed that. And I just didn't want to go to that kind of meeting. I was busy working on gamma interferon too, and I didn't want to take two or three days away from that. Then when we got the alpha papers published in Nature, I felt it was fine to go to this international interferon meeting in Washington D.C. I was fine: Go to that, hear all the talks, and present ours. I think most of the people there--the cloners at least--were still spending a lot of their time trying to get immune interferon.
Genentech Presentation on Interferon, 1981
GoeddelIt was exactly a year later--the meeting was in San Francisco in late '81--we had submitted our gamma interferon paper to Nature but it wasn't published yet. We had been able to keep it extremely quiet. Usually when you clone something it's hard to keep it quiet. But it didn't even spread over Genentech too fast because my lab kept quiet; we were worried about it getting out. At this meeting in San Francisco it was clear by the reaction, the shock, after the talk that the competitors had no idea where we were. It was, again, the complete story: identifying the sequence, expression in all systems, purification. Pretty much complete characterization, leaving really nothing for anyone else to do first.
Hughes
What year was that?
Goeddel
Late '81.
Hughes
Was any laboratory catching up with you in technical capabilities?
I don't think so. The time when we, as a company, probably dominated the most in what we could get done was '81 to '83. Biogen was the competition. We thought most of their power was still centered in their university labs, not in the company itself. So it was Weissmann's and Fiers's labs that we worried about more than Biogen the company.
Hughes
Wasn't Biogen having problems around that time?
Goeddel
Probably just due to the nature of how they were run. We were a bunch of young scientists and were the center of things. They were a bunch of famous established professors that all wanted the big thing in their lab, not in the company, and then they would spin out the applied stuff to the company. That just can't work as well, just no way. The structure at Genentech was real beneficial for us.
Cetus and Recombinant DNA
HughesWhere was Cetus in all this?
Goeddel
Cetus was there, and they were working on interferon. We never took them as seriously as Biogen.
Hughes
Why?
Goeddel
Biogen had Weissmann, Gilbert. Cetus had no big names in terms of molecular biology and cloning.
Hughes
Do you have any thoughts on why Cetus was behind Genentech and Biogen in applying recombinant DNA technology? Their scientific advisors in the mid-1970s, even before Genentech was founded, were Joshua Lederberg and Stanley Cohen.
Goeddel
I only know what Swanson told me, and that is that he went there before founding Genentech to try to work with Cetus. He told them about the insulin project, and they told him forget it; it would take ten years to do that. That's what Bob told me a couple of times. From the day Genentech started to clone and express insulin it took ten months, not ten years. We did it twelve times as fast. It sounds to me like Cetus could have had Swanson and Genentech.
Hughes
Swanson and Genentech, and Stanley Cohen maybe. Interesting how history would have been different.
Dealing with Increasingly Large Protein Molecules
HughesTell me about the difference in the molecular size and complexity of the interferons as compared to somatostatin and insulin.
Goeddel
The interferons were really pretty small; but they're ten times bigger than somatostatin.
How about compared to insulin?
Goeddel
Insulin is 51 amino acids total; somatostatin's 14 maybe. Growth hormone was 191, alpha interferon, I think, is 166, and maybe 165 for beta interferon, and gamma interferon is 143. These are all roughly the same size--20,000 molecular weight proteins. Still relatively small compared to some of the things that would come later.
Hughes
tPA?
Goeddel
Yes.
Hughes
Did you worry about what the bacteria might do with these large human proteins?
Goeddel
No, not so much. We were worried early on: Could we make any of them? After we found out growth hormone worked, then alpha and beta interferon worked--sure, gamma interferon should work fine. But we were going to have these other systems in case you need glycosylation (which bacteria can't do). You need some other modifications.
I don't think we were too concerned the interferons would be too big. It's hard to remember though. But what makes me think that is tPA came next, and it's about three times as big as interferon, say 60,000 molecular weight. The first thing we tried is, let's see if we can make it in E. coli. We tried and tried and it didn't work very well, so we went to these other systems. We probably tried albumin too, because that was a big one that had been cloned in another lab. Maybe with albumin we said, "Here's one example of a big molecule that doesn't work in E. coli. " But that didn't mean that maybe none of them were going to work if they were that size.
Hughes
There was discussion in the court transcripts in the U.C.-Genentech case that in growth hormone--which would have been late seventies--you were trying to get rid of any excess DNA because you didn't want to risk choking the bacteria.
Goeddel
Yes, we were trying to get rid of everything that wasn't coding region.
Hughes
Exactly. But with the interferons you were not worrying so much about that?
Goeddel
We still didn't want any extra noncoding region. In the case of interferon there's very little noncoding so it wasn't an issue. But sometimes you would clone something and maybe 20 percent of it encodes for the protein, and 80 percent is just junk DNA off the tail. Naturally, what we would do is, "Well this isn't going to help any, we certainly don't think; let's just chop it off, get it off there. We still make the same protein." That's probably what I was referring to then.
I would say, things having to do with expression change so fast that certainly the view at growth hormone time in mid-'79 versus the view two years later would have really changed. At some point, yes, we reached the conclusion, if very small is hard to make in E. coli and very big is hard to make in E. coli, there's this intermediate size that's good. When we actually reached that on the big side I don't recall exactly.
Clinical Trials
Research and Development Clinical Partnerships
HughesThe first clinical partnership was formed in connection with growth hormone
Goeddel
You mean what we called the R&D partnership to raise money, with Paine Webber?
Hughes
I'm talking about raising money for clinical trials.
Goeddel
Yes, I think they were called clinical partners, R&D partnership, or something.
Hughes
The first one was for growth hormone, right?
Goeddel
Yes.
Hughes
Was the clinical partnership a new idea?
Goeddel
That's what I've been told.
Hughes
Was that Swanson's idea?
Goeddel
I think he gave credit to Fred Middleton, who was the CFO [chief financial officer] early on and a college friend of Bob's. They had gone to MIT together. I don't know if they were roommates or what. Middleton worked with Paine Webber. I'm sure Swanson was behind it somehow, but I remember it came out at some point, "Why do we have this CFO? They never do anything." Someone saying something like that. And Bob would say, "What do you mean? Fred came up with this R&D partnership format that brought in all this money." That was great.
Hughes
What about the second R&D clinical partnership?
Goeddel
I don't recall. I thought there was one for growth hormone, one for tPA, and maybe one for TNF [tumor necrosis factor]. But there could have been one for interferon gamma.
Hughes
There was. I'm reading my notes: The first clinical partnership was for both growth hormone and gamma. [1] Nina M. Siegler, "Genentech," Paine Webber Mitchell Hutchins, Inc., March 15, 1983.
Goeddel
That makes sense. As we viewed it in research, it was just a funding vehicle; it brought in some money; it didn't affect us in research.
Goeddel as Project Leader on Gamma Interferon
HughesWere you involved in any way with clinical testing?
Goeddel
I was the project leader on interferon gamma, which meant I was responsible for getting it into the clinic and so on. I had done that on alpha interferon, and at the point it entered the clinic I felt, okay, I've made my contribution. Someone else took over from Roche. In the case of gamma, I turned over the project leadership even before it got to the clinic. That was just too much regulatory junk, I thought. But I still went to the project team meetings and headed up the research side. I think Costa Sevastopoulos was probably the project leader right after me. Soon after that it became Mark Levin. He's the CEO of Millennium now.
Hughes
Were these M.D.s?
Goeddel
No. They were project leaders who coordinated all aspects. Someone on the clinical side would be responsible for the actual clinical trial, but the overall program was run by a project leader. By that time we were getting more complicated. These project teams were more formal, and it was a lot less fun for a research person, compared to very early on when we didn't really know what we were doing and we could make a lot of decisions, maybe without having the right input.
At the stage interferon gamma was heading more toward the clinic, I was off doing science on other projects that were in earlier stages. As soon as interferon gamma ended, I went to work almost completely on tPA. Before that I was doing both. As the alpha and beta interferon wound down I was working mainly on gamma but also doing tPA work at the same time. There was always the next exciting project that would jump in right away. There was never a break.
Hughes
Which I imagine is exactly the way you wanted it.
Goeddel
It was pretty fun, yes.
Hughes
Who might be on these project teams?
Goeddel
It was kind of anyone who wanted to. People involved in the project who had been doing the cloning or the protein purification, they would go to it. Then new people would come in. Typically, the first ones would be in process science or process development and fermentation--people who were going to take the bacteria and scale up the fermentation and figure out how to purify the protein in bulk.
Hughes
Did you have any interaction with those people?
Goeddel
Yes, I had quite a bit, just because they took what we did on the benchtop in molecular biology and they scaled it up to the next step. From that to manufacturing--no, we didn't have any interaction; it was the process science guys that worked with the manufacturing people. Every scientist feels they have an idea of what clinical trial should be done. So I'm sure the clinicians always got too much advice and probably didn't listen to much of it; they knew what they wanted to do. Then you would get regulatory people to deal with the FDA. By the time something entered the clinic and got in the first patients, I usually completely quit going to the project team meetings. That reached the goal: We had discovered something, made it,
It wasn't really well organized. It was more like new people would just show up a certain week. How they got there, whether they came on their own or Swanson or someone said, "Hey, it's time for you to go to this," I don't know how that worked.
Fermentation Technology and Process Science
HughesCould fermentation technology be adopted from the pharmaceutical industry, or were there special requirements needed at Genentech?
Goeddel
I think it was all special. The pharmaceutical industry was largely making antibiotics, which are different bugs grown different ways. We were producing things in E. coli. We hired some fermentation people from the pharmaceutical industry. They came in and rapidly learned how to grow things in the small fermenters and then larger and larger ones. The guy I remember being there for the longest time--he's probably still there-- is Norm Lin. He had a couple of young technicians working with him and they interacted very well with the molecular biologists. We would create the bacteria, give it to them, and there would be an interaction. They would grow it up, maybe bring some cells back to us to analyze, to look on a gel: How many proteins are made of each type? What's the yield?
Hughes
Were there considerable differences in protein amounts when you began to increase the volume?
Goeddel
Sometimes you could make nothing. Other times they could make way more in fermenting than we could in a test tube. Eventually they got so they could always make more. One of the things that molecular biologists would often do early on is, "Hey, I've made a new bug," and run it over to have those guys do a small-scale fermentation to give us a lot of material. There was interactions where we would help them and they would help us, both ways.
Then after that comes the process science, the guys that purify it. Their interaction would be more with the biochemists in research, protein biochemists that had done the small-scale purifications. Now they interact with process science people who are going to do large-scale purifications. Probably then the molecular biologists interacted a little more with the fermentation people.
Supplying Reagents
HughesHow many of these reagents was Genentech from the early days supplying to others outside the company?
Goeddel
It's got to have been a lot, because over the years we would clone things, publish papers, and outside scientists would read about it and want to get the materials. They would request them. There still weren't a huge number of labs doing things. I would say probably only by 1990
Hughes
In the early days you and your colleagues would fill the requests?
Goeddel
Yes, but there weren't as many requests. Even though it was a very valuable thing, there might only be ten labs interested in it, or something like that. Some of the things that were requested early on we weren't allowed to send for patent reasons. But some point in the eighties, a position was created at Genentech and one person became responsible for supplying reagents to other labs.
##
Goeddel
It was probably 1986 and I think he was in the cell genetics department--whose job was to respond to all of these requests. Then that made it easier on us. We didn't have to worry about it; any letter could just come to him, and he would come to your lab and get the plasmid or the strain or the cell line. I would guess, early on, right after we cloned important things, people would figure out interferon is so valuable there's no way a company is going to give it away; so you didn't get too many requests. Requests were more maybe from some collaborators you would choose to collaborate with. It wasn't like it became by about 1990 where you would publish a new clone of something that's interesting and you would get literally hundreds and hundreds of requests.
Big Pharma and Biotechnology
HughesAt the beginning, only certain of the big pharmaceutical houses paid much attention to biotechnology. Eli Lilly and Roche of course are two. Monsanto got into the animal part of it. Why only those companies? And what were the others thinking? Or were they paying attention at all to the new genetic technologies?
Goeddel
[pause] I don't know. It's hard to say since I wasn't a business development person trying to work those deals. My guess is that companies like Lilly had someone near the top in research or on top of the company that saw, hey, this technology is going to be important and forced the company to go into it. The typical way a lot of interactions and collaborations work with pharmaceutical companies--and what we see at Tularik--is someone down in the research organization wants to collaborate on something in the same area, and they think the biotech company can help them. I think there were no good molecular biologists working down in the lab at any of those companies to go push and say, "Hey, let's go!" Those people weren't there; they were all in the universities. That's just my thought. The only deals that happened were pushed from the top, not from the bottom up, like a lot of deals happen now. I know in the Lilly case everyone gives credit to Irv Johnson, the head of research. He's the guy that said, "We have got to go do this!"
I talked with Hugh D'Andrade about Schering-Plough's connections, first with Biogen and then with DNAX [Institute of Molecular and Cellular Biology, Inc.] [1] See the interview in this series with Hugh D'Andrade, David Holveck and Edward Penhoet, "Regional Characteristics of Biotechology in the United States: Perspectives of Three Industry Insiders," 2001. He saw it more as an image thing than "We're going to get a product out of this collaboration." He and other Schering executives wanted to project the company as forward thinking.
Another way that this could have gone is that pharmaceutical houses could have said, "We have to allocate money, try to attract scientists, and get an in-house group going on the new technologies." But it doesn't seem to have happened until later, does it?
Goeddel
Right. I recall Swanson saying that Syntex was right down the road from us, yet he could never get them interested in anything. They just didn't believe anything was going to happen.
Goeddel's Proficiency at cDNA Cloning
HughesThis is a quote by David Goeddel in the UC-Genentech legal transcripts: "The method I was using gave the most efficiency in terms of the number of complementary cDNA clones per amount of complementary DNA." You were saying, I believe, that you and your lab had the most efficient operation in this regard at this time, which I presume, since it was about growth hormone, was the late seventies. Please comment.
Goeddel
If you looked at the publications then and talked to people that were doing cDNA cloning--Peter Seeburg, Axel Ullrich were the ones at Genentech--you could make very few cDNA clones. I had spent a fair amount of time--some of it with Heyneker, most of it alone--trying to work out existing techniques that were in the literature and put them all together, maybe improve the efficiency of cDNA cloning. To do cDNA cloning you probably had to do ten steps in a row, say. If I could make each one a little more efficient just by slight variations--
After a few months I was able to get what was considered huge numbers of cDNA clones out of a very small amount of cDNA. I could go through a standard prep that someone else might get 100 clones, and I would get 50,000, which really improved the efficiency. I wasn't aware of anyone or any lab anywhere that was doing that. Axel and Peter, for example, quit making cDNA libraries; they came to me to make theirs. I think we probably had a year when we had a big advantage at Genentech. If we had a little bit of RNA we could make a lot of cDNA clones. I probably got a little bit of efficiency in a number of steps, and a pretty big jump in efficiency in one or two steps. That really helped the numbers go up.
More on Publication Policy
HughesYou told me in the first session that you weren't bothering to publish these technical advances.
This was no big deal. I was never so interested in just increased efficiency as a scientific publication; I viewed as a breakthrough something completely new, rather than I took this guy's method, I copied it, and I changed a little bit here, here, here, and now mine's a little better. There are people who publish that, but I've never been interested.
Hughes
It was that premise rather than, Genentech is in a competitive situation and therefore shouldn't reveal its technical improvements?
Goeddel
It had nothing to do with that. Plus, it takes a fair amount of time to write a paper; it better be important. I always viewed a lot of method improvement papers as, "God, those labs must not have anything else to do. They must have a lot of extra time if they're just making a variation on something and writing it up."
NIH Guidelines for Recombinant DNA Research
HughesWhat attention were you paying in the late seventies and the eighties to the NIH guidelines?
Goeddel
Not much. Pretty much looking at it in general: Do we have the kind of lab we have to have for what we're doing? We did some of the early experiments in P2- and P3-type facilities that we had in one little lab at Genentech. When the guidelines were relaxed and we could do everything on the bench that was great. Dennis Kleid might have been our safety guy. [1] Kleid organized Genentech's early biosafety committee. See his oral history in this series. He was more concerned with those issues than I. I said, "You tell me how we have to do this, Dennis. I would prefer not to read all the regulations or go to the safety meetings."
Hughes
Genentech's funding did not come from the government so technically it didn't have to comply with the NIH guidelines.
Goeddel
We did voluntarily.
Hughes
Why?
Goeddel
Again I don't know. Probably just image--I don't know the true reason. That was the way it was, whether it was Swanson deciding it or Boyer saying we'd better do it.
Hughes
The recombinant DNA debate was pretty contentious for a while.
Goeddel
It didn't last so long. It was only about a year we had to go in that one specially built lab to do cDNA cloning experiments. It was actually kind of fun, "Okay today I'm going to work in that little lab."
Hughes
The weakened organisms you had to use under the guidelines weren't so persnickety that you had trouble getting results?
Goeddel
There was a strain for transforming cDNA clones that we had to use called chi 1776, and it was supposed to be very hard to work with. It was one of the steps we improved in the cDNA
It was actually fun, people working in that other lab. I don't know if it was designed intentionally or not; I think it probably was--by Swanson. There was a glass window so that visitors could look in and see people with their special lab coats working in the hoods in this lab. Once when Lilly came to visit, I think Herb Heyneker was working in that room. Dennis Kleid and I had gone in and said, "How's it going Herb?" and patted him on the back. We put a sign on his back that said, "Mad scientist at work." Then Bob Swanson came through with the executives of Lilly. Bob was so concerned about image and stuff. He saw that, and the Lilly guys were kind of snickering, "Ha ha ha." Bob was so embarrassed. He came by the lab and told us, "Don't ever do that again!" I think the Lilly executives actually liked it.
Part of it was we thought it was kind of ridiculous that we were on display. Here comes the tour: "Look, here are my guys doing these special experiments." Normally you wouldn't have cut a window in the wall so that everyone could see what you were doing. That was the main reason we wanted to put the sign on Herb. Later, what did Kleid do? I think he put a poster right in that window so no one could look in. Well, that had to come down too.
The Press Conference on Human Insulin, September 6, 1978
HughesWere you connected with the publicity that flowed from Genentech from the very start?
Goeddel
Insulin, there was a big press conference. I was part of that. That was in some ways exciting, in some ways strange. It was clear all along we were going to have a press conference; Bob really wanted one. I think the City of Hope went along with it.
Hughes
It was at the City of Hope.
Goeddel
Yes, it was at the City of Hope. That's where they decided to have it. It was a big thing with a lot of press there, spotlights, all of us scientists sitting up front at a big table, a guy talking from City of Hope, and Swanson talking some. I was excited I was going to one. I was a young scientist and we had done something important enough to have a press conference. But sitting up there I felt really weird.
Then they said, "Does anyone else want to say anything?" And Swanson leaned over to me and said, "Why don't you go up there and say something? You did most of the work." And I said, "No, I don't want to." I was embarrassed; I just didn't want to go up there. He kept saying, "Come on, go up there." He didn't look very happy with me. There was no way I was going up there. He could have fired me and I probably wouldn't have gone. Swanson went, "Come on, get up there." So I looked next to me and said, "Why don't you go Dennis?" Dennis Kleid was sitting next to me. I should have never done that because Bob was always afraid of Dennis talking. And Dennis goes, "Sure," and jumps up and starts talking and talking about all kinds of things.
The most amazing thing was when Dennis was just talking like crazy--Bob so furious you could just see him steaming. Bob was saying to me, "Get him down!" He was saying it loud enough that Dennis should have heard him. "Get him down!" I didn't know what to do. How would I go up and get him down? Then all the power went off; there was a power failure at that press conference. So during the power failure we went into complete darkness. Then Bob went up and said, "Get down!" After the power came back on that was the end of the press conference.
Then the reporters came up to talk to each of us. I was pretty embarrassed. Clearly, they made a beeline for Kleid because he had been the big talker and they were going to get some good quotes out of him. I don't think he had a good relationship with Swanson ever after that. But Bob got the publicity he wanted. He was very good at that.
Controversy over Commercialism of Science
HughesThat was one of the instances when Genentech was criticized for having a press conference before the work had been published in a peer-reviewed journal. Do you remember?
Goeddel
I think we had submitted a paper at about the same time [as the press conference]. I don't know what the date of the press conference was. I think we submitted the paper before the press conference because Art Riggs insisted on that. Riggs and I spent the whole Labor Day weekend writing the paper, and I think we submitted it, and then the press conference was a couple of days later. But I think there was still criticism.
Hughes
The papers weren't published; they may have been submitted.
Goeddel
Right, but I think there was a lot of general criticism of a lot of the things Genentech did early on. It was new and the academic community didn't like it. Especially, there was a lot of sour grapes toward Boyer from people who later on tried to become the next Herb Boyer but for a few years were always bad-mouthing him.
Hughes
Where was that coming from?
Goeddel
His colleagues at UCSF, as well as the Stanford guys--not only was it a guy going commercial but it was a UCSF guy. There's always been that competition between Stanford and UCSF.
Hughes
Double whammy. But it was mainly the stigma of an academic scientist founding a company?
Goeddel
It took a couple years before those guys realized the quality of the science coming out of Genentech was so good, it really didn't merit criticism. I think early on they thought, "This isn't even good science, and these guys claimed they did something. We haven't verified they've done it yet." I think if a scientist was running the company it would have been different. But Swanson had a good view of what he needed to do to raise money and visibility and create an industry; he had to go out there publicly.
Hughes
I don't take from anything you've told me that you had any problem--in fact almost the opposite--of doing applied science. What did it mean to you to be doing science aimed at having clinical significance?
I think it was great. My view always was that I wanted to do good science and I would love to get publications. Here I was doing stuff that was important and would become drugs, and it was good enough science that you got the publications too. You got both. That's why I always have trouble when I hear people say, "If I went to a company I would have to do applied stuff and I wouldn't get to publish." I think if you discover a drug you always get a good publication. In general, it's way harder to discover a drug than a lot of other science that you get published. You're guaranteed a good publication if you discover something that could be a drug. For years I thought it was just the perfect situation. I couldn't believe people would complain. There were very few people who got to do things that were commercially important and got published as major articles in the very best scientific journals.
Hughes
Were there ever occasions when if you had still been in an academic lab you would have pursued something further than you were able to at Genentech?
Goeddel
Sure. It was necessary at Genentech to be more focused, which in the end is probably better. I could imagine being at an academic lab, you do one thing commercial, then this tangent heads here and here, and before you know it you're way off for ten years on something that may or may not be important.
Hughes
But it could lead to basic understanding.
Goeddel
It could, but it isn't going to do it directly. Sure, maybe you would make different kinds of discoveries.
Basic and Applied Science at Genentech
HughesNow, you're at the other end, as an administrator at Tularik. Do you find you have to rein in some of your scientists and say, "Hey, get back to the project."
Goeddel
A little bit. I think that was necessary much more at Genentech since it was so new. Now it's clear that [biotechnology] is a career path, and if you go to a company like this it's the excitement of discovering a drug to help people. Most of our employees, that's what they want to do. If you say, "Hey, I think this project isn't going anywhere, and we have a better one that will give you a chance for a drug," most of them will say, "Great, let's all work on that." Whereas the first five years at least at Genentech there were a lot of people that wanted to take advantage of the technology and do whatever they wanted. They didn't care about the outcome as long as they got their publications and could take advantage of everything Genentech had inside.
Hughes
How did you deal with that?
Goeddel
I probably didn't deal with it. I ignored it for the most part. People that reported to me I had to put it in their reviews. If they were in my lab they'd better not do that. We had some extremely good labs run by people who were interested just in the science. Swanson would at least once every six months or so say, "Why don't you fire that person?" Or, "You have to make them change what they're working on." My comment would usually be, "Aren't you happy with the overall productivity of the department?" He would always say, "Yes." And I
It was always some sort of tension, but I certainly didn't want to take too much of my time going and managing them. I would rather do the work to get the products myself, do the work, and as long as they were good scientists it didn't really bother me. If someone was a bad scientist and then trying to spend all his time doing academic-type things, then I would want to get rid of him. I've changed enough since then that now I probably wouldn't put up with it. I would want everyone, like Swanson did, to be focused. But I think then it really helped Genentech to have a few labs of top scientists doing whatever they wanted--to have them around as part of the overall atmosphere.
Hughes
Regardless of whether it fit in with what Genentech was doing?
Goeddel
I could always say it fit in a way. What they were doing, that technology as soon as they got it I would apply to something. Even those guys over time did some things that became important commercially. They had different motivations; it was strictly so they could advance their standing in the scientific community, go to meetings and give talks. There was clearly a fair amount of that at Genentech.
Goeddel as CEO of Tularik
HughesDid your ideas change when you came to Tularik?
Goeddel
No, I think they were changing earlier. A lot of those people had gone off to do other things or had even gone to universities and got the kind of job maybe they should have had all along. I'm sure my ideas change here all the time too. Now I'm more concerned about projects at a later stage, ones we designate to go into the clinic, than I am about the early-stage research ones where my pure scientific interest always was, which I like doing myself. I have to be more concerned now with choosing between all the candidates: Which one do we make the investment to take into clinical testing?
Hughes
Do you find that you have the background to make those decisions?
Goeddel
I think it's just common sense, good judgment--just like doing science is in a lot of ways--and getting advice from the people that know more details. So yes, I feel comfortable making the decisions. We won't know for many years whether they're the right ones or not.
Hughes
Are you the one making those decisions?
Goeddel
I ultimately am responsible for the final decision, what we take into the clinic or not. We may have committees and groups that do it, and if I agree I say, "Fine." There have been times when I've said, "No, I don't think that's going to make it. We won't do it." There hasn't been a time yet where a review group says, "Don't do it," and I say, "Yes, we're taking it into the clinic." That hasn't happened yet, but that could happen too.
Failed Projects at Genentech
HughesWhat about that process at Genentech in the early days? Well, not in the earliest days because the first projects were clear, weren't they?
Goeddel
I think they were all clear, all the early ones, that we were going to take into the clinic. Everything did get taken in. These were protein drugs, and you could find out fairly soon if they were going to work or not. It's very different than how you have to test small-molecule drugs that are taken chronically as pills--how you have to test them. I think almost everything early on was taken to the stage where it was given to a patient.
Hughes
Even things that were ultimately not successful? I'm thinking of thymosin and tumor necrosis factor.
Goeddel
Tumor necrosis factor went right into the clinic. It just didn't work for cancer. Thymosin alpha 1 didn't. Epidermal growth factor didn't. There were a few that didn't. Thymosin alpha 1, I don't remember why it failed. At some point when we were working on it we just decided, this isn't any good.
Hughes
I read that it was somebody's pet project. Am I right there?
Goeddel
It was a new peptide that had some activity. City of Hope scientists made the DNA; I think Herb Heyneker cloned it.
Hughes
What was it supposed to do?
Goeddel
I don't remember. It was kind of a side project. I wasn't working on it. Heyneker was there cloning it, and then it just disappeared into oblivion. There wasn't a huge amount of effort put on it ever.
Hughes
What happened to tumor necrosis factor?
Goeddel
It went into the clinic. It went into a lot of tests, and it had extremely little anti-tumor activity and was dropped. And it had toxicity.
Hughes
Not a great combination.
Goeddel
There are some people still working on it, but it's been a lot of years. I don't think it will become a product.
Genentech Cloners: The Early Elite
HughesWould you--I know you wouldn't--would other people describe you as a scientist with golden hands?
[pause] Yes, I think some people would have in the late seventies, early eighties. I would think of it more that I worked harder and did more experiments and some of them worked. It wasn't that I could make every one work. Certain ones I could, but a lot of other times it was just more speed and doing it over and over, and something would work out. I've had postdocs in my lab that had better hands than me.
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Goeddel
Molecular biology is an experimental science. You have to do a lot of experiments.
Hughes
Probably by the late seventies or maybe 1980, there were divisions of labor at Genentech. Am I right?
Goeddel
Yes.
Hughes
You have DNA synthesizers, sequencers, cloners. Was there a pecking order amongst these groups?
Goeddel
Yes. The cloners were at the top. The molecular biologists really were the most important at that point. I think the molecular biology department viewed itself as being the department that made Genentech. It probably wasn't the right view to have, but clearly everyone in that group thought they were part of something special and this was where the power of Genentech was. It was almost an honor to be associated with that group. I think they viewed the other groups as almost service functions for them. It took a long time to get rid of that attitude, which hurt in later years.
Hughes
Hurt in what way?
Goeddel
Recruiting in other departments, morale maybe in other departments, and people thinking that molecular biologists were favored. Although that didn't last. They were favored early on, but it hurt the molecular biologists later when everyone thought they were being favored by Swanson or whoever, and they were no longer. In fact, he might have been harder on them because of that attitude that they had--arrogance I guess we had as a department. It's something that we've tried not to have here. I saw it, and I was a big part of it; I thought all the best guys were in this department of molecular biology.
The Cancer Research Institute in Vienna, Austria
HughesGenentech was associated with Boehringer Ingelheim [BI] in setting up a cancer research institute in Vienna. What was that about?
Goeddel
I think it came about because there were these huge estimates on what tPA sales were going to be. Bob Swanson didn't want all the profits to hit the market in one year; he wanted to hide some of the profits somewhere. There was an idea about having an institute, maybe even here in South San Francisco. Then we thought, well, there would be two classes of citizens: the guys who could do basic research and the other ones. That wouldn't work. And what about stock? I'm not sure who exactly came up with the idea. It might have been Dave Martin,
Hughes
It was being discussed in 1985.
Goeddel
So maybe it started in '86 or '87 even. They hired Max Birnstiel, a great scientist from Zurich, to run it, be director, and BI and Genentech split the costs. Very soon after that tPA didn't sell as much as expected. Genentech started to worry about budget and how to save money, and they started trying to figure out how to get out of it pretty soon after it started and eventually sold their half to BI. BI still runs it. It's still a very good institute. But I think it was really to hide these massive tPA profits they were expecting.
Hughes
Was there some scientific input as well?
Goeddel
Early on it was, have an institute that does great science, and it would be up to Genentech to figure out how to pull the things into Genentech that make sense--in some ways like the Roche institute where they just do what they want. Right after it started was when Genentech hit its toughest times.
Hughes
Genentech was really banking on tPA, wasn't it?
Goeddel
Yes.
Initial Public Offering, October 14, 1980
[Interview 3: September 12, 2001] ##
HughesDr. Goeddel, how much did you know at the time about the negotiations around the initial public offering in 1980?
Goeddel
Actually, quite little. I spent most of the time in the lab and I didn't know what doing a public offering really meant, other than as an employee you had a stock benefit. Those discussions were ongoing by the small management team, and once in a while I would get a little information, and usually that was from Tom Kiley who always liked to talk--my office was next to his. As it got closer to the time of really making the decision, Tom probably filled me in a little more than he had earlier. It wasn't something that was on my mind very much at all. Then near the end Swanson had a meeting with all employees where it was explained. That's when the IPO had a bigger impact because Bob made it sound like this was an important time for the company.
About that time I was spending more time talking with Art Levinson who had joined earlier that year. Art knew all kinds of stuff about the stock market. I didn't know anything, so he was explaining how this was a big deal. At the meeting where Swanson announced to all employees that we got shares at a 15 percent discount and everyone could buy 200 shares,
Hughes
Was your initial lack of focus on business matters just the way you operated, or was there an unstated policy that the business guys handled the business, and the scientists handled the science?
Goeddel
Yes, I think that's the way it was. I'm sure if I had gone to Bob and said, "What's going on?" he would have told me, but we had our own science to worry about. I think it was the combination of talking with Kiley, and Levinson getting interested. And then, of course, everyone was excited the day it happened, how big a deal it was. That pretty much kept people from working that day.
Hughes
Was there any anticipation that the IPO would have a large impact?
Goeddel
They were talking about twenty dollars a share, and then finally it got priced at thirty-five a share, which said there was a pretty good demand for it. There were certainly some people that thought it was going to go up because we also were given the ability to buy another 500 shares at market price, thirty-five dollars; you had to sign up the day before the IPO. Art Levinson talked me into it. He said, "It's going to go up," so he must have checked around. So I bought the 500 shares as he and others did.
Then everyone was checking quotes that day, and following as it went up to whatever it got up to at the highest, maybe eighty-nine. It closed in the seventies. I think that then got everyone's attention in the company. It changed the company because from that day on people talked about stock, and up until then they really didn't.
Science and the Stock Market
HughesThey talked about it, but did it also shape your science? Now you were a public company with certain reporting requirements and goals to meet.
Goeddel
I think I was oblivious to that. I guess the first time I really realized how the science could affect the stock was when--it must have been 1981--I gave a talk at a meeting in San Francisco. At the end of the talk I described how we had made interferon in yeast; before we had made it in bacteria. It was probably the beginning of '81. It was just another part of the scientific talk, and our stock went up in a matter of a half hour from thirty-five to forty-two dollars. So the value of the company had increased by twenty percent based on mentioning some scientific thing. I'm sure it was in Swanson's and the management team's minds, how do we deal with the science that's being done? But the fact we were public or private didn't affect at all how I did science.
Genentech's Publication Review Process
HughesGenentech had a review process for any public talk or publication.
Goeddel
The review process was originally put in place-- I could be wrong, but I'm pretty sure it was originally put in place to ensure high quality science: Everything that went out of Genentech should be of high quality. Over time the review process was used for a lot of things in addition to that, such as making sure patents had been filed before a publication went out, giving someone higher up the ability to say, "Hey, we shouldn't be talking about this at this kind of meeting."
Ultimately, on tPA, when we got to that point, the decision was made: Don't publish it because it's a competitive advantage to not tell other people how we got tPA and what the sequence is. But I don't think that was related to being a public company, more just our competitive advantage. The publication release form served a lot of purposes. But I think initially we wanted to make sure if something went out it had been reviewed for quality, and the scientific directors had some responsibility for that.
Hughes
You mean, reviewed for scientific quality?
Goeddel
Yes. We were trying to establish a very high-quality scientific reputation. Unlike a university where if someone at Berkeley publishes a lousy paper that doesn't mean that some guy in a different department at Berkeley is a lousy scientist. Each lab has its individual name associated with it, not the university one. But at a company it always seems to be, "Genentech did that." And you're all lumped together. So if someone publishes some questionable science everyone takes part. It hurts your recruiting and your scientific reputation.
The Hiring Process for Scientists
GoeddelAnother thing we did about the same time was have a hiring committee composed of scientists. So if a new scientist was getting hired they had to be approved by this committee; a scientific director on their own couldn't go make a decision. That was similar to the publication review, to have a peer group that said, "Okay, this is the quality that we want another scientist to be."
Hughes
You told me that you hired Yansura whom you had worked with in Colorado. That was before there was a committee?
Goeddel
Yes. Well, he wouldn't have had to go through it anyway because he was considered a technician or research associate. But for a scientist, which is the position beyond a postdoc where you actually run a lab, you needed a committee. We were competing with universities, and if the university hired that person he would be an assistant professor starting out, and there certainly would be a peer review committee at a university, so we essentially put the same thing into a company.
Hughes
Who initiated this academic approach?
I think it came out of our molecular biology department early on. There were six or seven of us. Another department would hire somebody and we would say, "Hey, that person isn't so good," and there would be discussion. I think it was reached by consensus in molecular biology: Here's something we should have. Mike Ross who headed up protein biochemistry at that point agreed. Then there was a new department. It was kind of like a pharmacology department, but it was called biology. This was actually the group that we were most concerned about. So it might have been Mike Ross, who was the research person on the management committee early on, who may have gotten Swanson or Kiley or someone else and just said, "We're going to have these review systems in place."
Hughes
Would Swanson more or less rubber stamp these decisions?
Goeddel
Sometimes. The hiring committee he was a little slower on. He said, "Every department should be able to hire who they want. You want to police how they do that?" "Yes." Sometimes he would see how serious you were. There were very few times where if I felt very strongly about something, and Bob wouldn't go along with it. He might try to talk me out of it--and a lot of times he could talk me out of things--but if he saw he couldn't he would usually go along. I'm sure now it's in a different format, but the hiring committee is a very serious thing throughout the whole company.
Genentech Gains Credibility in Academic Science
HughesBefore the late 1970s or even the early '80s it was not generally considered a good step for an academic biologist to take a job in industry. The assumption often was that the person was not of academic quality.
Goeddel
Over time we were reviewed scientifically more and more positively as we made different breakthroughs. We probably didn't get too much credit for insulin, for growth hormone we got maybe a little more, but by the time the interferon stuff starting to come out it was clear that we were going to continually do important things. For any one, thing maybe people could say, "They got lucky." But then when there was continually, every few months, another major paper in Science or Nature, we started to be recognized as at least having a few good scientists, and then eventually that Genentech was a powerhouse, which we probably reached by '83.
Hiring the First Vice President of Research
GoeddelOne of the things that hurt early on is we didn't have a scientific advisory board, like a Biogen, with a bunch of famous people so the word didn't get around as much. Then in '82 we started looking for someone in the beginning of the year to hire as head of research, because we had no VP of Research. We came up with a list of names and contacted some of them and started interviewing, brought them in. They were impressed with what they saw, even though the first few we couldn't get recruited. I think that helped get the word out that here's a good place.
Hughes
Can you give me some names?
I think the first person we interviewed was someone Swanson brought in from Merck--Lew Sarett--he was a very famous chemist who was old, at the end of his career, retiring from Merck. I think he first synthesized cortisone a long, long time ago. He was probably 65, just retiring from Merck, and Swanson thought he would bring some discipline, or maturity, or whatever. He was ready to hire him, and the scientists kind of revolted, one of the few times. We said, "We don't want him." Bob was so disappointed because I think he had told the guy, "We'll get you an offer." But when he could see no one wanted him, he said, "Okay."
Hughes
Why didn't you want him?
Goeddel
I wasn't nearly as outspoken as the rest of the people. I actually didn't care that much. It was not going to affect my work. He was just going to sit in meetings. I think it was mainly because he didn't understand what we were doing. He was a chemist from the old pharmaceutical industry. He was being brought in to manage us, not help with the science.
So after that we wanted more of a biologist. So then Bob brought in Don Fredrickson who had been head of the NIH. He was an MD, and he brought his wife and a son to the interview, which was kind of weird. We really pushed to attract him. Here was a guy who had run NIH who would look really good at Genentech. We went out to dinner with him, and Fredrickson seemed okay but his wife just seemed so strange, and it was clear she was going to be a part of the package. She was organizing him during the interview, and she was saying where her office would be.
Hughes
Was she a scientist?
Goeddel
I don't know if she was or not. She was a Dutch lady, I think. I remember her talking to Herb Heyneker and his wife at the dinner but in a way they kind of made it seem like the Heynekers must be lower-class Dutch people. She turned most of the scientists off, and I think Bob at the end said he didn't want Fredrickson around if she was going to be the one in charge. He didn't get an offer, and then he went off and ran Howard Hughes for a while until he got kicked out, is what I heard, because of things his wife did--spending tons of the Howard Hughes money on expensive artwork or something--I don't know what the whole story was.
And then we went to the more academic types. There are a number of names. We interviewed Mike Bishop at UCSF, and I don't think we ever made an offer. Maybe it wasn't clear that he would come. The first guy that got an offer was Arnie Levine who now is president of Rockefeller. He had been at Princeton, and I think he was at Stony Brook then, and then he went back to Princeton. Very famous scientist. He had been Levinson's graduate adviser. I thought we had him. He seemed ready to come and then at the last minute chickened out. I saw him many years later at a meeting. We had offered him a whole lot of stock. (That was after Genentech stock had done fantastic.) He said, "I don't know if I made a mistake or not; I still like academic science. But my wife never lets me forget about the financial mistake I made not going there."
Vice President of Science
GoeddelThen David Botstein got an offer in late '82, and I thought he was going to come, and he didn't. He came in '87 in a different position.
Hughes
What is the position?
Goeddel
We created a new position, VP of Science. When he came as VP of Science, he was under Dave Martin. We ended up hiring Martin for VP of Research in 1987. He was the next guy we interviewed after Botstein. We interviewed him, and everyone loved Martin, and he was ready to make the jump. He came from UCSF.
Then when we hired Botstein in 1987 we just wanted another scientific guru kind of guy, real smart guy. I and other people knew that he's very good with young people, real enthusiastic, very smart. Let him have a little lab and run around and talk to everyone about their projects. That would be great. So when Botstein came he was give the title VP of Science which didn't have any functional responsibilities. He didn't have anyone report to him. He had his group and he was supposed to do all this. He became too fascinated with how the rest of the company was running and spent a lot of time at management meetings and talking with Bob and Kirk Raab and in his lab and spent very little time on anyone else's science.
Then he got into battles with Dave Martin and Ralph Snyderman, and those became some of the ugly times, '88, '89 or something. He ended up leaving, went to Stanford, but stayed on as a consultant and has been extremely good. He would spend a day a week at Genentech, and then it was clear his contributions were as they were meant to be all along--advising on science issues. But I think industry was just so new for him. He had been at MIT all those years, and he said, "Science is something I've done all the time. I want to tell the marketing guys how to sell more tPA." He was doing things like that. He had an idea on everything.
Hughes
It is impressive, the caliber of people that you attracted and who showed some interest in coming. That in itself is a measure of Genentech's growing reputation.
The Scientific Resource Board
HughesWas it a conscious decision not to have a scientific advisory board, or did it just never get organized?
Goeddel
I don't know. I think it could have been the latter; Bob and Herb formed the company and didn't know you were supposed to have one. Maybe when Biogen had one, that said, "With future companies, let's get a bunch of scientific founders together and organize a scientific advisory board." But part of it could have been intentional on Herb's part: "Why do we need one? We have the best young scientists. They don't need anyone to tell them what to do."
Hughes
And Boyer himself was acting somewhat in that capacity.
Somewhat, yes. Later on, when they finally formed one, it was named differently, a scientific resource board instead of a scientific advisory board. I'm not sure if there's much difference in what they do.
Hughes
Do you know what prompted its formation?
Goeddel
It was discussions between Botstein and Swanson, at least partially. It may have arisen from Bob thinking we were further along, maybe we needed a group of smart guys to advise on major directions we were heading, new projects maybe--not so much evaluating in detail the science that was ongoing but to give high-level advice. Names were proposed. I think Botstein had a reasonably big part in selecting the names. Then his job was to recruit those guys to the position, which he did. So he coordinated the first couple of SRB meetings in the '87, '88, '89 timeframe, until he left.
Hughes
You're still on the board, aren't you?
Goeddel
I am on it, yes, but I didn't join it until very recently. Botstein left, and I coordinated it. I had the job of organizing the meeting and bringing the guys in every year. When I left in '93 that was it. I think maybe three years ago I got invited to join it, and I thought that would be great. I liked that group of people, and I had maintained the connections at Genentech. Dennis Henner VP of Research asked me to join it. He must have already cleared it with Art, and I've been on it since then.
Hughes
How does it relate, if at all, to what you're doing Tularik?
Goeddel
Not too much; there's an occasional overlap. There were some small-company collaborations that they were interested in that we were also, so maybe we were competing to get those. But I told Henner and Art ahead of time, and they said, "We trust you." I think the fact that they're mainly protein drugs; we're mainly small molecules, separates us pretty easily. They occasionally have a small-molecule project they're working with--very few. But maybe a few years from now, we might have some conflict and I won't be able to be on the board. But it's only once a year for two-and-a-half days, and it's a great fun meeting with a lot of real smart guys. Some of them have been on it from the beginning and some they slowly change.
Hughes
It sounds as though the board is intended to have a real function and not just function as a showpiece.
Goeddel
Right.
Hughes
How does that compare to other biotech companies?
Goeddel
I don't know much about that. I have heard there are some which have these guys they pay just to use their names to advertise. The Genentech board has been quite good, and we patterned the Tularik one somewhat after that. I would say it's 75 percent the same. I tried to take what I thought were all the good features and do a few extra things that I think allow us to get a little more out of it at Tularik. But it was patterned pretty similarly to how Genentech's runs. This group comes in; they're given a few major topics to look into to get feedback on directions and sometimes on people or whole departments. Genentech sometimes has made decisions that weren't right about people to be running a department or the ones that should have more responsibility, based on the feedback of the SRB.
The Early Board of Directors
HughesSo the board has real power. What contact with or knowledge of the early board of directors did you have?
Goeddel
I think originally it was just Herb, Bob, and Tom Perkins. I knew all of them. I wasn't sure what a board was, but it was clear that Tom Perkins was chairman of the board, and he in some ways was Swanson's boss; that was clear to me. Perkins was around a fair amount in the early days. I met him, talked to him. During insulin, at the end, I met with him and Bob in Bob's office. Perkins just kind of said, "I think you should go down to City of Hope and not come back until this is done." So he was actively involved. He came to our first company retreats or planning meetings, that were held at Silverado. Over time, as the company grew, Perkins took on a smaller role in terms of visibility, as far as I was concerned. But I think he still remained active as chairman for quite a while.
Then there was an investment made by Lubrizol. A guy from there went on the board with that investment.
Hughes
And Fluor.
Goeddel
Fluor, okay. There may also have even been a Swedish guy from Alpha Laval early on. So these were guys that Bob added to the board. Faulkner maybe was one of the names.
Hughes
Yes, that rings a bell.
Goeddel
And there was clearly the guy with the Lubrizol investment.
Hughes
Murfin.
Goeddel
Don Murfin. He might have been the Lubrizol guy. Then I think David Packard came next, and Swanson said he wanted someone with experience building a company and turning it into a business who had been with it from the beginning and seen the growth. That was considered fantastic when he got Packard on the board.
Hughes
Why do you think Packard came?
Goeddel
I think it was likely that Tom Perkins arranged a meeting between Bob and Packard.
##
Goeddel
I think anyone at that time who talked with Bob would be convinced here's going to be a new industry that's certainly going to be exciting and help human welfare, and I would love to be involved. My guess is it would be almost impossible for anyone to listen to Bob at that time and then turn him down.
Hughes
The science was exciting, and the commercial potential was exciting. Bob could translate this in a way that would grab people?
Yes, that's what I mean. I would think, anyone Bob wanted then, even though we were unknown and small-- Actually, we weren't unknown when Packard came on; we had had our IPO.
Hughes
You had had a lot of visibility.
Goeddel
Yes, so I'm sure Packard had heard of us.
Hughes
Were there consequences that flowed directly from those board meetings?
Goeddel
I don't think there was a lot of that early on. I was surprised when it was clear that all the board members knew who I was. I once got a note from Dave Packard congratulating me on something, or Swanson would tell me the board approved this much stock and this bonus for me. I knew from the annual report, from what the officers were getting, I was getting more than them. That kind of stuff had to be approved by the board. The things I thought they did at that time were approve stock and decide when the stock should be split. That would be the only thing we would hear, "Hey, we're going to have a two-for-one split."
Maybe in '87, '88, it was clear the board was having an influence, and Bob was feeling the pressure from them on certain things when times were getting a little more difficult. But in the early eighties, when there were scientific successes and we didn't really have a marketed product yet, I think the board was more in a positive behind-him mode, pushing to build the company.
Hughes
Did they seem to understand the science?
Goeddel
No. I presented at the board maybe only three times. Bob would ask me, "We're going to have a scientific update, will you come talk about this project?" I think it was a kind of a show-and-tell, just to have some scientists there. Some of the board members would be sleeping when you were talking. Herb already knew what we were going to talk about. There were members of the management team there, like the officers of the company, and we knew some of them didn't know what the science was about. I think most of the scientists who ended up presenting there thought it was just something you had to do to show the board what a scientist was, as opposed to teach them anything.
Hughes
How active was Herb on the board?
Goeddel
He was pretty quiet, laid-back--typical Herb. If he really believed there was something the company was doing wrong he would stand up for it, but most of the time he just seemed content to sit back and let other people talk. He'd throw in a word here and there.
Bob Byrnes, First VP of Business Development
HughesIs there anything else you care to say about the business side of the company in the early days?
Goeddel
I think a key hire early on for the company was Bob Byrnes. He really brought some experience and confidence and business smoothness to the company at a time when we probably needed it. Before he got hired, there was a lot of talk like, "Oh, this is a Madison
Hughes
Do you know why he was hired? And why he decided to come?
Goeddel
At the time I just figured Bob had talked another good guy into coming. Later on, seeing what Byrnes did, he was kind of an entrepreneur himself, and here was a new opportunity to get in early, stay a few years, collect some stock, and then go do something new in a different area. He seemed after a while to be the kind of guy who would have about a three-year attention span and then want to go do something else. But he was probably the perfect guy for Genentech at that time.
Hughes
When you say smooth, what are you thinking?
Goeddel
He could be in charge in a business meeting or even if it was tough negotiations, and he could run it in a very polite, nice way, get his way, but do it without coming across as a mean guy.
Hughes
Couldn't Swanson do that?
Goeddel
Swanson could somewhat, but every company needs some guys like Byrnes. We have a couple on our management team at Tularik that you know the perfect sentence will always come out of their mouth for whatever the situation is. There are other ones that are very smart but you don't want them talking when negotiations are going on. Byrnes also hired a good group of guys under him, so when he left the company was in good shape.
Hughes
Did he work with Kiley?
Goeddel
Yes, I think they were good buddies. They lived very near each other in Hillsborough.
Thomas Kiley, First General Counsel
HughesTell me more about your early interaction with Kiley.
Goeddel
He was a patent lawyer, had the office next to us, and just a very interesting guy--wanted to know what we were doing, liked to talk, liked to tell us things from his side. He got along very well with the scientists. Over a period of a year or two, he and I became very good personal friends; that's remained.
Hughes
You go fishing together.
Goeddel
He had never fished; I got him into that. I got him to do a lot of things he had never done before. He'll try anything. We went to Africa on a safari together with our kids. We're so different. He had never spent any time in the outdoors or doing anything, but I would say, "Come on, why don't you try this?" And he would go, "Okay, sure." And he would always
Serum Albumin
HughesWhere would you like to start in discussing the blood-derived products?
Goeddel
Serum albumin's very short, so we could do it. And then probably urokinase and tPA belong together, and then factor VIII, would be my guess.
Albumin was in the molecular biology department. I think most people thought, that's going to be the most boring cloning project we could have. It's the major blood protein; it's made by the liver. It should be pretty easy to clone; it's just a big protein. There wasn't a lot of competition of who wanted to work on it. It ended up as Dick Lawn's project. I don't know, maybe he really wanted it or maybe he just got handed it. He had helped out some on interferon, and here was one that was his project.
To get the cDNA clone was really straightforward. There's a funny story behind it. A technician in his lab named Dan Palermo didn't have a very good reputation for being a good research assistant or technician. He was one of the guys in Dick's lab working on this project. They used small synthetic DNA probes to screen the cDNA library to try to find the albumin clone. You do the hybridization. If you get a radioactive spot, that's maybe the clone. So they got a radioactive spot, they sequenced it, and it was the clone. Turned out it was only a partial clone, and the radioactive spot was just junk, an artifact, because the probe didn't even match up with the part of the clone they got. So by pure random luck, is what we all thought then, they had pulled out this clone. Only later did we know that 10 percent of all the liver clones were albumin, so they didn't even need to do the hybridizations. They could have just sequenced ten clones, and one of them would have been it, so they just happened to get that one first. People always reminded Dick about this great cloning project.
Albumin became, for many years, a very difficult expression problem--how to make enough of that protein.
Hughes
Which you hadn't anticipated?
Goeddel
Well, we knew we would have to make it very cheap because it was a blood product at that point, and you need a lot of it. We weren't talking about tPA, where you give micrograms or milligrams. We're talking about grams and grams; that's a whole different level. After a while it became clear that E. coli wouldn't work, mammalian cells were probably too expensive, so a lot of effort went on doing it in yeast in Ron Hitzeman's lab. They got the yield up pretty high, eventually to one gram per liter. But it still was not commercially viable, and the project was terminated eventually after a long time.
You started off by saying that serum albumin was in molecular biology.
Goeddel
Well, I'm not sure--in '79 or '80, there was a list of things that were potential therapeutic proteins to be done. Albumin was on the list because albumin was used commercially then. So it was a replacement, like replacing insulin. So there was a list of potential projects based on replacing known products, and then there was a list of other ones under it that might be attractive, ideas people had, some of these growth factors. It was an assumption from the beginning: serum albumin is one we have to do because there's a big market out there, so someone's going to do it.
Hughes
The project had to be in molecular biology to get the clone?
Goeddel
To get the clone, yes.
Hughes
How much overlap was there from company to company in product targets?
Goeddel
I think the list was probably pretty much the same, the few companies that were there. Maybe 80 percent. I would guess albumin was on the list for Cetus or Biogen or Amgen when they started.
Hughes
How does that molecule compare in size to what you had done?
Goeddel
It's the same size as tPA.
Hughes
So it's big.
Goeddel
Yes.
Tinkering to Get Better Expression
HughesWas its size related to the expression problems?
Goeddel
I think partially, but not only. If it was an intracellular protein of that size it wouldn't have been so much problem making it, but here was a protein that's normally secreted, and now we're making it inside the cells. That's why the yeast group had to figure out how to get it secreted, since yeast is efficient at secreting proteins. E. coli is not so efficient at secreting proteins, or at least it wasn't for us, so the protein would just gum up inside, and essentially the cells would stop growing and dividing if you made more.
Hughes
Did you have to find this out by experiment?
Goeddel
Yes. You do experiments and say, "Ah, okay I can see that problem. I'm going to change my expression vector a little," or, "I'm going to change the growth conditions." You keep thinking the next experiment you can solve it. Sometimes you make a little progress, "Okay, I'm on the way," but you keep hitting brick walls. There are so many things you can try that there's always a new idea.
When you say change an expression vector, would that be something like changing a promoter?
Goeddel
Yes, that could be changing a promoter, changing a ribosome binding site, changing the transcription termination site, changing the copy number of the plasmid, changing the strain of yeast you use, and then things such as putting on a different signal peptide to try to get it secreted. There were all kinds of different ideas then and tricks to try.
Hughes
Would you run through them routinely?
Goeddel
On this project it became pretty systematic when it was clear something wasn't going to work easily. Maybe you would make fifty different promoter constructs and test them all and take the best one of those, and then try the different ribosome binding sites. Usually what I would do since we had all this other work going on optimizing expression, and vectors being made, and little things developed--I would usually find something new. I would look at everything we had and say, "What do I think is going to give it the best chance of real high expression?" and make that expression vector right away--put everything in it at once. If that didn't work you kind of worked backwards.
Hughes
Was this the way everybody was working in other companies and academic laboratories?
Goeddel
I don't think anyone in the early eighties had the ability to look at expression the way we did, with so many systems, so many good people looking at it, so many different things to try. I don't think it was done that way at other places.
Hughes
Was serum albumin the first protein used in yeast?
Goeddel
Yeast was used first with interferon and with hepatitis B surface antigen to make hepatitis vaccine. I think albumin came along pretty soon after that, but we had already made reasonably good amounts of interferon in yeast. The first publication that came out on yeast expression, was with interferon.
Establishing Different Culture Systems
HughesHow big a deal was it to get different culture systems going?
Goeddel
At that time it was a pretty big deal. We had E. coli first, and then we decided we needed yeast and we hired Ron Hitzeman.
Hughes
He was the yeast expert.
Goeddel
He was a yeast expert from UC Santa Barbara. And then Art Levinson was hired to head up mammalian cell expression. Each was given some resources in their lab, and here were all these cDNA clones that different scientists had isolated. Here's the E. coli expertise we've built, different ideas, now let's apply those to these different systems. It was nice to be able to have whole groups whose job was expression.
Hughes
Was it tPA that first went into the mammalian cells?
Levinson developed the mammalian cell systems. I think the hepatitis B surface antigen was one of the very early ones there. We did interferon in mammalian cells, and he was perfecting and improving expression. So when tPA came along he was ready to go with it, had enough experience. It wasn't the first thing, but it was the one that showed us that the investment in that lab was really going to pay off for something. tPA was going to be the first protein that had to be made in mammalian cells.
Hughes
Was Genentech anticipating tPA when it hired Hitzeman?
Goeddel
Not that it would be tPA.
Hughes
But that you would need a mammalian cell culture system?
Goeddel
It was likely there was going to be something down the road that E. coli wasn't going to be satisfactory for.
Hughes
Genentech typically thought several steps ahead?
Goeddel
It was pretty good [at that]. A lot of companies don't think like that now, but I think it's just because of the time. This new field was blowing open; Genentech was in the lead. So you have the people that are leading scientists in it, and they're naturally thinking, what's next? And what do we need to do? In fact, there was a bunch of good scientists talking ideas. You would always come up with a new idea in discussion, and then it was the kind of place that was somewhat competitive: Well, someone better do that idea or the other guy is going to do it. So things were always moving along.
Most of the companies now can't afford to do that, to have groups working on something you might need in a few years. It's a luxury now. And there's so much stuff going on in university labs and all the other companies that even if you did, is that two-year investment going to pay off, or are you better letting someone else discover it and then license it? Then we always had the feeling: If we work on this we're going to be the first to get it done. We didn't worry that someone else was going to make the discovery six months before we got there.
Hughes
It must have been exciting.
Goeddel
Yes. I would say '78 through'83 were very exciting times.
Goeddel as Director of Molecular Biology, 1980-1993
HughesWere you still working like a fiend?
Goeddel
Yes. The department had gotten pretty big by '83, and I took over in September of '80 as director of molecular biology. Probably for a year of two I didn't do much as a director, but still did mainly lab science. Then I tried to be a little better director and spend some time on that. It cut into my actual bench time, but still the majority of time through '83 was spent with my lab. Even if I wasn't doing as many experiments I was in the lab talking to the people who
Hughes
Working on how many different projects?
Goeddel
Lots of different ones. There was always one major one that had the highest importance in terms of how the company was doing, but there were always some other very interesting ones close behind that had the potential to go there.
Hughes
You never felt that it was getting away from you?
Goeddel
Not then. Maybe in '86 when I had so much other stuff. I didn't feel it was getting away from me, but in my list of priorities if there were six things going on in the lab, and number six didn't get the same attention that it might have two years earlier, that's for sure.
Hughes
What was happening in '86?
Goeddel
The company and the department were just so much bigger and more complicated, and I had immunologists who were tougher for me to oversee than just having molecular biologists. The department was over 100 people.
Tissue Plasminogen Activator
Urokinase Leads to tPA
HughesDo you want to talk about tPA?
Goeddel
Yes. From as far back as '78 we talked about urokinase to treat blood clots.
Hughes
Where did you get that idea?
Goeddel
It was known that it had the activity. I remember talking about it with Heyneker at one point, and with Swanson probably during late '78. As we divided things up, tPA became Heyneker's project. He was getting started on it. Then we signed a deal with Grunenthal, to work on urokinase. And Diane Pennica joined Heyneker's lab as a scientist to work on this. Herb was a senior scientist. He sent her off to some meeting, maybe it was in Europe--I'm not sure exactly where it was--to learn about urokinase. She met a Belgian guy, Desiré Collen, at the meeting, and he had been studying and purifying plasminogen activator, tPA. He discussed it with Diane, or she heard him talk at a closed meeting the day before the big meeting, about this new activity he had. He may have even treated one patient with naturally purified stuff and dissolved a clot in a heart attack.
She came back all excited about working on this and said this guy would like to work with Genentech. I think it was Bob Byrnes working with Heyneker who actually got Collen signed up as a consultant and worked out the deal. It turned out to be very fortuitous to Genentech to have him signed up as a consultant and go to work with him. The project was in Heyneker's lab; Heyneker reported to me in my role as director.
Did Collen supply the initial tPA?
Goeddel
He supplied the cell line that was used to clone the cDNA, and he worked on the purification and supplied partially purified tPA that the biochemistry group at Genentech tried to finish purifying to get protein sequence that was going to be needed for the cloning. Heyneker's lab worked on urokinase and tPA at the same time. They also worked on E. coli expression, but that was about all they worked on. Over time I think it became clear that this tPA could be very valuable. The numbers were starting to look huge. Swanson became really interested in tPA.
Goeddel and Diane Pennica Take on tPA
GoeddelI was working on interferon-gamma right next door to Heyneker's lab, and about the time we got the interferon-gamma cloned, or were close to it, Swanson started pushing on me to take tPA into my lab.
Hughes
Why was Swanson enthusiastic about tPA?
Goeddel
I think because of the clinical data from Collen's couple of patients. Swanson always called it Drano for heart attacks. Bob said, "This is going to be the greatest drug." He was trying to talk me into working on it, and I said, "Well, I would like to work on it, but I'm director. I can't take a good project away from someone." So we had a few discussions about that. He said, "Okay, I'll just give Heyneker a little longer." Bob really liked Herb as a personal friend, but his view was he couldn't drive a project to completion, and he thought I could do it on any project, so he really wanted me to take it on.
It was kind of an awkward situation, and eventually I went and talked with Heyneker. Part of it was Diane didn't want to work with Herb anymore; she thought if she was in my lab she could be successful. It was a little weird. She moved to my lab physically, brought the project, and then I started working with her. Herb took it pretty well. I think he was a little upset for a while, but in the end he was okay; he still had urokinase.
Hughes
Swanson didn't think Heyneker was pushing it hard enough?
Goeddel
I don't know if it was push or focus or he knew I worked harder than Herb. I think with my record on each of my projects, he just wanted me working on tPA. He was always like, "Why don't you take on this project," or "Why have so many people in Heyneker's lab? Just move them." He was doing the same things I do now when I go into a project, "Get more people on it. Make sure it gets done faster."
In a couple of months we had identified a partial clone. It didn't take very long, and probably would have been identified even if the project had stayed in Heyneker's lab.
##
Goeddel
I looked at Diane's data every day, did a few experiments, and focused her in on what needed to be done. Then we got it, we had to get a full-length clone which actually turned out fairly
Working with Pennica
HughesTell me about working with Diane. It sounds as though mainly she was doing the bench work, is that right?
Goeddel
I was doing bench work on a whole bunch of projects and running the department. She was working full-time on tPA. She worked very hard at that time, but she was relatively inexperienced in the cloning, the screening, in the other things you do, but also extremely good technically. I thought she was perfect to have in the lab because if I would say, "Go do this; do it this way." She would always do it that way, and you would get data that you could interpret. Some people always have to change something, and then it goes wrong, and you're trying to figure out what happened. For a while the way we worked together was perfect because I like to design how to do things, and she liked to do it and see that her results worked. So our success together was actually very good. She worked pretty much seven days a week during that tPA time.
Hughes
Did she have a family?
Goeddel
No. She had a boyfriend we set her up with at Genentech. That was just how crazy that place was: Everyone kept telling this new guy, "Diane really likes you." He said, "I don't think so. She never even--" It was one of those things that eventually he was told this enough and went and bugged her and asked her out enough that eventually they got married. But it was all just a big joke at the beginning to see if this guy was enough of a sucker to believe it.
Getting Protein Products through the FDA
HughesI want to quote from "The Clonical." I think it was the earliest Genentech staff newsletter. This quote comes from a 1987 issue: "With tPA we've set a standard of purity and consistency of protein manufacturing from mammalian cells that other companies will have to match."
Goeddel
It's probably talking about the clinical product. Since tPA comes from mammalian cells, there's the potential worry about retroviral DNA or cancer genes or something. So on the manufacturing and process-science side they purified away almost every possible contaminant and then documented that. And by supplying the FDA with all the information on, "Look, there's no DNA in here; there couldn't be any cancer genes," and having assays for that, I think now the FDA had a standard. This was the first protein product to come out of mammalian cells. So future products were going to have to match that standard, even if they
Hughes
For everybody, not just Genentech.
Goeddel
Right.
Hughes
Did that indeed prove to be the case?
Goeddel
I don't know; I would guess so. But by the time things got to the FDA it was far beyond my point of interest. All that regulatory stuff, even though I knew it was very important, seemed so tedious and boring to me. There was so much more exciting science to go discover. Luckily, we had a lot of good people who could get the things through the FDA.
Hughes
What was the FDA attitude towards recombinant proteins? It could have had the idea that a different approval process had to be set up for this new way of making therapeutics.
Goeddel
I think there was some of that. I remember on growth hormone, some of the experiments that the FDA asked us to do just seemed so ridiculous. Why would anyone do that? For example, every time you grow up growth hormone for a batch, you have to sequence the plasmid? Why is the plasmid going to change? Swanson said, "No sense arguing with the FDA; we just have to get someone to do it." And I would say, "I don't want to do that." "Well, we have to hire someone then." The discussion was, "Well, are we going to hire anyone that is interested in science? But they have to know how to do science to do it." We eventually got this stuff done. But early on there were things that were requested, some questions, that made it seem like the FDA had no understanding and was also trying to be ultra-safe.
Art Levinson
Scientist, Colleague, and Friend
HughesWere you involved in the early stages of the scale-up and purification of tPA?
Goeddel
No. We had Levinson, who was great. And tPA wasn't like the E. coli products where you would make the strain, you would do some improvements, you would go over them with fermentation and work on them, come back, make some more changes. It just seemed completely natural: Show you had expression in mammalian cells and give it to Levinson's lab. That's what he was set up for. For the next few years that's pretty much how things worked in mammalian cells. If it was important to be done, it would move to Art's lab after the initial expression, sometimes collaborating with the previous lab. A technician, Liz Yelverton, who had been in my lab for many years, had about that time moved to Art's lab because she was very interested in mammalian cell expression. She worked on tPA for quite a while in his lab.
Hughes
Say something about Levinson's scientific style.
Extremely smart guy, knows what he wants to do, thinks very clearly, and even though he kind of stutters and gets talking real fast, he's very good at explaining what his thoughts are. Early on he would come around and ask a lot of questions; he hadn't done any cloning. I would give him advice, and I would think he was going to have trouble with his experiment. He would come back a day or two later and show me his data, and it was all done. And he would ask a few more questions. I just gave him simple answers, and he figured out how to do it. So I became impressed pretty fast: Hey this guy's pretty good. And he was fun to talk to about science.
The first year he was there we became quite good friends. We both would work late at night a lot and on weekends, and we ended up spending a lot of time talking about science and things that could be done. His style was, he had a very clear idea of what he wanted to do, and even though he made a big mess on the bench, his science moved around very cleanly. You might look at him work and say he had a big pile of junk, how could he get anything done? His office was a huge mess--papers everywhere. But such a clear thinker--just great fun.
For probably three years we collaborated on a lot of things in our lab. We even devised new projects almost to be able to work together. He's very quick at figuring things out too, which is always nice. And intense; didn't like guys holding him up. When he was collaborating with Ron Hitzeman on the hepatitis project, doing it in yeast, there was a time when Hitzeman was supposed to come in on a Saturday and they were going to set up and do something, even though yeast was Hitzeman's area and mammalian was Art's. Ron showed up two or three hours late, and Art just went ahead and did the experiment himself, which Ron didn't like. But Art wasn't going to wait around; he just did it. When Art went into research management and dropped his lab, I thought it was kind of sad because he was so good in the lab.
Art did have trouble somewhat in hiring people. He got some average and below-average scientists and postdocs in his lab. He could have really done spectacularly if he had gotten the average level that some of the other labs had. Almost everything good that came out of his lab--maybe that's an exaggeration--a lot of the good things that came out of his lab he did himself.
Hughes
Why do you think he missed on people?
Goeddel
I don't know. Part of it's just bad luck. He had one very good technician. Some of the others, I don't know. He had a string of bad luck, and then once he decided they weren't so smart or good, I think the person became even less productive because Art would get frustrated and wouldn't spend as much time with him. He had such high standards; in his mind there were a lot of people that weren't that good.
Seeing Eye to Eye on Staff Quizzes
HughesI can see how you two would get along.
Goeddel
Yes, it was pretty good. He's a lot different now in terms of not being so tough on people, now that he's chairman and CEO. Maybe he's tough on the ones that report directly to him. He used to give his lab group quizzes and then grade them and say, "How could you get such a
Hughes
Running a business, I guess, is a little different than running a lab. But is it? You should be able to speak to that.
Goeddel
I actually liked that quiz idea so much that when I came here, after I became CEO I gave a quiz at management meetings to the senior management team every few months on general things going on in the company that I thought everyone on the management team should know. The first time some of the scores were really pretty low, some were high, and I told everyone what their score was--not in a way to embarrass them, but it had an impact. The things they were low on they made sure they learned about that part of company. I remember telling Art about that. I said, "Hey, I'm using your quiz idea with management." He goes, "Really? I never did that at Genentech management meetings. I'm going to now." I had dinner with him a couple months later, and he says, "I did a quiz and I found out who knew what's going on."
Hughes
[laughs] That's amazing.
More on tPA
Controversy
HughesLet's go back to tPA. As you doubtless remember, there was some controversy associated with it, the GUSTO trial, for example. News articles compared tPA to streptokinase, which costs a fraction of what tPA did. What do you remember?
Goeddel
I remember by that time most of my effort was focused on the newest scientific project. My opinion all along was based on scientific assays--tPA was far more clot-specific than streptokinase or even urokinase. So this would be the drug of choice if you were thinking scientifically about what you wanted. Having worked on tPA, my view was: This is the best thing; this is what you would take; how could anyone choose streptokinase over tPA?
Now, pricing and marketing practices and everything else, that's a different thing.
There was a big study, GUSTO and tPA did come out better than streptokinase, but the margin was pretty slim, which to me was kind of surprising. I had just assumed all along, based on the biochemistry--maybe we were brainwashed by our own stuff for a while--that tPA was going to be far superior. So then when you hear all these arguments: Is it worth [it for] a hospital to pay five times more, ten times more, for something that saves only ten percent more lives? I always thought that argument was completely stupid. Yes, if it's your life you're willing to pay more. If you're a hospital, what ten percent of people are you willing to kill to go with the cheaper stuff? None of that ever made any sense to me, but I knew nothing about the insurance and medical practices.
I would make a decision like that early and then spend very little energy or effort even thinking about it; I put it all in the science. So I guess I was initially surprised by the data not being more dramatic of a win, but never thought much more about it. If I had the choice of what drug would I want for me and my family, it's going to be the one that works the best. The fact it's ten times more expensive, would people worry about it if it were a penny versus ten cents? No. The whole health care cost issue was kind of beyond me.
Then I started learning things about market analysis: Maybe if we reduced the price of tPA from-I don't even remember what the number was--maybe it was $2200 to $1700, take $500 off, that will be enough so people don't think it's overpriced; it will be used more, and the market will actually be bigger. I didn't understand all of those analyses. But there was a lot of talk about that: How do you maximize the market? How far do you bring down the price to maximize your profits? I guess pricing's something we'll have to worry about here at Tularik at some point--I hope we have to worry about it. But I was just glad we had the marketing and sales guys and businessmen to make that decision.
Hughes
It sounds as though you were pretty good at doing what you were hired to do, which was to direct and do the science, and you let other people worry about what came next.
Goeddel
I always thought I had so much to do anyway, and research was what I was better at, why go work on other things that I wouldn't be as good at? At the same time I saw a lot of people there that always wanted to be involved in what they weren't good at, which amazed me. I've never understood that.
Hughes
In life in general, have you always been focused?
Goeddel
I don't know if I've been focused as much as that. If I get interested in something I really get into it. I have to be interested. For example, in school, even if I knew something was important, I couldn't get focused and do it in depth unless I really was interested. Even if I knew that my grade meant what I would do next year, I just couldn't do it.
Tularik
Agreeing to Become CEO
GoeddelHaving a CEO job now where I have to worry about a lot of things is tough on me. [pause] But it's still better than being a scientist and wanting to be a CEO, where you're ignoring what you're good at and wanting to do something that no one wants you to do. The fact that people wanted me to be CEO and thought I could do it, I said, "Okay, I'm willing to try." But I couldn't imagine saying, "I want to go do that," especially without having demonstrated that I could do it. There are so many scientists whom I've seen who are very good scientists and then they want to do something else, but fail for exactly the reasons that they would never fail as a scientist.
Hughes
Why did you want to be CEO, since you seem to have been so engaged in science?
I didn't, but I founded the company and other founders and board members convinced me that for the success of the company at that time, 1996, when they wanted me to become CEO. Their arguments were okay and I bought into it with the view we'll see how it goes, and in a couple years if it doesn't work I'll go back and run research.
Hughes
How did you feel about leaving science?
Goeddel
Well, I was still able to do it. We were a small enough company that I didn't have to leave science completely. I still had a lab. When I first became CEO, I was just the guy that made the decisions about the company. I still spent most of my time on research; we were a research organization. So I think it's been much easier for me to have my lab involvement gradually disappear. Very different than when Art took over at Genentech where in one day he essentially dropped everything. I don't think I could have done that.
Hughes
Do you find being CEO as satisfying as doing good science?
Goeddel
No. It's different. There are certain things that are nice about it, and that's the ultimate decision making you have. But the inability to focus on anything in detail can be frustrating sometimes. If I find myself starting to get into it with too much detail then I get behind on everything else. But the way around it is you hire real good people. You have confidence in them, and then you can keep up with more things because they can give you a summary. You know that the information that went into the decision was all utilized correctly and the right decision was made.
Lessons Learned at Genentech about Corporate Management
HughesI assume that your Genentech experience has played a role in your position at Tularik. Where hasn't it helped? What have you needed to learn?
Goeddel
I think the Genentech experience was a huge help, and the things that I've had to learn I probably could have learned at Genentech but I ignored because I was happy just doing what I did. I had never gotten involved in finance, PR, IR [investor relations], facilities, a lot of things I could have, whereas I was involved in the science. I spent a lot of time on intellectual property, patent-type things that came up there. Some part of my Genentech experience influences an awful lot of the stuff I do as CEO here. Stuff comes up all the time where, "Ah, it's pretty clear what Swanson would have done here and why."
Hughes
Has your experience at Genentech served you pretty well as CEO?
Goeddel
Yes, I see a lot of things where I decide, okay, we have to do this this way. Then I'm thinking, oh yes, I remember way back at Genentech when as a scientist I disagreed completely with that, but Bob explained to me why we had to do it that way. I know what decision needs to be made now, and then I'll think back on how I felt at Genentech and say, "You never could have done that there," just because of the stage I was at as a scientist.
Art and I used to talk about certain things at Genentech when neither of us had any idea that we would ever be running a company. We would talk and complain and say, "If we were running Genentech that would never happen." And you also remember, "I'm going to make
Urokinase
Heyneker Rebuts a Competitor
HughesWe left urokinase floating. What happened to it?
Goeddel
Herb's lab worked on it off and on with tPA, sometimes not as intensely as on tPA. About the same time we got the first tPA clone after the project moved to my lab, they got a urokinase clone. So when we were working on expressing tPA and getting the full length cDNA, Herb Heyneker, and mainly Bill Holmes who was his technician, were working on urokinase. They got it cloned, expressed, the patent filed, and were clearly the first in the world to do it, and it was maybe going to be a product too. It was great. It was a success for Heyneker. It took him a long time to write the paper, which was typical of Herb.
There was a big meeting in Japan, called the Genetics of Industrial Microorganisms, or something like that. Herb and I were invited to speak, and a few other Genentech guys ended up going for different reasons without us knowing that we were all going. So there were seven scientists going to one meeting in Kyoto, Japan, which was pretty ridiculous. We would never have paid for that. And there were two or three businessmen going along to meet with Japanese companies. So Genentech had a whole contingent going there. We had a great time on the bullet train, all traveling together.
There was a guy from Abbott speaking right before Heyneker in his session, and his title was "Cloning Urokinase," and Herb's title was "Cloning Urokinase." Just before the meeting, I think, Abbott published a paper in PNAS. It was all artifacts, fake data, or something. It was just completely wrong, everything in it. If you knew anything about cloning, you knew that nothing could be right. So it wasn't clear if they were trying to fake people out or they were so dumb. It got communicated to PNAS by a chemist, and you can send a paper to PNAS-
Hughes
Without peer review.
Goeddel
Yes. Probably most people read the title and said, "Ah, cloning of this." Herb's a really calm guy, but that one really bugged him. We didn't know how he would take it. This guy got up and gave his talk and didn't really show enough data. He said they cloned urokinase, and there was nothing to prove that he had. He didn't discuss a lot of the junk from the paper, but still there was stuff that was clearly wrong.
I remember Heyneker getting up in front of about 2000 people in this meeting. He got introduced, and he said, "The first thing I would like to say, whatever you just heard, forget; it's all bullshit. I'm going to tell you what urokinase is really about." And no one could believe that Herb had said that--we were laughing so hard. He had to be really irritated to say that, insult the guy at a meeting in Japan especially, with everyone in a suit.
Do you remember what the response was to Heyneker's paper?
Goeddel
Herb was from Genentech, and there was Abbott. Any scientist there, even if he didn't understand either talk, by that time was saying, "I'm going with Genentech. The two papers were different; Genentech's got to be right." In '78 it might have been the opposite view, but by this time there was no question.
Patent Battles
GoeddelUrokinase is a plasminogen activator; it activates plasminogen. Abbott had filed a patent on that. The patent office had issued the patent, and it said a patent for plasminogen activators. They had it issued before our tPA patent--
##
Goeddel
So Abbott sued Genentech for patent infringement on our own tPA. I remember the negotiations, and Swanson talking to me, and David Botstein was there by then, so this must have been '87. Swanson and some other business guy suggested that if we paid Abbott a million dollars and gave them a license under our urokinase patent so they could sell their urokinase that they wouldn't sue us for tPA and we could sell our tPA for free. I just couldn't believe that. I said, "First Botstein and I should write a letter to Science magazine and say, 'This is scientific fraud;' read their paper, and go through it line by line and point out everything that's faked and wrong and see how Abbott responds, and then maybe they won't sue us."
Swanson said, "No, you can't do that; it's going to cost too much money. We would have to go to court. For a million dollars we get to sell our tPA and they're out of our hair." It's the nuisance factor. That's the business decision: Do you want to spend $30 million in court and win ultimately and have all these delays, or do you just pay the guys off? And Swanson made the decision, and I'm not sure of the details. I think it might have been a million dollars and some other cross-licensing, but to me that just shows how bad it is when lawyers get involved in science. There's so much wasting money, wasting scientific time, on all these court things. Every time you get a product you're going to be in court at some point.
What Abbott had actually cloned was a piece of E. coli ribosomal RNA, which had nothing to do with anything. We know that because they submitted their clone to the ATCC [American Type Culture Collection] which you used to have to do with your patents. But they still got a patent on it, and Genentech had to negotiate to get by that patent.
Factor VIII
A Difficult Cloning Project
HughesFactor VIII.
That was a great project. Very difficult, very rare protein, huge protein--the whole next step beyond tPA. When it was done it was the most difficult cloning project up to that time, a big effort. It was Dick Lawn's project after albumin, there was also a big effort in protein chemistry, and wasn't really going anywhere, even with the big effort. Eventually they got a partial clone out of genomic DNA, out of a cell line that had four X chromosomes, so it was a little easier to get. That was the breakthrough; it was the starting point. Then they couldn't get a cDNA, and couldn't extend the length of the clone, and it was clear the cDNA was going to be huge.
There were rumors that Genetics Institute, the company in Boston, had obtained something on Factor VIII, so again Swanson wanted me to work on it. I had a postdoc, Dan Capon, in my lab who was really good scientifically--probably experimentally the best postdoc I ever had, and a really smart guy, but also a difficult guy. I talked to him; he got excited, so he instantly went on the project. Then, to try to ease the situation, I told Dick Lawn I wouldn't be involved. "You just get this postdoc from my lab to help you on this project." I think he was reasonably happy with that. Some of the people in Dick's lab weren't as happy because they knew this guy was good and he might get more credit than they did. But it helped them work harder, and Dan played a huge role in getting the full-length clone.
Contention over Authorship
GoeddelI'm not sure it was ever resolved who got the clone first or who got it expressed first. We had a series of papers published in Nature. Genetics Institute had some papers in the same Nature. It was great, but it was one of the biggest controversies ever at Genentech in terms of authorship. You had Bill Wood who was in Dick Lawn's lab who had worked on it all along and made major contributions. You had Lawn. You had Gordon Vehar in the biochemistry group that purified the protein. And now you had Capon, the postdoc, who had made the breakthroughs that allowed the full-length cDNA clone, and he had a huge ego. So all these guys battling, almost going to kill each other, over who was first and last author on each of the three papers. It was a huge mess.
As director of the Department of Molecular Biology I had to get involved. At the end I gave my advice to Dick Lawn, "You have to decide; you're project leader, and I'll back that up." He came out with the orders of authorship that I thought were reasonably fair, but I don't think anyone was satisfied; everyone thought they should have gotten better recognition.
Hughes
Was authorship a common problem at Genentech?
Goeddel
There was some of that, but this was the worst case. It was partially because of the time it took to do the project, the number of people who had gotten involved, but also due to the personalities. These guys were interested in scientific recognition. It was considered the last great cloning project. There was the early stuff, then interferon, tPA, and what's the last real tough, big, rare protein? There was thrombopoietin later on. But there never again was a project as difficult as factor VIII was in its time. It was a great achievement for Genentech; a lot of guys collaborated well to get it done. But by the time the authorship battle was over there were hard feelings that probably never ended between some of the people.
When did this happen?
Goeddel
I think the full-length cDNA clone Capon got would have been at the very end of '83.
Hughes
I have a note here that says Gordon Vehar and Richard Lawn announced cloning of factor VIII in April '84.
Goeddel
Yes, that would have been about right. So the full-length clone was the end of the year, got expression early '84, and write up the papers.
You say, "Vehar and Lawn announced--" That was just the kind of thing: Both Capon and Wood thought they were the key scientists, and they should have been recognized. Why was it always Vehar and Lawn? I wonder where you got that. [1] David Perlman, "Bay Firm Clones Blood-clotting Gene," San Francisco Chronicle, April 25, 1984, p. 5. If Dan Capon and Bill Wood were sitting here and heard you say that their faces would go red. "Are people still saying that seventeen years later?!"
Swanson, a Non-scientist, as CEO
HughesOne last question: Swanson of course was a businessman and somewhat anomalous in the early days when many of the early biotech companies were founded and directed by scientists. What difference do you think it made that the man at the top at Genentech was not a scientist?
Goeddel
That's why we beat Biogen, I'm sure. He kept us focused. Every time someone would get interested in something scientific he would go back to, "This is a business." And he was in charge because he founded the company. Those other companies knew they needed to hire a businessman, but the scientific founders were always more powerful. You see that in companies all the time.
It would be really tough now for someone like Bob, a young businessman, to come into this industry and found a biology company that he's going to run. So the timing was right, and there were no other companies, no other experienced managers in the area, and he could use directly a lot of the stuff he learned from business school. What he had was enthusiasm, a vision, and prioritization or focusing ability: "We have to get this done and make everyone believe it." He wasn't changing the message; it was the same thing every day. And when it got done there was never a rest because instantly something else took on the highest priority: "This is what we have to do now."
I remember him telling me on insulin, "If we can get insulin first, we've got it made." After I got it he said, "Oh, all we have to do is get growth hormone, and we've got it made." Then it was interferon, and after about the fourth one of those I said, "Bob, every one we clone, as soon as I finish one, you say, 'All we need is this next one and we've got it made.'" And he goes, "Yes, I guess I always say that." After eight or ten years he stopped saying that; it was clear the company was going to make it. He had to use something else then.
He did feel eventually that the company had made it?
Goeddel
Yes.
Roche's Majority Share in Genentech
[Interview 4: October 18, 2001] ##
Circumstances of the Acquisition
HughesIn 1990, Roche bought a 60-percent stake in Genentech. Do you know what the circumstances were?
Goeddel
Yes. Part of them at least. It was probably in late 1989 Jurgen Drews, who ran research at Roche, came to visit Genentech. He was there a couple days, maybe even three days. David Botstein came around and said he was coordinating a visit with this guy from Roche--would I meet with him for a couple of hours and tell him my ideas about everything I was working on?--it was okay to tell him everything. That sounded very suspicious, and I said, "Oh, they want to buy us, so we're going to tell them everything? Because we've never done anything like that before." And David says, "Oh no, of course not. Kirk and Bob have told me that we might be able to get a good deal with them--they'll fund one of our programs. So we need to tell them everything." David lined up a bunch of people to meet with Jurgen. I think it was that evening I talked with Art Levinson, and he had the same exact feeling I did, that Roche was coming to see if they were going to buy us out. But no one else seemed to say much, and Art and I said, "That has to be what it is." Kirk and Bob were perfect to pick Botstein to coordinate it because he really believed them that it just had nothing to do with an acquisition, so he could show Jurgen around and declare he had no idea.
I don't remember when the acquisition was announced, maybe February of 1990. I got a call at home from Art early that morning, just before I came to work. In the meantime, Art had moved to the position of either VP of Technology or VP of Research, so he'd been told, I think, just the day before. The management team had kept it pretty quiet. He said, "Can you come into work right now and stop by my office?" He's going to go in early and he has some news to tell me. He said, "What do you think this is?" I said, "Roche bought us." He goes, "Yes. What price?" I think I said thirty-five [a share] and it was thirty-six, or I said thirty-six and it was thirty-five. I was a dollar off. Stock was trading at about twenty-one. That was just a random guess. Art said, "Pretty good, you're off by a dollar."
Swanson's and Goeddel's Reactions
GoeddelLater that day there was a meeting when everyone heard Bob give a talk and explain why it happened, that we had a big pipeline and a lot of things to develop and weren't going to be able to take care of all of these on our own. This acquisition was important to do. That's how he told the employees. That afternoon Bob came around--he used to walk the halls sometimes--sat down in my office and looked kind of tired, just sitting back. Then he said,
Hughes
I wonder about the connection with tPA. From what I've read, tPA was expected to be a blockbuster, and it wasn't.
Goeddel
Right. Certainly, if tPA had met marketing expectations they wouldn't have had to do this--if it had been a 500-600 million dollar drug instead of a 200 million dollar drug.
Hughes
One of the obvious alternatives might have been to cut down on the pipeline; pick out the most promising projects.
Goeddel
I don't think Bob wanted to lay off people. He was influenced by David Packard. He said that Hewlett-Packard had never had to lay anyone off. I think Amgen may have gone through even worse financial times than Genentech was in at that point. In retrospect, you can say Genentech probably could have made it on its own, even without cutting the pipeline.
Hughes
What was your reaction to the acquisition?
Goeddel
It actually didn't bother me. I thought it was okay. There are two reasons. One is I had never sold very much Genentech stock; it was almost like I couldn't. So here was a hunk of it, the piece we got cashed out; here was diversification done for me that I should have done all along. Someone made the decision for me. The second part was, through the late eighties, the last two years for sure, the research atmosphere at Genentech was not near as good as it had been earlier. We were losing some good people; there was no growth in research; research wasn't viewed as being as important. It was clear to everyone the day of the Roche announcement that Roche was doing this, not to get Genentech's marketing or business side, but to get the science. Pretty much from that moment on science overall was treated much better. My lab was always fine; I could have the resources I wanted. It was the labs of a lot of colleagues that weren't getting resources. They'd have someone leave and they couldn't replace them. That position would go to marketing or something. We couldn't take on as many new projects. A lot of the things that Genentech had always done real well. Right after that it was decided there would a big new research building. We'd been in the same really outdated labs forever. I think overall it helped research morale quite a bit.
Genentech Became a FIPCO without Roche
HughesI read in the San Francisco Examiner that some interpreted the Roche acquisition in 1990 as a sign that Genentech had become the integrated pharmaceutical company that Swanson had long envisioned. I wonder what you thought about that?
Goeddel
I don't agree with that. That wasn't the way he wanted to integrate. Bob wouldn't have agreed with that.
Hughes
In fact, it was almost the antithesis of what he was envisioning.
Yes, right.
Hughes
Did the company achieve that goal of FIPCO [fully integrated pharmaceutical company]?
Goeddel
Yes, I think that's what they are now. They're not independent, based on ownership, but they run pretty independently. After Bob got over the Roche acquisition, I think he was pretty happy with how things came along after that. Even when he was no longer chairman or on the board, he'd say things like, "I can't believe Amgen has a higher market cap than Genentech." So he was still thinking about what he'd built, wondering why Amgen was getting more credit from the investment community.
Kirk Raab
HughesWas it Raab that was responsible for a policy that favored other aspects of the company over the science?
Goeddel
No. I think Kirk actually came in knowing when he joined, it was Genentech research that got it where it was. He actually went out of his way to make people in research feel good. It was more Bob being prudent about what he had to do at each stage in the company. Research had to contract or stay the same for a few years. That probably happens at every company. My guess is it was more Bob than Kirk. There were conflicts between the two of them. Bob said, "We've got to be tough now. We've got to get through this next stage, then research will be okay."
Hiring Raab as Genentech President and Chief Operating Officer, 1985-1990
HughesTalk about the Raab era. Do you remember when he came to Genentech?
Goeddel
[pause] Maybe eighty-five or eighty-six he joined as president. I remember when we interviewed him. It was kind of quiet that we were looking for a second-in-command or someone to eventually take over from Bob. I got on the interview schedule. I wanted to do science; I didn't really want to interview a CEO candidate. I didn't know how to do that. I met with Kirk, and Bob came up the next day to ask me how it went, and I said, "It went okay--" He said, "Well, what do you think?" I said, "I can't tell. I guess I expected a big-shot president from a big drug company to be much more energetic, charismatic, and so on." And Bob laughed and said, "Kirk said he expected a famous scientist like you to be much more of that too." [laughter] That's what I remember from the interview.
Hughes
You went into the interview with no prior coaching?
Goeddel
Right. I think Bob was probably doing it more so I wouldn't be surprised. "Here's one of my top scientists. You can be on the interview."
Hughes
Who made the decision that Bob was no longer going to be CEO?
That happened later [1990]. When Kirk came in, the impression I had from Bob was, he wanted to bring in another guy with experience. Things I heard later, that I don't know if they're true or not, were that the board decided someone else needed to be brought in and the way to do it was to have him come in as president for a while and then become CEO. I don't know which was right, and I guess I never worried about it. Was Bob's story right or these rumors that came from marketing types?
Hughes
Did you hear rumors about what the board was thinking in making this change?
Goeddel
I heard rumors. I was very good friends with Herb Boyer all through this time, going fishing with him a lot. But I never asked, "What's the board thinking?" And he might not have said anyway.
Hughes
You didn't ask because you didn't think it was appropriate?
Goeddel
Right.
Hughes
So there was no discussion?
Goeddel
We discussed a lot of Genentech things and fishing things, but never, "Is the board unhappy with Bob or thinks someone else needs to come in as the company reaches a new stage?" No, there was nothing.
Raab's Administrative Style
HughesWere there obvious changes when Raab became president?
Goeddel
No, I think they were very gradual. Kirk was very slow in instituting anything that would be obvious changes. At some point he took over running the management meeting, but I wasn't a part of that. He ran it pretty similarly to how Bob did, maybe a little more organized agendas, or something. He worked very quietly behind the scenes. I think what he did over time was decide that he was going to get the board on his side. He was smooth and careful and slow and appeared to work well with Bob. But at the same time I think he did gather board support for taking over later. Nothing was done in a hurry, no drastic changes.
Tension between the Executives
HughesWas it apparent to scientists such as you that Raab had a different background from Swanson? Bob, of course, had come from the venture-capital world; Raab had come from Abbott.
Goeddel
Yes. I think most scientists thought, We now have two guys dividing management. The company's bigger and more complicated, and they work okay together. I don't think I realized there was a lot of tension between them. That became much more obvious later.
What caused the tension?
Goeddel
I don't know. My best guess is, this was Bob's company and he had his idea about what's best for everything, and when Kirk had a different idea, Bob might not have liked that sometimes. Kirk's goal, or he wouldn't have come, was to ultimately be the CEO and run the company. At some point, about the time when Kirk took over, it became more obvious publicly and in the meetings that they didn't always get along on everything. But for a couple of years they were very good at not showing, at least publicly, there were any conflicts between them.
Roche Respect for Genentech Culture
HughesMoving back to the Roche acquisition, was there any assurance of maintaining Genentech's culture?
Goeddel
Yes, I think Roche went out of its way and probably overdid it. The word we heard is that no Roche researchers or businessmen, and maybe only Jurgen Drews, were allowed even to call anyone at Genentech. They weren't allowed to visit. They were buying a research organization that knew how to do its own thing. They didn't want to interfere or mess it up at all. That was made very clear to us. There were times a year or two later, maybe a year later, when someone would want something from Roche and would have to beg, "Can we come visit and see what you have?" And then they'd say, "We're not supposed to talk to you guys." The Roche scientists resented how well Genentech was treated. Roche really overreacted, thinking that we would be offended or leave. You know the old story about what they bought wore tennis shoes and could leave at anytime.
Hughes
Roche took that to heart.
Goeddel
There was no big feeling, like you might imagine, of the scientists thinking, "Oh no! Roche owns 60 percent of us!"
Hughes
And yet scientists did leave--because of the acquisition, right?
Goeddel
[pause] I think there were more that left because of the things leading up to it. 1989 was a really tough year to be a scientist there, and if there were other opportunities, why not leave? Especially if Roche came in and cashed them out of some money. It would be interesting to see what the numbers were--you could probably get them from Genentech--for the turnover in '87, '88, '89, '90, '91, just before and just after the acquisition. In research I bet it was less after the acquisition than in the two years before. I'm sure that in other areas of the company it might have been greater after.
David Martin, Vice President of Research
HughesWas the exodus sufficient to interfere with the science being done?
No, science needed some new directions. I may be one of the few that thought Dave Martin was really good when he was there running the research. He got everyone thinking about biology, which they hadn't been, starting lots of new projects. They were all over the place. Where Dave was weak was he liked so many things he couldn't focus and couldn't pick a few to really put the effort on. He got all these programs started, and then when Art took over he was perfect to take all those things and figure out which ones were good now. I think the combination worked very well, having Martin there those years when the obvious products were getting to market--the growth hormone, tPA--and initiate all kinds of things. Then Art decided which ones were worth doing. I really think it was Martin that brought the biological view of things to Genentech.
Hughes
What exactly do you mean by "biological view"?
Goeddel
The company was product- and technology-related before: It was clear there was an insulin, there was a growth hormone, everyone had heard of an interferon. Can you solve the technical problems to let you clone interferon and make it?--that's what we were working on. It was mainly technical molecular biology. They were very tough problems, but at a certain point a lot of places beside Genentech could also solve these problems. So Martin was thinking, "What are we going to do next? Let's do the biology of cancer. Let's do the biology of endothelial cells. Let's do--." He had ideas all over the place. Get in there and start doing some basic work and see what pops up.
Hughes
Without a product in mind?
Goeddel
Well, the idea was to get a drug. Dave might even have an idea of how to start it, but he'd get so interested in the biology that things were spinning off all over. He definitely swung too far one way, but it was good for someone like me who had been very technically oriented. Then I became much more interested in the whole biological system and what are we going to approach next.
Hughes
Are there some parallels with the human genome project? That was a technological feat, and now we need to understand the biology.
Goeddel
Right. Art really appreciates the biology. If he'd been in charge all along, not as many things would have gotten started for him to then come in and choose from.
Hughes
Did he follow Martin as VP for Research?
Goeddel
In reality, yes. I think when they asked Martin to leave there was a committee doing it for a while. But it was also clear they weren't doing it. So departments like mine and Art's assumed we were in charge; it was almost the feeling we didn't have a boss. When Martin was there it was clear he was in charge, when Art was there it was clear, and I think in between there may have been Mike Ross, Ray Gomez, Ralph Snyderman, Botstein, who weren't the same presence. Just before we got Dave Martin, when I think it was Mike Ross I was supposed to report to, the boss stayed away from me; it was almost like he didn't want to tell me what to do, and so I was on my own.
Hughes
How did you feel about that?
Goeddel
Fine. I had plenty to do. I'd contrast it to the other way. I met about an hour-and-a- half every week with Martin in an official meeting and then discussed things a lot other times, and
Hughes
Why was Martin asked to leave?
Goeddel
[pause] That may have been something that Kirk and Bob agreed on. I did ask Boyer about that one. Boyer, Dave Martin, Tom Kiley, and I were going off fishing to Venezuela for a week. Boyer called me a few days before and said he needed to talk to me, that this was really bad: the board had decided it was okay to fire Dave Martin, and now we were all going fishing together. He felt really awkward and bad about that, knowing that as soon as Martin got back this was going to happen, and Martin would know that Herb knew during the whole fishing trip with him. I just said, "I like Martin." He said, "No new products were coming out. There were too many things being worked on. They were all exciting, but nothing was happening." Tough decision. But Martin took it real well.
Hughes
And he did go on the trip with you?
Goeddel
Yes, we had a good trip. I think he was told right when he got back. He came to me and said, "You knew when we were fishing, didn't you?" or something. I said, "Yes." "Okay, well thanks for not telling me and wrecking the trip." He stayed at Genentech for almost a year after that. He wasn't embarrassed by it, like a lot of people would be. He was able to say, "Okay, I'm leaving. I'm going to wind down over this amount of time." He kept his office there and his lab up to a certain amount. Never complained about it. He could have had a lot of things to complain about; it was an almost impossible job. He'd come in right after all the exciting things had gotten done, and then it was going to be a lag time to do the next things. When he left, by that point a lot of his things were starting to look good, and someone else then got to finish them off and get the credit. It probably bothered him, but he's not the type of guy who's going to worry about it. He probably knows himself what he did.
Hughes
Very mature.
Goeddel
Yes.
Hughes
Did he then go to Chiron?
Goeddel
That's very complicated. I think he was going to go to Chiron. Bill Rutter wanted him. Then at the last minute Roy Vagelos and Ed Scolnick at Merck talked him into running all of R&D at DuPont Merck. So he went to DuPont Merck, and I think it was pretty strange. What it sounded like is he was interviewed only by Vagelos and Scolnick, the two top guys at Merck, and they hired him without even telling the people that were going to report to him. Martin went there for a while, and I don't know exactly what happened. My guess is they probably got tired of him after a while, got rid of him, and then he came to Chiron.
Chiron was too unorganized for him. He wasn't there even a month. I talked to him once on the phone and he said, "No one knows what's going on here except Bill Rutter, who put all the pieces together without filling anyone else in. It's so complicated, so unorganized, some of the science is really bad." He just didn't seem too happy there. Then I think he went to Lynx and probably got in a conflict with Sam Eliter right away where Eliter wouldn't let him
Hughes
Changing worlds in more ways than one.
Goeddel
He went all over the place. He has so much energy, I think he has to keep working.
Monoclonal Antibodies
Recombinant DNA as a Production Method
HughesMonoclonal antibodies don't figure in the Genentech story at the beginning, as far as I know. Is there a reason?
Goeddel
[pause] Well, there were some antibody companies. We were a cloning company. So the way we looked at antibodies was probably when Riggs at City of Hope and Heyneker at Genentech decided, "Let's see if we can clone some antibodies and then produce them recombinantly," rather than from hybridomas.
Hughes
Did you do that?
Goeddel
Again, it was more of a technical thing. Yes, they obtained a patent. I think it's called the Cabelli patent because that was the name of the guy that was in Riggs' lab that worked at Genentech with Heyneker. His name started with "C", so he was listed first with all the inventors, listed in alphabetical order--
##
Goeddel
I don't think it matters what order inventors of a patent are in. The shorthand the lawyers used was to call it the Cabelli patent. I don't think people outside of Genentech called it that.
Herceptin
GoeddelThen there was a gradual realization that antibodies could become products. I think the first Genentech one, the Herceptin or Her-2 antibody, was very slow to gain acceptance internally. A lot of people take credit later, but for maybe two years Mike Shepard, a scientist in the pharmacology group, kept it alive. Then in probably '90 both Botstein and Levinson accepted, hey, this could work; let's push it. Then it got more momentum. But Shepard had really kept it alive. It was one of many projects that Martin initiated, with ideas thrown out all over. It could have easily died like a lot of other projects did.
Hughes
Was some of the apathy towards monoclonals because Genentech saw itself as a cloning company, not an antibody company?
I don't think it was as much that as antibodies didn't jump out as being better than anything else being worked on for a long time. There was always this question, Should we get into the cancer area? It's a real fragmented market; a lot of small products. There was no taxol then to show you how big cancer drugs could be.
Hughes
Do you think Genentech's history with interferon played a role, the fact that its hope was dashed regarding the interferons as big cancer drugs?
Goeddel
I don't think it was that as much as the concern, You have a mouse antibody; are humans going to develop an immune response, and how are you going to make a humanized one? It was a lot of work to humanize an antibody then. There weren't these mice that make human antibodies at that time. Maybe if Martin had said, "We have to pick the five best projects instead of the thirty projects we're working on." Getting a really tough evaluation, antibodies might have moved right to the top and gotten some support. But there were lots of projects with very few resources on them. Even though Bob was removed from research, there would be the projects that he would decide, "Hey, I'm interested in this. What's going on?" He'd go through the labs and say, "Are you working on this?" Or go tell Martin, "I want more people on this one." I think Herceptin was below Bob's radar screen.
Hughes
As we know, Swanson wasn't a scientist. Maybe he didn't have the knowledge to be able to judge monoclonals.
Goeddel
Right, and part of it was that this was a project that at least in part came out of Axel Ullrich's lab. Bob and Axel never really agreed on very many things. Bob's view was, Axel was interested in just what he could publish and not what products would come out.
Hughes
Do you think there's some truth to that?
Goeddel
I think right now, at this stage of his career, Axel's probably only interested in seeing what products can come out. At that point he was almost a pure academic scientist, and I think he came to Genentech with the idea that he could use the technology and publish a lot of good papers. That probably was why he went there. But then most scientists as they get old like to see something practical come out of their work and they can change a lot.
Impact of Patents in Biotechnology
HughesIt's quite well known that [Cesar] Milstein and [Georges] Kohler decided against patenting their hybridoma technology, yet Stanford and UC did patent recombinant DNA. How has that the absence or presence of a patent shaped the history of each of those fields, or has it at all?
Goeddel
I don't know. I have never even thought about that. [pause] I guess I don't think Cohen and Boyer or UC and Stanford patenting changed anything; the universities just got some money out of it. Bob would have still started the company. There would have still been other ones. People would have realized the importance of patents and had patents around their products.
Hughes
Bob had started the company.
Yes.
The thing that maybe would have changed on the antibody side is that if Milstein decided, Let's start a company; maybe it would have been a better company with more commercial potential if they had all those patent rights. What was the first antibody company? Hybritech in San Diego was there a little while, and Lilly bought them out.
Hughes
There was another one in Washington state.
Goeddel
Yes, that Bristol-Myers bought. Genetic Systems, was that it?
Hughes
I think so.
Goeddel's Record Regarding Commercial Products
HughesYou have the honor, as I read it, of being the scientist who has more products to your name than any other in the industry.
Goeddel
I think that's probably right.
Hughes
How many are there?
Goeddel
Well, it depends on how other people decide on theirs, I guess. There are five that I did with my own hands, and others that either came completely from or a major part came from the department I ran. In other places people will claim a product if they're head of that department and it's done there. I always was more stringent in saying, "Okay, this is the work I did at the lab bench." That's five. Other things like factor VIII, DNase--which is called Pulmozyme--and Herceptin, big parts or all of them came out of the molecular biology department I directed. But I get much more satisfaction out of the five I did.
Hughes
What would you name as your biggest accomplishment at Genentech?
Goeddel
[pause] I guess growth hormone and interferon gamma.
Hughes
Why?
Goeddel
Interferon gamma was the most competitive project, with all the best labs working on it, and the most unknown. Growth hormone because when we got it expressed that was the moment I realized, hey, the industry will work; we're going to be able to do a lot of things. Close behind that was insulin, just doing the first product that came out of the industry. So probably those three things. Those were all a long time ago.
Hughes
Is that what makes it for most scientists in industry? The ultimate achievement is the product that reaches the market?
Goeddel
Yes, I think so. I only realized later how lucky I was, because most scientists would be completely satisfied if one thing that they had played a major role in became a product. I had a streak where it was one a year for five years.
[laughing] That's pretty remarkable.
Goeddel
That I wish could happen again sometime.
DNase or Pulmozyme
HughesWe haven't talked about all the Genentech products. Do you care to talk about DNase?
Goeddel
That's a scientist-initiated project. A guy named Steve Shak was hired because of Martin's view that in the various biology groups we should have some M.D. scientists who understood diseases. Shak was an allergist who came in, was told to look into the literature, find something to work on. He worked with Dan Capon who was a very good scientist but a tough guy to work for. Shak had read some papers and decided he could clone DNase and use it to treat cystic fibrosis. He said it was all there in the literature, laid out with cow DNase.
Then he talked to me and asked me to help him because he hadn't cloned anything. I was the department director, and I said, "Why don't you ask Dan? He's great. He's your boss. He can clone it." "I don't want him to know about it. I want to do this without him because he either won't let me do it or if it's a good idea he'll just take it and do it himself." So I said, "Okay, I'll help you out a little." I think after a while I told him, "You have to tell Dan. You've got to tell your boss." He got started on it and said, "I'll do it at night, in my spare time." It was a very simple thing to clone at that time. It was just his idea this would work, and he could explain it in simple terms. Bob really liked the idea, and it was one Martin liked too. I think everyone got on board with it. It didn't take many resources; it was going to go fast, so it was just the kind of project the company needed and made him very famous inside Genentech.
Hughes
What else about Genentech, before we move to Tularik? Are we leaving huge gaps?
Goeddel
Sure, but someone else can cover them. As far as I was concerned, the first five years there were like no other time there, so they're the easiest for me to remember. There are probably other people who recall their first five years as well who came in at a later time.
III Tularik, Inc.
Foundation
Robert Tjian, Instigator
HughesLet's go to Tularik then. Tell me the foundation story.
Goeddel
It's no great story from my side. In mid to late eighties I started going fly fishing once a year with Bob Tjian, a professor at Berkeley. We'd met each other in 1976 at Cold Spring Harbor and knew we each liked fishing. Then I came out to Genentech; he came to Berkeley, and we'd occasionally see each other at meetings and talk, but we were both so busy. Then he joined the Genentech Scientific Resource Board in the mid-eighties. He'd come over to Genentech for that and I'd talk with him. More than once we decided, let's go fishing. We had a great time fishing together. We had the same style which was fish all day and never take a break, don't eat lunch, and go do it again the next day.
Hughes
Sort of the way you do science. [laughing]
Goeddel
It was perfect because neither of us had fished with anyone that had that style before.
It was during a trip in '88 or '89--probably '89--when Tij started talking about, "I'd like to start a company some day." I'd just kind of go, "Yeah, sure." And he'd talk about ideas and I'd help him out; I'd give him my thoughts. My view was he'd want to go do it like Boyer did--stay at a university. He was just getting my advice how he should do it. Every time we'd go fishing there would always be some conversations about this, but I don't think he had an idea what the company would be about.
Then it must have been the spring of '91 we went to Christmas Island in the Pacific and talked some there. Tij says, "I think there's got to be a way to make drugs around the basic work I'm doing on gene regulation, gene transcription." So I talked to him about it and said, "Yes, maybe there is." He said, "Why don't we start a company?" I said, "What do you mean 'we'?" He said, "You, too." I said, "Well, I'll think about it a while." So there were several months I thought about it, and I got back to him. "Let's talk about it more."
Steve McKnight
GoeddelThen Tij said, "Well, there's one other really top scientist in transcription, Steve McKnight, at the Carnegie Institution in Baltimore. What would you think if we got him involved? If you don't want to, we don't have to." I knew Steve by reputation and from occasionally talking with him at scientific meetings. I said, "He's great, but I bet he wouldn't want to do it." We called him and he said, "I'll come out for a few days and meet with you guys." So we met and talked about it.
Hughes
Had McKnight thought about forming a company?
Goeddel
No, but he said he liked the idea. We drove up to northern California, went fishing, and drove back. Most of the time was spent in the car, a long drive.
Hughes
Is McKnight a fly fisherman?
Goeddel
Well, he'd done a tiny bit. We said, "Do you want to go with us? We'll drive to a pretty place and talk." That got him into fly fishing. He was very close to being a beginner then.
Hughes
This sport focus is interesting. When I've talked to biochemists, it seems to have been tennis. Now with molecular biologists, it's fly fishing.
Goeddel
It's fly fishing as you get older, maybe.
Goeddel Hesitates to Commit
GoeddelSo we got together and I said, "I still don't know if I want to leave Genentech. I'm having a good time there."
Hughes
When was this?
Goeddel
This is the summer of '91. Both of them put the pressure on me. They said, "We'll do it, but only if you do it too." If I didn't, then they were going to stay at the universities and they wouldn't start a company. They were going to start it only if I was involved.
Hughes
Why did they say that?
Goeddel
Well, I had had experience inside a company. They were smart enough to know that it isn't so easy to do, that you don't just get a couple of professors and start a company. They were probably more aggressive than I was about doing it, but also they wouldn't have done it if I hadn't agreed. I said, "Okay, I'll think about it." I spent about another month and then in September I said, "Yeah, I think I'll do it, but I may want to stay at Genentech and work one day a week at the new company if Genentech would allow that, have the company near by, and be on the board, help recruit." And they both said, "Okay."
Raising Capital
Mayfield Venture Capital
GoeddelThey came out again in September or October. Probably September. They wanted to meet with a whole bunch of venture capitalists, and I said, "I don't want to meet with a whole bunch; I just want to meet with one." If they give us the money we can go with them; let's not waste time. That was Mayfield, which was basically because of Mark Levin being there, who had been at Genentech. So we went down and talked with them.
Hughes
Did you set up that connection?
Goeddel
Yes, I set it up. I'd met with Mark since he'd left Genentech. I probably met with him once every six months to have lunch. He was always saying, "If you ever start a company, I want to be the one to fund your company." He was always pushing it. He'd done a good job helping set up some other companies, like Cell Genesis; I'd seen how he'd gone about it. His approach was he'd be acting CEO from the first day of putting in the money so the company could really get going, and that attracted me.
So I met with them and the next day--it was very fast--Mayfield came back with a proposal and said, "We want to fund it all. We don't want you to go to any other VC firm." I liked that because that meant we wouldn't have too many VC's on the board. We could get started right away; we wouldn't have to go do this. Usually you go to a few and get money from all of them. So I talked to Steve and Tij.
Word had leaked out somehow that we were doing this right about the time when we were ready to accept the Mayfield offer, which was not that generous. They were going to help out; it was a small company; I hadn't committed to it yet, and they were going to put in three million dollars. David Blech, who was pretty infamous in biotech financing, called Tij and said, "Hey, don't do anything. We'll give you twelve million dollars and a thirty million evaluation. What are you getting?" Tij didn't tell him, but we were getting three million and seven million evaluation. So Tij was real excited. We met to discuss that, and it sounded pretty good. I was even tempted, but I said, "No, I'd rather get it from a good firm that we're going to be happy to work with." I thought it was going to be a big battle, and but Steve and Tij said, "Fine, if that's what you want to do, we'll just go with Mayfield." So we signed up, and no regrets on that.
Genentech Invests
GoeddelI'd talked with Art, who was my boss at that time--he was running research at that time--and with Swanson. Bob didn't like it, but a couple of years before I'd been tempted to do something and I talked to Bob, what did he think about me doing something else? I had some other opportunities. He said, "Don't leave now. We need you now." This was about '89.
Hughes
During that bad period.
Yes. And he said, "But," he said, "if you stay now, when you decide you want to start a company, I'll help you." I said, "Okay." He asked me, so I stayed.
When I went to talk to him this time, he said, "Aw, I can't try to talk you out of it this time, because I told you before. So I'll help you out. But can I invest?" So I let him make a small investment. Then I went and talked to Kirk. At that time Kirk was CEO; Bob was chairman. Kirk was worried about how the Roche guys on the board were going to get pretty upset at him when he had to tell the board I was going to leave.
Hughes
Roche didn't want to lose one of Genentech's top scientists?
Goeddel
Yes. If you asked the Roche guys at the board level what scientist did they know the name of when they bought the company, probably just me. I could tell Kirk was worried about that. He said, "Do you think Genentech could buy 10 percent of the company so at least I can tell the board we have an investment in this spinoff type thing." I said, "It's not really a spinoff." He said, "I know it's not a spinoff, but if I tell the board it is--" We were spinning out no Genentech technology at all. So I said, "Well, if you contribute something. The VC's are contributing something. Maybe access to reagents or things we need as we're starting up." And he said, "Fine." So that got worked out. Genentech put in $700,000 for 10 percent of the company at the start.
When it was announced, there was an article in the Chronicle about the foundation of Tularik that I didn't think was that bad, but Bob really didn't like it. He came by and said, "This isn't good for our company to see this article about you starting another company." I said, "I never talked to the Chronicle, don't worry." Bob always thought you should be able to control the press. He even fired PR people when the wrong kind of articles came out.
Other Venture Capital Firms Show Interest
GoeddelThen some of the VC firms started pressuring us: Why did we only go with Mayfield? They would have paid more money. They should have got in. Kleiner Perkins, which was the big-name VC firm in the Bay Area, was real upset that we hadn't talked to them. Tom Perkins was pretty much retired then, but I got a call from him and he said, "How could you do this? The people at Kleiner Perkins are real upset. We funded Genentech when no one else did. I would have thought if you were leaving to do something you would have come to us." I said, "I probably would have if you were still there." I actually felt bad. He said, "I'm calling from the hospital." I knew his wife was dying. "I think you should reconsider." So then we let Mayfield organize meetings right away to bring in other VC firms. We decided, with this kind of a demand, they were going to pay a lot more than Mayfield paid, which I thought was reasonable. But they thought Mayfield was really just trying to screw them. That isn't how VC companies work together, getting each other in on the deals.
So Mayfield invested at a dollar a share, and this next round was closed very soon after, before we had built or done anything, at $2.37 a share. In the end, Kleiner Perkins could not handle that psychologically. Even though we'd done all this secondary stuff for them, they didn't go in. They demanded that they have the same price as Mayfield. We just said we're not going to do that. They wanted to look like they were a co-founding VC firm.
Why was there so much interest?
Goeddel
There was too much, and I think it was only because of my reputation in the biotechnology industry. We gave our talk to Mayfield about what we were going to do. We didn't have a business plan; we just said, "This is how we think we're going to do things." And they went, "Oh, that's so exciting." My view was it probably wasn't that exciting, and I could have probably gone there with any kind of business plan, and they would have said, "Okay, we'll do it." It made me realize how that works: if you have a track record, you can get money for everything; and if you don't, and it's a great idea, you might have to go around forever to get someone to invest.
Hughes
And maybe never get it.
Goeddel
Yes.
The Science of Gene Regulation
HughesWhat did you know about the signal transduction field?
Goeddel
Oh, I knew something about that. But what we were really looking at then was regulation at the level at the gene. I knew the literature. McKnight and Tjian were experts in the basics. But it wasn't clear how you'd get a drug. I think all the Mayfield guys that we were talking to probably didn't understand what we were saying.
Hughes
Did you make it clear that you didn't know how to get a drug?
Goeddel
No, you never do that.
Hughes
But if a scientist had been in the room--?
Goeddel
Our general approach was right. Mayfield had scientists they brought in. They always wanted to bring in people to evaluate the company. They decided to fund it instantly. Grant Heidrich said, "I don't care exactly what it is. If you fund a good group of people and they're original plan doesn't work, they figure out something else that will." Whereas Mark Levin was more concerned, "Well, let's get all the transcription experts in; have a meeting." This was after they'd committed to funding. Mark said, "Now, as we're planning the company, let's get all these guys." He'd send one of his associates out to get a list or look through the literature, and he'd come back with this huge list of fifty people.
Organizing the Company
GoeddelMcKnight and Tjian are so tough in evaluating their field. Mark would sit down at a meeting. We'd usually meet on Saturday and half a day Sunday. That way we could keep working during the week. McKnight would fly out here from Baltimore on Friday night. I'd pick him up very late at the airport. We'd usually talk most of the night, and we'd go down to Mayfield
Hughes
And these meetings were to arrange the financing?
Goeddel
This was all the planning: Who are we going to hire? What are the business plans? What are the first projects? Where are we going to get a facility? Who are we going to get on the board of directors? All the stuff of putting a company together. Mark Levin was a very hard worker; he'd work all week on it too. Then we'd have these meetings; and we'd have big agendas; and we'd crank through a lot of stuff.
I remember the meeting when Mark brought in the list of experts, and he said, "Okay, why don't we bring in this guy from Stanford?" And McKnight and Tjian would go, [gagging sound] "That guy doesn't know anything." Mark would go, "Okay. Well what about this guy, this guy?" Tij would say, "He's a dork! We're not going to talk with him." And then Levin would say, "Is there anyone good in this field?" And they'd look through the list and say, "Yeah, those three guys. If you don't believe us, ask them."
Then we put together a scientific advisory board. We had each person in on a separate Saturday to meet with us for a couple of hours. All of them wanted to join, so everyone we brought in said, "I would love to be on the board." That impressed Mayfield; they liked that. At the end of each two-hour meeting, Grant Heidrich, who didn't understand the science, would always ask the prospective board member, "What do you think of this gene-regulation approach, this idea that these guys have? Do you think it will work?" And all of them were so good; they'd say, "Oh, it's fantastic! It's got to work. It's brilliant." Grant would always get excited when he heard this. We actually tipped off one SAB member to this question and asked him to play a joke on Mayfield. He answered the inevitable question with: "I think this approach sucks--it will never work, but I'm happy to get some stock by being on the advisory board." Grant Heidrich looked stunned, and gave Mark Levin a look that said, "What did you get us into?" Then all of us broke up laughing.
##
Goeddel
Soon thereafter we hired Jim Gower as CEO. I thought he'd be good. The problem was I remembered him when he was very good in marketing. Then later on, as he advanced beyond just Business Development and Marketing at Genentech, he probably wasn't as effective. I had always thought that he would be a good CEO candidate. McKnight and Tjian met him, but they said, "We don't know what a CEO is. If you think so then he's okay with us." And Mayfield interviewed him, and we hired him. Steve joined the company to run research, and I was going to be close by.
Hughes
Did you have a title?
Goeddel
No, just founder and I was on the board.
McKnight moved out here from Baltimore in September of '92, and that was the same time we'd gotten a lab on East Grand Avenue in South San Francisco. Before that, we'd been in a tiny place we had rented in San Carlos, but we just had four or five employees there. Then we really began hiring and expanding at the time we got the new lab.
So McKnight started there in September, and then I went to a day and a half at Tularik. There were more things going on that needed help. The first hour, every time I went there, Steve would say, "Come into my office and talk. Look, we started this company together. You've got to come here too. I'm here full time. There's too much to do." I could see he was having trouble getting along with Gower; they were clashing. "Why do I have to go to this stupid meeting? If you were here, we could divide those up. This is your company too!" I said, "What about Tij?" He goes, "Tij will never come, I know that."
Goeddel Commits Full-Time to Tularik
GoeddelI think by the end of '92 Steve was getting through to me; he was never going to give up. He was just going to keep saying, "You've got to come here too." There were a lot of things to do, and it was exciting, and maybe it was too easy at Genentech. I was paid very well at Genentech, had a big lab, I could do whatever I wanted. Here was something more challenging to do from the start one time. I figured I had spent fifteen years at Genentech, maybe if I go somewhere else from the beginning for fifteen years that's the total amount you can do.
Hughes
Did it ever occur to you to do neither?
Goeddel
Genentech was a really cush job then for me. I had a very good group. I could get the best postdocs; I could make the department as small as I wanted; I got paid very well, a lot of stock options, new lab--everything. When I told my wife Alena, I said, "I think I'm going to move to Tularik full time and take a 50-percent pay cut and give up all my unvested options."
Hughes
What did she say?
Goeddel
"Are you sure?" I said, yeah, I just want to try this.
Hughes
I'm glad you gave that answer, but a third alternative, as I see it anyway, is that you could have said, "I've had enough of this, and I don't really need to work. I'm going to go fish."
Goeddel
There were times I thought of that, but usually when you're out fishing and having a good time you're having a good time because you're doing it for one week. Maybe if I was doing it for a whole year--[laughter]--I wouldn't be fishing the way I did, which was every minute of those trips. I was pretty excited about Tularik. It was tough to give up my lab at Genentech, being involved in the basic research. That was actually tougher than leaving Genentech,.
Hughes
Could you bring your research with you to Tularik?
Goeddel
I didn't want to. I wanted it separate. So I took a long transition time. I decided at the end of '92 that I would move full time in August of '93. I told Art in December, "Nine months from now I'm going to leave." I might have even told him earlier than that. I think my departure was announced in January of '93. I might have even told him three months before it was announced.
Hughes
What was Art's reaction?
[pause] He tried to talk me out of it for a few minutes, but we'd been good friends for a long time and he knew-- Then it was just, "Okay, what's the best way to make the transition? What do I do with the department?" We decided to recruit a new director, and transfer people from my lab to different labs. It worked out very well. I think it took about nine months to do it. And then we agreed that the first year after I left I would still work a day and a half a week at Genentech; it would be a reverse transition. I'd stay on the thrombopoietin project, which was active then, oversee that program, help get the new director Michel Aguet really integrated into Genentech. That worked pretty well. At that point I was up to about a day and a half at Tularik, and then when I made the move in August, I just reversed that--it was a day and a half at Genentech.
I started recruiting a new lab, but a small lab, that I would have at Tularik. During that time when I interviewed postdocs I told them--if they were good enough to get an offer-- "I'm going to move to Tularik, so it's going to be different--smaller lab. You can come there and help start up, or I can find you a postdoc position at Genentech." The best-quality postdocs were applying to me, scientists at Genentech would be happy to have one of them go to their lab at Genentech. The ones I had at Genentech either finished in that transition time or moved to another lab for a few months and stayed. So I didn't have any that were Genentech employees and then moved to Tularik, so there were no complications.
The decision took me a little while to make, but then as soon as I made it, it was easy. I said, "I want to do a transition like this." Art was very happy to have me stay and work a day and a half a week. I think he knew me well enough that there weren't any issues on stealing information or keeping things separate. There was a period of over a year where I was working at both places. Then I worked out with McKnight how to divide things up at Tularik. He had the title Director of Research; I was VP of Research. Officially I was his boss. He was building the biology group, and I was overseeing research more broadly. We worked very well together.
Genentech as a Model for Tularik
HughesTo what degree, and in what ways, was Genentech a model for Tularik?
Goeddel
Essentially my whole career had been there. Things that worked well at Genentech were obvious to me: Okay, that's the way to do things; no sense in doing them any different; that works real well. But I also learned a lot of ways not to do things. I remember talking with Heyneker very early on, and then Levinson in the early-eighties, "Boy, if we ever started a company we sure wouldn't do it this way."
Hughes
Do you remember what the issues were?
Goeddel
Things like what type of people you hire, and what kind of responsibility you give them. Genentech had a lot of really outstanding people. Then it had certain areas and other people that were terrible that got hired early on, and that would actually drag the company down. I remember clearly a lot of conversations with Art. We might say, "Genentech has 200 people now. If it only had 150, and you got rid of the worst fifty, it would actually be a way better company." One thing that I've always tried to do here is to keep the same standards as the
I think the biggest difference is, early on Bob did not want to fire anybody; he wanted it all to be one big happy family. If you hired someone that wasn't good, he'd tell the good people, "Just work with them. Really help them out." He hadn't started a company before. I think later on he had no problem--if someone didn't fit, get rid of them. But early on this idea that they were all his family, and how could you fire somebody? It was real tough on him. I think if you start a company, if people don't fit, you have to be willing to get them out of there.
Hughes
And indeed have you done that?
Goeddel
Yeah, and probably I'm still not as good as I should be. It's always easier to do it when it's someone else's area.
Goeddel Is Named CEO
GoeddelWe replaced the CEO here. That would have happened anyway, but McKnight pushed it more. McKnight did not get along with Gower on a lot of different levels. McKnight can be very tough and very hard to get along with. But some of the things he saw that he didn't like about Gower had a lot of truth in them. When the board discussed it at a special conference call without Gower being around--Gower was on the board--the things Steve pointed out, the board members had to say, "Yes, I've seen that. You're right." Then Steve says, "Dave's essentially running the company anyway, why don't you just make him the CEO?" The board members asked me. I said, "I never wanted to be a CEO, but I'll think about it." Then Steve and Grant bugged me all the time, and eventually I saw that if Tularik was going to be successful then at least at that point I was the best person to be the CEO. That was a tough decision because it was going to change how I spent my time and my involvement in science.
Hughes
Why did you decide to do it?
Goeddel
Because I wanted Tularik to be successful. Who else was going to do it? If you go out and recruit someone, that's going to take six months, and you don't know if they're going to fit. For companies the size of Tularik, with the type of scientific founders we had, and the type of science going on, it's tough to find someone to come in and take over as CEO who doesn't have that background in building that company and knowing the science in detail. Plus you had McKnight and me both working there. It's probably almost impossible for most non-scientist CEO's to have two scientific founders working at the company.
Hughes
Did you have confidence that you could do this job well?
Goeddel
No. There were some concerns. I thought at that stage Tularik was mainly a research organization. But I had been in the industry a long time. The board I knew would be helpful. They wanted me to do it, so they mind that there were certain things I didn't know how to do.
Goeddel Consults Bob Swanson
GoeddelThe first thing I wanted to do and set out to do almost instantly was recruit Swanson to be on the board to help me out. I had actually gone to Swanson during the time I was trying to decide if I should agree to be CEO. I said, "The board is going to get rid of Gower" or has gotten rid of him. I guess it was at the point they were going to. "They want me to be CEO. What do you think?" I went to his house and met with him. He just looked at me and said, "I don't think you would like being a CEO." I said, "What do you mean?" He said, "There's too much stuff that would irritate you. I just don't think you'd like it." Then I went back to talk to him later. I said, "If I agree to do it, would you join the board and help me out?" He said, "Sure. I promised you I'd help you. I'll join the board, but it's your company; you're running it. All I'm going to do is advise you. I'm not coming in to be a chairman that's going to run the company or get suckered into being the CEO when you decide you don't want to do it anymore. I'll be an advisor; that's it. If you agree to that then I'll join the board as chairman." That was the agreement.
Hughes
How did Swanson help out?
Goeddel
He was tough, helped me focus, ran good board meetings, pushed on management. Anytime I wanted to talk to him he was available. Usually we'd meet and he'd say, "I think you're doing it right." He was a positive influence. He didn't want to spend all of his time doing Tularik stuff, even if he was chairman, but if there was an issue he was always willing to do it. He helped out on recruiting, which was real good. He helped push me toward what kind of a management team to hire. He gave advice on that. Just having him there to bounce ideas off was real helpful.
Hughes
At this point he had started K&E Management?
Goeddel
[pause] I don't know. I think that might have been later. I was first called president, for one board meeting, one month--maybe March of '96. Then in April the board said, "You're doing fine. You can be CEO too." I still remember the board meeting. The first time when they said, "You're president," they didn't want to say, "You're running the company; you're CEO." I said, "Okay, I'll do it." McKnight was so funny, the way he said, "How come Gower was CEO and Dave is president? What's going on here?" Grant Heidrich says, "They're kind of the same thing." Steve goes, "I don't think they're the same thing. There must be something we don't know about why you don't think Dave should be CEO and Jim was." It made a really hilarious board meeting. Then the next meeting they sent me out of the room, and I came back two minutes later. They said, "Okay, you're CEO now." Steve goes, "See, I knew there was something!"
First Board of Directors
Hughes[laughing] Who was on your original board?
Ed McCracken, who had gone to Silicon Graphics when they were tiny, maybe fifteen people, and built it into a huge company, at least when it was very successful. Paul Marks, who was CEO of Memorial Sloan-Kettering, the big cancer facility in New York. Grant Heidrich, Mark Levin--both from Mayfield, although Levin moved on to run Millennium. And myself and McKnight.
Hughes
Pretty high power.
Goeddel
Swanson joined as chairman soon after April of '96. I'm not sure exactly. Then at the end of '96 we added Peter Sjostrand. He came with a big investment we got from Switzerland.
Hughes
I thought it was Sweden.
Goeddel
Sjostrand is Swedish, but the company, PharmaVision, is Swiss.
A Fishing Encounter Leads to Investment
HughesTell that story.
Goeddel
It is kind of funny how it came about. Tij and I had wanted to go fishing in Russia for Atlantic salmon--we had never done it. Right about the time Swanson joined the board, we took a week and went to the Kola Peninsula up in the Arctic Circle and went Atlantic salmon fishing. It's a long helicopter flight from Murmansk, Russia. When you get in it's late in the afternoon. There are twenty-four hours of daylight in June up there. They take you to your tent and say, "Okay, we'll have dinner tonight and then start fishing tomorrow morning." Tij and I went down to the river, which was close by and started fishing right away. I think we pretty much fished all night.
We came to breakfast in the morning. Some guy had seen us fishing. He came over and sat at the table with us. He introduced himself as Peter Svennilson and said, "I saw how you guys were fishing. What business are you in?" Tij said, "We started a company, but I'm a professor and he runs the company." "What kind of company? What kind of industry?" Then he said, "I just want you guys to know that I'm a banker, and anyone that fishes like that, I want to invest in what your work is. Do you guys need money?" We said, "Well, we've got to raise some money sometime, yes." He said, "I can help you raise money." He had no experience in biotech; he was a young banker. But watching him fish through the week, we say that he was really a gung-ho guy, and he was learning how to fish. I saw him fall in the river and get swept way down river--in freezing water. I was way downstream of him. I saw him coming down. Finally he crawled to shore and I thought he'd just run up to the camps to get by the fire. He just walked back up to where he had been fishing, dumped the water out of his waders, and started fishing again--he wanted to catch one. It's really cold water. I thought, "That guy's pretty tough."
At the end of the trip, he said, "I'd really like to help you guys raise money. I think I can do it. When can I come visit you in San Francisco?" I said, "Let us know when you want to come." I didn't really believe he would. He said, "How about next week." I said, "Fine." He sent me an email and he said, "I'll be on this flight. I'm coming in." He arrived in South San Francisco. We met with him that day. I brought in Swanson, and Swanson was a little leery
So Peter organized a trip to Europe. Yasanori Kanako, who was our business development vice president, and myself went off with him and visited a bunch of potential investors. We were making slow progress; someone was going to put in a million here, there. Then Svennilson said, "I have one more guy I want you to meet." I was on a business trip somewhere else to meet with a pharmaceutical company. He said, "If you can just give this guy a half hour and meet him for breakfast in New York City at this hotel--" So Yasanori and I made an extra flight, a red eye, and had breakfast with this guy Peter Sjostrand. Sjostrand was on the board of PharmaVision.
We told him about Tularik and he loved the idea and said, "Why don't you come meet with Martin Ebner?" Ebner is the guy that runs the BZ Group and the PharmaVision fund. So I flew over to Switzerland, went to Ebner's house and met with him. We talked all evening about all sorts of things, and then he said, "Okay, I'd like to invest in your company. Can I invest 30 million dollars?" I couldn't believe it. We were hoping to get one million here, two million there. I said, "Sure," and he goes, "Okay," and we shook on it, I went back, and we finished the deal in about a week. This was Svennilson's first deal out on his own, but he could use this leverage saying Ebner's putting in thirty million. Are you in or out? We're closing. And all of a sudden we raised $62.8 million, which was the biggest private biotech financing up to that point. Since then the record's been broken. At the next board meeting I remember Bob saying, "I think we should allow Dave to go fishing any time he wants if he brings home money like that." [laughter]
Hiring and Firing Scientists
HughesTell me about recruiting scientists and other early employees. Who did it and how did you go about it?
Goeddel
Steve McKnight spent the most time on it because the first scientists we hired were biologists and molecular biologists. That was his department. I think my presence at the company helped a lot because I'd talk to young scientists, finishing postdocs, and I'd say what it had been like for me at Genentech: if you go to a company early you get stock; you don't have a lot of bosses; you can make your own name; the company recognizes what you do because there's not someone else to take credit for it; and you can do great science and publish. So they would see me as an example. McKnight would find them, bring them in and organize everything. But I really felt that my experience made it a lot easier for that first couple years to recruit young scientists. A lot of them said, "Oh, yes, that's just what I'd like to do: go in like you did, discover some drugs, run a department." I would say, "Well, this is the place to do it. You'll get the opportunity. If you're good, you'll be able to move up fast." So we had very good success at recruiting.
Have those early people lived up to expectations?
Goeddel
In the first group of eight scientists hired as biologists in 1992, Steve asked two to leave after about a year or two. They went off to other companies and did fine. They were solid, but they weren't up to the standards we'd set here. They were clearly lagging the other six. One of the others left about two years ago, went back to be chief scientific officer of a company in Germany; he was German. It was clear he was going to go back someday, and he left for a kind of a McKnight position as VP of Research. The other five are still here and are very key to our success. They have progressed, are running departments, and are still young scientists.
Hughes
So you made some good choices.
Goeddel
Yes. Then we hired directors and other things, but I think the first corps of the eight scientists hired were more critical than anything. Steve came to me and said, "These two aren't quite as good as the rest. What should we do?" And we decided, "Well, we should let them work somewhere where they can be successful and replace them." That's maybe a difference from Genentech where they would have stayed around longer.
Hughes
Is firing hard for you to do?
Goeddel
It was easier then because McKnight hired them; they worked for him. It's only hard when you're actually telling them, even if you know it's best for them. At the end they were almost relieved;.they were smart enough to see they weren't contributing at the same level. We said, "Okay, you have three months.
##
Goeddel
We had such a good scientific reputation then that if someone here applied for a job somewhere else they usually got offered a promotion to go. That helps the people inside because they see that someone that wasn't cutting it at the same level is no longer there, and they actually like that these people got a better job. Now they realize that anytime they don't like it here that they should have no problem getting a good position somewhere else.
Building a Pharmaceutical Company, Not a Biotechnology Company
Tularik's Goal
HughesI read that Tularik was founded with the goal of creating "the first pharmaceutical company based on molecular biology." That came from a Chase H&Q report. [1] Chase H&Q, July 11, 2000, p. 2.
Goeddel
No. Analysts write all kinds of stuff. We wanted to create the first company that had a goal to make drugs that work by regulating genes. Genentech was based on molecular biology. These analysts hear something and they get words mixed up.
I wondered what they meant about Tularik as a pharmaceutical company.
Goeddel
Our goal has always been to build a pharmaceutical company as opposed to a biotech company. Amgen should be considered a pharmaceutical company; they're still considered a biotech company by most people. What I mean by building a pharmaceutical company is, you discover drugs; you develop them; you market them; you sell them--you do everything. You're fully integrated, and you're competing with Merck and so on. Where the difference comes now is, Amgen is considered biotech because they have protein drugs. Well, we're going to make small-molecule drugs just like the Mercks and the Pfizers. We're going to be competing with them, not with the protein companies. But it's still possible that we'll be as big as Genentech or Amgen, have drugs on the market, do everything ourselves, and we'll still be called biotech. It will be because we started at a later time. Biotech at one point meant protein drugs. Those lines have been made fuzzy.
Hughes
When you say "biotech" nowadays, does people's thinking embrace small-molecule drugs?
Goeddel
I think what "biotech" means now is any company that started in any related field since Genentech started. I think that's what the true definition is, even though no one says that. If you were founded after Genentech in health care and doing some research, you're a biotech company.
Hughes
The goal of becoming a pharmaceutical company in the way that you describe is essentially doing everything in-house--
Goeddel
Yes, it affects how you do business, so most start-up companies need to get deals with big pharma companies. They end up having to do it in a way where they give away their products for royalties. Genentech did that. Genentech gave away interferon, gave away insulin. We've done deals with the idea that at the end we want to sell the product and get the profits, so we haven't given away anything. The most we've given away is 50 percent of worldwide marketing rights.
Hughes
You were able to do that because you had a pot of money?
Goeddel
Yes, because we had enough money--or at least we were able to make the pharmaceutical partners, or some partner, feel that we could walk away and just do it all ourselves unless we did a deal under the terms we liked. So it helped in negotiations. Some companies did walk away. For example, we could never get a deal with Pfizer because they just refused to do a deal unless they could get worldwide rights, and we refused to do a deal unless we could keep at least half of all the U.S. rights. In the end, neither side would budge, and we wouldn't have a deal. Luckily there were other companies willing to work with us. But still, it's very difficult to become a pharmaceutical company.
Hughes
You say that now after X-number-of-years' experience?
Goeddel
I think I knew it then. It's pretty clear--how many companies have there been in the last fifty years that became pharmaceutical companies? I say Amgen is that now.
Hughes
What about Syntex?
Goeddel
Yes, Syntex was the last before Amgen.
Expand on why it's so difficult to build a pharmaceutical company.
Goeddel
It's difficult because there are so many things you have to do, and you're always competing with these much larger companies. A lot of people start companies with the idea they want to get rich. You can do that a lot easier and faster than you can make a pharmaceutical company. You build a company very differently if your goal in five years is to sell it to a pharmaceutical company rather than always asking, "How are we going to be the strongest in twenty years?" It even affects our stock price. We don't make decisions, as a lot of companies do based on: "How do we get our stock up for this quarter, or the next quarter, or something?" We've got to work on this program, and maybe we won't talk about it for three years. If we talked about it now we'd know our stock would be higher. Same thing on doing deals. We've had a lot of people--banker types--advise us that we need to do a few deals with the Mercks and Pfizers,; then our stock will look a lot better.
Hughes
It's that credibility issue.
Goeddel
But I think people are coming around to seeing that we've always done what we said, that we're not going to give up product rights, and we're going to build things slowly and methodically, really get a corps of biologists first, then high-input screeners, and then chemistry, and build a big expert group in each area. That's a different approach when a lot of biotech companies have one product idea and then they have one or two people in every discipline to work on it and get that done. We've done it just the opposite: build the big corps of biology first, discover the targets. What are the programs we want to do? And put all those in high-throughput screening, and then all those into chemistry. We're just now getting to building clinical development. If we had taken a different approach, we could have maybe had something in the clinic in three years. Then you look better to go public early.
Hughes
Has it been hard to build the company in this deliberate way?
Goeddel
I think for me it's been easier this way--thinking about what you want to do and how to get there, rather than responding to all these other external forces that help other companies make the decisions. And the board has been very good. It's this vision that this is how we're going to try to do it, and everyone's on board with it. Employees buy into it.
Hughes
This model of taking the necessary time to build the steps, isn't its goal the FIPCO that Swanson used to talk about?
Goeddel
Right.
Hughes
It allows you to build on Tularik's initial strength which is the science and the strong scientific leadership at the administrative level, and also a program that at least initially was unique in the industry. Is that true?
Goeddel
Yes.
Hughes
So you're not trying to do everything at once.
Venture Capital Skepticism about Long-term Corporate Goals
GoeddelThe way we talk about it is, we're building the company one step at a time.
Hughes
And investors are okay with that?
Goeddel
Some are, a lot aren't. There were people on our IPO, when we went out and talked, who said, "You've been around almost eight years. How come you don't have anything in the clinic, just one product? What have you been doing?
Hughes
And what do you say to that?
Goeddel
I try to answer in as nice a way as possible. It's clear they're not going to invest. You just say, "This is our approach. This is what we've done. We're happy where we stand now."
Hughes
But it does require a different philosophy of the investment world, doesn't it?
Goeddel
That's why it's been so great having Ebner as a major investor. When he put in the money he said, "I like what you guys are doing. As long as you keep making progress, you can count on me to be an investor for ten years." That's really good when you get a quarter of the company that you know isn't going to be sold, stock isn't going to be freely traded, and it's going to be ten years. There are a lot of CEOs that would love to have one investor like that. Our goal now is, can we find a second one like that?
The Scientific Concept behind Tularik
HughesDescribe the technology, and why you think it's competitive.
Goeddel
There's probably nothing in the technology that's so special except there's a lot of pieces that have to be put together right. The concept is that every human disease has associated with it genes that are not regulated correctly, that are either too active or too inactive, and that if you could correct those you could treat the disease. I think the simplest way to describe our approach is we want to understand the mechanisms of the inappropriate gene expression in disease, and then use an understanding of that biology to find small-molecule drugs that will get in the cell, bind certain regulatory components, and restore normal gene expression.
Rheumatoid arthritis, that's one of our examples. What genes are expressed wrong? A lot of that's known in the literature already. But what regulatory components in the cell have turned those genes on that shouldn't be on? Then our biology can really go to work and make the discoveries of the components. Now we take those components, make recombinant proteins, for example, and develop assays, where we can test hundreds of thousands of chemicals to see does any chemical affect the activity of that regulator. If it does, then we can test in cells and so on.
But there's the step of the medicinal chemistry. You get a lead compound that works--it's not a drug. Now you have to go to work, just like the big pharma companies do, and refine that chemical structure into a real drug structure that's orally active, has the right half-life,
Hughes
You describe the basic process--the turning on and off of genes--in a very simple fashion. Does that belie the fact that you realize how very complex it is?
Goeddel
Yes, it's extremely complex.
Hughes
You don't find that daunting?
Goeddel
[pause] In some cases it turns out to be more complicated than we'd like. Other cases nature's incredibly simple. So there's both kinds, and it's maybe recognizing the projects as you're going along, Okay, this one's really going to take us a long time to sort out. It might even not be possible from what we've done on previous projects. So we've learned a lot from our experience. Then we might recognize another one: Oh, we've done a similar project before. Let's jump on it; it's going to go fast. Even our failures in the past on certain projects, now we can take advantage of that information.
And that's very similar to how Genentech was. Early on, we tried expressing everything in E. coli. Some proteins worked and some didn't. It finally got to a point, because we'd done so much of it, we'd get a new clone and you could look at it and say, "This one's never going to work in E. coli; let's not even take any time with it." So even from the failures, you learn something that the competition doesn't.
So yes, gene regulation is very complicated, but we slowly make steps and progress along, and it's clear we're going to get some good drugs out of it.
Hughes
It is?
Goeddel
Yes. It takes a long time.
Hughes
Am I right in thinking of this system as a network with many, many things, including environmental factors, impinging on what ultimately is a disease process? And that what you are conceiving of doing is taking one of those key components out, or putting it in, so that it disrupts the pathologic process?
Goeddel
Yes, basically. I think the way to imagine that most of our drugs should work is, they bind to a pocket on an enzyme or a regulatory molecule and disrupt its action. If you disrupt some key component in a pathway, you can shut off that pathway, and that could turn down a gene. But most pathways are complex and also have negative regulators. You can inhibit the negative regulator, take it out of the pathway, and now turn a gene on. You can do this if you have a good understanding of where to hit in various pathways. In many cases, it's just as easy, if you have that understanding, to turn something on as to turn it off.
Nature doesn't provide compensatory mechanisms? If you turn something on or off, might something else reverse it?
Goeddel
It appears not to in most of our programs. In some cases, yes. If you do it during development, then it may be more easily compensated for. As simple as it may sounds, it turns out that essentially every drug on the market regulates genes. There are the direct regulators and the indirect regulators. Maybe the way to look at it is, drugs like cortisone that have been around for a long time directly bind to a transcription factor and regulate the activity of a number of genes activated by that transcription factor. When the drug was discovered, no one knew that's how it worked.
Then there are drugs like the statins which are the cholesterol-lowering drugs that sell--it must be 10 billion dollars a year among Merck, Pfizer, and Bristol Myers alone. They inhibit an enzyme that is required to synthesize cholesterol. Everyone thought that's how the pathways work. But what ends up happening is you do get some compensation and your cells try to make more of that enzyme. When you make more enzyme, the inhibitor blocks it too, and the body tries to compensate. But the pathway it turns on to compensate not only makes more of that enzyme, it makes more of the receptor on the surface of the cell that sucks out cholesterol. In the end the drug works by up-regulating the LDL receptor, but that's done indirectly. It doesn't work by inhibiting the enzyme. That mechanism wasn't figured out until years later. It was actually figured out by two people on Tularik's Scientific Advisory Board, [Michael S.] Brown and [Joseph L.] Goldstein in Dallas, the Nobel Laureates. That's a gene-regulation project.
As those things came out, it became obvious to us that what we want to do isn't going to be impossible; all drugs someway or another work by regulating genes, it is possible you understand the pathways and how they work-- Pharma companies didn't understand the mechanism of many drugs they discovered. Now we can say the big drug companies try to take a more mechanistic approach. Our major competition on most of our projects is probably big pharma companies and not biotech companies.
Hughes
Is that so?
Goeddel
Probably. I'm sure we have competition that we don't even know about. But on each of our projects, if you ask the project team leader, "Whom do you fear the most that might get there first?" it's usually a big pharma company.
Tularik Culture
HughesDo you want to say something about Tularik's culture? What is it like to work here?
Goeddel
It's harder to say as a founder. It was easier for me to describe Genentech's culture because I really think the young scientists establish the culture, and you can't as a boss say what the culture's going to be. The first people you hire have a huge influence on that. The best way I would describe the culture here is-- [pause] We have a company that's based on contribution and productivity. Everyone that comes in has this feeling that they themselves have to produce. You can't hide anywhere; you can't get credit for other people's stuff. Maybe it's just no BS.
Very open and debating-type culture. Anyone can challenge anybody's ideas--how to do a project, what the budget should be next year, whatever. There's an almost scientific discussion of viewpoints even on nonscientific things, and decisions are made based on the merits and not on politics. There's almost zero politics here, which I'm pretty happy with. Most people here seem to really like that. To try to get things done other ways doesn't work. The fact that anyone can challenge anything is really a popular part of the culture.
Hughes
How do you incent your scientists?
Goeddel
Give them exciting projects. We have a very aggressive stock-option reward system where we look at all employees every year, and the top half get additional stock options, and maybe the top 5 to 10 percent can get really substantial amounts. That's a pretty good incentive. That's something I got from Swanson. He gave me, as a young scientist, more stock than he gave most of the officers each year. That tells you, Ah, look, I'm being appreciated; I'm going to work harder. I would say our stock plan is somewhat modeled after Swanson's original one. It changed over time, and wasn't administered based on title. If you really contributed to the success of the company, you could get a lot more stock that year than your boss got.
Hughes
Amazing.
Goeddel
Yes, it was a pretty generous program. Every year another 3 percent is created to go just to employees.
Policy on Intellectual Property
HughesPlease comment on Tularik's policy towards intellectual property.
Goeddel
We try to protect as much as we can. Also modeled after Boyer at Genentech, we encourage publication of outstanding work. Where needed, we count on the fact that the patents have been filed. The one difference is the way chemical structures are versus biological discoveries. Maybe you discover a new protein, and it's a protein drug. You get a patent on it; you're covered. There's a lot of things that can happen on the chemistry side, so we tend to publish new chemical structures at a later time, the timing to coincide with publication of the patents. Otherwise you're really competing against yourself, which you're not in biology. So we've adapted more of the approach of the pharmaceutical companies on our chemical discoveries, and of the progressive biotech companies on the biological discoveries. But we definitely believe in trying to get patents to protect our intellectual property. We've spent a lot of money on that.
Hughes
What more on Tularik?
Goeddel
Well, we're ten years into it, and in ten more we'll be a pharmaceutical company. McKnight, Tjian, and I at the beginning said it would probably take twenty years to make a pharmaceutical company, so we're just halfway there.
The Human Insulin Project
[Interview 5: January 15, 2002] ##
Collaborating with Riggs and Itakura at the City of Hope
HughesAt what stage was the insulin project when you arrived at Genentech in March of 1978?
Goeddel
I think most of the fragments of synthetic DNA had been synthesized in Keiichi Itakura's lab at City of Hope. I'm not sure exactly if they were all done, but it was about the point someone was needed to start putting them together. At least by April 1st all the fragments were completed.
Hughes
Did you do that?
Goeddel
No. The individual fragments were synthesized by a number of people in Keiichi's lab, and then Dennis Kleid and I began assembling them. That started--I think it might have been April 1st. We went down to City of Hope. Actually, I probably went down first, before Kleid. I can't remember exactly.
Hughes
Kleid came to Genentech a month after you.
Goeddel
Yes. I remember flying down to City of Hope and meeting with Art Riggs and having a discussion on getting going. Dennis might have been there very soon; probably on the second trip down there. He was soon after me. The first week or two I was at Genentech was largely ordering stuff, getting things ready in the lab before going down to southern California.
So yes, we started putting fragments together to make the two synthetic genes for the A-chain and the B-chain. Each visit to City of Hope we took it through the stage of assembling the fragments and then cloning and then would bring the clones back up here, either to the lab at SRI or to the new lab at Genentech, and do the sequencing.
Hughes
Why was that?
Goeddel
Convenience. There also must have been some deal that Riggs was going to be involved in the cloning. So rather than just sending DNA fragments up here to assemble, which might have been more efficient, it was done at City of Hope. But then Art agreed that sure, we could take the stuff back to sequence it. It's always easier to work in your own lab.
Hughes
Although you hadn't had much experience at that point in your own lab.
Goeddel
It's still where you normally live and are comfortable with. Down there we always got this one little room to work in that wasn't the main part of Art Rigg's lab. It was off to the side and in a very small area. I think that was mainly to keep the radioactivity confined to one area.
Hughes
He wasn't working with radioactivity?
Goeddel
No, I think he was. This was space we got initially. I think we wouldn't have been able to get better space. They were very careful there and they figured out we were fairly sloppy scientists. We were in a hurry, and they could always find traces of radioactivity anywhere
Hughes
What did Riggs think of you youngsters?
Goeddel
I think overall he thought we were good and we knew what we were doing. He was impressed we were fast and worked hard. Our style wasn't the same as his lab's. His lab was pretty easy going. They didn't work very long days in general; they made sure they had afternoon tea; took a full lunch hour, and things like that. When I went down there it was just how quickly can I get this done and get back home? We worked pretty much an around-the-clock schedule the times we were down there.
So we assembled the various pieces. The gene for the A-chain could be assembled in one piece for cloning.
Research Strategy
HughesWas it obvious that you would clone the A-chain and the B-chain separately?
Goeddel
No, you could either make proinsulin, in which you would clone one gene, and then worry about processing, or you'd have to do the A and B separately, make the separate A- and B-chain peptides, and then reconstitute them to be insulin. So there were two different choices. The selection they'd made, which I think was the right one, was to make the A and B separately. We had another second-priority project, to try to do a mini-proinsulin.
The B-chain was big enough to clone anyway, and we were worrying about mistakes. It was actually assembled in two separate pieces that were cloned separately, sequenced, and then the inserts excised and reassembled. That turned out to be a good way to do it because we kept getting the wrong sequence over and over. It turned out that Itakura's lab had made a mistake on one fragment and there was no way we could get the right sequence. So that had to be redone, which was actually done reasonably fast, too. I did that cloning work with Herb Heyneker--recloning the half of the B-chain. That was at the end of May. He was out here to look for a house because he was going to join Genentech in September. He was here from Holland. I was able to talk him into taking the Memorial Day weekend to go down to City of Hope, and that's when we redid that half of the B-chain.
Hughes
I think he went home, so the story goes, without looking for a house.
Goeddel
I don't know if he did or not. But that's why he was out here. He got really excited--sure he'd like to be involved with insulin.
Hughes
Aside from the competition, was there also a feeling that the success of this company, the future of this company, depended on a good outcome for the insulin project?
Goeddel
That was my feeling. I didn't know much about companies or anything, but there hadn't been any companies doing this, and I couldn't imagine that the company would survive if we didn't get there first.
Swanson's Participation
HughesHow much was Swanson in the picture?
Goeddel
I'd say almost every day that we were working here in South San Francisco he'd come in the lab. He always wanted to know, what's going on? How's it going? I think it was very tough on him because he understood in general what we were doing, but he was not yet comfortable with the idea that experiments you do fail. So he'd come, we'd be looking at a result, and he'd say, "Did that work?" And we'd go, "No." He'd be a little bit depressed: "Oh no, what can we do about it?" We'd say, "Don't worry, it will probably work next time." So I'm sure it was tougher on him than us. But at the same time, you could tell he really was interested. He was always coming around: "How's it going? Can I see that result? Explain to me what you did."
Hughes
So that was another form of pressure, wasn't it?
Goeddel
From him it was pretty positive pressure, at least for me; that at least you're doing something someone thought was important.
Hughes
Did the others take it that way too?
Goeddel
I don't know. I guess I never really have felt pressure from someone else, so I always took it as Bob being interested. But I did hear later, when Bob would come around about projects, people didn't feel good about it.
The Competition
HughesHow aware were you of the race for human insulin and the fact that there were two rather formidable competing groups?
Goeddel
I was always aware of that. Where they stood at any one time, I didn't know. I guess I wasn't completely confident we'd win, but I felt pretty good about it because I thought our approach with synthetic DNA would get there faster than the cDNA approach.
Hughes
I know from talking with Dennis that some of that optimism took a dive in the summer of '78 because somebody had heard a radio report that the Gilbert group had cloned and expressed insulin. Was it you that heard that report?
Goeddel
[pause] I don't remember who heard it first. There was some rumor going around for a little while; then it was a mistake.
Hughes
But you didn't pay much attention?
Goeddel
[pause] Not enough to be overly concerned. I can't really completely recall it. I would have probably felt, "Well, maybe they made some fusion protein; they've still got to process it. How are they going to make insulin?"
Hughes
And it turned out to be rat insulin.
Yes. I know where Gilbert went wrong and what actually happened, but I don't recall being concerned. If I had been, I think I would remember it better than maybe just another rumor that came in.
Hughes
The two competitors are the Harvard group and the UCSF group, right?
Goeddel
Yes.
Hughes
There was nobody else in the race?
Goeddel
Well, there was a group at Cornell also.
Hughes
Who was that?
Goeddel
It was another group taking the synthetic DNA approach that I heard about. But I didn't see how they could beat Itakura, synthetic DNA wise. Ray Wu was the molecular biologist. The chemist that made the DNA was Saran A. Narang.
Hughes
Narang was a student of Khorana, right?
Goeddel
Right. And Narang had trained Itakura.
Hughes
The Cornell group was using the diester approach?
Goeddel
Yes, correct.
Hughes
Is the triester faster?
Goeddel
Yes, what Itakura had done was to take the existing chemistry and make it fast enough that you could think about doing something like this.
Hughes
Was that the root of your confidence that indeed you could beat these other groups?
Goeddel
Yes. The somatostatin work had shown what could be done. This insulin project was a larger version of that, more complicated. Swanson told us that Itakura had already made most of the DNA, so we believed that. If the DNA was there, we thought we could do the rest.
The Agreement with Eli Lilly
HughesWhat stage did you think negotiations with Lilly were in at that point?
Goeddel
I didn't. I just would hear from Bob that we were in discussions with Lilly and we were going to get a deal. I knew nothing about how those deals worked. As it got closer and closer to the end of the summer, and we didn't have a contract quite yet, then I think I started feeling that Lilly probably was just going to wait and sign with whoever did it first. At some point--it might have been about the time we did the cloning and expression--I thought, now they're not going to want to miss out on this, so I bet we get a deal pretty soon. And we did.
Earlier on, I'm sure the first few times, I believed Bob, yes, we'll probably have the deal soon. And then, as nothing happened, I gradually shifted toward thinking, "We're going to have to get this done to get a deal."
Hughes
Was it common knowledge that Lilly was also negotiating with the UCSF team, or negotiating with UC?
Goeddel
I think it was common knowledge.
Hughes
So that made the competition pretty clear.
Goeddel
Yes.
Hughes
In contrast to the other groups, you were doing this for commercial purposes. You needed a product. The others, at least ostensibly, were doing it for basic science reasons. What difference did that make?
Goeddel
[pause] I guess I don't really think they were doing it for basic science reasons. UC was negotiating a deal with Lilly that gave them some kind of payment in royalties. Unlike a company where the royalty money goes to the company to grow, those guys would have benefitted directly; the royalties go to the inventors. They can make huge money off that. As an inventor, you can benefit more financially being in a university than at a company. Knowing who those people were, or who they are now, they weren't doing it just for academic reasons.
Hughes
I don't know about Wu, but the other ones, in no short order, had corporate connections, didn't they?
Goeddel
Yes.
Division of Labor
HughesWere you doing the cloning? And who was doing the sequencing? Or was that a changing array of people?
Goeddel
I probably did most of the cloning, but Kleid and Heyneker did some too. Sequencing, we all did some early on until after Dan Yansura joined Genentech in about mid-June 1978. Then his role was really focused on sequencing for a while. I think after he joined I probably only did sequencing one time. Then he took over. My role was mainly deciding how we were going to assemble these things, doing the assembly and cloning, then the next step, the expression work.
So after we had a synthetic gene assembled we had to fuse it to a gene encoding most of beta-galactosidase, make the expression plasmids, and then grow up the bacteria and purify the fusion protein. Then chop the insulin chains out of the fusion protein and then reassemble the two chains.
Pressure to Produce a Product
HughesDid those steps go fairly smoothly?
Goeddel
[hesitating] I thought so. It was probably early August when we got to the purification-- That was something we had to do at City of Hope. I believe I was working on some other constructs, and Dennis went down by himself to City of Hope to work on the purification of one of the chains, and it didn't work very well, or nothing happened. Because Kleid was flying back unsuccessful. So I got called into Swanson's office when he was meeting with Tom Perkins, the chairman. I remember this very clearly. They pretty much said, "We want you to go down there and work on this. And don't come home until it's done." That was almost the only time I got any orders like that: "We think you ought to go down there, and you ought to stay until it's done."
Hughes
Was that mainly coming from Perkins?
Goeddel
I think it was Perkins probably having a meeting with Bob that day, saying, "What's going on?" Bob got an update and said, "Well, it's not working." It didn't work with that guy [Kleid]; we have one other guy [Goeddel], let's see if it works with him.
Hughes
Perkins was worrying about the money he'd invested.
Goeddel
I think Perkins had put some pressure on Bob.
Hughes
Yes, I can imagine. The actual joining of the A- and B-chains went without a hitch?
Goeddel
Yes. Riggs had worked out the process. That was done before in the scientific literature. You could take pig insulin, break it apart, and make the A and B, and reconstitute. He'd gone through the scientific literature and put a detailed protocol together that should work. One of the things I did while I was down there was go through that in a trial run using pig A- and B-chain. Yes, it worked, just like it should have. I was there just following Riggs' procedure that he'd written out.
Early Intellectual Property
HughesWhy is it the Riggs-Itakura patent?
Goeddel
I think the whole history behind it is Riggs and Itakura wanted to synthesize somatostatin gene and clone it, to demonstrate they could do this. Genentech funded that work and filed the patent, and Riggs and Itakura were the inventors, even though Heyneker, Boyer, Bolivar, and some of these other guys did some of the work. The concept of doing it with the synthetic gene was Riggs and Itakura's. Then that gave a priority date. So rather than filing a separate patent for insulin, they folded it into the original patent since it used similar techniques. So you don't hear of "the insulin patent," or even "the somatostatin patent." You hear, "Riggs-Itakura."
I think it was Tom Kiley who described the Riggs-Itakura patent as the corporate counterpart of the Cohen-Boyer.
Goeddel
Yes, that's at least what they tried to do. Some of the stuff wouldn't fit under it later when we made things by very different ways. But yes, as much as could be stuck into there the better it was for Genentech.
The way Genentech did patent filings and determined inventors changed years later; they did it differently. It didn't make any difference, but five years later I would have been an inventor on insulin, because they put down who made it work technically, because there were certain things that only certain people could get to work. It wasn't just a protocol that you give to anyone and they could do it. So I think what Genentech viewed constituted inventorship changed over time. In fact, at the time of insulin, I didn't know anything about invention. I didn't even know about a Riggs-Itakura patent, or that it was filed or updated with insulin work.
Hughes
Did the protocol change at Genentech or did patenting in biotechnology shift?
Goeddel
Well, there weren't any lawyers at that time. Kiley wasn't at the company then.
Hughes
Who wrote the Riggs-Itakura patent?
Goeddel
I think Kiley.
Hughes
But he was still at Lyon and Lyon?
Goeddel
Yes. I didn't know anything about patents until the growth hormone work, when all of a sudden I was an inventor on something that was being filed.
Hughes
Had that concept shifted then?
Goeddel
Well, I don't know. Later, we had patent people on site, and they saw what was happening. I never even talked to Kiley about insulin. He might have been getting all the information just from Riggs directly, and Riggs might have said, "Keiichi and I figured all this out, and we have some technicians help us put it together," or something. I don't know.
Hughes
The way I got it from your previous statement was that it was essentially a conceptual inventorship, that the idea was the important thing, not making it. Well, functionality is one of the prerequisites for patenting--
Goeddel
And that's how inventorship was supposed to work, but just over time there was this component that even if someone could think of something and write it all down that was very different. Someone with normal skill in the art couldn't necessarily do it, and maybe it took someone of super skill, and then they became an inventor. I don't know how Genentech's doing it now, but pretty much through the eighties if someone did almost all the work on a project, they were an inventor. Genentech tended to put multiple people on patents.
Hughes
In the Cohen-Boyer patent application, there was controversy over the fact that only Boyer and Cohen were named as inventors. It was the concept that counted, not the golden hands, not the people that actually did it. That's interesting; I hadn't heard anybody say that before.
But people at Genentech I don't think worried-- Well, some of them did; there was always some fighting. But it didn't matter if you were on a patent or not. There wasn't the royalty coming to yourself. The scientific publication was what was important. When people would complain about patents in my group in later years I'd say, "It doesn't even matter. Whether it's your patent or not, the money's going to Genentech. You're not going to get a job based on your patent; you're going to get a job based on your scientific literature."
Two Published Papers
HughesAs you know, there were two papers published on the insulin work. [1] David V. Goeddel et al., "Expression in Escherichia coli of Chemically Synthesized Genes for Human Insulin," Proceedings of the National Academy of Sciences [PNAS] 1978, 76: 106-110; Roberto Crea et al., "Chemical Synthesis of Genes for Human Insulin," PNAS 1978 75: 5763-69. Can you tell me the context?
Goeddel
[pause] I seem to recall that Itakura wanted his own paper so that he could be last author on the chemistry, rather than putting it all into one paper. Or it could have been that he said, "If there's one paper, I'm last author." And Riggs wanted to be last. I don't know. But they'd agreed there would be two. That was determined by City of Hope guys. As it was getting near the end, sometime in August 1978, Riggs and I talked about how we would do a paper and maybe divide it up. I went and met with Boyer once to see if he had any ideas on things. He gave some general comments on an outline.
Hughes
You mean how to compose the paper?
Goeddel
No, it was more here's what we had; did he want to be involved and to help write it? He goes, "No, this is your guys' work." He gave some advice, but it was pretty general.
Hughes
Is he on the paper?
Goeddel
No.
Hughes
And you're first author.
Goeddel
Yes.
Hughes
Crea is first author on the synthetic one.
Goeddel
Right. [pause] The guys who were on the synthetic paper probably shouldn't have been on the second one, but they got on both.
Hughes
Why?
Goeddel
I don't know. Maybe because the cloning and expression was the big one. They wanted their own separate paper but they didn't want to miss out on the important one.
Hughes
And you didn't care?
No, it wasn't that significant. It had so many names it was just going to be Goeddel et al. anyway.
Hughes
Did you have to fight to be first author, or was that clear?
Goeddel
There was never a word mentioned about it. I think it was assumed all along. It was clear enough who did the most work. A lot of times, it goes unsaid; everyone knows who's going to be first author, it's so obvious. It's only the times when it's close that there's discussion.
Hughes
And it wasn't close.
Goeddel
No. I didn't think so. I don't think anyone thought so.
Riggs and I decided we would try to write the paper, and then we had a meeting up here with as many of the authors as would show up. I think it was Labor Day weekend of that year, because we finished the cloning, had the expression done on August 25th. Labor Day weekend we met up here at Genentech and wrote the paper that weekend. I think it was probably a three-day weekend, and maybe the first two days everyone was involved with drafts and comments and getting together, kind of doing both papers together, finishing off the synthetic gene paper. Then the third day I think it was just Riggs and me finished it off and it was done. So it didn't drag on a long time.
Publicity Prior to Publication
HughesThe press conference at City of Hope was on September 6th. Had that date been pre-established?
Goeddel
There were some major arguments between Riggs and Swanson on the press conference date. Riggs wasn't going to agree to a press conference saying that we had done this until there had been a scientific seminar discussion. I think Riggs didn't want to give a scientific seminar until the paper had been submitted. So Bob had set a date he wanted to do the press conference, and I remember Riggs saying, "I probably can't get the paper done by then, we're going to have to wait," and Bob saying, "Well, you better figure out how to get it done. I don't see you working on it." This was a meeting down at City of Hope right around the end of August. I said, "Well, I think we can get it done in a week." Riggs really didn't look very happy about that, but agreed, and came up here and we got it done. So yes, there was a time when he was pushed by Swanson for the press release, which then would allow Bob to get the deal with Lilly.
Hughes
And get Perkins off his back.
Goeddel
Yes. I could imagine how Riggs at that point being more senior than me and established there would feel that as undue pressure. But it seemed to me that this is how we should work: we did it, let's write the paper, let's get on to the next thing.
Hughes
Genentech was criticized. That was the era when it wasn't enough just to give a seminar. You were supposed to have the work published before you announced it publicly. Do you remember the flack?
Yes, there was criticism. I guess I didn't worry about it too much.
Hughes
[laughing] I knew you were going to say that.
Goeddel
I knew we'd done it. It wasn't like fake science or anything. We had it and there was a paper submitted. That stuff [criticism] only lasted a year or so, and then people started believing that if Genentech said they did something they probably did it.
Hughes
There was also some criticism of the fact that you hadn't indicated, at least to the biologists, that the insulin was functional.
Goeddel
Oh that one, yes. That was going to take another year or something. So what did they think? If it's derived from a cloned gene that it won't be active? We had shown our insulin was immunologically active. This was the appropriate demonstration--
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Goeddel
--since we didn't have enough to stick in an animal and shows it works like insulin. Yes, that was going to take a long time to get that amount, and I was long gone onto another project. The paper got accepted and published. That part of it, not showing the insulin was functional, I thought was just sour grapes. Whereas the argument that you shouldn't publish in the press--yes, they probably made a good argument about that. Bob wanted the publicity, he really did, for raising money for the company.
The B-C-A Project
HughesI saw reference to the B-C-A project. What was that?
Goeddel
Insulin is normally synthesized as a B-chain followed by a connecting peptide C-chain and then the A-chain. We had a mini-C project, where we took a very small C-peptide, made a gene for that, hoping that we could express B-C-A altogether and then cleave out C. So it was just a way to make a shortened version of proinsulin, and we had that going on at the same time.
Hughes
That was what Kleid calls "your fall-back."
Goeddel
Yes, I guess.
Working with Dennis Kleid and Herbert Heyneker
HughesKleid maintains that you were pushing ahead in one direction, and he was doing fall-back experiments in case your approach didn't work.
Goeddel
It wasn't just that. He was more preparing stuff behind the scenes and new reagents. I always thought he liked it better that way too. It was great for me, but I could never figure out why he
Hughes
I think it was you told me that Heyneker also was often in the picture making different procedures more efficient.
Goeddel
That was later, when he was at Genentech full time. The first time I ever worked with Heyneker was on that Memorial Day weekend when we went down to fix the B-chain. From that first day I loved working with him. He was very good. We had a similar style in the lab. It was very efficient work. Then I didn't work with him again until sometime in late September when he rejoined Genentech. He wasn't here in between. He was a big help that Memorial Day weekend, just jumped in. It was like we'd been working side-by-side for years.
The Moment of Success
HughesCan you describe the moment when you learned that the experiments had worked, that you had made insulin?
Goeddel
Yes. [pause] I had worked for a few days--I don't know how many--pretty hard, with almost no sleep, maybe a couple of hours a day. The last night, the night of August 24th, I think I didn't have any sleep at all, finishing up things, working with Roberto Crea a lot. He stayed maybe until 2:00 or 3:00 in the morning, I don't know. Then I was doing the reconstitution experiments and other things and going to have the key experiment sometime that morning, 9:00, 10:00 or something. I still remember being at the scintillation counter, having all the vials loaded up and starting to count, and here came Art Riggs, his normal arrival time at work. He walked in, "How's it going?" I said, "Well, we should know in a few minutes." He stood there with me at the scintillation counter. We got the result; it was positive. For him it was just perfect timing. [laugher] He wasn't there early at all. He'd gone home the evening before.
Hughes
How did you feel?
Goeddel
[pause] I can't remember completely. I think I felt like it was going to work, so I probably would have been more disappointed if the result didn't come out. I think right after that I felt great; we got this done. Then it hit me: I was pretty tired.
Hughes
Did you call Swanson right away?
Goeddel
Yes, I think I called either Swanson or Kleid and ended up talking to both of them. I flew back here, and then we were right back down there a day or two later to talk with Riggs about the publication and so on.
Hughes
What was Swanson's reaction?
Goeddel
I think he was a lot more excited. He's outgoing. "Fantastic, fantastic!" Oh, I think he may have done what he used to do back then with us when we were pretty young. He goes, "Have
Hughes
You didn't mind having to do that?
Goeddel
No, not really. Bob didn't understand the science. He'd started the company; Herb was the man in cloning. That went on for about two years. Then, my guess is, Herb probably told him to quit doing that.
Hughes
Or you indicated to Swanson that you might know what you were doing.
The Genentech and Gilbert Methods for Expressing Insulin
HughesTalk about the expression a little more, because I understand that Gilbert had a different way of expressing insulin.
Goeddel
[pause] Yes, what we did was fuse the gene for this big bacterial protein, beta-galactosidase, to the A-chain or the B-chain gene. Then the bacteria make this big, massive, protein which has a little insulin tail on it. It was connected with a methionine amino acid, and that allows you to treat it with a chemical, cyanogen bromide, that cleaves off the methionine and leaves the insulin. It also chops up this other big protein, beta-galactosidase. So you have to purify the chain you want, and there is a purification aspect, but you get exactly A-chain. You do it again; you get exactly B-chain on the other one, and then you can reconstitute. Those are clean.
Gilbert's was a less exact method, where you fuse randomly in the cDNA sequence. You might get extra beyond insulin, or you might get less than insulin, depending on how the fusion went, because he did not use synthetic DNA. I think, at that point, his fusions were into a bacterial protein called beta-lactamase. Under certain conditions, it gets secreted, so that would allow the insulin to come out of the cell hooked to beta-galactosidase. But there was no easy way to cleave that, and you always had extra or fewer amino acids, even if you did get cleavage. They could detect with an antibody that the insulin was hooked onto something else. There was no way that was ever going to be a commercial process.
Hughes
In a sense they hadn't made insulin, had they?
Goeddel
When they first did it, they made a fusion protein that included insulin sequences.
Hughes
What about the folding problem? Were you worried about that?
Goeddel
You mean with A- and B-chains?
Hughes
Yes.
Not really. Maybe I was just naive. But these were small peptides that after you cleaved them out and had them they should behave like a chemically synthesized peptide or one isolated from pigs or anything else. Folding becomes a problem with bigger proteins, so we were really looking at peptides rather then big proteins that had their own 3D shape.
The Press Conference
HughesLet's move to the press conference which we mentioned in passing. Tell me how that went?
Goeddel
I can't remember all of it, but there were some really funny parts. I was quite nervous, and we flew down there early in the morning. There were several of us. I know it was Swanson and Kleid and me. Dan Yansura might have come. Fred Middleton came, who had just joined the company. We sat up on this big bench, big table in the front. There were a bunch of City of Hope guys on one side and the Genentech guys on the other. These really old guys from City of Hope that must have been famous old scientists there. So it was completely different than anything I'd ever participated in. There were a lot of people--a lot of press and lights shining on us and cameras going.
Hughes
Who had rounded up the press?
Goeddel
Probably Swanson. Swanson with some PR firm. I don't know. This was a pretty big deal, it seemed like. Some of these guys got up and talked, and I didn't even know what they were really talking about. They went on and on. Then I think Swanson talked a little. Oh, and he told me ahead of time that he wanted me to say a few words. I said, "I don't want to. I'd be embarrassed doing that." He goes, "No, no, you've got to." I hadn't really agreed. So we're sitting there, Swanson, me, Kleid. When one of the guys was talking, Bob turned to me and says, "You're going to talk about this a little, aren't you?" And I didn't really answer. When the guy kept talking, I turned to Dennis and I said, "Wouldn't you like to talk?" And he goes, "Yes, I'd love to." I thought since Dennis let me do the good science, I'll let him do the talking.
Hughes
Were you shy?
Goeddel
I just didn't feel comfortable doing that. What would I say? If they asked me a science question I could answer it, but I wouldn't know what to stand up and say.
This one guy kept talking about all the great stuff City of Hope had done, and that was just burning up Bob. So he turned to me again, "Time to go up there and talk." So I just turned to Dennis, and Dennis jumped up, and Bob's face--. I hadn't realized so much that he just didn't want Dennis talking, because he'd already learned that Dennis could say anything at anytime. And Dennis got up there and loved it. He was going on and on. Part of it was good. I was really relieved.
But Dennis said two things that I remember that Bob just was like this [head down, shaking]. After the first one, Bob says, "Go up there and get him down." Like I was going to go get him down? I just ignored Bob. He said, "Go up and get him down." What Dennis had said was, "To say that we made insulin is a lie." Then he waits, and he said, "It was the bacteria that made insulin." But just saying that it was a lie! Bob afterwards said, "Why would you say
Hughes
They must have had a reporter there.
Goeddel
So Bob had arranged things pretty well.
More on the Lilly Agreement
HughesThe contract with Lilly was signed around the time of the press conference, I believe.
Goeddel
It was right around that time.
Hughes
You were right in your previous observation that Lilly needed to see that the Genentech group could actually produce insulin before Lilly would sign an agreement. Did you at that point know anything about the contract and the benchmarks?
Goeddel
At some point I had heard what the benchmarks were, that we were going to have to increase the yields by significant amounts at different points, and had thought that that sounded pretty hard to do--how is that ever going to happen? But it was Boyer that said, "Stuff like that, you'll work it out."
Hughes
Had he been involved in making the agreement with Lilly?
Goeddel
I think he knew what was in it, yes. Swanson must have run it by him to say, "Should I sign a deal that requires us to do this? Is that possible?" Bob kept us completely out of any negotiations, hardly letting us know what was going on. He was fairly secretive about that, and I think he wanted the scientists to focus all their energy on the science. He'd always just say, "It's going okay, it's going okay. Don't worry about it." Later we saw what we had to achieve. But I didn't work that much more on insulin after that point.
Hughes
You went to interferon?
Goeddel
I went to interferon fairly soon after, and then growth hormone.
Lilly's In-house Expertise
Hughes[pause] What about Lilly's in-house expertise on recombinant DNA at this stage? Was there any?
Not really. They had a group that I think Irv Johnson had put together to try to get insulin. They were the first pharmaceutical company to recognize what could be done with genetic engineering and to say that they wanted to do it. But they went about it internally the wrong way in taking people that had had a career in other areas, that were established, and telling them to become the recombinant DNA group. That's just never going to work. It was a whole new technology; they needed to hire the kind of people Genentech had hired.
I do recall the first meeting with Lilly people like Irv Johnson and Paul Burnett, at Genentech. Then the second meeting they came back and we reported what we'd accomplished since the first meeting, and they reported what they had done. What they had done was to take the bacteria and plasmid we had given them, isolate the plasmid from the bacteria, and then retransform it into bacteria to prove they could do that. So they were doing these beginner control experiments, and they actually reported on it. They were really happy with what they had done, and they hadn't done anything. We thought it was really funny. But now looking at it, you see companies do that. They want to get into a new area: Do you hire or spin out and create something new? Or do you take people that were trained in something else and say, "Become a new kind of scientist."
Hughes
I believe you sent two types of clones to Lilly. You sent the proinsulin clone as well.
Goeddel
We probably sent everything we had.
Hughes
Why, if Lilly had a bug that was producing insulin, did they have to know anything about recombinant DNA or synthetic DNA?
Goeddel
They didn't have to, but probably they wanted to learn things from us, and to have this DNA group, and this would be perfect practice experiments for them. Maybe they assumed all along their group wasn't going to do anything, but they could start working with this Genentech group and do practice experiments and learn how to do something for later on.
Hughes
Do you think that was Irving Johnson's idea? That out of the contract Lilly would get not only a bug producing insulin, but it would also get expertise in recombinant DNA?
Goeddel
I would have to assume it was his idea. He was the smart guy behind, let's get into this area when other companies weren't doing it.
Hughes
There was of course a different way of acquiring expertise in a new area, which to some extent was done with Schering-Plough and its relationship with DNAX a little later. To a degree, the recombinant DNA work was done at DNAX, and the development work was done at Schering-Plough, not without difficulties, I must admit. [1] See the interview in this series with Hugh D'Andrade, David Holveck and Edward Penhoet, "Regional Characteristics of Biotechology in the United States: Perspectives of Three Industry Insiders," 2001.
Goeddel
I think they never got a drug.
They didn't.
Lilly and Johnson and Johnson Try to Buy Genentech
GoeddelLilly did try to buy Genentech at some point.
Hughes
When?
Goeddel
I only found out later from Swanson. He didn't talk about it at the time. I think Lilly might have offered $60 million or something. It was probably somewhere in the growth hormone time.
Hughes
Obviously, Swanson turned them down.
Goeddel
That didn't go very far. Later I know J& J was interested. Bob had a big dinner with them and was trying to get them to interested. But they didn't go nearly high enough in price, I guess. There was a big dinner at Tom Perkins's house that was very formal with all these J&J people. I only know about that because I think at that point I'd probably done growth hormone also. So maybe the J&J guys had heard of me, because I couldn't figure out why I was included. I got invited to this dinner at Tom Perkins's house on a Saturday night and told there would be these J& J guys there and it had to be confidential. So Bob, Herb, Perkins, and I think Fred Middleton and Bob Byrnes, who was the business development guy, were there.
I showed up late. I'd been in the lab working all day and just came in my regular old clothes. A butler in a tux answered the door and asked what I was doing here. I said, "I came for dinner." He goes, "No, no, this is a private party." I go, "I'm supposed to be here." Finally, Perkins came over and said, "It's okay, you can let him in." Then I noticed that everyone was completely formal, and there were servants with the meal, and I was just a complete slob. Bob came over and said, "Thanks for coming." I said, "Sorry I'm late. I didn't know it was going to be formal." Bob thought it was actually good. I said, "I apologize." He said, "No, you look like a scientist. This is great."
Hughes
A scientist who's come straight from the lab. No wasting time to change into a tux. That's a great story.
Because the party was at Perkins's house, do you gather that it was his impetus that set up this evening?
Goeddel
I don't know. Bob lived in an apartment, and what's the nicest dinner you could give to the big shots from J&J? Probably have it at Tom's house with this great view of San Francisco and everything.
Hughes
And nothing came of it?
Goeddel
Nothing.
Hughes
[pause] Anything more to say about Lilly's subsequent connection with insulin? What about the construction of plants in this country and in England?
I really had almost nothing to do with that.
Hughes
I read that Swanson, and I can't tell you when, approached Novo Nordisk about insulin. Do you know anything about that?
Goeddel
No.
The Human Growth Hormone Project
Selecting Growth Hormone for Development
HughesPlease give me some background on the selection of human growth hormone as a potential product.
Goeddel
It was one of the few proteins that we talked about early on that this technology should be able to do. There was an existing product; it was made from pituitary extracts from cadavers; and if you could replace that there should be a market. But the market was thought to be reasonably small, so early on it wasn't a super important project in terms of becoming a big selling drug. It was more the next stage of what we thought the technology could do. I remember hearing $6 to $8 million as a market for it early on. It would require some cDNA and some synthetic DNA.
Hughes
Why was that the assumption?
Goeddel
Because the molecule hGH was about four times bigger than insulin, and to make that much synthetic DNA was doable but it would be a lot of work, and we thought it would increase the chances of making a mistake, too.
Hughes
You'd already had a lesson in that.
Goeddel
Yes. Heyneker and I, with input from others, came up with this idea of using synthetic DNA and cDNA, and combining them to get around, I guess you might call, the Gilbert issue: How do you make the exact protein you want at the front end? We decided to try to do direct expression with the hope that you could make the whole protein in bacteria. It would fold right, and it wouldn't be degraded. That all turned out to work.
But there was no big conceptual breakthrough on having growth hormone on the list. From early on, the first day I met with Bob Swanson I think, insulin was on the list and so was growth hormone. They were things that were known that you could do, and then there was interferon, the unknown magical protein. Could you use cloning, could you eventually do that? They came in that order. There were some other things: Thymosin, which was going to be a small synthetic peptide that some people thought might be of medical value.
Initially, I wasn't even going to work on growth hormone. I wanted interferon. I thought that sounded harder. There was a lot of thought out there that interferon might be something to
Hiring the UCSF Postdocs: Peter Seeburg, John Shine, and Axel Ullrich
HughesSo you, to a degree, got swept away by the hype about interferon?
Goeddel
Yes. And scientifically it was going to be a harder project. Plus, after we did insulin, these postdocs from UCSF that Swanson had been trying to hire all along, Axel Ullrich, Peter Seeburg, and John Shine, were invited to come down to Genentech again. We presented the insulin work, and they all signed up. They said, "Okay, we'll join." I probably wouldn't have had a job at Genentech if they had signed up earlier. Swanson wanted them.
Hughes
That's an interesting thought, isn't it?
Goeddel
That's who he wanted, the famous UCSF postdocs, not some young guy that was at Stanford Research Institute. So they all joined. Heyneker joined in September 1978, those guys joined around the end of the year, although John Shine never did, even though he signed the employment agreement. He ended up going to Australia. His wife said she wasn't going to stay, or something. As soon as they agreed to join it became clear to everyone: Well, growth hormone should be Seeburg's project. He was the famous growth hormone postdoc at UCSF--let him do it.
Hughes
Did you know anything about his work prior to his arrival at Genentech?
Goeddel
I'd read some of his papers, and Heyneker had told me that these guys, Ullrich and Seeburg, were somewhat difficult Germans, but very good. They were a lot more experienced than me. They'd never done the synthetic DNA stuff, but they'd done five-year postdocs; I'd done a six- month postdoc. So it was pretty exciting to have more good guys join. It improved the chances that we'd make it.
I knew I probably couldn't get two projects, so I was pushing hard to get interferon. Before we started working on interferon, we had this design that had been put together, largely by Herb Heyneker and me, for how we'd do growth hormone. It required a new expression vector, so I worked on that through much of September. Herb worked on it a little. We had that done before Seeburg arrived. I also spent some time on this mini-C insulin or the B-C-A insulin. Then, sometime late that fall, we started working on interferon. It didn't go anywhere for quite a while. Giuseppe Miozzari was working on it; I was working on it; Heyneker some. I was putting most of my time on it.
Then Seeburg arrived to work on growth hormone and had a lot difficulties early on; he didn't come to work a lot. There were rumors he was an alcoholic, that he was on drugs, that he had trouble at UCSF--
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Goeddel
He'd come in at eight in the evening and work until midnight or something, and that might be it for the day. You never knew when he would arrive. Heyneker kept saying, "Well, he's really
Goeddel Joins Genentech and City of Hope Scientists Working on Growth Hormone
GoeddelSwanson put some pressure on and asked me if I would help out on growth hormone. Interferon was going pretty poorly, so I thought, well, if I had another project going at the same time, at least one of them should be working; I'll just work on two at the same time. I began working on growth hormone and Peter seemed to do less and less. He had some research of his own he was interested in that was old UCSF stuff.
Hughes
You mean on growth hormone?
Goeddel
Yes, trying to clone the growth hormone gene instead of getting the cDNA. But he wasn't being productive and doing much. This couldn't have been the guy I'd heard about--he was just completely different.
Itakura's lab was making the synthetic DNA. That was something Swanson had agreed to with them, that even though we had Roberto Crea at Genentech now, Keiichi would get to make the growth hormone synthetic DNA. Roberto didn't like that; he thought we should do it at Genentech; why do it at City of Hope? But I think Swanson was just honoring his word that he told Keiichi he could do it.
I assembled that gene that encoded the first twenty-three amino acids of growth hormone, and then had some difficulty with the cDNA cloning because I hadn't done much. I'd been working on it, and eventually got the cDNA cloned for the rest of the growth hormone. About the time I was getting ready to assemble it into the final expression vector, Seeburg I think saw that, hey, this project that was his is going to be done by someone else. Then he started hanging around more and came and saw me. He wanted to get involved in the design and the discussion. He was really trying to make himself part of the project, which was good in a way, but very strange in another way, because all the time before I'd been trying to make him part of the project, because it was supposed to be his, he wasn't doing anything. It was only when the results were all about there that he became interested.
Hughes
What was the source of the cDNA that you were using?
Goeddel
The cDNA came from RNA, that came from pituitary tumors, that came from UCSF. We'd been getting pituitaries all along from Kabi, whom Swanson had done a deal with, and from some other sources. Giuseppe Miozzari had found some. Those had pretty degraded RNA, so we'd go through and do the cDNA cloning and screening and find very small cDNA clones, not the full size we needed, but smaller ones.
Seeburg had pituitary tumor RNA that he'd brought with him from UCSF. So as soon as I used that for cloning, it came out pretty much right away.
University of California v. Genentech, 1990s
GoeddelThen there was this whole UCSF lawsuit with Genentech that went off and on for years on different things. I think it started earlier. At least there were lots of depositions earlier. At the end, UCSF, through their unethical lawyer, claimed that it was the UCSF cDNA clone that I used in a secret deal with Peter Seeburg.
Hughes
Why would you have done that?
Goeddel
Well, there was no need to do it. It had nothing to do with the case; it was a patent case. But the UCSF lawyer was trying to make the jury think that everything Genentech did was lowdown, and that Genentech couldn't have done it without UC. It was just part of this whole smokescreen scheme.
I wasn't there for his part of the case, but apparently they got Seeburg to say that he and I had a secret pact. But I had everything in my notebook, the whole record of all of it. Seeburg had zero in his notebook of course, because he didn't do any work then and didn't have a notebook. So here was a guy that wasn't there at work claiming he had a secret deal with me.
Hughes
What would have been your motivation?
Goeddel
What they were claiming was that Bob Swanson put undue pressure on us, saying it had to be done, and Seeburg felt such pressure, and so did I, that we decided to use a UCSF cDNA clone that Peter had. It didn't make any sense, because the day Seeburg apparently said he did this was after months of work when all the pieces were already there, assembled and documented.
Because of the bad press that Genentech was getting, it put up a website where Dennis Henner had actually gone through my notebook and explained every experiment in detail, and the results, and those couldn't have come from any UCSF clone. They used a different site for cloning and everything else, and not even the same vector that I used. You couldn't get the restriction fragment sizes I had. So there was no way.
It just shows to me how legal cases get distorted when they get to court. Everyone's under oath except the lawyers, and they can make up anything they want. And the UCSF guy had been really bad during all the depositions too, just a complete slime ball. Apparently in Boyer's deposition--I heard from a couple people, and I asked Herb and he goes, "Yes"--that Herb lunged across the table and tried to strangle the guy, tried to grab him, because he was telling Herb that he was just trying to rip off UCSF, take their discoveries for his own money. And here Herb had donated all his Boyer-Cohen royalties to UCSF and given them another $30 million to build their hospital, and this guy telling him that. This lawyer makes you want to hit him in these depositions. It was pretty funny that Herb actually went after him. The lawyers had to call for a break after that.
Negotiations over the Paper on Growth Hormone [1] P.H. Seeburg, S. Sias, J.P. Adelman, H.A. deBoer, J.S. Hayflick, P. Jhurani, D.V. Goeddel, and H.L. Heyneker, "Efficient Bacterial Production of Bovine and Porcine Growth Hormones," DNA 1983, 2:37-45.
GoeddelSo yes, Seeburg, at the very end, got interested. Then, when I wrote the paper, Seeburg volunteered to help out. He wrote the introduction for the paper. He wanted to make sure he was involved in the writing. And then he started his typical thing that he did time after time over the years, and that was to try to make you feel sorry for him: "I've been working on growth hormone my whole life, and now, this paper, if I don't get to be an author and be recognized in a good spot--" and so on and so on. Heyneker and I fell for it, and put Heyneker second author and we let Seeburg be the last author. So again, in court, that comes out, "Well, he must have been the leader of the effort." And when you say, "We only did that because he didn't do anything, but we felt sorry for him," then they say, "Well, what's the normal way last author is determined?" So all these things come back to bite you at the end. But Kiley set down in the patent application who did what. The patent was very clear: 90 percent of the experiments were done by me; Heyneker contributed to the intellectual stuff, in addition, on the design and everything. So there was no Seeburg contribution and Seeburg was not on the patent. We were trying to help him out of his personal difficulty with the publication.
A Celebration with Future Implications
GoeddelA side story: Several years later when growth hormone was approved as a drug, there was a big party with a tent and fireworks and everything. Swanson wanted me to come up on the stage with him to get recognition for it. I was director then of the whole department, and Seeburg reported to me. He'd recovered very well and was doing good science then, so I thought it would be good to get some recognition. He also associated himself with growth hormone, and I hated recognition myself, getting up there in front of the employees. So I asked Bob, "Can we have Peter come up, since he'd started work at UCSF years earlier on growth hormone before I even knew about it, and say he'd spent his whole career on growth hormone and now we had a drug." Bob really didn't want to do it. He just never thought Peter was that good or thought that he wasn't committed to the company--he was always in it for himself--but Bob agreed to do it. That was great--I didn't have to do it. Peter got up there and the employees clapped and he was happy, so it was all good. Now fifteen years later or something in the trial they ask me, "Well, when you guys celebrated the growth hormone approval, who was the one employee that got special recognition?"
Hughes
Did you have a chance to give the story you just gave me?
Goeddel
No, the lawyers don't let you. They said, "Who was it? Who did Genentech recognize?" Then you try to answer more, and they say, "No, that's it." Lawyers on a case like this where they had fifteen years to prepare are very good at finding every little possible thing, and then weaving it into a story that supports their case.
UC's Allegations Threaten to Block Genentech's Initial Public Offering
HughesI understand there were previous litigations in which this story had not come out.
Goeddel
There were previous ones. UC brought up stuff right when Genentech was trying to go public and tried to block the IPO. (If you sue someone when they're going public they can't do it.) There was a discussion, and Genentech gave some amount--I don't remember exactly--maybe $1 million to UCSF to settle this false claim. Well, the claim was that Seeburg and Ullrich had stolen materials from UCSF and brought them to Genentech. And they did bring stuff from there. That was normal, what people did when they left labs. I brought stuff from my graduate school and from SRI, just different reagents. So they brought stuff.
Heyneker and I remember when Bob said, "Yes, we're going to pay UCSF, get this out of the way. It's all done; they've signed off, and we can go public." Half of that money went to the inventors, and Heyneker and I were saying, "Why? That means Rutter and Goodman and these guys are all going to get $100,000 each. They didn't do anything. Why should they get Genentech money?" We were thinking $100,000 was really bad. And Bob, and I think Tom Kiley, said, "Well, that's how business works." We were pure scientists saying, "That is ridiculous! Better not to go public than to give them money for something they didn't do." That was supposed to be the end of it.
Further Comments on the UC-Genentech Case
GoeddelI think Seeburg's personal cut of the recent settlement of the UC case with Genentech was $17 million. Art Levinson told me that each of the five guys got $17 million. I also heard from one of Peter's friends, Karoly Nicoliks, who I knew because he was renting some space in our building, that the UCSF side did these practice trials where they'd have a jury come in or something and ask questions. One of the questions that Seeburg got asked to see how he would respond was, "For $20 million, wouldn't you be willing to lie about what you did?" And Peter said, "Of course." They had to stop and say, "No, no, that's not the right answer." [laughter]
The UCSF story was a bad story to come out in public so much later and just is so goofy and had nothing to do with who did what or what the inventions were. You have a jury that's composed of people off the street that don't understand any of the science, and the patent part's too confusing for them, so you make up some other stories that they can latch on to: That Genentech wasn't capable of cloning this, and I was a beginner, Peter had more experience, and it didn't matter what my record was, because of all these things were done later.
Hughes
How did you take all this?
Goeddel
I wasn't very happy during the trial and for a little while after. Some of the press stuff was ridiculous. I think that The Wall Street Journal did a good, solid job. The San Francisco Chronicle guy wrote something pretty stupid. He clearly just talked to the lawyer on the other side. Get over it, [Goeddel admonishes himself]. I got a lot of e-mails from people who said they know what Seeburg's like and what I'm like and don't worry about what the press says.
The first trial ended in a hung jury. Genentech did a lot of legal work and decided they should settle rather than going to trial again. It was going to keep dragging on. I really appreciated that Art Levinson called me and said, "If you want to just keep fighting it, we'll do it. It's better for the company to settle, but if you'd rather fight it--" I said, "Fine, I don't want to go to court again. I've got to run a company here. It took too much time the first time."
Goeddel's Views on UCSF Contributions to Growth Hormone Research
HughesDo you consider that UCSF made any contributions to the growth hormone project?
Goeddel
Only indirectly in that the work Seeburg and Shine and Goodman had done earlier showed what could be done on the cDNA cloning side. But they didn't have a clue about how to express or make a protein, absolutely none, just no idea. [pause] I think that's one of the reasons guys like Seeburg and Ullrich joined Genentech. We were way ahead of them in the design of things to make what you wanted to make. But a lot of the pioneering work in cDNA cloning had been done at UCSF.
Growth Hormone with Methionine
Hughes[pause] Tell me, please, the significance of growth hormone with and without methionine.
Goeddel
[pause] You have to put a methionine codon on to initiate translation. When we first made growth hormone, we didn't know if the bacteria would take the methionine off or not because some percentage of the normal proteins made in E. coli don't have a methionine there. Since they had to start with it, there must be a process for removing it. When we first analyzed what we made, some had met and some proportion didn't. I think more of it still had the met. Some of it was removed.
I guess we felt, probably incorrectly, at the time that one extra amino acid on 200, that's nothing. A lot of proteins have a met anyway. That's no big deal; it's just growth hormone. Then when clinical results started coming in years later we heard there was an antibody response developed against it in some of the patients taking the growth hormone. There were a lot of possible things you could imagine, but the easiest one was, maybe it's the methionine.
So our molecular biologists got together and had a meeting and said, "We have to figure out how to get around this." We had a big discussion and said, "Well, let's try to secrete it from E. coli hooked to a signal peptide that will get cleaved so there's no methionine. It will get cleaved and we'll make secreted growth hormone." Eventually that got accomplished and the antibody incidence was a lot lower. Still, some people got antibodies, but it's pretty obvious methionine played a big role in that. I think from then on we tried to make everything absolutely authentic with no extra amino acids.
Hughes
The antibody reaction caused a delay at the FDA, did it not?
Goeddel
I'm not sure it did or not, because the first growth hormone that got approved had the met on it.
I know that something slowed down approval.
Goeddel
There were results with antibodies. It may have got slowed down all along, but rather than start the whole process over, the new growth hormone molecule, the secreted one, followed along after the original one, and they both got approved.
UC and Genentech Compete to Publicize and Patent the Growth Hormone Work
HughesGetting back to the issue that we discussed in the insulin project, namely this announcement versus publication, I noticed that in the case of growth hormone you made a presentation of the results at a Miles symposium in Baltimore?
Goeddel
Yes.
Hughes
Genentech had made the announcement the day before. Why in that order?
Goeddel
I wish I could remember exactly what happened there. There were a lot of phone calls late at night. The Miles symposium was early July 1979, soon after the July 4th, weekend. I worked with Kiley by phone. I think on July 4th he filed the patent. Or maybe he wrote the patent, finished it up on the 4th, and filed it on the 5th.
Hughes
If it helps you, the Genentech announcement was on the 12th of July.
Goeddel
And what day was the Miles symposium?
Hughes
On the 13th.
Goeddel
So maybe the patent got filed on the 6th then, after the three-day weekend. I think what happened on the announcement, word had leaked to UCSF, and they were going to announce they had something. Because I remember some phone calls at night with--I can't remember who. It was Swanson, maybe Kiley, maybe Fred Middleton. It would be interesting to see if UCSF had an announcement.
Hughes
You're right. UCSF realized that Genentech was going to make an announcement and rushed its own announcement. [1] According to a medical news publication: "By a margin of only a few hours, Genentech was the first to go public with news of the bacterially synthesized hormone. It issued a press release [dated July 12, 1979] that, a day later, was followed by formal presentation of the firm's results by David V. Goeddel at a polypeptide symposium in Baltimore. Alerted to the Genentech disclosure by local newspaper reporters, the UCSF team--whose work was still in press for publication in Science this month--quickly issued a report of its own achievement." ("Rival Claims Staked Over Gene-spliced Growth Hormone," Medical World News, August 6, 1979, p. 20. Did anybody note that UCSF had made a fusion protein?
Goeddel
I don't think so. I think the UCSF guys figured out they shouldn't be talking to Ullrich and Seeburg, so I'm not sure how much information was available. But I was never in on the
Hughes
But did the rest of the world know that?
Goeddel
Yes, I think so. I think when our paper came out people slowly began to realize. That was the first designed, direct expression of a reasonably-sized protein. At that point, unlike now, Nature was the number one place to publish a paper, not Science. Ours was in Nature, the other one was in Science as a communication or something. Ours was a major article in Nature, and got a little separate editorial written up about it in Nature, too.
Hughes
By whom, do you remember?
Goeddel
Peter Newmark wrote up something. He'd been at the Miles symposium. He was the Nature editor, or the biological sciences editor. He'd heard my talk there. [pause] I think our paper was probably considered much more novel and breakthrough. UCSF had already published cDNA cloning, and now they had another step: they fused it to a protein.
Hughes
Did Newmark point that out?
Goeddel
I don't remember.
The Contract with KabiVitrum
HughesThe contract with Kabi, in contrast to the contract on insulin with Lilly, was signed, sealed, and delivered early on. It struck me as a bit unusual that a company would fund what at that point was close to basic science with no certainty that a product would emerge. Why would Kabi have taken that risk?
Goeddel
[pause] Well, we'd done insulin, so we'd proven we could do something. I think Bertil Åberg, the guy that did the deal with Swanson, probably believed we could do it. Swanson on all these agreements had a very clear time line he'd give the company. So Kabi probably had this information: We'll be at this stage here, here, here. It's not going to take that long. Do you want to be the one that works with Genentech and gets a recombinant drug? I think Bob could probably make it very attractive at that point after having done insulin and gotten the money there, having a deal with Lilly. I was not involved in any of that negotiation either, but that's what Bob would have been best at, convincing someone they'd better go with us or we're going to go with someone else.
The Impact of the Growth Hormone Work on Genentech's Future
HughesYou made a comment about the significance of the larger size of the growth hormone molecule. What was the impact of the insulin work versus the growth hormone work in terms of what this technology could do?
Goeddel
For me, growth hormone had a bigger impact. The fact that we did growth hormone and it worked the first time--you could directly express--all of a sudden made it seem like any gene was eventually going to be possible to express. That was my own personal view. So after growth hormone I was much more excited about the potential of Genentech and what could be done. Then I was convinced almost anything was doable.
Insulin you make in this huge protein, beta-gal, with a little piece of insulin on it. So the bacteria looks at it and just thinks its making beta-galactosidase. So there were all these unknowns: if you put a completely foreign protein in and had the bacteria churning it out, is it going to be able to do it? In retrospect, it should have worked. At that point, growth hormone was more of a surprise to me, I guess, than insulin. I still remember discussions with Kleid and Heyneker after we did it: "Wow, we can do anything now!" That was the breakthrough moment.
Hughes
UCSF had an arrangement with Lilly. Do you know anything about that, and was that a factor in what was happening at Genentech?
Goeddel
I don't know. They had some sort of deal with Lilly, we heard. Lilly was paying for some research, and I'm sure Swanson was concerned about things like that. But through at least '82, the way I worked was all my energy just on the science project, and I assumed other people would take care of the other things. I think it really helped me scientifically; I never got distracted by other issues. I wish I could do that now sometimes.
Hughes
[laughs] Well, you wouldn't be running a company, if that were the case. [pause]
You probably didn't have much to do with Kabi and the commercial development of growth hormone?
Goeddel
Even when there were meetings or reports we had to write, someone, probably Giuseppe Miozzari, would take care of them for me.
Hughes
Is the same true of the first clinical partnership, which I believe was set up for growth hormone?
Goeddel
Yes, same thing. It wasn't until interferon that I had to do these other things. I did that almost by choice: "Yes, sure, I'd rather run the project than have someone else run it." It became a big program.
Further Comment on Interferon
HughesWhy did you make that decision with interferon?
Goeddel
I felt that interferon was really mine.
##
Goeddel
When we originally decided to work on interferon, it was harder than any other of the projects, in my view. I also spent more time; it took longer to get there. It wasn't a six-month project like insulin and growth hormone were. It was a two-year project, or something like that. Then we were going to try to push it fast into the clinic, and I wanted to see how it'd work in the clinic, and I got the opportunity to run the project. It just seemed like the thing to do. I enjoyed it for a while, but after I was done with it I said, "Okay, I've done that once. I'm not sure I want to do it again. [laughter]
Hughes
And you didn't?
Goeddel
I did interferon gamma for a little while until I turned it over to someone else, but not for as long as I did the alpha interferon program with Roche.
Thoughts on Doing Science
HughesWhat is it in science that most turned you on?
Goeddel
Solving a difficult problem. That was always the most exciting. And if it was competitive that made it even better. You knew there were very good people out there trying to do the same thing. How you could measure how well you were doing is if you won. So the science was exciting, the potential to make drugs was exciting, and the day-to-day problem solving--figuring out how to do it was exciting. But it had to have the competition element, I think, to make it completely attractive to me.
Hughes
Well you had that.
Goeddel
Yes, there was good competition. And you kind of knew who it was, which was nice, too.
Hughes
The top people in the field in all those early Genentech projects, wasn't it?
Goeddel
Yes.
David Martin as Vice President of Research, 1983-1990
HughesWhat was the impact on the research enterprise at Genentech when Dave Martin came in as Vice President of Research, which I think was 1985?
I think he came in the beginning of 1983. Well, we needed someone, and we'd interviewed several people, and some that Bob wanted to hire that the rest of us didn't. Then there were a couple that we wanted to hire and wouldn't come. Then Martin came. I actually liked him a lot. I always thought he was quite good. It was clear we needed someone representing research on the management side, and we probably didn't have the right people to do it.
Hughes
Why couldn't you have done that?
Goeddel
Because I wanted to do science. I had zero interest in a job like that. I think Bob knew the company would be better off if I didn't have to manage everything. I never got offered it. There were other people fighting to try to get it. I talked to Bob about that. I said, "It shouldn't be one of those two guys that want it." He goes, "I agree, I agree." I think I was in a strong enough position if I had said, "I want this job," I would have had it. But I was just not interested at all.
It was kind of rough on Martin because before he came we cloned all these things, boom, boom, boom, right in a row that were going to become products, and there wasn't anything as obvious to do next. And he came in right then, and I think Swanson was expecting, okay, what's going to come out is going to even be better now, and it was a slower period for a little while. But Martin built up the biology very well so we were not just being a technical company that could solve technical problems, but start thinking about the broader picture--what do we need to work on next? Some people never liked him, but I always thought he was great.
The only thing Martin couldn't do well was focus. So when things came out of this biology, he was so interested in everything that he couldn't just say, "Okay, here's one we have to do; we're going to put enough people on it. And maybe this other project is second priority." He wanted to go after all of them. That was his weakness. But we should have had other people to prioritize.
Hughes
The biology was designed to explore areas that might eventually lead to a product for development?
Goeddel
Yes. He said, "We shouldn't focus around cloning," like we had. That was great then. "Let's focus around immunology, metabolic diseases, or biological areas. Then we apply the technology." And that was probably the right thing.
Hughes
Did he choose one of those areas?
Goeddel
He got us into a whole bunch of them, lots of things. He was a professor who'd seen the power of the technologies and said, "Wow, look what we can do!" And maybe he got too many things going.
Hughes
You and your scientific colleagues had been pretty much calling the shots up until then. Was it difficult to have more of a structure to what you were doing?
Goeddel
Some of them probably didn't like it. After insulin, I was almost never told what to do. You I could see what needed to be done and could chart my own way, and do it. So Martin didn't interfere with me really at all.
Goeddel as Director of Molecular Biology, 1980-1993, and Other Honors
GoeddelIn 1980 I took over as Director of Molecular Biology. I was probably a very poor administrative director for at least two years because I spent all my time in the lab. All I'd do for the guys that reported to me is give them a review once a year. But we didn't have weekly meetings or anything else. If they wanted to talk to me, they'd have to come stand at my bench when I was working there. I got more organized over time, but usually I didn't answer mail. I had the job because of my science, and they respected me enough that I didn't have to meet with them a lot or tell them what to do or organize them. So it worked out okay.
The department got up to about a hundred people, counting the lab heads and the people under them. Then there were had personnel issues. Then all these other things came up and ate into your time. So in about '86 or something I really didn't enjoy the Director of Molecular Biology job very much. I spent some time with Martin saying, "You've got to make this department smaller. I want a different structure. And that took some time. We went through a couple of iterations and finally found one that was good. I had just a few labs. I'd hire new, young scientists, get them going on an area, and then they would transfer to another department. So anytime a department would start to grow, an equal number of people would move out. Then it was good again.
Hughes
Did you still have that title, Director of Molecular Biology?
Goeddel
From '80 on I had that title. Then in '81 I was also made Staff Scientist, which was Swanson's way of rewarding me without becoming a manager. He sent out a memo to the company saying, "This is the highest position on the scientific track. It's equivalent to vice president for someone that chooses the management track." So I always got paid like an officer.
By '88, more Staff Scientists had crept in. For a few years it was pretty good; it was just the very best. Art Levinson became one. But then it deteriorated, I thought, and others agreed. We had about a dozen staff scientists, and each time a new one was added it probably took the standards down a little bit. In about '88 they called me a Genentech Fellow, which was a separate category. So even though I was a director, the fellow title recognized my science. It was a good honorary title, and it was just because I was the only one in the company that had it. I don't think it came with any extra pay or anything else. But the pay was always very good there. Swanson was very good at rewarding people on the basis of what they contributed, not what their title was.
Goeddel's Genentech Experience and Management of Tularik
HughesYour comments make me think of what could be a dilemma for successful companies such as Genentech, in that success usually means more employees, more complication, also more dilution of the culture, which in Genentech's case in those early day, was very distinctive. Now you're directing a company which either has or may soon have similar problems. How do you keep that entrepreneurial, turn-on-a-dime outlook and combine that with commercial success?
I think my Genentech experience influences a lot of things. Most of the time I was there I wasn't thinking I was going to have a new company. But I was always thinking about everything that happened, "How could this have been done better?" There are a lot of things Genentech did very well that I remember and try to incorporate here, and there are things that I think it didn't do well. As soon as some similar issue comes up I say, "We're not doing it that way. I've already seen it fail that way."
I remember talking with Art Levinson about it when Genentech was about a hundred people, and a big number of them--twenty, thirty, forty--that you could replace, and it'd have no impact on the company. Maybe if you just got rid of them, the good people would do even better. How do you keep only the good ones for as long as possible? So that's always been a goal here at Tularik to continually reevaluate people and groups and have the same high standards across the company, and try to build that into the culture, that everyone in the company has to be a contributor. We're at almost 400 now, and I think we're pretty close to 100 percent contributors. People see what they do, and if they don't contribute they don't feel good about being here, and they're either leaving on their own or they're asked to. But at some size it becomes impossible.
Genentech and Tularik Cultures
GoeddelGenentech was the first company in the industry, and being there from the beginning and going through everything, I saw a lot of mistakes that Genentech had time to make because they were the only company. They were in the lead. They could make the mistake, correct it. Now you don't have the time to make so many mistakes. But the culture's very different here than it was there. Cultures happen on their own based on the time and on people who are there early on. I don't think you can ever recreate one that's just like some other one.
Hughes
How would you differentiate the cultures?
Goeddel
[pause] Tularik is more serious, focused. In the early days Genentech was really wild, crazy, practical joking, and outrageous things--stuff that you couldn't do now; you'd be in jail or something. There are so many rules and regulations now on what's allowed and what's not, and how you interview people--everything. Genentech early on was a completely wild place. It was part of the excitement of being there. Young people doing breakthrough science and at the same time having real fun. The practical joking got to pretty high extremes in some cases that just couldn't happen now. It couldn't happen at Genentech now--paint someone's car or smash it or put fake memos about them out. You're probably going to get fired if you do stuff like that.
Hughes
From what I understand, you had something to do with those forays.
Goeddel
Yes, I had a great time with it. There were plenty of other people, too. Everyone trying to outdo everyone else.
Hughes
Competition once again, right?
Goeddel
Yes.
Do people at Tularik have fun?
Goeddel
Yes, but I think it's in a different way. It's focused on getting the science. And they probably have more of a life outside of the company. Probably only at the very beginning of an industry do you have the kind of work that some of us did at Genentech early on, where you're there all the time and it's the only thing you're doing. The entire industry is at a different stage now. It's more mature. It's clear what you have to do. Some of the drugs take longer to get. You don't get these breakthroughs by one or two people working 120 hours a week. A whole team has to be integrated and working well together. The small-molecule drugs we get here at Tularik after the molecular biologists are done take a huge team of chemists and then pharmacologists. By the time we get a drug here at least fifty people have played a role, and probably a hundred or more. In the early days at Genentech one or two or three people could do the major amount of work to take an idea to the compound that was a drug.
Hughes
If you were a young scientist today, would you come to Tularik?
Goeddel
I would have come here when we started up, when it was small. I probably wouldn't come to a 400-person company. But I'd go to a place that had the very best science, and I think Tularik could qualify there. Probably up to the point where Tularik was sixty, eighty people or so, I would have been very attracted to go there. But now I'd probably go to a startup.
Hughes
Is there anything more you care to say?
Goeddel
No. I don't remember what I said [at the earlier interviews]. [laughter]
Hughes
Well, that's all at the moment. Thank you.
Transcribed by: Jessica Ross Stern
Final Typed by: Julie Allen & Kathy Zvanovec-Higbee
Appendix
Tape Guide--David Goeddel
Interview 1: August 1, 2001
Interview 2: August 23, 2001
Interview 3: September 12, 2001
Interview 4: October 18, 2001
Interview 5: January 15, 2002
Index--David Goeddel
- Abbott, 78-79, 85
- Åberg, Bertil, 136
- Aguet, Michel, 100
- Alberts, Bruce, 8
- Alpha Laval, 63
- American Type Culture Collection, 79
- Amgen, 24, 83, 84, 106
- Bachman, Keith, 24
- Bernstiel, Max, 56
- Betlach, Mary, 24
- Blech, David, 95
- Biogen, 31, 33-34, 42, 48, 59, 61, 81
- Bishop, Mike, 60
- Boehringer Ingelheim, 37, 40, 55
- Bolivar, Paco, 24, 117
- Botstein, David, 61, 62, 79, 87, 89
- Boyer, Herb/Boyer lab, 8, 17, 18, 21-22, 23, 24, 29, 49, 51, 61, 63, 88, 93, 111, 117, 119, 122-123, 125
- Brown, Michael S., 110
- Burnett, Paul, 126
- Burns, John, 36
- Byrnes, Bob, 64-65, 70, 127
- Cancer Research Institute, Vienna, 55-56
- Cantell, Kari, 31-32
- Capon, Dan, 80, 81, 92
- Carlock, Sharon, 19
- Caruthers, Marvin/Caruthers lab, 6, 8-9, 10, 11, 12-14, 15
- Cell Genesis, 95
- Cetus, 42
- City of Hope Medical Center, 112, 117
- Cohen-Boyer recombinant DNA patents, 90, 118, 131
- Cohen, Stanley, 8, 42
- Collen, Desiré, 70, 71
- commercialization of science, 51-52
- Crea, Roberto, 25, 122, 130
- D'Andrade, Hugh, 48
- Derynck, Rick, 40
- DNA/cDNA cloning/cloners, 8, 10, 12, 14, 15, 16, 21, 25, 30, 31, 48, 49-50, 54-55, 116, 128, 139
- DNA/cDNA libraries, 14, 32, 33, 48
- DNA repair, 15, 16, 18
- DNA sequencing, 24-25, 116
- DNA synthesis/synthetic DNA, 8, 9-11, 12-13, 25, 34, 112, 114, 115, 128, 129, 130
- DNAX Institute of Molecular & Cellular Biology, 48, 126
- Drews, Jurgen, 82, 86
- Dupont Merck, 88
- Ebner, Martin, 104, 108
- Eli Lilly, 36, 47, 50, 91, 115-116, 120, 125-127, 136, 137
- Eliter, Sam, 88
- fermentation technology, 46
- Fiers, Walter, lab, 34, 40, 41, 42
- FIPCO model, 83, 84, 107
- Fluor, 63
- Food & Drug Administration, 72-73
- Fredrickson, Don, 60
- Genentech
- board of directors, 63-64
- cell culture systems, 68-69
- clinical partnerships, 44, 137
- corporate culture, 86, 141
- facilities, 19
- hiring committee, 58, 59
- Initial Public Offering, 56-57, 64, 133
- lab procedures/schedules, 22-28
- molecular biology department, 55, 59, 66-67, 69-70, 91, 132, 140
- patents/patenting, 30, 118-119, 135
- process science, 46
- product scale-up, 45-46
- publication, 24, 29-30, 48-49, 51, 52, 58, 80, 119-121, 132, 135-36
- publicity, 120-121, 124-125
- Scientific Resource Board, 61-62, 93
- Staff Scientist position, 140
- stock/stock options, 28-29, 56-57, 64, 65, 83
- vice president of research, 59, 86-89, 138-139
- Genentech projects/products
- DNase/Pulmozyme, 91, 92
- epidermal growth factor, 54
- factor VIII, 79-81, 91
- growth hormone, 32, 34, 43, 44, 73, 87, 91, 118, 125, 128-137
- hepatitis B, 68, 69, 74
- Herceptin, 89, 90
- insulin, 26, 36, 50-51, 63, 91, 106, 112-128, 129, 136, 137
- interferons, 30-42, 43, 44, 45-46, 57, 59, 65, 68, 69, 90, 91, 106, 125, 128, 129, 130, 137, 138
- monoclonal antibodies, 89
- serum albumin, 66
- somatostatin project, 17, 115
- thrombopoietin, 80, 100
- thymosin, 54, 128
- tPA, 28, 29-30, 45, 55, 56, 58, 69, 70-73, 75-76, 78, 79, 83, 87
- tumor necrosis factor, 54
- urokinase, 70, 71, 75, 78-79
- gene regulation, 108-110
- Genetics Institute, 14, 80
- Genetic Systems, 91
- Gilbert, Walter/Gilbert lab, 42, 114-115, 123, 128
- Goeddel, Alena, 99
- Goeddel, Barbara, 2, 4
- Goeddel, Cindy, 2
- Goeddel, Mitch, 2
- Goeddel, Peter, 2
- Gold, Larry, 7, 12
- Goldstein, Joseph L., 110
- Gomez, Ray, 87
- Goodman, Howard, 133, 134
- Gower, Jim, 98, 99, 100, 102
- Green, Pat, 24
- Grunenthal, 70
- Heidrich, Grant, 97, 98, 102
- Henner, Dennis, 62, 131
- Hewlett-Packard, 83
- Heyneker, Herb, 17, 18, 20, 22-23, 24, 25, 26, 28, 32, 35, 36, 41, 48, 50, 54, 60, 70, 71, 78-79, 100, 116, 117, 122, 128, 129-130, 132, 133, 136, 137
- Hirsch, David, 14
- Hitzeman, Ron, 39, 66, 68, 73
- Hoffmann-La Roche, 32-37, 39, 45, 47, 65, 82-83, 86, 96, 138
- Holmes, Bill, 78
- Hybritech, 91
- Institute for Molecular Pathology, Vienna, 56
- Itakura, Keiichi/Itakura lab, 10, 25, 112, 113, 115, 117, 118, 119, 130
- Johnson & Johnson, 127
- Johnson, Irv, 47, 126
- Kabi, 130, 136, 137
- Kanako, Yasanori, 104
- Khorana, Gobind/Khorana's lab, 7, 8, 10, 115
- Kiley, Tom, 29, 30, 56, 57, 59, 65-66, 88, 118, 132, 133, 135
- Kleid, Dennis, 15, 16, 17, 18, 19, 20, 25, 26, 27-28, 29, 49, 50-51, 112, 116, 117, 121-122, 124-125, 137
- Kleiner Perkins, 96
- Kohler, Georges, 90-91
- Kornberg, Arthur, 8
- lac operator/repressor research, 7, 9-11, 12, 13
- lambda bacteriophage research, 14
- Lawn, Dick, 14, 66, 81
- Lederberg, Joshua, 42
- Lerner, Irwin, 36
- Letsinger, Robert, 7
- Levin, Mark, 45, 95, 97, 98, 103
- Levine, Arnie, 60
- Levinson, Art, 39, 56, 57, 60, 62, 68, 69, 73-75, 77, 82, 87, 88, 89, 95, 99-100, 134, 140, 141
- Lilly & Co, Eli.
- See Eli Lilly
- Lin, Norm, 46
- Little, John, 15
- Lubrizol, 63
- Lynx, 88
- Lyon & Lyon, 118
- Maniatis, Tom, 14
- Marks, Paul, 103
- Martin, Dave, 55-56, 61, 86-89, 90, 92, 138-139, 140
- Mayfield Venture Capital, 95, 96, 97, 98, 103
- McCracken, Ed, 103
- McNight, Steve, 94-100, 102, 104, 111
- Middleton, Fred, 44, 124, 127, 135
- Millenium Pharmaceuticals, 103
- Milstein, Cesar, 90-91
- Miozzari, Giuseppe, 32, 129, 130, 137
- Monsanto, 47
- mountain climbing, 1, 2-3, 4-5, 6, 11, 15
- Murfin, Don, 63
- Nagata, Shigekazu, 40
- Narang, Saran, 10, 11, 115
- Newmark, Pater, 136
- Nicoliks, Caroly, 133
- NIH Guidelines for Recombinant DNA Research, 49
- Novo Nordisk, 128
- Packard, David, 63, 64, 83
- Palermo, Dan, 66
- patents/patenting, 30, 90-91, 116, 118-119, 135
- Pennica, Diane, 70, 71, 72
- Perkins, Tom, 63, 96, 117, 120, 127
- Pestka, Sidney, 34-35, 36
- Pfizer, 106
- pharmaceutical companies & biotechnology, 47, 126
- See also specific companies
- PharmaVision, 104
- plasmids, 24, 25
- protein/gene expression/expression systems, 21, 34, 36, 38, 43, 66, 67-68, 68-69, 73, 108-110, 123, 128, 134
- Ptashne, Mark/Ptashne lab, 14, 40
- Raab, Kirk, 61, 82, 84-86, 88, 96
- reagents, supplying, 46-47
- recombinant DNA, 12, 16, 30, 125-126
- recombinant DNA controversy, 49
- Riggs, Art, 10-11, 51, 79, 112, 113, 117, 118, 119, 120, 122
- Riggs-Itakura patent, 117
- Roche Institute, 34
- Ross, Mike, 59, 87
- Rutter, William, 39, 88, 133
- Salzer, Winston, 14
- Sarett, Lew, 60
- Schering-Plough, 34, 39, 48, 126
- Scolnick, Ed, 88
- Seeburg, Peter, 48, 129-134, 135
- Sevastopoulos, Costa, 45
- Shak, Steve, 92
- Sheehan, Brian, 19
- Shepard, Mike, 89
- Shine, John, 129, 134
- Silicon Graphics, 103
- Sjostrand, Peter, 103, 104
- Stanford Research Institute, 15, 17, 18-19, 112
- Snyderman, Ralph, 61, 87
- streptokinase, 75
- Svennilson, Peter, 103-104
- Swanson, Bob, 15, 16, 17-18, 19, 20-22, 24, 25, 26, 28, 32, 36, 41, 44, 48, 49, 50-51, 55, 56, 57, 59, 60, 61, 81-86, 88, 90, 95- 96, 100, 102, 103-104, 114, 115, 116, 117, 120, 122-123, 124-125, 127, 128, 129, 131, 132, 133, 135, 136, 137, 139
- Syntex, 48
- synthetic DNA.
- See DNA synthesis
- Taniguchi, Tadatsugu, 40
- Tjian, Robert, 93, 95, 97, 98, 99, 103, 111
- Tularik, 47, 52, 62, 65
- Ullrich, Axel, 25, 48, 90, 129, 133, 134, 135
- university-industry relationships, 16, 18, 59
- UCSF-Genentech growth hormone lawsuits 131-134
- UCSF insulin team, 115, 116
- Vagelos, Roy, 88
- Vapnek, Dan, 24
- Vehar, Gordon, 80, 81
- venture capital/capitalists, 95, 96
- Weissmann, Charles/Weissmann lab, 31, 33, 34, 40, 41, 42
- Wood, Bill, 80
- Wu, Ray, 10, 11, 115
- Yansura, Daniel, 9, 10, 13, 58, 116, 124
- Yelverton, Liz, 73
- Zimm, Bruno, 5-6
CV: Sally Smith Hughes
Graduated from the University of California, Berkeley, in 1963 with an A.B. degree in zoology, and from the University of California, San Francisco, in 1966 with an M.A. degree in anatomy. She received a Ph.D. degree in the history of science and medicine from the Royal Postgraduate Medical School, University of London, in 1972.
Postgraduate research histologist, the Cardiovascular Research Institute, University of California, San Francisco, 1966-1969; science historian for the History of Science and Technology Program, The Bancroft Library, 1978-1980.
Presently research historian and principal editor on medical and scientific topics for the Regional Oral History Office, University of California, Berkeley. Author of The Virus: A History of the Concept, Sally Smith Hughes is currently interviewing and writing in the fields of AIDS and molecular biology/biotechnology.
Courtesy of Regional Oral History Office, University of California, Berkeley,
http://content.cdlib.org/view?docId=kt467nb7wh&brand=oac4
Title: Scientist At Genentech, CEO At Tularik
By: Sally Smith Hughes
Date: 2001 and 2002
Contributing Institution: Regional Oral History Office, University of California, Berkeley,
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