Oral History Center, The Bancroft Library, University of California Berkeley

Oral History Center University of California The Bancroft Library Berkeley, California

Keith Robert Yamamoto, PhD

Politics, Ethics, and Transcription Regulation in the UCSF Biochemistry Department

Interviews conducted by Sally Smith Hughes, PhD in 1994 & 1995

Copyright © 2018 by The Regents of the University of California Oral History Center, The Bancroft Library, University of California Berkeley ii

Since 1954 the Oral History Center of the Bancroft Library, formerly the Regional Oral History Office, has been interviewing leading participants in or well-placed witnesses to major events in the development of Northern California, the West, and the nation. Oral History is a method of collecting historical information through tape-recorded interviews between a narrator with firsthand knowledge of historically significant events and a well-informed interviewer, with the goal of preserving substantive additions to the historical record. The tape recording is transcribed, lightly edited for continuity and clarity, and reviewed by the interviewee. The corrected manuscript is bound with photographs and illustrative materials and placed in The Bancroft Library at the University of California, Berkeley, and in other research collections for scholarly use. Because it is primary material, oral history is not intended to present the final, verified, or complete narrative of events. It is a spoken account, offered by the interviewee in response to questioning, and as such it is reflective, partisan, deeply involved, and irreplaceable.

All uses of this manuscript are covered by a legal agreement between The Regents of the University of California and Keith Yamamoto dated August 27, 2014. 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. Excerpts up to 1000 words from this interview may be quoted for publication without seeking permission as long as the use is non-commercial and properly cited.

Requests for permission to quote for publication should be addressed to The Bancroft Library, Head of Public Services, Mail Code 6000, University of California, Berkeley, 94720-6000, and should follow instructions available online at http://ucblib.link/OHC-rights.

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

Keith Robert Yamamoto, “Keith Yamamoto: Politics, Ethics, and Transcription Regulation in the UCSF Biochemistry Department, conducted by Sally Smith Hughes in 1994 & 1995, Oral History Center, The Bancroft Library, University of California, Berkeley, 2018.

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Keith Yamamoto, 1982 Photograph taken at Cold Spring Harbor by Herb Parsons Courtesy of the Cold Spring Harbor Laboratory Archives

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This oral history with Keith Yamamoto is one in a series documenting science and technology in Northern California. Its focus is Yamamoto’s years in the UCSF Department of Biochemistry which he joined in 1973 as a postdoc, rising to full professor in 1983. He recounts in detail his research on the glucocorticoid receptor and, more generally, on DNA transcription regulation. He was a first-hand witness to the invention and early application of recombinant DNA technology and the research breakthrough it represented as well as the public controversy it raised in the 1970s over its safety and commercialization. Yamamoto remains a persistent voice in issues pertaining to research ethics and responsibility in science. A second oral history recorded in 2014 chronicles his later career as UCSF Vice Chancellor for Research, Keith R. Yamamoto: UCSF Biochemist, Vice Chancellor for Research, and the Mission Bay Campus. A third oral history was recorded as part of the Sandler Foundation Project, Keith R. Yamamoto: The Sandler Foundation and the Program in Breakthrough Biomedical Research at UCSF. Oral History Center, The Bancroft Library, University of California Berkeley v

Table of Contents— Keith Yamamoto

Interview History by Sally Smith Hughes

Interview 1: September 26, 1994 1

Early Influences — The Internment of the Japanese during World War II — Parents and Sister — Religion — Family Values — Interest in Science — Undergraduate, Iowa State University, 1964-1968 — Research as an Undergraduate — Attraction to Molecular Biology

Interview 2: October 5, 1994 18

Graduate Student, Princeton University, 1968-1973: Assignment to Bruce Alberts' Laboratory — First Research Problem — Paper Presentation, Cold Spring Harbor — The Princeton Milieu — The Biochemistry Faculty — Interdisciplinary Tensions — Bruce Alberts — Choosing to Focus on Eukaryotes — Research on the Estrogen Receptor — Finding that the Estrogen Receptor Binds to DNA — Combining Scientific Approaches — Political Involvement: Campaign for Eugene McCarthy — Campaign for George McGovern — Alberts' Program in Science Education — The Dissertation Project — Detecting Specific Binding Sites for the Estrogen Receptor — Arthur Riggs' Discovery — Two Theoretical Papers — Fellow in Biochemistry, UCSF, 1973-1975 — Gordon M. Tomkins, M.D., Ph.D. — Research on the Glucocorticoid Receptor — The Tomkins Lab — Early Impressions of the Department — Scientific Communication

Interview 3: November 4, 1994 55

More on Postdoctoral Fellowship in Biochemistry at UCSF, 1973-1975 — The UCSF Department of Biochemistry — Faculty Recruitment — Decision to Emphasize the Basic Sciences at UCSF — Tensions — Biophysics — Biomathematics — Postdoc Factory — Postdoc Competition — Research Problem as a Postdoc — UCSF faculty member — Opinions about Cell — Order of Authorship — Different Understandings about Authorship — Pierre Chambon — Harold Varmus — Directing His Laboratory Group — — Less Time in the Lab — Science Manager — Institutional Context

Interview 4: November 14, 1994 79

Program in Biological Sciences as a Model for the Clinical Sciences — Role of Genetics at UCSF — Division of Genetics, Department of Biochemistry and Biophysics — Debate about the Campus Role of Human Genetics — Departmental Retreats — The Ralston Center Retreat, Mill Valley, ca.1976 — Early Asilomar Conferences — Current Asilomar Retreats — Social Occasions in the Department — Howard Goodman's Wine Gatherings — The Chelsea Pub — Spring and Halloween Parties — Departmental Camaraderie — Building a Departmental Reputation — Administrative Styles — Utilizing Joint Appointments — Comparing Biology at Berkeley, Stanford, and UCSF — Open versus Hierarchical Governance — The Collective Model — New Technology Oral History Center, The Bancroft Library, University of California Berkeley vi

Interview 5: November 28, 1994 101

The Recombinant DNA Controversy — Cohen-Boyer Experiments — Paul Berg's Experiments with SV40 — Hearing of Early Recombinant DNA Research — First Public Announcement of Recombinant DNA, June 1974 — The Asilomar Meeting, February 1975 — The Recombinant DNA Research Moratorium — Communicating Scientific Knowledge — NIH Recombinant DNA Guidelines — Threat of Federal and State Regulation — The pBR322 Plasmid Episode in the Race for Human Insulin— Possible Commercial Applications — The Scientific Process in the U.S. — The UCSF Biosafety Committee — Changes in Laboratory Safety Procedures — The UCSF P-3 Laboratory — The Public's Role in Science — Ownership of Ideas in Science

Interview 6: December 22, 1994 125

A Conversation with Gordon Tomkins — Personal Problems with Ownership: Gordon Ringold — Goal-oriented versus Open-ended Research — Competition — Issues around Distribution of Biological Materials — Publication and Public Domain — Authorship Claims — Requesting Information — Requesting Payment — More on Authorship — Ethics in Science — Research on DNA Transcription Regulation — Bacteriophage and Universality

Interview 7: January 24, 1995 154

DNA Binding Sites — Long-range and Combinatorial Regulation — Insertion Sequences — A Mechanism for Evolution — Allan Wilson — More on Transcription Regulation— The Binding Site — Discovery of Three Classes of Glucocorticoid Receptors — Cell- specific Gene Expression — Research in Yeast — Long-range Regulation as an Evolutionary Driving Force — Stories about Signaling — Steroid Molecules as Cholesterol Derivatives — The UCSF Collaborative Spirit

Interview 8: February 20, 1995 184

Controversy over the Commercialization of Academic Biology — Technology Transfer and Patenting at the University — Scientific Advisor to Tularik — More on Commercial Ties in the Biochemistry Department — More on the pBR322 Plasmid Episode

Interview 9: March 27, 1995 207

The UCSF Biomedical Resource Center — The Biochemistry Department’s Administrative Structure — Chairmanship Styles: Bill Rutter and Bruce Alberts — Dan Koshland and the Reorganization of Biology at Berkeley — The University’s Growing Leniency for Faculty Outside Commitments — Faculty Community Service — U.S. Military Use of Recombinant DNA Technology — Testimony on Biological Defense Research before the Senate Government Affairs Committee — Writing Scientific Papers — Science Journals and the Shaping of Science

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Interview 10: April 13, 1995 235

Determining Author Order on Science Publications — Graduate School as a Time to be Daring in Research — Issues as Editor of Science Journals — Misconduct in Science: The National Academy of Sciences Committee — Importance of Record Keeping in Science — More on the NAS Committee on Misconduct — Teaching Scientific Ethics — Yamamoto Lab Culture — Thoughts on a Life in Science

Tape Guide

Tape 1, Side A 1 Tape 1, Side B 10 Tape 2, Side A 18 Tape 2, Side B 28 Tape 3, Side A 38 Tape 3, Side B 47 Tape 4, Side A 55 Tape 4, Side B 64 Tape 5, Side A 72 Tape 5, Side B blank Tape 6, Side A 79 Tape 6, Side B 87 Tape 7, Side A 94 Tape 7, Side B blank Tape 8, Side A 101 Tape 8, Side B 109 Tape 9, Side A blank Tape 9, Side B blank Tape 10, Side A 117 Tape 10, Side B 124 Tape 11, Side A 125 Tape 11, Side B 133 Tape 12, Side A 142 Tape 12, Side B 150 Tape 13, Side A 154 Tape 13, Side B 163 Oral History Center, The Bancroft Library, University of California Berkeley viii

Tape 14, Side A 172 Tape 14, Side B 181 Tape 15, Side A 184 Tape 15, Side B 192 Tape 16, Side A 200 Tape 16, Side B blank Tape 17, Side A 207 Tape 17, Side B 216 Tape 18, Side A 224 Tape 18, Side B 233 Tape 19, Side A 235 Tape 19, Side B 243 Tape 20, Side A 252 Tape 20, Side B 261

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Interview History

Keith Yamamoto was interviewed at length in 1994-95 for a project on the UCSF Department of Biochemistry as it began its rise in the 1970s to a premier position in biochemistry. He tells in this richly informative oral history of the promising science, sometimes tumultuous culture, and internal and external political issues shaping the department from his arrival as a postdoctoral student in 1973 until his departure in 1994 to become chairman of the UCSF Department of Pharmacology. His abiding passion for basic science is transparent in his nuanced account of his career-long research on the glucocorticoid receptor and, more generally, DNA transcription and regulation. Thoughtful and articulate, he paints a picture of molecular and biochemical research at a time when new tools for investigations in cell and molecular biology were opening up exciting new avenues of research.

Yamamoto joined the department at a critical moment for biological research. Herbert Boyer, a UCSF microbiologist and Stanley Cohen, a Stanford geneticist, published in 1973 the first of three papers on what became known as recombinant DNA technology. The relatively simple procedure allowed for the first time the selection and reproduction (cloning) of specific DNA segments and genes. It was a breakthrough quickly recognized in biology worldwide. UCSF and Stanford garnered attention as leading sites for the application and refinement of the technology as well as providers of the required enzymes and plasmids. But not all the attention was favorable. The so-called Recombinant DNA Controversy about the safety and regulation of “gene splicing”, as it was colloquially called, engaged scientists, government officials, and the American public for the rest of the decade. A moratorium was placed on recombinant DNA research in 1975, halting experiments using the technology until research guidelines were worked out. After contentious debate, the first iteration of the NIH Guidelines for Recombinant DNA was in place by 1980, allowing most experimentation using the method to continue.

As Yamamoto explains in the following pages, for him the issue was not recombinant DNA’s safety that was of prime concern but rather efforts within the School of Medicine and at a few other universities to apply the technology commercially.1The movement to capitalize on its industrial potential by forming startup companies to manufacture recombinant pharmaceuticals and other products was a new phenomenon in academic biology. For Yamamoto it was a troubling one. He viewed commercial ventures at the time as a potential threat to the academic tradition in bioscience of unfettered basic research. (For alternate viewpoints, see the oral histories with Boyer and Rutter cited below.) Yamamoto describes his efforts to convince the biochemistry faculty of the pitfalls he perceived, particularly in deflecting students to industrially oriented research problems. His warnings fell largely on deaf ears. He claims herein that his fear was largely unjustified, helping to explain his decision some years later to consult for a biotechnology company formed by colleagues. Yet Yamamoto’s concern for fostering responsibility and ethical behavior in science continued as manifest in his publications and service on national committees on research ethics.

1 In 1976, Herbert W. Boyer co-founded Genentech. Five years later, William J. Rutter co- founded Chiron Corporation. For their views on the commercialization issue, see their oral histories by searching http://ucblib.link/OHC:

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Despite decades of my urging to review the interview transcripts, Yamamoto, frantically busy and prioritizing other responsibilities, never made the time to do so. As a result, this oral history stands without his additional comments and corrections. Text in brackets reflects my best effort at clarification. A second oral history, recorded in 2014, with Yamamoto as UCSF Vice Chancellor of Research chronicles his later career as university administrator and player on a national stage.

Sally Smith Hughes, PhD Historian of Science and Interviewer/Editor University of California, Berkeley Fall 2018

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Interview with Keith Yamamoto Location: Dr. Yamamoto's office, School of Medicine, University of California, San Francisco Interview 1: September 26, 1994 [begin tape 1, side A] Hughes: Let's start with your upbringing and early education.

Yamamoto: I was born in Des Moines, Iowa—it always appears in seminar introductions, and some people think that's very funny.

Hughes: Des Moines, Iowa, is funny to Californians.

Yamamoto: That's right. I grew up there, went to public schools in Des Moines, went to college thirty-five miles north of there, at Iowa State University [1964?- 1968]. I was interested in science from just about as early as I can remember.

Hughes: What intrigued you?

Yamamoto: I don't know. I think that my father influenced me strongly to be systematic in my thinking. I know that that's true. And so embedded in all of that came a respect for people that did that kind of thinking for a living. So there was a lot of esteem value placed on that sort of thing in my household, to pay attention to detail, think about things analytically.

It was also the case that I have an uncle who was training in biochemistry, but I don't recall that that had much influence on me. I didn't know him very well. He visited rarely. So the fact that I had a relative who was doing this business I actually don't recall having much influence.

Hughes: Training at what level?

Yamamoto: He's a Ph.D. I think he has a clinical biochemistry lab in Hollywood, does clinical lab tests, makes a lot of money.

Hughes: Still today not much interaction between the two of you?

Yamamoto: No. Very different.

Hughes: How did your father come to have this analytical approach?

Yamamoto: I don't know. His father was a successful dentist in San Francisco; he was born here. His mother was a famous flower arranger. I think I've heard that Oral History Center, The Bancroft Library, University of California Berkeley 2

she was the first female flower master in the history of Japan, or something. Being a master is the equivalent of being knighted. So she taught courses, taught flower arranging in the States. She was brought here at an early age, I think through the auspices of Better Homes and Gardens, which is published in Des Moines, which is the reason that we ended up there after the war.

I was born in 1946, after the war had ended. My parents moved there in large part, I think, because Better Homes had helped at this early stage when the Japanese were forced off the West Coast and into concentration camps. They had helped move some of the families, important family valuables, into storage in Des Moines. So the family ended up going there.

Hughes: Was it because of your grandmother's importance, or was this something Better Homes did for many families?

Yamamoto: It was the importance of her to Better Homes.

Hughes: Otherwise, you would have ended up in a concentration camp?

Yamamoto: Well, concentration camps were closed by the time I was born.

Hughes: But they could have been interned.

Yamamoto: Well, the family did end up there. They weren't given that option. They had one week to divest everything they owned. My father's family owned two houses, two cars, a lot of things.

Hughes: How did they feel about that?

Yamamoto: They don't talk about it. It's almost impossible to get my parents to talk about it. I've tried on and off several times. When I was growing up, I didn't have a clue about it, because they wouldn't talk about it. I heard about "camp," but to me, camp was Y camp and Boy Scout camp, and they didn't treat it any differently. And of course the internment wasn't taught in school at that time.

After I was grown and learned what camp was, I remember trying to get them to discuss it, and failing. They would always instead bring up friends that they had met there or a garden that they had planted or songs that they had sung. And I think that that is just, as far as I can see, very characteristic of that generation. I only came to even get a glimpse of understanding of it a few years ago. My parents lived for many years in Washington, D.C. They now live here. I have one sister here—whole family's here. Oral History Center, The Bancroft Library, University of California Berkeley 3

The Smithsonian had an exhibition on the internment of the Japanese from the West Coast. My mother and my father and I went. Of course, it must have been tremendously powerful for them. It was tremendously powerful for me, so think for them. There were some pictures of my grandmother there. And when we got home, we had, for something of that impact, a remarkably brief conversation about it. My father said something to me that finally gave me a little bit of insight about the whole thing, because I was puzzled about how such a thing could have happened.

I know that the Asian culture, the Japanese at that time, placed great value on being able to accommodate to your situation and overcome it, if it's a hard situation, and not to make big waves about it but simply in fact to defeat the problem. But this [internment] seemed extraordinary; this was quite different; this was a purely racist act. Germans were not being moved off the coast. And Japanese all went off to the camps.

My mother's family was in a camp, and her two brothers were fighting in the U.S. Army in western Europe. That's the 442nd, the most decorated unit. Her father was teaching Japanese to U.S. Naval Intelligence officers, and the rest of the family was in concentration camp.

My father said something that suddenly made sense to me, and that is that to those that were in camps, the main thing that they wanted to do was to prove to everyone that they were Americans just like the guys with the guns at the watch towers. And they were: they were born in the States; almost all of the younger people were born in the States, and had grown up here. This was their country. So what they wanted to do was to certainly show that they were like everyone else. So why, in that context, would they raise hell? It was very interesting.

Hughes: Do you have a feeling about why your parents did not want to talk about this? Was it self-protective, or were they trying to protect you?

Yamamoto: I think it was both. My family is, I think, like other families of that era of Japanese Americans. My parents were both born in 1915. They were born here. Both of their parents had come to the States at relatively early ages, so I'm a third generation American, and that's a long time. But the culture was strong; they lived in Japan Town here in San Francisco, and so the community was still very cohesive. There's not much emotional interchange. They're pretty closed down.

I regard my family as very tight-knit, but in a very atypical way. There are no demands for us all to be home for holidays or to get together in certain ways. I see them fairly often, but if I didn't see them for months on end, upon seeing my father, he would shake my hand in a very kind of casual Oral History Center, The Bancroft Library, University of California Berkeley 4

sort of way. There wasn't a lot of touching or hugging. That kind of emotionality was very much suppressed. And they're still that way. So for them not to talk about something was not— I was used to it. And that's just the way that they are.

The generation splits were very sharp at that period of time, as one can imagine, because of the stresses of the war. Some Japanese Americans who are a few years older than I am are extremely angry, very activist about this whole business. I met a woman on an airplane on the way back from Boston once, who was probably eight or nine years older than I am, who remembered growing up in the camps and was very angry. She brings her kids back to the site of the camp every year. She was really pissed off at me that I wasn't doing it.

So there's my parents not saying anything; there's that group, some of whom are real agitators; and there's my group, who are largely ignorant of the whole thing and have been kind of cut off from it. So there are these very sharply delineated generational splits over a few-year period.

Hughes: Is your sister older or younger?

Yamamoto: She's three years older, so we're pretty much the same. She happened to be born in the camps, but she was an infant when the camps ended. She doesn't remember anything about it.

Hughes: What does/did your father do?

Yamamoto: Did—he actually just retired. Finally got around to retiring.

Hughes: [laughs] What is he, seventy-nine?

Yamamoto: Yes. It's amazing. He was a very good photographer. At the time of the war, he was actively taking photographs and ended up getting the only photography job he could get when he went to Des Moines, which was in somebody's portrait studio. But he still took a lot of other kinds of his own photographs and has won lots of awards. Then he started at the Veterans Administration Hospital in Des Moines, and became chief of medical media there, and became well respected in his field. He was president of the Biological Photographers Association and on that board for years. He's a fellow of that society. Our family vacations were always comprised of getting in the car and driving to wherever the BPA convention was. [laughter] So I got to see those people.

He was chief of medical media at the Des Moines VA for many years and then went to the central office in Washington in 1970, which was Oral History Center, The Bancroft Library, University of California Berkeley 5

convenient for us, because I was in Princeton at the time. And then convenient after I came here because I've always gone to Washington. So he worked at the VA until just a couple of years ago, and they finally convinced him to retire, and then they moved back here.

Hughes: And your mother?

Yamamoto: My mother never worked, so she was always my mother. Did a terrific job of it. So they're still together, and things are going great. I see them often.

Hughes: And your sister?

Yamamoto: My sister, Judy, is three years older, and she has been through lots of different kinds of work incarnations. Right now she's an administrator for a big vehicle leasing and maintenance firm. A wonderfully social, vivacious person that again I love very much but we have very little in common.

The rest of my family's social focus is on the Presbyterian church, which is the way it was when I grew up. I was moderator of the youth group, blah de blah, the whole show. So their life very much focuses or revolves around, I should say, the church and its various religious and social and organizational incarnations. My dad has always been on the Board of Elders and running the show. My mother's always active in the various other sorts of groups.

So it's not that they're so tremendously devoutly religious, although I think they are, but that's not what really shows through in talking with them. It really is the other sorts of interactions that a church—any kind of social organization—spins off, and that's where a lot of their friends come from. A lot of other things that they do come from there. The same is true with my sister.

Hughes: And you and religion? What happened?

Yamamoto: When I was a senior in high school, I was on the state youth board of the Presbyterian church, and I organized a big meeting that I called, "Faith or Indoctrination," or something like that. And I decided that I didn't believe it. [laughter]

Hughes: You talked yourself out of it.

Yamamoto: Yes, exactly. So I stopped going to church when I went off to college. And absolutely typical of my parents—they must have been seriously Oral History Center, The Bancroft Library, University of California Berkeley 6

distressed by this—never once did they sit down and tell me I was making a big mistake.

Oh, I should tell you—this is important—that one of the most important principles in my family, which my father was and is tremendously strong about, is the recognition of responsibility as being one of the key organizing principles of one's life. And if you happen to be smart, then that means that you have extra responsibilities. If you are moderator of the youth group and you've agreed to do that, that's a nice honor, but it means that you have extra responsibilities, and it means that if something needs to be done on the Friday night that your high school is playing its cross- town rival, gee, that's how it goes. You accepted this responsibility.

So there weren't really rules in my house, even though my father is a very strong personality, and everyone knows what he thinks is the right thing to do. He didn't really lay down [rules]; he wasn't autocratic.

Hughes: But it nonetheless was transmitted.

Yamamoto: It was completely transparent in fact. [laughter] I can't remember why I started to tell you that. So that was a key thing in my life.

Hughes: Was politics important?

Yamamoto: In my household at that time? No. Politics wasn't discussed at the dinner table, but again I knew what my father thought was right. He was very much a Democrat. My mother liked Ike just because he was Ike. I think the closest I ever came to actually arousing my father's ire sufficiently to get him to do something autocratic and lay down a law was when I decided to join a fraternity in college. That just drove him crazy. I think he came very close to telling me I couldn't do it. Otherwise, he didn't do that.

Hughes: Why was that particularly offensive?

Yamamoto: It represented—and I agree with him now—an institutionalization of a social structure that is abhorrent to him because they exclude other people. And of course, obviously the fraternity that I joined didn't exclude me, but that doesn't mean that the social structure was not [exclusionary].

I actually knew from passing understanding of conversations at dinner and hearing him on the phone that he'd been invited to join a men's club in Des Moines when he got some award or won some photography prize or something and had decided not to do that because they had a clause against blacks. So I think that my joining a fraternity was just completely turning my back on that kind of ethic. Oral History Center, The Bancroft Library, University of California Berkeley 7

I felt I did a lot of good in that fraternity, and in the system as a whole. I changed a lot of things. I made [the acceptance process] not secret, and we changed a lot of the hazing stuff, and the service projects for the campus. My fraternity became the best scholastic fraternity on campus. I felt we did a lot of things, and I think that that was fine with him, but he really was bothered by my decision to do that. And I now agree with him. I don't know what I would have done differently if it was my son.

Hughes: You said that you have been interested in science all along. Was there anybody or any particular event that crystallized things and pointed you in certain directions?

Yamamoto: Yes. My father subscribes to an enormous number of magazines. I didn't know why, and now I do. If you came to my house, you would be amazed at how many magazines I have, and how few of them I read.

Hughes: On all kinds of subjects?

Yamamoto: I have them, man, I have them. I have the Atlantic and Harpers and New Yorker. That's a way to really torture yourself.

Hughes: Just keeping up with those three! [laughter] There's your feeling of responsibility going crazy.

Yamamoto: Especially the god-damned New Yorker. That's enough to kill you, lack of editing. And so there was always a lot of magazines. Scientific American was one of them. When I was in junior high school, an article came out by Francis Crick in 1960, maybe '61, about messenger RNA.2 He recounted how he had developed a theory that there must be messenger RNA. That is to say, there must be a molecule between the DNA coding the code itself and the protein. I found it absolutely fascinating.

At that time, I was interested in chemistry. When I read that article, I remember thinking, now, this is a really interesting version of chemistry, much more interesting than the kind of stuff that I'd been taught so far— how to synthesize a small molecule or how to classify molecules into different chemical groups. So I remember that very distinctly. I remember actually reading it, where I was in the house when I read the article. So that was kind of a galvanizing event.

Hughes: Had you had any biological background at that point?

2 F.H.C. Crick, L. Barrett, S. Brenner, J. Tobin-Watts. General nature of the genetic code for proteins. Nature 1961, 192:1227-1232. Oral History Center, The Bancroft Library, University of California Berkeley 8

Yamamoto: No, not at the molecular level. And so it wasn't a Eureka! thing. I didn't say, "Aha, now I know my life's destiny!" But it obviously had a strong impact on me. So I paid much more attention to that sort of thing and began to think maybe this is what I'd like to focus on.

Eventually, when I went off to Iowa State—I took this bold plunge to go thirty-five miles from home to go to college—I chose to major in biochemistry, even though I really didn't have much of a really good grip on what it was that a biochemist did when he came in in the morning. And at the same time, because when I was in high school I did a lot of social things, I was worried, because I was afflicted by the stereotypical image of scientists as sitting by themselves in a dark corner of a dank laboratory, pondering over some microscope and never talking to another soul. That seemed not so good to me. So I felt the tension about whether I wanted to go out [for biochemistry]—and of course all of it was born of ignorance. I didn't really know what a biochemist did anyway, and I obviously didn't really know that they sat by themselves in a corner and never spoke with another person, but I was carrying around these little stereotypes.

Hughes: There was nobody on the high school faculty who could help you with this sort of question?

Yamamoto: There probably was. I probably didn't avail myself of it.

When I was between fifth and sixth grade, I was pulled out as a candidate to go to a special class for gifted students, which would mean that I would have to leave the security of my grade school and go to a different school where there would be kids coming in from all over the city and joining this one class that they were going to have with a special teacher. I guess there was an experiment that was going on at Des Moines, because they had control groups that were also considered to be very gifted that would stay on their home turf mixed in with other kids.

So I remember my parents telling me that I had this possibility, so I fretted about it a lot, because when you're a sixth grader, you're finally at the top of the hill in your school. [laughter] But I went, had a wonderful time, and began even at that early stage, I remember, doing projects on weather and learning about different kinds of clouds, and how they formed, and all that sort of stuff. So I was interested in that sort of natural sciences sort of thing, but hadn't [forked] this way.

Then in high school, I was in the special science track that had this BS-CS biology program, which was an experimental biology program, which actually was extremely good. I was in the pilot program, so we had these loose-leaf [binders]—there was no textbook yet; they were just developing Oral History Center, The Bancroft Library, University of California Berkeley 9

it. I don't think that I made very good use of that. When I think back on the way that I was a student at that time, I just don't think that I was very scholarly about the way that I studied. I was a good student.

Hughes: Are you meaning that you didn't carry it further than the assignments?

Yamamoto: Yes. I didn't really avail myself of what could have been a more penetrating intellectual experience.

Hughes: Were others around you doing it?

Yamamoto: I don't know. That's a good question. I was aware that it was a pilot program; it was special, but I didn't feel like I got much or put much extra [effort into it].

Hughes: So there wasn't a lot of intellectual ferment amongst the students themselves?

Yamamoto: No, I did science fair projects, but they weren't very interesting. They were more show and tell than they were experiments. So I don't think I really extracted as much from that as perhaps was available. So I went through it all, and obviously it was influencing me, I'm sure, the whole time, but it wasn't something that clicked and I said, "Now I know what I'm going to do." I guess it was just kind of mulling along there.

Hughes: Was the decision to go to Iowa State largely because it was thirty-five miles away?

Yamamoto: I think so.

Hughes: Nothing to do with the caliber of the Department of Biochemistry?

Yamamoto: No. I don't know whether it was because my parents didn't know that it was important to start really prepping me to get ready to go off and do this sort of thing or whether it was because they consciously were letting me find my own pace. But I finally got around to writing off for [college application] materials from various places. I don't remember them ever saying, "Hey, why don't you get it in gear and get some of this figured out? Let's sit down and look at catalogues and figure out what you're going to do." It was a whole different scene then.

And of course being in public school at that time was not like being in public school now. You went to your school. There was no fighting to get Oral History Center, The Bancroft Library, University of California Berkeley 10

into Lowell3, which is where my father went to high school by the way. So you just went off and you did your thing. Education was much more passive than it is now, where kids have to fight to get into preschool. It was just, you're in this grade, you're in this neighborhood, go to that school. It was extraordinary that I would go out to some other neighborhood to go to school.

So when it came time to apply for college, I think I was quite late in the process. I applied to a few places around—MIT, Purdue—and I don't really know why I picked the places I applied. I'm sure there were conversations with counselors, but I don't remember this being a major sit down and slug it out and figure out what you're going to do. And yes, I think I went to Iowa State because it was close. I got a big scholarship to go there that paid for everything.

Yamamoto: And there, the advisor that I had was named Jack Horowitz. He was a very strong influence on me. He was an assistant professor. It was fall of '64, I entered. He had come from a postdoc at Columbia, big-time place. He'd worked for a famous guy named [Erwin] Chargaff, who is the guy who had recognized that G=C and A=T, but didn't really know what it meant, as [James] Watson always points out.4

Hughes: I'm sure Chargaff liked that. [irony]

Yamamoto: Oh, yes. [laughs] So it just felt like Jack really was an energetic young guy who really kind of knew what it took to make it in this business. And also an extremely kind, thoughtful person. I remember sitting down with him and my parents on the first day I was there. He kind of took me through the, "Oh, you have this special scholarship, congratulations, you're clearly going to do well, and we're glad to have you in this major." I was one of the few people, I think, that started in a major and finished in the same major. In fact, there were forty of us who started in biochemistry, and four of us finished. It was a relatively new undergraduate major, and most places didn't have that major at the time.

I was always told that the average Iowa State student changes major two or three times. The only time I came close to changing majors was my

3 A San Francisco public high school with high academic standards and admission requirements.

4 For discussion of the reasons why Chargaff allegedly missed the significance of base pairing, see: From biochemistry to molecular biology: DNA and the acculturated journey of the critic of science Erwin Chargaff. History and Philosophy of the Life Sciences 1980, 2(1):3-60. Oral History Center, The Bancroft Library, University of California Berkeley 11

sophomore year when I liked writing a lot, and I liked English a lot. I was taking a lot of English courses and some composition courses. I decided toward the end of my sophomore year that maybe I should change the major to English. That maybe is the only other time my father came close to saying no when I told him I was thinking about doing that. He probably had a long response, but I remember the short version of it was essentially, "And how do you propose to earn a living being an English major?"

Hughes: Was that argument convincing to you?

Yamamoto: It worried me. At the time, I was getting along well with the creative writing teacher I had, writing short stories, and I thought, this is fun; I want to do this. Much more social, much more interactive [than science]. See, I was still hung up on that. And I was doing a lot of social things obviously; I was in a fraternity after all. So that was important to me.

I think a lot of things that I did were based on my wanting to assimilate and fit in. Here I was, a Japanese American from Des Moines, very few of me around, at an age where kids are absolutely the most vulnerable to peer pressure, conformance pressure. I was immersed in a society where all of my peers' fathers had just come home from fighting the Japanese in the war. I think that I paid tremendous attention to just trying to be like everyone else. So I did everything to do that. I think it colored everything I did. I'm sure that it was a major influence on my joining a fraternity.

Hughes: Were there episodes of discrimination?

Yamamoto: Very occasionally, very minor. Nothing very striking. I've never had a date with an Asian woman in my life. It's amazing. My image of what was attractive to me was formed by what I was growing up in the middle of. So first of all, Asian women weren't available; they weren't around. But even when they were, it wasn't something— I had already bought the whole other program.

Hughes: Well, the early to mid-sixties, which is when you were at Iowa State—you graduated in 1966?

Yamamoto: No, I graduated in '68. So I was there from '64 to '68.

Hughes: That's a pretty interesting time in molecular biology. Was any of the excitement seeping down to the undergraduate level?

Yamamoto: Oh, yes. I started doing research, I guess at the end of my sophomore year.

Hughes: Was that somewhat unusual? Oral History Center, The Bancroft Library, University of California Berkeley 12

Yamamoto: Yes, it was pretty early.

Hughes: How did that come about?

Yamamoto: I guess I was doing well in the courses. I was never an extraordinary student; I was never a 4.0 student. I think my grade point average when I graduated was 3.6. It was okay. I couldn't have gotten in here [UCSF], and I wouldn't be able to now. I was always doing a lot of things, and I wasn't as intensely interested in performing well on a test as I was, I think, in trying to do a lot of things. So I was working in the lab, and doing a bunch of social stuff on campus, and doing well in courses, being on the dean's list most of the time. So the grades themselves were not all that important. I wanted to perform well, but I didn't feel like there was a drive for me to get all A's, because I just didn't work on that as much. Instead, I became quite attracted to working in the lab pretty early on.

So at the end of my sophomore year, I started in the summertime working in the laboratory and then just kind of continued. That was not with Jack Horowitz yet, but I ended up in my junior year working with Jack who was my original advisor and continued to be so. I worked there throughout the year. I had my little desk in the lab and then in the summertime would work full time.

Hughes: Was this on the same research project?

Yamamoto: Yes, it was related all the way through. I worked on a couple of different molecules, but I was working on translation. Jack worked on ribosomes and was interested in a topic that is now exceedingly timely, and that is what the role of the RNA molecule was in--[phone rings] protein molecules. At the time, of course, we all thought that RNA was the scaffolding on which the important stuff was operating. Looks like it's probably going to turn out to be the other way around. But he was very much interested in the RNA. So I was substituting the bases in the RNA with modified bases and trying to see what would happen to the performance of the ribosome.

I got to know that whole [scientific] culture well. I watched him get nervous about whether his papers or his abstracts would be accepted and be excited when they were, and watch him lecture his graduate students when he thought they weren't working hard enough, and would praise me if he thought I was, while I was doing all these other things.

Hughes: I don't think of Des Moines as being the hub of the universe. Was he nonetheless in the scientific circuit? Oral History Center, The Bancroft Library, University of California Berkeley 13

Yamamoto: Not really. He was at the level that most scientists are, which is that they send an abstract to the federation meeting and try to get in to be able to present their abstracts on the platform with a ten-minute talk rather than a poster. There's 11,000 people at the meeting. But to me, I didn't know the difference. If you go to a meeting in Atlantic City, New Jersey, that's a big deal.

Hughes: I was actually meaning in a broader sense than just getting papers accepted. Was he in touch with other labs working on ribosomes, for example?

Yamamoto: Yes.

Hughes: Was there a lot of communication with other groups?

Yamamoto: Yes. At the level that I understood, he was. He's still a working scientist, and I know him well and have a lot of regard and affection for him. He's not a major player, but his stuff is good, solid. It's right. It's kind of old- fashioned, but it's good. He had a network of people with whom he kept in touch. So we would hear about something he'd heard, gotten a letter usually rather than a phone call, or about a rumor that he'd heard that somebody had done something, or a method to do something better. There was a sense that there was a community to which he was connected, and I very much had that sense.

Hughes: Was this clicking with you in light of your previous worry about the isolated scientist with his microscope?

Yamamoto: Yes, I liked that. I liked that a lot. And this whole thing about going off to a big meeting and giving a talk in front of all these people, that seemed exciting. He was taking on this other aura, although until you mentioned it, I never thought about it that way. But that's true. I did identify with that and think, huh, this is exciting. You're not by yourself. Yes, that's a good point. I did get that impression from him. And that scientific progress represents a continuum which is born of communication.

Hughes: Yes, the whole thing is that.

Yamamoto: Yes, that's all there is. It's funny that I would have thought about it any other way, but I didn't know.

Hughes: Well, what more to say about Iowa State? Is there anything else formative? Oral History Center, The Bancroft Library, University of California Berkeley 14

Yamamoto: Gee, I don't think so. My first paper on my CV, which I guess you have, is with Jack Horowitz.5 And again, there was this sense of community, because the first author on that paper was someone that I only met when she came back to visit once. Her [work]—I think it was part of her master's thesis, I'm not sure—formed some of the primary experiments in there. My project was finishing up one little element of what she was doing.

Another secondary author on the paper was someone that I had worked directly with in the lab, so I knew him and where he'd gone. He'd gone off to the Air Force Academy. So I was beginning to get this sense of community. I'm glad you brought that up—I think it was a major part of what kept me going along in it [science?].

Hughes: Obviously by the end of the four years, you had made a commitment.

Yamamoto: Oh, yes.

Hughes: Had you entered with the idea of going to graduate school? Was this always a goal?

Yamamoto: I don't really know how to answer that question. I'm not absolutely sure that I thought that far. Again, I knew that my uncle was a Ph.D., so I knew what that was. It's kind of embarrassing, but all I can say is that I— everyone, but I included—was much more passive about education. Education was something that happened to me. When you were in seventh grade, one of the things that was going to happen next was that you were going to be in eighth grade. [laughter] Right? And so I was doing well. I was going to publish a paper as an undergraduate.

With Jack's help, I got one of these NSF [National Science Foundation] Undergraduate Research Participation awards when I was a senior. So obviously things were going well. And I had role models in front of me, because he had graduate students in his lab, some of whom I thought were really smart and some of whom I thought were complete idiots. I'm sure he did, too. So being able to see that spectrum made me know—I don't know how well I internalized it—that yes, I could do this [graduate work], and I should probably do this somewhere. Jack wanted me to go somewhere pretty good.

Hughes: Because he saw your ability?

5 J.L. Johnson, K.R. Yamamoto, P.O. Weislogel, J. Horowitz. Some properties of transfer ribonucleic acids from 5-fluorouracil-treated Escherichia coli. Biochemistry 1969, 8:1901-1908. Oral History Center, The Bancroft Library, University of California Berkeley 15

Yamamoto: Yes. So he had a big role.

Hughes: Did he point you in certain directions?

Yamamoto: Yes and no. By then I was reading the literature. I was amazed by the literature. I guess that's the other thing that actually made me realize that there was a huge community out there. For all I knew when I was starting out, Jack knew every other scientist. Like we think our parents know everything. And I was astonished to go to the library and start reading papers. The Journal of Molecular Biology—I'm an associate editor now— started in 1959 or 1960. The famous [Francois] Jacob and [Jacques] Monod paper in 1961 is in volume 3.6 So it was early on in the days of the Journal of Molecular Biology, and that was a bible.

When that would come every month, I would sit down and look at it, and I was amazed at the research that was in there. I remember looking at that thing every month and thinking, wow, this is really exciting, and it's amazing. Here's a group from Russia, here's a group from France, and they're all doing this stuff, and it's so impressive and interesting, and so powerful, this methodology. So that journal in particular I remember having a big influence on me, and realizing there was a huge community out there doing, thinking about these problems.

Hughes: Did you have any appreciation at that time of the potential of molecular biology as a discipline? Or were you even thinking molecular biology?

Yamamoto: Yes, I was thinking molecular biology. I was doing biochemistry, and when I was reading molecular biology, I was seeing how immensely powerful it was. That's what captivated me about that journal. I remember watching for that journal to show up among the others.

My first paper is published in Biochemistry. That's where Jack published. For all I know, he's never published a paper in JMB. So I don't think I appreciated where molecular biology was going to go, of course not. But I was really awe-struck by its power, what could be done. And that had a big influence on me.

Hughes: Now, when you say "what could be done," are you thinking in terms of conceptual breakthroughs, or are you thinking of the technology itself, or some combination thereof?

6 F. Jacob, J. Monod. Genetic regulation mechanisms in the synthesis of proteins. Journal of Molecular Biology 1961, 3:318-356. Oral History Center, The Bancroft Library, University of California Berkeley 16

Yamamoto: What I was thinking of at the time—I do remember this pretty distinctly— was that it was a substantial quantum leap, move, in the quality of both the questions and the answers from the biochemistry that I was doing. And that I could make a conclusion about my biochemical experiment, about the way that the fluorouracil substituted by this RNA would allow ribosome to assemble in my in vitro reaction. But if somebody asked me if that's what happened in the cell and how I would know that, then I would be stuck. Because at the time, I was fiddling around with magnesium concentrations and buffer concentrations.

And so if someone then said, "Well, is this what happens in the cell?" I would know that I didn't know, because I could change it in my test tube. So this molecular biology that allowed that bridge to be made, that combined the use of genetics and biochemical analysis in the way that it was doing, was really amazing to me. And it was opening up an understanding of genes that was incredibly exciting.

Oh, the other thing that amazed me as I was reading the literature was Cold Spring Harbor [Laboratory]. There were all these Cold Spring Harbor symposium volumes. The library at Iowa State had a row of red books like that [points to bookshelf]. I remember the first time I was reading a journal paper that led me off to Cold Spring Harbor. I didn't have a clue what Cold Spring Harbor was, not a clue. But I had to go to the library, find this thing, and there was this big row of red books.

So now there was another kind of dimension. Not only a lot of people out there, but now historical or temporal dimension of these books going back, way back. I didn't know where Cold Spring Harbor was. I don't remember even caring. I thought it was a peculiar name. And when I opened up those books, they were filled with amazing things. So I was suddenly beginning to realize I was really immersed in this huge continuum that represented a lot of people and a lot of years, looking at these questions, and that molecular biology was really an amazing force that was coming into play, or that I was finally learning about; I didn't really know which at the time.

Hughes: Well, the way you tell this, it sounds as though it were more a discovery that you made yourself; you weren't particularly getting this insight through the people in the laboratory.

Yamamoto: Yes, I know. Isn't that funny?

Hughes: I'm getting that they were more focused on strictly biochemical questions.

Yamamoto: Not only that, but my courses were that way, too. The courses were very traditionally taught. But I was taking graduate level—500-level courses, Oral History Center, The Bancroft Library, University of California Berkeley 17

so early graduate level courses—that made us go to the literature, so I had to go read these papers. But you're quite right again that what got me excited was my own discovery of these things. And I don't know whether it's because the courses weren't very well taught or I wasn't paying very much attention. [laughs] It could definitely be that!

Hughes: Was there perhaps a generational problem here? It's not of course impossible that biochemistry be perceived at that time to have natural tie- ins with molecular biology. Was the conceptual block due to the fact that that wasn't the faculty's background?

Yamamoto: Yes, that's right.

Hughes: I mean, it was not a natural thing for them to extend themselves in that particular direction.

Yamamoto: That's right. They were very classical biochemists, very much so. And when I began to think about graduate school, I know that I was gravitating toward the places and people that were doing exciting molecular biology. So unlike my applications to undergraduate school, in my applications to graduate school, I was much more paying attention to specific people that would be doing something very interesting, and it was on that basis that I began to choose where to look around.

Hughes: That's a good note to end on.

Oral History Center, The Bancroft Library, University of California Berkeley 18

Interview 2: October 5, 1994

[begin tape 2, side A]

Yamamoto: I had wanted to go to Princeton because of a guy named [N.] Sueoka who was doing genetics on bacillus. He was mapping genes by DNA transformation. He would move bacillus genes from one bacillus to another, and he had discovered he could see characteristics come out as a function of time, so he could tell which genes were linked to other genes.

So I applied to various schools around, and at each one—well, I guess it's not true that at each one I had a target person, but that was certainly who attracted my attention at Princeton. I didn't know anything about Princeton. And so I got accepted there, and I decided to go there. Biochemistry wasn't even a department at that time. It was a program about biochemical sciences within the chemistry department.

Hughes: I noticed your Ph.D. was in the biochemical sciences, as opposed to biochemistry. What is the significance there?

Yamamoto: Well, it just meant that [the discipline] was just beginning to grow. While I was there, it became a department while I was a student.

Hughes: But biochemical sciences per se? Was there some distinction made between that and biochemistry?

Yamamoto: There was a biology department down the street that was at odds with biochemical sciences. Are you going to talk to Bruce [Alberts]?

Hughes: I hope so. He's on my list of future interviewees.

Yamamoto: He was on the faculty in biochemical sciences. He would know a lot about this.

Princeton had offered the option of going there the summer before classes started. They would just assign me to a scientist, to a laboratory to work in for the summer, just to kind of get the lay of the land, what the place was like, where the pipettes are, and where the grocery store is. And gee, that seemed like a good idea, so I did that. So after I graduated from Iowa State, I stayed a couple of weeks to finish up the work I was doing in the lab and then climbed into my car and drove to Princeton.

Hughes: Was your summer research going to be an extension of what you had been doing at Iowa State? Oral History Center, The Bancroft Library, University of California Berkeley 19

Yamamoto: Unrelated, except it was still in bacteria—bacterial genetics instead of the biochemistry I was doing before. So it was quite different. I think I mentioned before that I was really captivated by the Journal of Molecular Biology.

Hughes: Right.

Yamamoto: And this was the kind of stuff that was appearing in that journal, and I thought it was just amazing, and so I wanted to do something like that. But other than that, I think I was quite naive. I don't think I really understood how powerful [molecular biology] could be or what all the implications of it were. But it seemed exciting and interesting, and it seemed that there was an endless number of things that could be tried, although I don't think I could have reeled them off if somebody challenged me to. So I just got in the car and I drove out there.

Unfortunately, I arrived at Princeton on graduation day, so I couldn't find any place to stay—typical pre-planning on my part. [laughter] But I finally did. Then I went and met the chairman of the department, Charles Gilbert, and he assigned me to work in this guy's lab, Bruce Alberts, who I'd never heard of. He was a young assistant professor. This was June of '68, and I think that Bruce had started as an assistant professor in '65 or '66.

Hughes: So it made no difference to Gilbert that you had really come to Princeton to be in a different lab? Had you told him that?

Yamamoto: No. I don't think I would have told him that; I don't remember if I told him that. But the idea was not that they would park you in a lab where you wanted to work; they just wanted you to work, to broaden your ecumenical approach to science, and this was their first shot at me. They had a rotation program like ours, or we have one like theirs now, whereby one worked in a couple of laboratories in your first year [as a graduate student], so this would give you just another lab to be working in.

And I think it was a very good idea of theirs—I don't know if it was an idea of theirs [originally]—to assign people to young faculty that we, the students, might not otherwise have heard of and certainly would not have chosen. So I didn't know who Bruce Alberts was; didn't have a clue, never heard of him. But, okay.

I think you're right: I think I remember being a little bit disappointed that I wasn't going to Sueoka, but I think I was too shy to say anything. I'm quite certain I didn't say anything to Gilbert about it, because he wasn't the sort that would countenance such impertinence. Oral History Center, The Bancroft Library, University of California Berkeley 20

So I went off to meet Bruce. Bruce occupied this tiny laboratory in the chemistry building and had in his lab one technician and one graduate student. I think there were four lab benches total, and Bruce's office was across the hall in the lab of another assistant professor. That's really incredible, because in fact the way that Princeton was set up, these professors were really competing with each other, because they hired more [faculty members] than they were going to keep.

Hughes: And everybody knew it.

Yamamoto: Oh, yes, absolutely. Bruce seemed absolutely totally at ease with the whole thing, but there were other assistant professors that weren't, that's for sure.

So I met him, and he kind of told me what he was doing, and I vaguely understood it. I mean, really vaguely. He was working in DNA replication and bacteriophage. I had had to study some bacteriophage stuff in my undergraduate biochemistry course, but didn't really have a good grip on what phage did what, which different bacterial viruses would behave in certain ways. But he went through it with me.

Bruce had an idea of what he wanted me to do, which was to develop a method to isolate virus particles. So to do the biochemistry on the phage, you had to be able to make a lot of it, and making a lot of it at that time was a real pain.

Hughes: How did you do it?

Yamamoto: Bruce had an idea of how to do it, and he had already started doing some pilot experiments. I learned only later that he had an elegant notion of how to start new people off in the lab, which was to ask them to develop a technique. Not ask them to plunge into one of the projects of the laboratory, but develop a technique that if successful would help everyone in the lab, and if unsuccessful, would do the job of teaching you where the pipettes were.

Hughes: So the lab would get something out of it.

Yamamoto: Yes, right. So that's what he did with me. He showed me what he had done already using this [method]. The idea was quite interesting, which was to dump in this stuff called polyethylene glycol, which essentially played the function of taking up space in the aqueous solution. The bacteriophage are happy in water, but they're not happy in nonaqueous solutions. Polyethylene glycol is a long chain of hydrophobic molecules, so even when it's sitting in water, molecules don't like to be around it unless Oral History Center, The Bancroft Library, University of California Berkeley 21

they're hydrophobic. So essentially what it does is, it makes the water solution part smaller. What that does is to concentrate all those things that have to be in water into a small space, and as you do that, if you concentrate them enough, they come out of solution. So then you can just do a low-speed sedimentation, and they go to the bottom of the tube. That was the idea.

Hughes: So you're really treating viruses biochemically. I mean, you're treating them as particles.

Yamamoto: Yes. Exactly as particles. In fact, we showed later that once that [method] began to work, that we could isolate ribosomes this way, back to what I used to work on [in Iowa]. And any particle that liked to be in water would be volume excluded so you could sediment at low speed.

The problem before this method was developed was, [in order] to isolate bacteriophage in large amounts, because they're very small particles, required that you put them in an ultracentrifuge. And there weren't really high-capacity ultracentrifuge rotors at that time, and there still aren't high- capacity ultracentrifuge rotors that will handle anything like the volumes that we needed to handle, which was liters of solution. So here you could just take a very low-speed centrifuge that wouldn't go around very fast and dump in a bunch of polyethylene glycol and spin the things, and the phage would come right out. There it was. I showed they were viable, and we wrote a paper.7 I guess it was my second paper. My first one was out at the lab at Iowa State.

Bruce was amazing. Not only was it his idea to begin with, so I was just kind of coming in and being his hands while he was doing other things that needed to be done. But he'd come in and we'd talk about what could be going on. He taught me a lot that way.

Hughes: So you had a lot of interaction with him?

Yamamoto: Yes, it was very nice.

And then he had applied to go to the phage meetings. There were meetings every summer—I think there still are—at Cold Spring Harbor, and he thought it would be nice to describe this work. So here was Cold Spring Harbor, the red books that I'd seen at Iowa State. I thought, wow! This is

7 K.R. Yamamoto, B.M. Alberts, R. Benzinger, L. Lawthorne, G. Treiber. Rapid bacteriophage sedimentation in the presence of polyethylene glycol and its application to large scale virus purification. Virology 1970, 40:734-744. Oral History Center, The Bancroft Library, University of California Berkeley 22

amazing. And those meetings were in August [1968]. So in two months of working in the lab, with his help, I had made enough progress on the project that it was ready to talk about. Of course, he arranged for me to give a talk, not him. He wouldn't do that; it was my work. It wasn't my work really, but he said it was my work. So I hadn't even started graduate school yet, and here I was giving a talk at this place.

Hughes: And that was highly unusual, wasn't it?

Yamamoto: It was very unusual. It was Bruce; that's the way he is. So I practiced my little talk, and I gave it, and it was a big deal for me.

Hughes: Well, those are big-deal meetings, aren't they?

Yamamoto: Absolutely.

Hughes: The cream of the cream attended.

Yamamoto: Absolutely. So it was a big deal. And the method was very good. In fact, the method is still used.

Hughes: How was it received there?

Yamamoto: Very well. People liked it. Everyone knew Bruce, even at that time.

Hughes: And he introduced you?

Yamamoto: No, he didn't introduce me, but it wasn't hard for him to engineer it so I could give a talk. He was well known and well regarded. He wasn't the super big shot he is now, but he was well regarded at the time even though he was just an assistant professor.

So that's how my Princeton career got started, and of course it had a tremendous influence on how I felt about Bruce, as you can imagine.

Hughes: Yes, of course.

Yamamoto: Because a lot of other things about Princeton were quite hierarchical. I can recount one story to underscore that, which is that during my first year, I took a course from Arthur Pardee, who is a great scientist, who actually did one of the classic experiments with Jacob and Monod in the late fifties that showed how gene transcriptional induction worked. So Pardee was a very famous scientist, and he was at Princeton, and he taught a course that I took in my first year. Oral History Center, The Bancroft Library, University of California Berkeley 23

After I took his course, he took me aside and suggested that I apply for an NSF fellowship, pre-doctorate fellowship. That was very nice, because I did okay in his course, but I didn't think I was spectacular. But he asked me if I had a fellowship and I said no, and he suggested that I apply for one. I thanked him, and I went back and I told Bruce. He said, "That sounds like a good idea." So I got the forms, and I went to Gilbert, the chairman, because I needed a letter from the chairman. Gilbert looked at me and he said, "Well, do you know who else of your peers has NSF support?" And actually I did, because one of my roommates and a couple of my friends [did]. They were the best people there. I said, "Yes," and I listed a couple of them. He said, "Well, do you think you measure up to them?" It was obvious it was a rhetorical question, so I just kind of slinked away and I never did apply for a fellowship.

Hughes: Was that his intention?

Yamamoto: I'm sure it was, absolutely.

Hughes: Why?

Yamamoto: I think he didn't think I was good enough. Bruce said he thought that it was because I got a B+ in his course. [laughter] In fact, years later when I got a job offer at Princeton, Bruce recommended against my taking it because he said that Charlie Gilbert would always treat me like a B+ student. [laughter]

So a lot of things were quite hard and stiff about Princeton. It was a nice place, but it was a little town, and it was a small department, or fledgling department actually. So to have someone like Bruce, who is unique anywhere, being Bruce in that milieu was quite amazing. He was always like he is now, as far as I can tell. Just a remarkable person. So that changed the nature of my rotations, and I never really did get around to rotating to Sueoka.

I rotated with Jack Fresco [sp?] who, when Bruce was a graduate student at Harvard, had been a postdoc in the lab where Bruce worked, and had kind of been Bruce's student so to speak, and had I think been extremely influential, if not the key person, in bringing Bruce to Princeton. I'm not sure about that; Bruce would have to tell you, but that was my impression. It's the impression that Jack gave to [me] and a couple of other people I rotated with. Then I acted like I was vacillating, and then I went to Bruce's lab.

Hughes: Biochemistry was a division? Oral History Center, The Bancroft Library, University of California Berkeley 24

Yamamoto: It was a program.

Hughes: A program in the Department of Chemistry?

Yamamoto: Yes.

Hughes: Was there much interaction between the chemists and the biochemists?

Yamamoto: Not apparently. I was a first-year student, and I didn't know any of the politics that was going on. But there wasn't much interaction with the chemists, as far as I could tell. Biochemistry was on its way to becoming a department; there was undoubtedly some funny stuff going on, but I never was aware of it.

Hughes: How forward-thinking was the group?

Yamamoto: That group became to my mind one of the greatest collections of young people that had been put together, and they all ended up leaving Princeton because of the way they were treated by the administration.

Hughes: Meaning what?

Yamamoto: Just lack of support, non-promotions, and that Princeton seemed to just treat them like: well, if you guys leave, it's no big deal, we'll just get more. And they had in their hands some of the good people who are really the great people now.

Hughes: Now, you're talking about postdocs or the faculty itself?

Yamamoto: The faculty. There are students who came out of that program who are now very, very well regarded, and some postdocs as well. So I didn't really recognize it at the time, because you're in the middle of what you're in the middle of, but it was a tremendous collection of people. Princeton essentially lost it all. Now they've rebuilt some of it, and it's a good place again. But it was a really remarkable collection of young people that they hired and then lost, squandered. So it was an amazing environment, very rigorous, very interesting place to do science, it turns out. It was a very good place to be at that time.

Hughes: Was there communication and collaboration amongst the labs?

Yamamoto: It was pretty good. The biology building was down the hill, so it took a little effort to go running up and down there all the time. But people did it. There was clearly some political tension going on that then kind of exploded when the place imploded. But I was free of all that; I was just a Oral History Center, The Bancroft Library, University of California Berkeley 25

student, and I was having a good time. I thought the communication within the place was very good. I thought it was a very good environment.

But there was the old Ivy League hierarchy, and there were things wrong with it. Because Princeton was a small place that was kind of insular by default because it was in the middle of New Jersey and there's nothing else around, communication with the rest of the scientific community depended I think largely upon the seminar program, which brought people in, and how outgoing, social in a way, your advisor was. And Bruce was great, so people wanted to come and see Bruce, and so they did. So that's how we grew up. That was how his lab [group] was always being treated—somebody coming through that wanted to see Bruce.

Hughes: So it was a good place for networking as well as for science?

Yamamoto: Oh, yes. It was great.

Hughes: I'm thinking of the conversation we had off tape: the tension in that dialogue from Chargaff's book, Chargaff representing the classical biochemist conversing with the young upstart molecular biologist.8 Was there anything like that going on at Princeton?

Yamamoto: That's a very good question. I hadn't thought of it in that way, and I don't know how Bruce would answer that question. There was clearly tension between the molecular genetics types and the classical biochemists. The classical biochemists were very much in power, and the molecular geneticists were the younger people, or there were some old classic geneticist types who were doing molecular genetics who were not at the top of the power structure. And then there were classical biologists who were down in the biology building who were doing biochemistry, who we didn't regard very highly, even though some of them were terrific scientists, and that was a mistake on our part. So I think that tension was there.

Now, I don't know to what extent it was the Chargaffian struggle of a real judgment about the approach that one takes to asking questions. I don't know whether that was what was going on or if there were other political things that came into play. I wasn't sophisticated enough to understand what was going on there.

8 Erwin Chargaff. Amphisbaena. Essays on Nucleic Acids. Amsterdam: Elsevier Publishing Company, 1963, pp. 174-199. Oral History Center, The Bancroft Library, University of California Berkeley 26

So here was Bruce's lab, which was doing phage DNA replication, which is bacterial virus replication. Bruce graduated from Harvard and did a postdoc in Geneva, which at that time was a hot, a super-good, highly regarded molecular biology place.

Hughes: When was this?

Yamamoto: In the early and mid-sixties. And what did he do while he was there? He invented DNA cellulose. Did he do a lot of hot shit? No, he didn't do any of that; he invented DNA cellulose, which is just a way to glue DNA molecules onto a cellulose matrix so you can make a column and then dump things through and see what sticks to DNA.

He told us in the lab that during the time that he was there, [James] Watson came through. He had been one of Bruce's professors at Harvard. And on learning what Bruce was doing—I think this is an accurate depiction—told Bruce, "What are you doing wasting your time gluing DNA? Why don't you do something that fits this incredible environment that you're in? Quit being so stupid." And Bruce probably laughed, for all I know. He was not intimidated by that kind of treatment, or doesn't seem to be. So it meant that the people in his lab would then adopt projects that could use DNA cellulose to study a problem.

So once I had committed myself to going to that lab, I knew that that's what I was going to do. So I was casting about for problems to work on. I was already starting to think about working on eukaryotes instead of bacterial viruses.

Hughes: Why?

Yamamoto: I can't remember the answer to that question. Obviously things that I had read that year, but I can't remember if there was a trigger.

Hughes: There was nobody else in the program working with eukaryotes?

Yamamoto: Yes. There was a guy working with single-celled eukaryotes, Euglena, but not doing stuff that I was interested in. But most people were doing things with bacteria.

Hughes: You were reading about research on bacteria in the Journal of Molecular Biology?

Yamamoto: Yes, that was the hot stuff. And I don't actually remember what began to turn my attention [to eukaryotes]. But I remember that when I talked to Bruce about coming to his lab, I told him that, and absolutely Oral History Center, The Bancroft Library, University of California Berkeley 27

characteristic of Bruce, Bruce said, "Okay, let's find something." So I joined the lab without really having a clue what I was going to work on. But in a way, it was just complete confidence in Bruce. I hadn't thought about it that way, but I'm sure that's what was going on.

And then Bruce began to bring in problems that were bacterial because that's what he knew, that's what he had been working on. I was interested in gene expression even at that time, so I clearly wanted to work on that, and all the stuff with the lac operon had broken. That was being understood. I had read the paper by Jacob and Monod even when I was an undergraduate. And then the year before I started graduate school was the year that the Harvard groups of [Walter] Gilbert and [Mark] Ptashne had isolated the lambda lac repressor proteins and showed that they bind to DNA.9

So that was conceptually a very, very important thing. It said that the regulation was at the level of allowing DNA to be read out or not. So I was very excited about that, and it was very consistent with my being excited about reading [Francis] Crick's review, for example. I cannot tell you why I was interested in eukaryotes; I just don't remember.

Hughes: And that didn't faze Bruce at all?

Yamamoto: He seemed absolutely nonplussed by it.

Hughes: Even though that meant getting a whole new system started in the lab?

Yamamoto: Yes. In fact, I don't think I would be so kind about it if someone in my lab waltzed in [and suggested doing something like that]. Bruce is different. I think he's got, deservedly, a lot of self-confidence and figures he can do stuff.

Hughes: Do you think he would have said that to anybody, or did he size you up and figure you could handle it?

Yamamoto: I don't have a clue. But he started bringing in bacterial problems, and I was reading around and not doing very well at finding a eukaryote problem.

A lab at the NIH, Ira Pastan's lab, turned out a postdoc by the name of Harold Varmus. He had just shown that there was in bacteria a protein that

9 W. Gilbert, B. Muller-Hill. Isolation of the lac repressors. Proceedings of the National Academy of Sciences 1966, 56:1891-1898. Oral History Center, The Bancroft Library, University of California Berkeley 28

bound to cyclic AMP that genetically was acting at a site on the DNA and might be a transcription regulator, which is exactly what it is. So it turns out there's a cyclic AMP receptor protein in E. coli that is off of the DNA until cyclic AMP binds to it, or it binds to cyclic AMP. That's the small molecule signal that then tells this protein, okay, go find a place on DNA. It sits down next to certain genes, and at that time what it did was to activate them. Now we know that [other genes repress them?] It regulates transcription.

So at that time, all that was known from the Pastan lab was that there was a gene product that was involved in running the cyclic AMP response, which had been characterized in several labs before. So the lac paradigm was in place. We knew that there was a repressor protein that bound to lactose and that that interaction would change the binding of the repressor protein. Even though today, when I tell you this, it seems like a very small paradigm leap, it was at that time a substantial one to argue that the opposite thing could also happen. A small molecule could bind to a protein and cause it to bind to the DNA, instead of causing it to come off, and that that would turn a gene on instead of removing the block to gene expression.

Hughes: This is all about 1968?

Yamamoto: Yes, '68, '69. So Bruce came in with that paper and said, "Hey, I'll bet this protein binds to DNA and that cyclic AMP binding will change its capacity to bind to DNA." So you could take an extract of E. coli and either add cyclic AMP or not and put it through DNA cellulose columns and ask if the protein was there or not.

Yamamoto: Then Bruce came in with another paper a couple of months later, or a month later, day later—later—and it was about the estrogen receptor. A guy at Illinois named Jack Gorsky had done a very nice experiment and had shown that if one takes uterine cells from rat uterus, grinds them up, and adds radioactive estrogen, the estrogen binds to a protein in the cell as judged by doing sedimentation experiments. The protein would not be labeled by the hormone but would go into the gradient. Obviously the model was exactly the same, but this was a mammalian protein. Maybe estrogen binds to this protein and that makes it bind to DNA and that's how estrogen regulates gene expression. So now we're really talking. Oral History Center, The Bancroft Library, University of California Berkeley 29

So here was Bruce, this guy who worked on bacteriophage in the sixties. Anybody who worked in bacteriophage in the sixties must have looked at people who worked on rat uteri as being completely nonscientists.

Hughes: Because it was so complicated?

Yamamoto: Yes. You couldn't do anything interesting. But here he was saying, "Yes, here's a problem." It's amazing.

So I read these papers. We could really make the same model with the two. I honestly don't think he cared which one I worked on. So I decided to investigate the uterus [model] in more detail.

Bruce took me down to the biology building and found the guy that worked on some kind of endocrine stuff in rats, who taught me how to take a uterus out of a young female rat, and we began to do experiments. Grind them up, repeat this paper in PNAS, and then begin to ask if [the protein] would bind to DNA, if adding the hormone would make a difference.

Now, at that time, it was more complicated. I've simplified the story. There was a paradigm in the field that steroid receptors— It was shown the next year that they went from cytoplasm to the nucleus as consistent with that idea [clarify.] The notion in the field was that the receptors would bind to a chromosomal protein. It was clear that the DNA of eukaryotes was covered with protein, and I think it was largely felt that it was completely covered with protein, so that if any protein would bind to the chromosome, it would bind to the chromosome protein. So that was the model that we started with.

So I started working on the problem because Bruce encouraged me to do that. I played around, with tremendous failure but a lot of energy.

Hughes: What particularly was failing?

Yamamoto: Everything. I mean, I worked very hard, and everybody in Bruce's lab worked all the time. It was an incredible little community of students. We took real pride in just being there all the time, and on New Year's Day and Christmas Eve.

Hughes: Other labs weren't particularly doing that?

Yamamoto: No, not particularly. I think everybody at Princeton worked pretty hard, but I think our lab took special— It was quite a little collection of people. I Oral History Center, The Bancroft Library, University of California Berkeley 30

don't remember ever doing anything socially where I didn't end the evening by stopping at the lab.

Hughes: And you didn't mind?

Yamamoto: No. I was married by that time, and it was just part of our life. We always stopped at the lab. It was also part of my divorce. The lab dictated everything. So people were always hanging out there.

I was doing many experiments and trying many things. I was trying to figure out chromatin and trying to make columns in which the DNA on the column would mimic chromatin. I was stripping chromosomal proteins off of chromatin and trying to put them back carefully onto a DNA column, and then adding the receptor and seeing if that made a difference. That wasn't working.

The whole idea of biochemistry is to open up a cell and understand a reaction inside of the cell at the level of detail of being able to purify the components to homogeneity and put them together and get the reaction to work correctly. Then biochemically you can conclude that you understand it. Obviously, at the atomic level or genetically, you can't. So I was a biochemist, and so that's what I was trying to do.

I had an idea that removing all the chromosomal proteins and expecting to find magically the right conditions where they would go back on correctly was really not a good idea. So I was looking for ways to take them off in little pieces—changing the salt or using detergents. I was using a reagent, dextran sulfate, that I thought would work well.

Hughes: You thought it would work well because that was common knowledge?

Yamamoto: No, it wasn't common knowledge. Bruce had done some stuff with dextran sulfate when he was a student or postdoc and thought it would selectively remove chromosomal proteins, and I did some experiments showing that it was doing that. It would leave some. So what you want is not just something that removes half of all the proteins; you want something that removes all of one protein and leaves all of another protein behind— fractionation. It looked like it was doing that. It was leaving the histones and taking off the non-histone proteins. So that looked pretty good.

I spent a year filling up notebooks with dextran sulfate experiments, and then it slowly dawned on me that everything I was doing was a really bizarre artifact that would have been hard to just divine by reasoning. This is a terrible thing when this happens, when you have a year invested in Oral History Center, The Bancroft Library, University of California Berkeley 31

this, and you slowly begin to do experiments, and you realize that everything you've been doing is wrong.

Hughes: What clued you in that it was going wrong?

Yamamoto: I'm not sure I can even recover exactly what was going on. I was stripping chromatin with dextran sulfate, taking those fractions and putting them back on to DNA or not, adding the receptor to either the now protein- coated DNA or the naked DNA, and then putting those complexes through a gel permeation column which separates things on the basis of size. So the very biggest things can't fit into the holes of the gel, so they come through the column first. The very smallest things do fit into the holes of the gel, so they come through the column last because there's more things to go through. So the receptor protein was, according to this gel, a small molecule. That is, the holes of the gels were very big, and so the receptor proteins could go in but a DNA molecule could not. So the receptor protein would come off the column late, and a DNA molecule would come off the column early.

The experiment was simply to ask, if you coat the DNA with the right proteins, the proteins that the receptor cares about, it should now come through early, whereas with naked DNA it will still come through late. And it was working. It was working. I had dextran sulfate fractions that would make the receptor come through with the DNA, and I was very excited. I just was filling up notebooks with this stuff.

So the obligate control in such an experiment is to make sure that the residual dextran sulfate that's still around is not itself screwing up the receptor and somehow making it act like it was great big. So to think back: I isolate this chromatin from rat cells and then treat it with dextran sulfate and that strips off some of the proteins and leaves behind others. And then I take that stuff and then treat my pure DNA with that and let the things [proteins] go back on. And then I separate the stuff that's gone onto the DNA from the stuff that hasn't, and that should also take out the dextran sulfate because it's done as a function of size. So then you should have essentially just protein DNA complex and dextran sulfate and the non- bound proteins and all this other stuff should be gone. But there is probably some residual dextran sulfate, so you need to prove that a little bit of dextran sulfate isn't going to make all the receptor blob together that big, otherwise you're screwed. So I did those controls, and that worked fine.

While it was true that a little bit of dextran sulfate, much more than could have conceivably be still stuck to this complex, didn't do anything, it turned out that dextran sulfate stuck to those chromosomal proteins did do Oral History Center, The Bancroft Library, University of California Berkeley 32

that. So the receptor was aggregating, and it wasn't really bound to this protein. So it slowly experimentally dawned on me that this was all wrong.

Hughes: How did you feel?

Yamamoto: Terrible.

Hughes: That was a year of work.

Yamamoto: Terrible. I think Bruce felt worse. I don't know, maybe not, but I think he felt bad that he hadn't thought of anything that would— But it was such a bizarre artifact that there was no way one would have predicted such things. What I should have done was work out independent ways to ask whether the protein was really on the DNA or if it just happened to be running at this great big size, which is eventually how I figured it out.

Hughes: Yes, but that's so easy to say in retrospect.

Yamamoto: Yes, of course.

Hughes: Then what?

Yamamoto: Then came a break, which was that in the course of that next year— That must have been my third year in graduate school, so I hadn't published anything except that first phage paper. Actually, I don't remember that ever bothering me, to be honest with you.

Hughes: Was that a function of being associated with Bruce?

Yamamoto: I think there was a couple of things. One was that it was a function of being associated with Bruce, and the other was that people didn't publish as much then. It wasn't that big a deal. There wasn't this kind of freneticism about publishing. I wasn't worried about the publication, but I was worried about the fact that I just lost all this time.

I could show you the page out of my notebook—I had it somewhere in the office here, because I've shown students—the day that I did a different controlled experiment and did my DNA cellulose columns under much different conditions than I normally did.

Hughes: How did you pick the conditions?

Yamamoto: Why did I change?

Hughes: Yes. Oral History Center, The Bancroft Library, University of California Berkeley 33

Yamamoto: I changed because I no longer had to worry about all the funny business of keeping chromosomal proteins on. I was doing a controlled experiment, just naked DNA but under different binding conditions. I found the receptor bound just to the naked DNA. Now, that had to be an artifact, right, because the dogma said the receptor didn't bind to DNA; it binds to chromosomal proteins. There was lots of literature out there that said that. But it was very clear it was on. I remember writing in my notebook, because I just took it out a couple of years ago, that this must be an artifact, and I'd have to do a bunch of controls to show that. But isn't this interesting, and maybe I could use it in some way, blah blah blah.

So it turns out that is what it binds to; it binds to DNA. It doesn't bind to chromosomal protein. Actually, we know now there are proteins that are themselves bound to the DNA. But the key thing is that it recognizes DNA sequence and, just like the lac repressor and the cyclic AMP protein, it doesn't bind to chromosomal protein; it binds to DNA sequences.

So over the next year, I quickly did a series of experiments on DNA that showed that in fact, indeed, exactly consistent with the original model, estrogen greatly increased the capacity of this protein to bind to DNA, and that allowed us to create a model for how estrogen works. That was all very exciting, even though a lot of the field didn't believe it. They just thought DNA cellulose columns, what [do they have] to do with the cell?

Hughes: That would seem to me to be a common problem in selling biochemistry results.

Yamamoto: It is. And it's justifiable that it's a problem, that any biochemical experiment is subject to the question of biological relevance but provides the opportunity for doing highly mechanistic studies. And any genetic experiment is clearly biologically relevant but has the problem of having a very hard time making any firm conclusions about mechanism. So you really do need to put the two things together.

Bruce's lab was really biochemical. The phage replication arm of his lab used mutants, not made by him, but used mutants that were generated by the molecular genetics community that were defective for various aspects of DNA replication. What he was trying to do was very much apropos our conversation: use the genetic handle that others had generated to now do mechanistic studies in biochemistry.

Hughes: So there was a real understanding that these different approaches somehow had to be brought together in order to reach an explanation? Oral History Center, The Bancroft Library, University of California Berkeley 34

Yamamoto: I'm not clear how much of an understanding there was. I sensed that there was kind of a duality of thinking, so I'm sure that the insightful people understood it absolutely clearly.

Hughes: There's another strand; that's the structural.

Yamamoto: Yes, that's right.

Hughes: So these three strands were going along in parallel still?

Yamamoto: The MRC [Medical Research Council] lab was very much based on understanding function through structure. And there were people at Princeton who also bought that notion.

Hughes: But never the twain shall meet, to a degree?

Yamamoto: To a degree that was true.

Hughes: Is that because people do what they're trained to do and think how they're trained to think?

Yamamoto: Yes.

Hughes: And it's hard to make disciplinary leaps?

Yamamoto: At that time in biological research, the lines were sharply drawn between disciplines. So you were a geneticist or biochemist. You worked on E. coli, or a few people probably worked on yeast, not very many; or you worked on a whole organism, a mouse; or you worked on bacteriophage; you worked on nucleic acids, or you worked on membranes. And that was it, and that's what you did.

Now, it's just the opposite. But then, things were really separate. So that was the time when it actually made sense to have departments of physiology and departments of biochemistry and departments of genetics. Now, of course, it makes no sense. But at that time, it was very easy to know which department you should be in. So yes, it was a dichotomy. Why was I saying all that?

Hughes: Because I interrupted you with a question. [laughs]

Yamamoto: It was a good question. So I was taking you through these biochemical approaches. It's a constant battle to understand whether something [an experimental finding] means anything. And I was always afraid of that. Oral History Center, The Bancroft Library, University of California Berkeley 35

Hughes: So that was a concern of yours? You wanted it to mean something in terms of the living cell?

Yamamoto: Oh, yes. And so what I was trying to do was to correlate it. So I had a little handle. There's no rat genetics, right? That wasn't going to happen. So what could I do? I could correlate my biochemistry. I could show that when I added estrogen to this receptor—it was just an extract, but it had the receptor in it—that it now increased by more than an order of magnitude its probability of binding to DNA. That really fit with the idea that when you added estrogen to a rat, then the receptors that were out in the cytoplasm would end up in the nucleus.

Now, at the time there was other stuff going on. There was activation of nuclear localization capacity and a whole bunch of other stuff that we didn't even imagine existed. But in fact, DNA binding is one of the drives for moving these proteins into the nucleus.

So I took the biological observation as kind of a quasi-genetics. It was saying, see, I can make the receptor on my DNA cellulose columns act like it does inside the cell. And I wrote papers that essentially said that. So the whole DNA binding era began at that time, after the chromatin thing just collapsed under me.

Now, there's another subtext to this whole thing, and that is I began to get involved in politics.

Hughes: Yes, I want to hear.

Yamamoto: It is an important part of me, that's for sure. I first went to Princeton in June of '68, so that was a presidential election year. Eugene McCarthy was running for president. Bobby Kennedy jumped in; got killed. I was working for Gene McCarthy, literally slave work, handing out buttons and bumper stickers and leafletting in factories, just at that level. Going door to door. That was my first entre into straight party-type political action. The [Vietnam] war was going on.

Hughes: What prompted you to enter politics?

Yamamoto: It was the war. I got involved with the Princeton Peace Center, which had started up I don't know when, but it had just started up. It was almost in the backyard of my lab, so I would go over there and work, just doing peace stuff—organizing bus trips to Washington, peace rallies, and the whole thing. Oral History Center, The Bancroft Library, University of California Berkeley 36

In 1970, Nixon bombed Cambodia and Kent State students were killed. So a group sprang up right before the time of the bombing called Movement for a New Congress. It was a bunch of graduate and undergraduate students and faculty who were dedicated to trying to elect Democrats and to trying to stop the war. So I got involved in that, again beginning at a low level and then moving to an intermediate level.

During a Movement for a New Congress rally at the big gymnasium at Princeton—it was incredibly dramatic—somebody ran in with a note that said, "Four students have been killed at Kent State."

Hughes: What happened?

Yamamoto: It was just chaos for a while, and then we organized a march, and a lot of people went to Washington to protest this kind of behavior. The number of volunteers for the Movement for a New Congress, the number of volunteers jumped by an order of magnitude, literally overnight. We just fanned out on the East Coast, and I went to Connecticut and worked for six weeks for this guy named Joe Duffy, who was a Catholic priest running for a seat around New Haven. I worked in East Haven and West Haven and small industrial towns that surrounded New Haven.

I came back to Princeton to vote on election day and turned on the tube and CBS News projected Duffy getting beat. The guy who beat him was Lowell Weicker, probably one of the greatest people ever to serve in Congress, certainly one of the strongest friends science has ever had in Congress. I had never heard of Lowell Weicker; as far as I was concerned, he was obviously a killer of some sort. [laughter] But I was pretty engaged by then in trying to do something at the political level about the war.

Hughes: What was happening to your science?

Yamamoto: Well, again, this is typical Bruce. [laughs] There were two students in the lab, a guy named Glen Herrick, who was a year older than I was, a year ahead of me, [and me], and the draft lottery was still going. So we were very nervous about what our number was going to be. The war was in full bloom. Those were the days of body counts. We talked big about going to Canada or going to jail. I don't know what we would have done [if we'd been drafted]. I don't know what I would have done, that's for sure. We both ended up with low numbers, the 200s, so it was clear that we were going to be okay.

Activism at that level wasn't common, but it wasn't uncommon. Bruce was sympathetic. He never said anything to me about it. Oral History Center, The Bancroft Library, University of California Berkeley 37

Hughes: You say you worked for Joe Duffy for six weeks.

Yamamoto: Yes, I was up there a lot.

Hughes: You weren't checking your experiments on a daily basis?

Yamamoto: No. The last couple of weeks [before the election], I was there all the time. Before that, I was up and back a lot. I don't know. I don't remember what was going on in my [research].

Hughes: That must have been a big interruption.

Yamamoto: Yes, I'll say.

So by then, I was a known entity in the peace center and with other peaceys around. In '71 I started to work for McGovern, and quickly rose until I was coordinator of that campaign in that county. I had a lot to say about what was happening in central New Jersey and decided to take a leave of absence in my fourth year of graduate school, a critical time in graduate school. I asked Bruce what he would think about my doing that, and again typical Bruce said, "No problem. Go for it. This is important, and I know you really believe in it. Just do it." I said, "Okay," and—

Hughes: What precisely were you believing in?

Yamamoto: I mostly wanted to stop the war. I wasn't a big believer in American party politics, but I thought that McGovern had a chance to really say something that would make a difference.

Hughes: Did this have any tie-ins with what your parents had gone through?

Yamamoto: No, not a thing.

So my wife and I got very engaged in working in the McGovern campaign. She was a grammar school teacher in Princeton, so she couldn't put the hours in that I did, but she would come after work.

Hughes: Where did you meet?

Yamamoto: We had met in undergraduate school. That's an interesting story in its own right.

So Bruce said okay. I said, "Could you arrange to have my stipend shut off until I come back, and then I'll get it restarted?" Stipends at that time were $2,400 the first year, $2,600 for intermediate years, and $2,800 your final Oral History Center, The Bancroft Library, University of California Berkeley 38

year. And you know, Bruce never quite got around to shutting off my stipend. So we defrauded the government. I was on a training grant, and I always got paid. Got $225 a month.

I would ask people in the department to do things for me, to go leafletting or organize a little rally, or have a wine and cheese party at their house, or go to Trenton with me to talk to some Democratic machine guys. They were great. Princeton, of course, was an easy organizing base, but if you go outside of Princeton, it changes drastically. [laughter]

Hughes: Well, that's true of many universities.

Yamamoto: So I depended heavily on that base to help me get established. We gloated like crazy after we beat Humphrey in the primary, and of course they didn't forget that. So when we really tried to call the chips in at the end, they weren't there for us.

I was talking with people I probably never would have ever met in my life, lifetime Democratic machine guys from Trenton, upstate Essex County, who probably never wanted to lay eyes on me again, as far as they were concerned. Here was this guy from Princeton, after all, trying to run their lives. I mean, what would I know? I'm a kid. It was a great year actually. It was a tremendous experience.

Hughes: What difference did it make to you, being forced to move out of your natural social circle?

Yamamoto: I think it made a huge difference. The first couple of times I had to give political-type talks, I was terrified. I was nervous just giving a science talk, but at least I could go from slide to slide. [laughter] Organizing staff and getting them to work together and then giving talks to them about going out and doing various things—it had a huge influence on me.

Hughes: Was it an experience that you later pulled on?

Yamamoto: Oh, yes. It had a big impact. Also, the broadening experience of realizing that there were lots of people out there with lots of different concerns and points of view, who nevertheless shared many of the same concerns and problems, insecurities. And I really appreciated that for the first time. Princeton is disgustingly homogeneous, and New Jersey of course is not. I really actually didn't like Princeton very much. Even though it was a gorgeous and wonderfully comfortable place to be, it was just too stuck on itself. So I went to New York a lot. It was good experience, even though we got annihilated in the general election. But that was a good lesson for me, too, about how we acted after the primary, and how all those things Oral History Center, The Bancroft Library, University of California Berkeley 39

came home to roost. We were really swaggering around because we beat Humphrey soundly. But it's easy to win a primary if you're dedicated to organizing. It's very hard to win a general election.

Hughes: Bruce now is known for his teaching and his interest in science education. Were you seeing signs of that in him at that time?

Yamamoto: Yes, absolutely. Not just signs of it. I'm really glad you brought that up. When you talk to him, he will be able to tell you about things he did in Cambridge with respect to education when he was a student. But when he was an assistant professor, before he got tenure, and I absolutely know this, he somehow hooked up with a biology teacher or teachers in Trenton High School. He suggested to them that wouldn't it be interesting to bring the whole class to Princeton for a day during the summer when school was not in session, and that he would organize students and faculty to spend the day with these kids and show them how interesting biology is.

I didn't know all of that; all I knew is that one day he came into the lab and sat down with me and a couple of other people and said, "Wouldn't this be fun?" And we agreed that it would be because Bruce could always make things sound great. [laughter]

Hughes: He could sell anything.

Yamamoto: Yes. So we did agree, and it was fun. He got me and a couple of other students and a couple of the junior faculty [to participate in a program for high school students].

Arnie Levine was now the chairman of molecular biology at Princeton, who started as an assistant professor the same day that I started as a graduate student, and we were very good social friends as well. We still are. So Arnie got roped into all of that, and other people too. We developed experiments. I had some fun experiments of making DNA and growing bacteria. We had another experiment with photosynthesis that was fun.

We brought these kids up [to Princeton]. One of the messages that Bruce wanted us to make sure that we hammered on was to stay in school and finish school. We immediately encountered problems that I hadn't even known existed. I had these kids who weren't understanding how to follow the protocol for putting penicillin into half the culture because they didn't speak English; they couldn't read English. So that was pretty illuminating, but it was a great time, and I loved it. I just loved it. We gave them lunch, and we walked them around the campus. The kids grew up in the middle of Trenton, which is terrible, and here is Princeton, which is an Oral History Center, The Bancroft Library, University of California Berkeley 40

unbelievably beautiful place—the trees and pretty buildings, and then doing these experiments. They were fascinated by making DNA. I still am when DNA spools out on a glass rod.

So Bruce decided, this is really working; I'm going to apply for NSF [National Science Foundation] money. Here's Bruce, an assistant professor, doesn't have tenure, is supposed to be knifing his fellow assistant professors at every opportunity, thinking that he would apply for NSF support for this summer program. Gilbart told him, "You have a job here; I suggest you do it. Forget about the school kids at Trenton. Just become a successful faculty member at Princeton. That's your job. Don't go running off and applying for NSF money." Bruce didn't care; he did it anyway. I don't remember if he got it, but I think he got it. He can tell you that.

I'm almost positive that he had started some stuff when he was a graduate student at Cambridge. For me, when he started SPC here, it was absolutely no surprise. Completely in the pattern. So the fact that he's chosen that as a priority at the academy,10 for me, it's continuous. You probably didn't hear me introduce him at the lecture last year.

Hughes: The [Chauncey] Leake Lecture [May 27, 1994]?

Yamamoto: Yes.

Hughes: Yes, I heard it.

Yamamoto: So to me, that's the kind of continuum it was. It just follows. He does these little experiments, and when they work, he takes the successful elements and then moves up to the next thing. The key there is not that it's a little experiment, but that he always begins from the source. He doesn't try to figure out a way to establish power and then tell people down below what to do; he goes to those people and he starts working with them because he figures they're going to tell him best.

So that's his approach, and that's why he would start with a class of kids at Trenton, and then begin to move up to now the presidency of the [National Academy of Sciences], because he's talked to all these people. It would be the last thing that Bruce would adopt as an attitude and say, "Oh, good, I've finally made it to the top of the National Academy; I can finally tell these stupid people what to do and they won't be able to talk back to me anymore." That would never occur to him. He's quite a guy.

10 Bruce Alberts was president of the National Academy of Sciences from 1993 to 2005. Oral History Center, The Bancroft Library, University of California Berkeley 41

Hughes: We haven't talked specifically about the dissertation project.

Yamamoto: That's what worked. The dissertation project demonstrated that this estrogen receptor binds to DNA, that the presence of the hormone greatly increases its affinity for DNA, that when the hormone is there, it becomes potentiated for DNA binding. It was altering its molecular weight as if it was acquiring another subunit. That's still not fully understood, but I was probably seeing dimerization. I didn't know that then.

Once I had those results in hand—oh, yes, this is important. While I was off dilly-dallying with our friend McGovern, before I had started the leave of absence, I had done many experiments to begin to look for the specific sites at which the receptor bound. Other people weren't convinced by my experiments, but I was convinced, and I think Bruce was convinced that that's the way it was going to work: there would be sequences just like the lac operator that the receptor would bind to, and next to that sequence would be the genes that it was controlling.

And there was no way to find them at that time. There was no cloning. There was nothing. So I was simply doing experiments comparing mammalian DNA to bacterial DNA and looking for selected binding to the mammalian DNA that I could begin to chew down and look for its specific sites. I had done lots of experiments; complete failure so far.

While I was off spending my time with the Democratic party, an absolutely classic paper was published in 1972 in JMB by a fellow named Arthur Riggs from City of Hope [Medical Center]. Do you know Art?

Hughes: I know of him.11

Yamamoto: A very good guy. That paper, which was on lac repressor binding to DNA, told me why my experiments weren't working. It almost took me by the throat and said, "You idiot." All it said was that there's a thermodynamic problem, which I can explain to you very easily, and that is: the mammalian genome is made of three billion base pairs, as you know, and let's imagine that there was one site of twenty base pairs that the receptor bound to. Okay, so there's one site of twenty base pairs, so that means that there are three billion minus twenty that are the wrong site.

This reminds me of a funny story I have to tell you. This is about the nature of significant figures in science. Guy goes into a museum and is looking at a dinosaur skeleton, and he says, "My goodness, this is a wonderful skeleton." He goes to the curator of the museum and says,

11 Hughes later interviewed Riggs. Search oral history at http://ucblib.link/OHC Oral History Center, The Bancroft Library, University of California Berkeley 42

"How old is this skeleton?" The curator of the museum stiffens up proudly and says, "That dinosaur skeleton is ten million and three years old." Guy said, "That's pretty accurate. How do you know that?" Guy said, "We had the world's expert on dinosaurs come and look at that skeleton, and he said it was ten million years old. That was three years ago." [laughter]

So you have three billion minus twenty [which are the wrong site]. Now, thermodynamically, in order to see the one [binding site?] compared to the three billion minus twenty, the ratio of being able to pick out the right site has to be enormously huge in order to keep from getting swamped out by even a crummy affinity of binding to the three billion, because there's three billion more of them.

So what Riggs' paper showed, which was so elegant, was that the famous lac operator that we all knew and loved by then—as a graduate student, I grew up studying it—if he looked for it on all of E. coli DNA, which is much smaller than mammalian genome, he couldn't find it, and he showed why. And it's what I just told you: that yes, it's true that the lac repressor binds to the rest of DNA with a lousy affinity, but there's so much of it that you can't see this one little guy against this sea of other binding.

Man, that really made it clear I was wasting my time. So biochemically how did they see the lac operator? Well, the way they saw it was they by genetics put the lac operator onto a little ring of DNA, a little phage DNA. There was nothing fancy about the phage DNA. What the phage DNA was was the E. coli DNA minus 99 percent of the wrong sequences. And now the ratio was much more in its favor, and Riggs could see it. So the way they saw it was to compare a phage called phi 80 D lac, which was a phage called phi 80 that had the lac operon stuck on it with the normal phage DNA. Now they were comparing two small pieces of DNA, one of which had the lac operator, and they found it. He published this elegant paper in JMB documenting that up and down in ten different ways, and I realized that I was wasting my time.

Yamamoto: So I said to Bruce, "Oh, my god, what am I going to do now; I'll never graduate." So we ended up doing this very fun thing, which was to write a theoretical paper. We actually wrote a couple of theoretical papers, first of all, Art making that case and calculating how many specific binding sites could be hidden in the mammalian genome and you wouldn't even be able to see them. We showed that we couldn't see any difference between mammalian and non-mammalian DNA, and then we did a series of [theoretical] calculations that we published in, I think it was in Cell—Cell was just starting—showing that these sites could be hidden, cryptic, and Oral History Center, The Bancroft Library, University of California Berkeley 43

you wouldn't be able to see them.12 There was no other way at that time to do anything like that.

Hughes: Were people paying attention to this theoretical paper and the dissertation,13 which was more experimental?

Yamamoto: At that time? I don't know. When I came here [UCSF] for my postdoc, I had started already giving talks about the fact that we can't find specific binding and here's why. I know that that was not well received here.

Hughes: Why?

Yamamoto: Well, I came to work for Gordon Tomkins, who was working on the glucocorticoid receptor, and I chose that receptor for specific reasons, and I'll tell you when we move into the San Francisco phase. John Baxter was in his lab, and John was a very aggressive young man. We were competing with each other at the time. He was doing parallel experiments with [genome? at the same time I was in Princeton doing estrogen receptor experiments. We had somewhat different answers and very different interpretations of what things meant.

So when I joined Gordon's lab as a postdoc, when I gave my first kind of entry seminar, it resulted in a huge argument between me and Baxter. So they regarded my theoretical paper as kind of a capitulation, that I had tried to find specific binding sites and failed. So the paper was an excuse. Now, I don't know how the rest of the community looked at it, but I felt aggrieved here. [laughter]

Hughes: Are there any more loose strands in the Princeton story?

Yamamoto: There's one more thing I'll say about Princeton, and then we can start San Francisco. Oh, and I need also to tell you how I came to choose Gordon Tomkins, which as usual—you'll see the common thread here—will always come back to a Bruce Alberts story. He is the influential person in my scientific life. There is absolutely no one [else] that comes close.

The conclusion of the theoretical papers was that somehow one had to find the equivalent of a phi 80 D lac. That is, somehow one had to find a mammalian gene that was on a small piece of DNA—and that gene had to

12 K.R. Yamamoto, B.M. Alberts. The interaction of estradiol-receptor protein with the genome: an argument for the existence of undetected specific sites. Cell 1975, 4:301-310.

13 K.R. Yamamoto. In vitro studies on the estradiol receptor protein and its interaction with DNA. PhD dissertation, Princeton University, 1973. Oral History Center, The Bancroft Library, University of California Berkeley 44

be under hormonal control after all—in order to hope to find this right thing. There was no cloning, you remember, so that you couldn't just say, "Let's clone something." It didn't exist. So one had to just hope that that might happen.

So to jump ahead a tiny bit, when I came here, I wanted to write a fellowship to look for the mammalian version of phi 80 D lac. So all I could think of that would come close to that would be to look for a virus that by chance would have a hormonal responsive gene on it. Either Bruce or somebody else on the Princeton faculty advised me that that was a really bad idea for grantsmanship purposes because people would think it was just too flaky, that you're just going to get viruses and ask whether there happens to be [genes] under hormonal control? That wasn't science; that was just kind of cataloguing. And your chances of success are so ridiculously low that the fellowship would be laughed out of court. So I didn't write my fellowship on that, and I'll tell you in a minute what I did write it on.

But when I came here, I started as a very active side project just looking through viruses, because that's what I really wanted to do, not that I wasn't very engaged in what I was doing. But I spent a lot of my time chasing people down who knew virology—I wasn't an animal cell virologist at all—and finding other postdocs who came to San Francisco or virologists here in San Francisco, and getting them to teach me enough about their systems so that I could do an infection with their virus and then just ask whether adding hormones would do anything. So that was my little side project that I wasn't officially funded to do.

Hughes: Well, explain how you got from Princeton to UCSF.

Yamamoto: Okay. I'm afraid to say, this is another Bruce Alberts story.

Bruce went to a meeting in 1970. I don't remember what the meeting was; it might have been the genetics society meeting, and he met Gordon Tomkins.

Hughes: Who was here at UCSF?

Yamamoto: Who had just moved here from the NIH. Gordon moved in 1969. I knew Gordon Tomkins from the literature, but I didn't know him, never met him, never laid eyes on him. Bruce came back and he was very excited about this guy, and said, "This guy is really interesting. He's funny, imaginative, thoughtful, knowledgeable, and he's really great. You've got to meet him. Maybe you should go and do a postdoc with him." Oral History Center, The Bancroft Library, University of California Berkeley 45

Hughes: So going for the personality more than the science?

Yamamoto: Yes. That's a very good point, because the super-rigorous, hot-shit Princeton faculty mostly frowned on Gordon Tomkins' work. Gordon was not a rigorous scientist. He was an imaginative scientist; he was an eclectic visionary. But he didn't nail things down; he didn't really care about that. It's an important thing for us to know that there's lots of ways to contribute in this business [science]. Lots of ways not to, too, but there's not a single mold by which to make a major contribution. People like Gordon—there aren't many people like Gordon—play tremendously important roles.

Hughes: You mean by that that they catalyze the field and then other people come in and do the fine work?

Yamamoto: No, actually that's not what I mean, not in the way that I normally think of the statement you just made. There are people that flit about and do the first couple of experiments to get a field going and then leave. Gordon actually did not do that. He was very dedicated to studying hormones and endocrinology, but the experiments that he did were not quantitatively rigorous. He would have some wild idea and then begin to study it in ways that were not always considered to be careful.

I know that when I decided to come to Gordon Tomkins' lab that there were Princeton faculty who thought I was making a big mistake, and that here they had trained me to be careful, and now I was going to go work with this flaky guy in San Francisco. I know because a couple of them said things to me: "Don't lose your critical capacities when you go out there."

Hughes: Well, why did you do it?

Yamamoto: So Bruce was excited about the guy. I went off then to a couple of meetings and heard him give talks, and I was very excited. I met him; he visited at the lab once. He was incredibly exciting to talk to because he had this capacity to make anyone feel that their work, no matter how down in the dumps you were, was tremendously important, had endless potential, and he would just start thinking, free associating, things where it could be useful. Now, if you took literally what he said and ran off and started doing the experiments that he suggested, your career was over. [laughter] But if instead you kind of took the Gestalt and began thinking in this more open way about your problem, it was tremendously powerful. So first of all, he was a remarkably engaging human being, clearly brilliant, and very broad-ranging. Oral History Center, The Bancroft Library, University of California Berkeley 46

A little bit of background on Gordon: he graduated from UCLA in philosophy, went to Harvard Medical School, and played jazz saxophone with Charlie Barnett while he was in Boston. He then went to the NIH, organized as a still young man what has to be one of the greatest labs ever put together at the NIH, just tremendously good scientists. By [his] account [in] an amazing afternoon I spent with him, Gordon thought of experiments that were absolutely critical to what ended up being two Nobel prizes to other people, the genetic code and the allosteric notions of Jacob and Monod—a riveting day for me. And a remarkable sense of humor, absolutely amazing. French people told others, including me, that he spoke accentless French. He spoke French absolutely like a Frenchman, and he'd only learned it a few years before. When he died, he was learning to play the flute, and his flute teacher said, "You play like an absolute natural." And as I said, a very good clarinet and jazz saxophone player. So I was very engaged by him. Everybody was. Everybody who met him and could at least identify a little bit with his brand of being a human being found him enormously attractive.

Hughes: All this talent wasn't overwhelming?

Yamamoto: He absolutely was not intimidating in his style. So he was amazingly attractive, a tremendous magnet, and most of the junior faculty who were here when I came here as a postdoc were here because of Gordon, quite literally. If you talk to Christine Guthrie or Reg[is] Kelly or Jim Spudich, those people came because of Gordon. So after I met him a few times, I was sold.

Hughes: You doubtless know that he was asked to be chairman [of UCSF Biochemistry] and declined.

Yamamoto: Oh, yes. He had gone through a flirtation with Yale just before the San Francisco [offer]; was going to be chairman there, and then backed out.

Hughes: Why?

Yamamoto: I guess they didn't clear out some of the objectionable folks who were there before him. But I think he just didn't want to be chairman. He wanted to not be burdened with that kind of stuff but instead attract people other ways.

And so when I decided to come here, it was purely because of Gordon, and I didn't have a clue what UCSF was. I didn't have any idea. Was it part of Berkeley? Was it the school that Bill Russell played basketball for? I didn't have any idea, honestly. I had been to San Francisco once in my life when I was eight years old, and that was it. Oral History Center, The Bancroft Library, University of California Berkeley 47

Gordon accepted me, so I decided to come here. I was very interested in him first, and then began to think about the glucocorticoid receptor really seriously, and decided in fact that was the perfect protein.

[begin tape 3, side B]

Gordon convinced me that the glucocorticoid receptor had an interesting feature in it that the estrogen receptor didn't, and that was that glucocorticoids function in all cells of the body, whereas estrogens obviously don't. But what they do from cell to cell is different. So that's weird. By then, I was really engaged in the idea that [glucocorticoid] was a transcription regulator, that somehow someone would show that it bound to specific sites on DNA, like the lac repressor, and that the ligand, the small molecule, obviously a well-known, completely characterized specific molecule— If the model was right, then if you really took the lac repressor model and just mapped it right onto the glucocorticoid receptor, then there was no way it could do different things in different cells. It didn't make any sense.

What excited me about that and made me think that this could actually be magnificent was that it had to mean— To be honest with you, I didn't actually entertain the idea that there could have been multiple receptors, and I don't know why. And actually now we know there's only one glucocorticoid receptor. But it needn't have turned out that way. In fact, there are multiple retinoid receptors; there are multiple other receptors. But anyway, I didn't even think about that.

Hughes: Luckily.

Yamamoto: [laughs] But I thought, if there's only one receptor, and there's only one hormone, and it's doing different things in different cells, it offered what to me was really an exciting possibility, and that was that it must mean that in those different cells, it interacts with different things. Although what I thought, we now know is not quite correct, I thought that those things would be the secrets of what make the cells different. So you would take this common reagent that we should be able to get our hands on, we could follow around with radioactive hormone, and then just simply ask, what does it bump into from cell to cell? And those will be the keys to what make the cells different. So I was really excited about that.

Now we know that's a bit naive, but basically the principle is right. What makes the receptor do different things from cell to cell is it interacts with other things. And that's really the operating principle in our lab. The philosophy of the lab really is that if one wants to understand a complex process, then find one thing, one molecule, that's involved at every step of Oral History Center, The Bancroft Library, University of California Berkeley 48

the complexity, and then simply study that molecule to death. It will tell you about everything else you need to pay attention to. If you do biochemistry, it will bind to other proteins. If you do genetics, you'll get mutations that make it act funny in one cell but not in another.

Hughes: So that's been the integrative theme of your research?

Yamamoto: Absolutely. I decided to stay with steroid receptors not because they'd been that good to me—I had to write this funny paper about hidden sites— but because I really wanted to study gene expression, transcription, and I really thought it was fabulous to have a system where I could throw the switch of the regulatory factor being on or being off, just by adding hormone. And the hormones were commercially available really hot, radioactively labeled hot. So I could actually look at the protein. I couldn't really look at the protein; I could look at the radioactivity, and I'd know the protein was there. There weren't other regulators where you had anything remotely like that handle. So I thought that was great. Other people, I think, thought hormones were a backwater, but I liked that aspect of [biochemistry] a lot.

But what really engaged me in glucocorticoids was this discovery, as I read the literature to get ready to come here, to write a fellowship, that they worked in all cells but did different things, and that was fantastic.

Hughes: Did that concept turn Dr. Tomkins on, too?

Yamamoto: He liked that I thought about it that way, but I think he liked anything anybody said. But yes, I think he did.

Hughes: This was 1973. What were your first impressions of the lab and of the department and the institution as a whole?

Yamamoto: Not good. The lab was great big. There were fourteen postdocs.

Hughes: Was that the largest in the department?

Yamamoto: Bill Rutter and Gordon both had huge labs. They were the two guys that had been imported here. Everyone else had tiny labs. So those two guys had over half of the students and postdocs in the department, and everyone else had the other half. It was quite a mix of people. There were some really good people, some of whom are now on the faculty here and other good places, and there were other people who I thought, why are they here? Oral History Center, The Bancroft Library, University of California Berkeley 49

There were papers being published out of the lab that I thought were not good. That in fact was the beginning of this long afternoon that Gordon and I spent together where I insulted him tremendously by asking him if he thought all the papers coming out of the lab were good. He got very angry, and that was the one time he really got very obviously angry [with me]. I wouldn't like that so much if somebody asked me that.

Hughes: Because to him, it was unquestionable?

Yamamoto: Well, what ensued was an afternoon-long explanation for why he published so much, that he did not want to be responsible for preventing someone in his lab from getting credit for an idea, even if all the data weren't there yet. He didn't say it that way, but he spent the whole afternoon essentially saying that.

Hughes: So it was obviously an important point to him.

Yamamoto: Yes. And I think it's because he really feels like he was behind the ideas for two of these two Nobel prizes, and he never even was elected to the National Academy.

Hughes: Was there some bitterness because of it?

Yamamoto: Maybe a little bit. I found this day that we spent to be really important to me, in my time here and my understanding of Gordon and the currency of science, how important credit is and recognition by your peers. But it didn't come across as bitterness. It might have been there. It wasn't the sort of guy he was. He was an immensely generous and charming person; he came across that way. Just wonderful to talk to, although not everybody in the lab felt that way. He ignored most of the people in the lab and talked to a few people. So there were people that were angry at him because he ignored them; their problems were foundering. There wasn't a direct mapping of how good he thought the people were whom he talked to, especially if—[laughs] I get to edit this?

Hughes: Yes. [laughter] You get to edit it.

Yamamoto: It was said that he always had some French postdocs around because he could speak French with them.

Hughes: Why this fascination with French?

Yamamoto: I don't know. Maybe because of the Jacob-Monod thing. His wife [Millicent] probably will know. Oral History Center, The Bancroft Library, University of California Berkeley 50

Hughes: So the people he talked with were the people whom he found challenging intellectually?

Yamamoto: Yes, or maybe the people he thought were funny, or the people that he thought would do what he wanted. It wasn't clear to me how he decided whom he was going to talk to. But he happened to talk to me a lot, and that was very nice for me.

Hughes: Was everybody working on some form of hormone receptor problem? I mean, could it have been that Tomkins had more affinity for some problems people were working on rather than others?

Yamamoto: Yes, could have been. He was doing several things. They all revolved a little bit around hormones, but the relationship was more remote with some than others. My problem was in the very heart of the steroid receptor problem. But by then he'd become very engaged by cyclic AMP and had several people working on cyclic AMP as a regulator. He had also become engaged in a closely related problem, which was growth control in general—how cell division is regulated—and had a few people working on that. Fortunately for me, he had a couple people working on some virus-infected cell colonies, so I learned how to do polyoma-SV40 virus infections from some of those people.

And then Gail Martin, who is on the faculty now, came to the lab to begin to work on [kerato?]carcinoma cells and the differentiation of mouse embryos. She came in with that problem and went out with that problem, and she continues to work on it. That was just to demonstrate that people could also bring their own problems and that was okay with Gordon. But most people were pretty much focused on the series of problems that he was working on.

My impressions of the lab were that it was overly large; it wasn't very well organized, a lot of nice people; I liked it a lot. Lots of heterogeneity in the quality of the science going on. So I was very critical of some problems and not of others. I'm sure that was true coming my way, too.

Hughes: I get the idea that your Princeton background was very rigorous.

Yamamoto: Yes. That wasn't so here. I considered it to be soft, and the people didn't work very hard. The department was essentially not real— There were very few students here. I think there were less than ten students in the program when I came, and they were not good. There was nothing really departmental about the way things were organized. The courses were terrible, and there were only a couple of them. Even after I was here, I Oral History Center, The Bancroft Library, University of California Berkeley 51

didn't understand what the relationship of this place was to the rest of the University of California. So sometimes I wondered what I was doing here.

Hughes: Dr. Rutter had been here for three years or so at that point.14 What was your impression of him, and what were his goals for the department?

Yamamoto: I knew him because he was famous.

Hughes: Famous for what?

Yamamoto: Well, he was famous for discovering the three RNA polymerases in eukaryotic cells. He'd done a lot of good enzymology before that, but I didn't know about it. But in 1970, he had demonstrated that there were three classes of eukaryotic RNA polymerases,15 and he always had a huge army of postdocs laboring in the cold room [laughs] to bring out these polymerases and study them.

I was probably completely wrong, but I didn't have much of an impression, looking up from my postdoctoral bench, that Bill had big plans to develop this department into the huge endeavor that he did develop it into. Although by the time he got around to recruiting me, he actually told me that. So maybe it was always there; maybe he just made it up on the spot when he was recruiting me. I don't actually know. Knowing Bill as I do now, I would weigh more on the former than on the latter. But I didn't realize that as a postdoc;16 that wasn't my impression of him.

My impression of him was that he had found a position where he could have a great big lab, not be troubled with the other stuff that revolves around being a university professor, like teaching courses, and be left to do his work. Sounded like a good deal.

Hughes: You weren't very much aware of him in his departmental functions?

Yamamoto: No.

14 After several years of vacillation, Dr. Rutter assumed the chairmanship of the department of biochemistry and biophysics in 1969. (Unprocessed correspondence of William J. Rutter, UCSF Library, folder: WJR correspondence on chairmanship. Hereafter: WJR correspondence.)

15 R.G. Roeder, W.J. Rutter. Multiple forms of DNA-dependent RNA polymerase in eukaryotic organisms. Nature 1969, 224:234-237.

16 For Rutter's ideas concerning the development of the department and the basic science enterprise at UCSF, see his correspondence with Lloyd "Holly" Smith, Burt Dunphy, and others responsible for recruiting him. (WJR correspondence, folder: WJR correspondence on chairmanship. Oral History Center, The Bancroft Library, University of California Berkeley 52

Hughes: He was the scientist in his laboratory.

Yamamoto: Yes. That was my impression of him then. He changed.

Hughes: Was there still a residue of the old classical department that he had inherited?

Yamamoto: I only had a vague consciousness of that. I would hear, in socializing with faculty, about [Manuel] Morales and that there were these people that had been shoved out the door when Rutter came in.

Chris Guthrie got here just starting on the faculty one week after I started as a postdoc, so we became good friends right away. They moved her into an office in the west tower [Health Sciences West] on my floor. She started by moving into the lab of two guys who were retiring, and they were still there. It was really awkward. She had to set up her lab; she had to ask them if she could move some of their things around, and oh, god. So that was the way things worked.

Gordon's lab was so crowded that when I first got to his lab, I spent the first month at a desk in the corridor, which was before the fire marshals cared about such things.

Hughes: That was where you were doing your lab work?

Yamamoto: No, there was no place to do lab work because I had to wait for the postdoc who was going to vacate my bench to leave. So I spent a few weeks just reading and thinking about what I was going to do. I felt very awkward. There was no space. So the place was a mess. It was before the fire marshals came down about things in the corridors, so the corridors were just an unbelievable maze of equipment and desks and bicycles and carts and radioactive vials and stuff like that. There was just no sense that it was a university at all. It was kind of a bizarre mess.

Hughes: What was the relationship between the lab groups? Was there much interaction?

Yamamoto: Not much, although I've had this great fortune of working with two wonderfully social individuals. So people came to Gordon, and they came to him not only from all over the world but also all over the university. So there were actually a lot of people passing through our place. He attracted a lot of the young people here, so they were always coming by to see him or have a cup of coffee with him or talk to him about their experiments and complain about something that was going on in the university. Oral History Center, The Bancroft Library, University of California Berkeley 53

Gordon had started a collaboration with Ken Melmon, who was chief of clinical pharmacology—is that right?

Hughes: Yes, I think so.

Yamamoto: He had a young fellow in his lab named Henry Borton [sp?], who was [later] the chairman of pharmacology right before me. So I met Henry back then when he was just starting as a clinical endocrinology fellow under Melmon. So we got to meet people that I normally would never have run into.

There was surprisingly little organized scientific interaction with the Rutter lab. The two labs took up the whole ninth floor of the east tower [Health Sciences East] except for one little corner where John Watson was, which was even smaller than the little corner he's in now. It's the same corner. Otherwise, it was Rutter and Tomkins, and that was it.

Hughes: Why do you suppose there wasn't more interaction? Some of the scientific problems seem to have overlapped.

Yamamoto: Yes. I think Bill and Gordon talked a lot, but we didn't. I knew the postdocs in Bill's lab, but there wasn't any organized joint group meetings or anything like that. It just didn't happen.

Hughes: What about seminars? There surely were things like that which pulled you together.

Yamamoto: Yes, there were, but it didn't feel cohesive. At Princeton, the place felt very cohesive compared to this one. This was kind of a bunch of labs running along. I remember that our friend Howard Goodman started Friday afternoon wine and cheese hours in his lab, and I had friends in that lab, so I'd go over and join them, and I thought that was really cool. But there weren't other things like that that brought people together.

Hughes: It's amazing, considering the myth, which I want to hear more about, of the department's cooperativity and cross-disciplinarity.

Yamamoto: The myth!

Hughes: Well, I've picked up on a few discordances along the way.

Yamamoto: Oh, sure.

Hughes: From what you're describing, cooperation and collaboration did not immediately arrive with the appearance on the scene of Dr. Rutter and Dr. Oral History Center, The Bancroft Library, University of California Berkeley 54

Tomkins; it took a while to develop. And it took at least three years to develop, because that's when you arrived [1973].

Yamamoto: In that sense, that's true. I need to say that it was clear that while there may not have been this kind of scientific ferment, first of all it may have been there more than I realized, and secondly there was clearly kind of this familial feel to the department. This [what I'm going to say next] is incredibly indirect, so you have to talk to somebody who actually experienced it. I never experienced it, but I heard. I would be sitting in the [department] library, and every Tuesday noon, the faculty of Biochemistry would have lunch in the Biochemistry office. They all fitted in there; there was only nine of them, eight of them, whatever it was. Clearly, Gordon would carry on and tell jokes, and they would all be falling on the floor laughing and talking. So every Tuesday, they would eat together.

Hughes: Everybody did? That was a routine?

Yamamoto: Yes. And they clearly had a great time.

Hughes: And it was social more than scientific talk?

Yamamoto: I don't know. I was always hearing them laughing their heads off. But that's because whenever you were around Gordon, you were going to end up laughing. That was it. That was the way it was going to be.

So first of all, there could have been more going on than met the eye of a naive postdoc. But secondly, there was stuff going on. I don't mean to say there was a complete vacuum in terms of interaction or cooperation. But my perception is it was nothing like it is now.

Interview 3: November 4, 1994

[begin tape 4, side A]

Hughes: Dr. Yamamoto, in the annual report of the department for 1973, one of the points that Dr. Rutter makes is that the department's success was really predicated upon the recruitment of outstanding new faculty, which I believe was his primary goal at that stage.17

Yamamoto: That's right.

Hughes: Why would a promising scientist come in 1973 to this department?

17 Department of Biochemistry and Biophysics, University of California, San Francisco. Annual Report, 1973. Published in May, 1974. (Biochemistry Department library, Medical Sciences Building, UCSF) Oral History Center, The Bancroft Library, University of California Berkeley 55

Yamamoto: I feel probably for a couple of reasons. I've never talked with Bill about why he came here in '69 from Washington. I know that that recruitment involved a co-recruitment of Gordon Tomkins from the NIH, and they kind of came together.

It's interesting that you asked the question in the way that you did. When I came here in 1973 as a postdoc, it was called the University of California Medical Center in San Francisco. I had no idea what the relationship of this place was to Berkeley, or to other institutions in San Francisco, like the University of San Francisco, of basketball fame.

What I knew though is probably the same sort of thing that would make this place at least initially potentially attractive to a person coming on the faculty, and that is that Gordon Tomkins was here, and there were a few other people here that were in my consciousness. But I never really associated them collectively in one group.

Rutter was famous because of the big break in 1970 with RNA polymerase, where he recognized that there were three eukaryotic RNA polymerases, and that they were doing distinct jobs.18 And Gordon had this enormously magnetic and charismatic personality. So I think for someone who would look in from the outside, there would be a small group of people with name recognition. And there was San Francisco sitting here. That had a lot to be said for it.

I was certainly only a naive postdoc, but I spoke with faculty members at Princeton where I was a student, who really didn't know what this place was. And when told that Mike Bishop and this new guy, Harold Varmus, were here together, that microbiologist Herb Boyer, who was doing some interesting experiments with restriction and modification, was here, and Gordon and Bill were both here, many of them would be surprised. They knew all these people were "somewhere out there," but they didn't know that they were all together.

So I would think that someone looking at this place for a potential faculty position would be attracted to that set of circumstances: a small corps of interesting, high-quality scientists, and San Francisco sitting here. And there may have been some visionary folks at that time who saw the potential to be able to build a basic research community together with a very good clinical setting, but it certainly never entered my consciousness. I don't know to what extent it did for other basic scientists who came here.

18 R.G. Roeder and W.J. Rutter. Specific nucleolar and nucleoplasmic RNA polymerases. Proceedings of the National Academy of Sciences 1970, 1970, 65: 675-682. Oral History Center, The Bancroft Library, University of California Berkeley 56

There were some charismatic people who spoke well and had interesting things to say, both scientifically and about the prospects for this place. And San Francisco.

Hughes: You weren't aware that there had been a decision at the administrative level to place more emphasis on the basic sciences? Holly [Lloyd Hollingsworth] Smith, Stuart Cullen, and [J. Englebert] Dumphy were part of that initiative. I suppose the beginning of the rise of the basic sciences was the foundation of the CVRI [Cardiovascular Research Institute] in 1958 and the hiring of [Julius H.] Comroe, which of course was well before your time here.

Yamamoto: I think it's very true. It's certainly as I understand it as well. The way that Comroe put together the CVRI was a real revolution, and with the express purpose of trying to bring together research in the basic and clinical sciences. That was a pretty revolutionary idea in his time, and he had a strong personality that was able to pull it off.

I certainly hadn't a clue when I came here as a green postdoc in 1973 that that had gone on, that there was that sort of history behind it, and that there was an explicit decision to begin to move in the basic sciences. In retrospect, it's clear that simply bringing Rutter and Tomkins here was an expression of a decision of that sort. I think having them here made a big difference. But I have to say that when I came in, I knew that I wanted to work with Tomkins, so I was going to go where he was.

When I came here, I was disappointed in what I saw as kind of a low-key, slow-speed academic program. It was because the place was just getting started, but I didn't know that. It was just beginning to be rebuilt under Bill and Gordon. There was a very small number of students, a very modest menu of courses, and not taught with a particular vigor. I would sit around with some of my fellow postdocs, and we would talk about the way things were at whatever institution we came from, and that things weren't as good here. So I don't think I really had any perspective of what was coming and the kinds of attempts that were being made to build this into the place that it is now.

Hughes: Leslie Bennett talks about the dissension in the preclinical departments because of the disparity in salaries with the clinical folk.19 Were you aware of any of those tensions?

19 The Research Tradition at UCSF: Conversations with Dr. Leslie Latty Bennett. N. Rockafellar, ed. San Francisco: UCSF Oral History Program, Department of the History of Health Sciences, 1992. Oral History Center, The Bancroft Library, University of California Berkeley 57

Yamamoto: Not at all. I was getting by on my little postdoc fellowship, and I knew nothing of any of that.

Hughes: There were quite a few resources funneled into Biochemistry which, after Rutter became chairman, became sort of a test department. This was where the administration was going to try this new agenda, so to speak. I think Dr. Rutter was pretty good at playing upon that basis as well.

Yamamoto: Fantastic.

Hughes: I'm wondering if it created tensions in other departments.

Yamamoto: We could feel it. I think it was apparent to many of us that Biochemistry was the big deal here. It was being treated that way. The new resources were flowing in that direction, and new hires were coming into this department. Brian McCarthy had arrived by that time [1973], and he was a famous professor who'd come down from Seattle as well. But definitely, Rutter and Tomkins had the big pieces of real estate, and they had the vast majority of the territory on HSE 9 [Health Sciences Building East, floor 9]. It was just their two laboratories. John Watson was there as well, but had a small lab. In the west tower [Health Sciences Building West] were some young faculty, and Brian had a good-sized lab there.

So yes, it was apparent that there was a power structure that had been deemed from somewhere in the institution that Biochemistry would get a lot of the goodies, and it was being mounted under these very strong senior people who would attract young people to come in. That was where the new labs were being built and a lot of stuff was happening. So it was exciting.

Hughes: Biophysics becomes officially part of the department just before Dr. Rutter officially arrives in 1969.20 It was one of the stipulations that he made in coming. What kind of role did Biophysics play when you arrived, and how has that changed over the years?

Yamamoto: Well, I have to say that I wasn't really conscious of it. What was clear was that there were some people that were kind of on the outs, and the biophysics group was in that [category]. I had heard little stories about power struggles before Bill came in and just after about who would really have influence in the way the department took shape. This was true on the biophysics side, and maybe we'll talk later about the genetics side as well.

20 W.J. Rutter to S.P. Cullen, October 28, 1968; L.S. Bennett. Announcement, November 25, 1968. (Special Collections, UCSF Library, AR 90-56, carton 1, folder 19.) Oral History Center, The Bancroft Library, University of California Berkeley 58

It was pretty obvious to anybody who was breathing that there were some real resentments and some old history of people who felt that they'd been shoved off to the side of the road. And so in that sense, the biophysicists here didn't seem to play—again, from my vantage point from the outside—an influential role in setting policy in the department. In fact, quite the contrary, they had been put off to the side, and Bill was assuming his influence as an outside person coming in laying out his turf. And he was very good at that.

Over the years, the biophysicists—Manuel Morales and people like that— systematically were not an in-group that was consulted about decision making in the department. They very much had to operate from the periphery.

Now, I'll tell you my impressions, because I do have a direct involvement later, and that is that there was also a biophysics program separate from the department that for a long time was a joint program between UCSF and Berkeley and included the radiobiology group here. I don't think I was even aware of that for a long time into my being a faculty member here.

When the Berkeley and San Francisco sides of that program split, I was involved in helping facilitate that and putting together the program here under Tad [Irwin D.] Kuntz. Only then did I become aware that there was this parallel track operating that was filled with terrific scientists and was attracting very fine students, and it was just going along. A lot of the administration was done within the pharm[aceutical] chem[istry] department, which is in the School of Pharmacy, and therefore wasn't often in my consciousness, even after I became a faculty member, in terms of the kind of faculty that we run around and deal with and mount programs with and train students with.

And that's really changing now. The biophysics program is terrific; there are many biochemistry faculty that are now in that program, and there's much more common mix between the programs and students and goals. The biophysics students come to the [biochemistry department's] Asilomar retreat, for example.

They have chosen not to enter the PIBS [Program in Biological Sciences]. They've been invited multiple times to join the PIBS program, and Kuntz' point of view about this I think has some clear merit, although I don't agree fully with it. And that is that there are many people that come into the biophysics program from backgrounds that are much more diverse [than that of] the average student coming into the biochemistry program, coming in from math and physics in particular and from chemistry commonly. As outsiders from math and physics, they would not be Oral History Center, The Bancroft Library, University of California Berkeley 59

interested in being in a program that was so cell- and molecular-based and was demanding so much expertise in those areas. Therefore, Tad didn't want to saddle his program with a set of requirements, even if it meant staying out of a program that I think he fully supports and acknowledges is very good. I think there's merit in his argument. I don't think everyone has to be cut from the same mold, and I think that's all he's saying.

You're telling me for the first time that the Department of Biochemistry added biophysics [to its title] at Bill's request. That makes sense, knowing Bill's background—lots of protein chemistry and macromolecule expertise, enzymology. At his behest, biophysics was added, but when he came in, he promptly seemed to move some of those people aside in what looked like a power struggle. I don't know if it was, but it looked that way from the outside. And those people really didn't play much role. At the same time, there was this parallel track of biophysicists that were going along in Berkeley and San Francisco, and then at San Francisco. I think now they're finally beginning to converge.

Hughes: Of course, one of the not incidental side effects of that move was to add FTEs [Full-Time Equivalent positions].

Yamamoto: Oh, yes, absolutely.

Hughes: Which I'm sure was part of the thinking.

Yamamoto: Absolutely. Bill was a master at that.

Hughes: Well, what about biomathematics?

Yamamoto: Oh, yes, that's another one. [laughs] Well, it was my impression, that group was both strong and influential in the old, pre-Rutter department and was allowed essentially to grow old and wither on the vine after he came in. I was aware that there was a group [under] Hugo Martinez and a group [under] Herb Landahl, [both] biomath-focused members of the department who again were senior members but not in the mainstream of departmental decision making. They eventually got shunted off to smaller and smaller offices until they retired.

Hughes: In both cases, biophysics and biomathematics, was it primarily a matter of keeping the reins of power in one set of hands, or was it that the focus was really on a different sort of research?

Yamamoto: I think it's certainly the latter, and also had the effect of the former. [laughter] I don't know how to describe what the fractional effort in each of those two directions was. I certainly didn't mean to shortchange Bill Oral History Center, The Bancroft Library, University of California Berkeley 60

here. I think he's a person with tremendous vision. He's remarkable in many ways, but certainly that's one of them. No one would dispute that. I think people look at this department as a real marvel, and the fingers end up getting pointed very much at Bill for making that marvel happen. And it was because Bill had a very strong and clear vision of what he thought needed to be developed here. He would not let go of that. Basically nothing could sway him from that, because he was quite certain, he had strong convictions, and he was confident of them, and he stayed with it. So yes, it's true that that was a major part of the whole thing.

Hughes: I talked to Gary Van Nest some time ago, and he termed the Department of Biochemistry, and he was talking about the period of the seventies, "a postdoc factory." Would you see it that way?

Yamamoto: Yes. That's a good short description of what I was talking about when I said that the academic program here was not impressive. There wasn't an evident major focus placed on the recruitment and training of graduate students, the mounting of excellent courses in a coherent curriculum, things of that sort. Instead, the labs tended to be filled with postdocs. Gary was in Bill's lab, and Bill and Gordon both had lots and lots of postdocs, in the fifteen to twenty range, maybe more, I don't know. I think Gordon's lab when I was there had fifteen postdocs and a few students, and that was true in Bill's lab as well. So postdocs were definitely the prime currency here; there's no doubt about it. So I can understand his description.

Hughes: Are there deeper implications to that terminology?

Yamamoto: Well, one can draw them. I think it's still held around the country in the American scientific enterprise that one reason that faculty members choose to go to medical schools is that they don't want to teach, and that this was a good escape from the rigors of a real job. [laughter] Our colleagues in Berkeley feel that they have the real work to do, teaching undergraduate courses and having large numbers of graduate students and smaller numbers of postdocs, and that we get the cream from them. We don't have to do the work; we teach a couple of hours a year, and don't care much about that at that. So we've found a little slot to occupy in this profession that allows us to do science without doing much other sorts of work. I think that's no longer true here, but there was that point of view about this place, and I think that that point of view maintains in some circles around the country. It's probably true in some circles. So one could extract that kind of point of view.

Another way to look at that same statement, still on the negative side, is that faculty were able to come to this place, and by virtue of it being the sort of place that it was— Well, let's face it, graduate students finishing Oral History Center, The Bancroft Library, University of California Berkeley 61

their research almost anywhere when they look around for postdocs [postdoctoral positions], if they see something available in San Francisco, they'll pay attention. And so really because we're here is one of the reasons that we're able to attract postdoctoral applications. We like to think it's because of our glittering personalities and scientific research, but in fact at least a part of it has to be that the Golden Gate Bridge is in our back yard. So that just accrues to us; we have the opportunity to fill our labs with postdocs.

When the postdocs are all here, shoved together in their little rooms, trying to get the attention of the PI [principal investigator] so that their letter of recommendation is better than the letter of recommendation of the person next to them, then this factory feeling really comes out. There's the guy at the top in the big office with the big cigar talking on the telephone and playing with the puppet strings, and everybody is doing stuff that will get more accolades [from] the big person. It can feel that way in the heat of all of that other stuff.

Yamamoto: Scientific groups are very interesting in the sense that in order to work well, there has to be a really cooperative spirit attached to it. People really do need to feel that they're going in the same direction, and I think a lot of people are aware of that. But at the same time, it's also true that you're not only a collaborator of the person next to you, but you're [also] a competitor. Keeping all of that straight gets complicated as the number of those collaborator-competitor relationships goes up, and that's one of the things that can happen in a big group. Obviously, there are counter examples, but it's not uncommon.

Hughes: Did you experience that competition yourself when you were in Tomkins' group?

Yamamoto: Oh, sure, absolutely. I think everyone did.

Hughes: You said that you were in direct competition with John Baxter.

Yamamoto: Yes, that's true. [laughter] I said that, eh?

Hughes: Yes, you said that.

Yamamoto: Well, by then he had started his faculty position [Assistant Professor of Medicine and Lecturer in Biochemistry, 1972-1976]. But he had just moved into a small room off of Tomkins' lab and still came to the Tomkins group meetings. That's right, I remember this. And yes, right away, there was some tension there. Oral History Center, The Bancroft Library, University of California Berkeley 62

One of the projects that I started working on was really in the mainstream of things that were going on in Gordon's laboratory, so consequently there were a couple of us working on closely related parts of the project, taking different approaches. But as the results began to come in, we would begin to look at some of the same mutants or some of the same strains or use some of the same methods, and then it would feel a bit competitive. It was really up to us or Gordon or both to sort all of that out and get it resolved. The risk is there in any sized group, but the probability of problems goes up [with size].

Hughes: The sorting out simply involves defining whose turf is whose?

Yamamoto: Well, "simply" is the wrong word.

Hughes: [laughter] Yes, I can see that.

Yamamoto: That's a very interesting question. Let me try to think of a specific example for you, without going off on too big a tangent.

When I was a postdoc, Gordon had had this idea a couple of years before I got there that in order to study steroid receptors well we needed a way to do genetics. In fact, that's the reason I came to his lab; it was what I got my fellowship on. At that time, there was no cloning. There were no isolated genes for anything. So the notion of doing genetics on mammalian cells meant either doing genetics on mammalian organisms, like mice and to some modest extent humans, or doing genetics on mammalian cells in culture—somatic cell genetics. You recognize the problem there is that somatic cells are diploid. And in fact, cells in culture are very commonly more than diploid—they're polyploid, and very commonly greater than diploid. So the notion of doing somatic cell genetics is at the outset immediately a little bit confusing. If you have a marker that will be recessive in its genotype, then how will you ever find it if there are two copies of the gene there? Nevertheless, the field was at that time a well- recognized and strong field, even though people didn't know the basis for why it was working.

So Gordon had an idea. The nice idea that Gordon had was to exploit the fact that rodent T-cells, when the thymus cells of the mouse or rat develop, pass through a phase in which they can be killed by high levels of glucocorticoid hormones, for reasons that are still not known. If you do this with a human, you can give pharmacological glucocorticoids or you can simply stress the organism and physiological glucocorticoids go up in response to the stress. If you do this with a human, the T-cells stop growing. If you do it with a mouse or a rat, the T-cells die. There are tumors of T-cells that are trapped at that stage where they're sensitive to Oral History Center, The Bancroft Library, University of California Berkeley 63

being killed by glucocorticoids. So Gordon's idea was simply to take such cell lines and give them glucocorticoids, and everybody drops dead. But of course, not everybody drops dead. A few mutants survive. That was the idea.

Now, it's a very attractive idea. I wrote a fellowship proposal based on that idea, and I proposed some specific things to do and got the money and came here. I was also doing other things as a hobby, as I think I told you.

Hughes: Yes, I remember.

Yamamoto: My winning that fellowship was based on an idea that was directly derivative of Gordon's idea and was directly derivative of work that was going on in Gordon's lab. That's commonly the case. A few really bright people, which I was not, come here with some startling idea of their own. But most people don't. Most people come here and say, "I want to come to your laboratory. What do you think would be a good thing to work on?" Or, "I want to come to your laboratory, and I want to work on this idea that you've had that you've begun to develop." And that's what I did. So when you come in, you're immediately setting yourself up as a competitor of somebody.

I was fortunate in that Carol Sibley—

[begin tape 4, side B]

Yamamoto: —was just finishing her thesis when I arrived. So to put it crassly, she was out of the way. Carol's a wonderful person, and I certainly don't mean it in that way, but you know what I mean. So I was lucky in that the person who really had started the work was not continuing it at that moment when I was arriving.

There was another person, Ullrich Gehring, who was a postdoc—senior to me of course; he was here already—who had started working with Carol and was taking a different tack than I was. Another postdoc, Martha Stampfer, who arrived I think a week or two before me from MIT, from Dave Baltimore's lab, eventually decided to work on that project as well, again taking a different strategy. There was lots of room on this project. So there were at least those three of us who were working along. There may have been a couple of others as well.

Things went well for the strategy that I took, and we were pretty soon in a position to write a paper. Martha and I by then had settled into a collaborative situation, and Ullrich was going along taking a somewhat Oral History Center, The Bancroft Library, University of California Berkeley 64

different strategy, actually more focused on a smaller number of mutants. What Martha and I were trying to do was expand the set and make lots of mutants and study them, categorize them. As we categorized them, some of them would fall into the little cluster that Ullrich was focusing on. There were different areas, but there was an area of direct overlap in the way that we were going about things. I ended up analyzing some of the same mutants that Ullrich was analyzing, some that predated my arrival, and some that Martha and I made.

So when it came time for me to write a paper on this topic, Ullrich felt clearly the push to write a paper on the topic at the same time. Absolutely valid. He was going along fine. Would we write one paper or two papers? Well, Ullrich and I were in the same [laboratory] bay, and it was a cordial relationship, but not without some tensions. But we always spoke and shared information. So probably in consultation with Gordon, we decided to write two papers. And then the question was where would they be sent?

This is in 1974; this was the first year that Cell was published. So there was this new journal Cell on the scene, which as you know is now the journal that students and postdocs fight and kill each other over to get into, for reasons that I am absolutely unsympathetic with. But be that as it may, they do.

Hughes: Well, explain that remark.

Yamamoto: [laughter] You don't mind these concentric circles?

Cell is a journal that has developed around a person, Ben Lewin, who's its editor. He was editor since its inception; he's founder and editor. He runs the journal in a way that I think actually does a disservice to scientists and the training of scientists.

Maybe I should start by saying that there's some absolutely superb science that's published in that journal. No one would not read Cell; I would never cancel my subscription to Cell. Well, I wouldn't say never, but I can't imagine canceling my subscription to Cell. It's a fine journal.

But the way that Lewin runs it has a very autocratic feel to it. I could give you some hair-raising examples, and maybe I will sometime, documenting what I mean by autocratic. But it's really his journal, and he runs it that way. He has an amazing capacity to assimilate information and categorize it on a conceptual lattice of his own, which is incredible. He has a taste about what is hot and what is not. The journal really runs strongly on that principle, in my opinion. I'll say this in two ways: he's set himself up as a trend-setter of what is exciting science. The other way to say it of course is Oral History Center, The Bancroft Library, University of California Berkeley 65

we've handed to him the mantel of power of defining for all of us what is exciting science to do. I think the truer statement is the latter one; I think this is our field, and we've given it to him, and we shouldn't have.

So this whole notion of hot science has grown up. I should say, it's grown up of course embedded in a society that's engaged by hot everything, so it's just a microcosm of that, but it is there. So hot science has grown up in the midst of all this other hot stuff. So people want to be current and hot. It was the first journal with a glossy cover, with colored stuff on the cover that changed every month. He will just systematically exclude some sorts of work as uninteresting because it's just details of stuff that we already kind of think we know. And of course, I don't think that's how scientific knowledge is really pushed. The details turn out to be important. Controls get left out and discussions are cut short. To me, it's very hard to tell where you are in a field by reading a Cell paper. So I don't like that journal.

Well, 1974 was the year that Cell started. People on the East Coast had never heard of it. A lot of the editors were on the West Coast. In fact, a lot of them were here. Harold [Varmus], Gordon Tomkins, and several other people here were on the original editorial board. In fact, Harold was on until he moved to the NIH [as director, in 1993].

So when Ullrich and I began to joust about where we would send our two papers, the battle came down to whether one paper would go to PNAS, the National Academy journal, and one paper would go to Cell, this new journal. Gordon was on the editorial board, so Gordon was kind of pushing Cell. I didn't want to go to Cell. It was a brand-new journal; who knew if it was going to survive? It kind of looked like a pamphlet. It was a little, tiny journal. I remember showing it to Bruce when I was back at Princeton visiting one time when I was only a year out of his lab. I said, "Have you heard of this new journal Cell? Gordon's on the editorial board." He hadn't heard of it. I showed it to him, and he looked at it and he said, "This is a journal?" That's what I say now. [laughter]

So this little battle arose. I "won," I got to send my paper to PNAS,21 and Ullrich got stuck with Cell.

Order of authorship is commonly a battle ground, although in this case we had two papers so it didn't matter. Really, [scientific] recognition of that

21 K.R. Yamamoto, M.R. Stampfer, and G.M. Tomkins. Receptors from glucocorticoid-sensitive lymphoma cells and two classes of insensitive clones: physical and DNA-binding properties. Proceedings of the National Academy of Sciences 1974, 71: 3901-3905. Oral History Center, The Bancroft Library, University of California Berkeley 66

sort is our only currency. We don't get million-dollar bonuses and things of that sort, although I think maybe that's coming now. The money part is coming into play. But certainly at that time, it was never anything except whether you got credit.

So [even with] projects that begin relatively well delineated, it's not so uncommon they'll end up with at least a portion of overlap that will then become the jousting ground for what's going to happen with publication, and that's what happened in this case.

Hughes: In jousting for authorship, does a figure such as Tomkins enter into those decisions?

Yamamoto: Oh, yes.

Hughes: What factors are considered in determining order of authorship?

Yamamoto: The details probably vary a little bit from lab to lab, but in general it's fairly obvious who should be the first author: the person whose primary project is the topic of the paper. It can get cloudy fast though because the way that a paper is framed can be very different from one viewpoint to another. The two people, the two adversaries as it were, looking at the same work might frame the work in very different ways, each to his or her own advantage. Or more benevolently, to their vantage point.

Hughes: Yes, you can't separate the two.

Yamamoto: Yes. So that's what happens. And then in principle what should happen is that the PI needs to enter that fray early and defuse it if possible, make it a non-battle, and just say what's going to happen and why, and just take a strong stance. But whether that happens or not is very much a function of the way that the lab is governed.

Hughes: Yes, and there probably are other factors as well. I have heard that a senior faculty member sometimes will defer because the junior person needs first authorship as a leg up. Author order is not determined strictly on the basis of science. Would you agree with that?

Yamamoto: Oh, absolutely, and here’s an example. I had a postdoc, Didier Picard, who is Swiss and is now a professor at the University of Geneva, who developed a project in collaboration with Pierre Chambon in Strasbourg who is arguably the most powerful biomedical scientist in Europe. As the project evolved, we agreed on a collaboration on a visit that Chambon made to San Francisco, and then we had a very difficult time getting from Oral History Center, The Bancroft Library, University of California Berkeley 67

him the necessary reagents to continue the collaboration. So Didier went on on his own and did the project.

But one of the clones that he used that was critical for making the project work, and one of the reasons that we proposed the collaboration at the beginning, was already in the lab. It was the estrogen receptor cDNA [complementary DNA]. So he used the cDNA. It had been published for five years, and we had gotten it from Chambon for other reasons. So we went ahead and used that and made other reagents that we needed to continue the project, wrote a manuscript, sent it to Pierre, and said— I guess we didn't say anything. We just sent it to Pierre because we would send out preprints of papers in which we used someone else's reagents.

We got an unhappy response from Pierre, who's a good friend of mine, saying, "You're not supposed to use that clone. We gave you that clone five years ago for this reason, and we said so in the letter with which we sent you the clone." I'm sure that that's true. I never put any conditions on any clone we send out, and so I probably was sloppy in paying any attention to the things coming in the opposite direction. I think that when things are published, they're in the public domain, and people can do whatever they want to with them. Other people don't think that, and Pierre doesn't think that. So he was unhappy that we had used the clone for an experiment that had not been approved by him when he provided it to us. I didn't pay much attention to it. I just wrote back and said, "Okay, sorry about that. We have different styles about how we do these things, and I assume it's okay, and I apologize." And he was not happy.

In the end, after a lot of back and forth, I in exasperation sent him a quasi- sarcastic fax that said, "Look, if you really think that you've contributed to these experiments in this paper," which of course they didn't even know about, "why don't you let me know the name of the postdoc that you think made the biggest contribution, and we'll put that person's name on the paper." And I thought that he would say, "Well, you're right of course. We didn't even know about the experiments, so let's just forget it." Instead, he sent me back the postdoc's name to be added to the paper.

Hughes: All right, what did you do? [laughter]

Yamamoto: It is an interesting ethical dilemma. The reason that it plays out in such an intriguing way is that I did it. And the reason has nothing to do with science whatsoever, and that is that at that point, Didier had just accepted this professorship in Geneva. A remarkable thing happened to this guy. He was offered a full professorship out of his postdoc here. His postdoc was very successful, and he's a very bright guy, and he's doing well, but it was Oral History Center, The Bancroft Library, University of California Berkeley 68

unprecedented. So a lot of Europeans were kind of raising their eyebrows about this whole thing.

Being a professor in Europe means that you're essentially a department head, and you have to organize a department. So he had to go to the University of Geneva and organize a cell biology department, so he would be the professor of cell biology. He felt that if he began his new professorship by pissing off Pierre Chambon then he was in a world of trouble. We talked a lot about this. So all the discussion ended up centering on that and not on the science, and we ended up adding the names.

Hughes: Was there something else going on as well, namely national styles in science? Was Chambon used to being on a paper for doing nothing more than supplying a reagent?

Yamamoto: Yes. We used to say that it's more common because of the way that the European system works, having a Herr Professor sort who oversees a large group.

Hughes: It's much more hierarchical.

Yamamoto: Yes, much more hierarchical, and so it's much more common to recognize that hierarchy by adding names to papers. So yes, I think that's part of it. [tape interruption]

This is another story of the same ilk, but it brings things home and out of the European versus American style of science. Harold [Varmus] and I had an extremely productive collaboration through a student in his lab who became a postdoc in my lab, Gordon Ringold. [The incident] had a profound influence on my career. This was based on my little hobby of looking for virus-infected cells.

The introduction is that Harold told me when I was a postdoc that the people who work on mammary tumor virus used dexamethasone as a reagent to increase their virus titers, and I paid no attention because mammary cell development is so complicated. Gordon while he was still a student in Harold's lab and I got together, and we together with our own hands did this experiment that convinced me that it was much more interesting than I had suspected. By blocking protein synthesis and adding dexamethasone to the cells, we saw mammary tumor virus RNA increase. And the key observation there is that because you block protein synthesis the effect must be very direct. You don't have to make new proteins in the cell in order to enable the cell then to make mammary tumor virus RNA. Oral History Center, The Bancroft Library, University of California Berkeley 69

Subsequently, Gordon came to my lab as a postdoc after I became a faculty member. In fact, at that time I was going to MIT, and Gordon was going to join me at MIT. Then eventually I stayed here, and he stayed here with me. And we continued. Gordon was enormously productive. Many of the papers that he published here were published jointly with Bishop and Varmus and with my lab, with him as first author. That's not strictly true because several papers were published just out of my lab, but a lot of them were joint, and it was merited. That was true.

At that time, cloning was just underway, and a lot of the things that people did were essentially preparatory to doing interesting things, [like] creating a restriction map of a piece of DNA. That was a big deal at the time. It was a lot of work to make the enzymes, and [the experiments] gave us a lot of information on which we could base future experiments. But by themselves, they weren't startling breakthroughs in biological knowledge.

Gordon collaborated with a postdoc in Harold's lab, Pete Shank, who is now a faculty member at Brown. They mapped the mammary tumor virus provirus, proviral DNA, with restriction sites and did a few other nice experiments. We closed the circle on the study; it was time to write a paper. It seemed to me that it would be nice for those guys to write the paper by themselves.

So we were sitting around my lab one night talking, and I proposed that, and they got very excited. I think it was because there was a little bit of dueling, jousting, now that we begin to talk about this, between Peter and Gordon about who was going to be the first author. I said, "As far as I'm concerned, why don't you guys just publish the paper yourselves, the two of you?" They were both senior postdocs, it would have a big influence on their CVs and a small influence on my and Harold's CVs. I thought that would be fine.

I have had a tradition in my lab of having senior postdocs wherever I could publish papers without my name on them, because it has a big impact on them. It's one more thing I learned from Bruce. Because one of the papers that I published out of my thesis was just with my name alone on it,22 which I thought was not merited, but be that as it may. But it was very nice and had a big impact. So I proposed this maybe as a way to head off some sort of duel about authorship that I saw down the road, but also because it just seemed like it would be fine. What's the big deal?

22 K.R. Yamamoto. Characterization of the 4 S and 5 S forms of the estradiol receptor protein and their interaction with deoxyribonucleic acid. Journal of Biological Chemistry 1974, 249: 7068-7075. Oral History Center, The Bancroft Library, University of California Berkeley 70

Harold exploded. He was up in my office the next morning and said, "Don't you tell me how to run my laboratory." He was very unhappy, to say the least. He said, "You're not going to define who are authors on papers out of my lab," et cetera, et cetera. So I said, "Okay." It was clear that his name was going to be on the paper. So then my name had to be on the paper. I was an assistant professor; he was a full professor. I felt, jeez, what's the big deal? This guy is famous. I'm just a little nothing, and I thought it was nice for those guys [to be sole authors]. Bruce had done the same sort of thing for me, and I had already started that tradition in my lab. I think we've published twenty papers or so from this lab without my name on them.

Hughes: Is that a matter of personality, or could that be also institutional history? I'm not trying to say that you wouldn't have developed this philosophy on your own, but certainly Alberts gave you the idea—

Yamamoto: Absolutely.

Hughes: What about NIH where Varmus had come from? Was it the idea there that everybody even peripherally involved would be on a paper, that you didn't do these favors for postdocs?

Yamamoto: I think that could be. That wasn't the only time that I did battle with Harold over papers and authorship. I don't recall that I ever won. [laughter] Harold's a tough guy. The reason I said that to you is that it was a curiosity to me that Harold would always say things that implied that he was just a little guy coming along, and he and I were not really any different [in academic rank]. I thought that was a little curious because by then he was a full professor and I was an assistant professor. Obviously, he was on a skyrocket to fame already. It was already apparent. So I just didn't get it.

But in retrospect, I think I do get it. He would say, "What are you talking about? Everywhere I go, I hear your name, and people know who you are." And maybe that was true, but I don't think that was the reason. Harold came here as a postdoc, as I did, and had gone through and had become a faculty member, as I did. But his mentor Mike [Bishop] was still here, and mine wasn't. I think he felt that the university always treated him as Mike's postdoc, and that Mike always still put his name on papers, and maybe Harold didn't always think that that was merited. I don't know, but maybe. So Harold was feeling a little bit squeezed here.

Hughes: It makes sense. Oral History Center, The Bancroft Library, University of California Berkeley 71

Yamamoto: It didn't make sense to me at the time, but I think in retrospect that may have been a component of what was going on. When he would raise these issues about he and I being the same, I couldn't figure out what the hell he was talking about. But I think that he may have actually felt that way.

Where were we? We were talking about big labs in the department.

Hughes: Have you gotten past Cell and the decision to publish in the PNAS?

Yamamoto: So I "won" that battle is the wonderful curiosity of all this. And then I adopted as much romantic ideal about Cell as everyone else did, and then eventually I threw that away. I try not to publish any papers there. The rule in my lab about that is— There aren't rules about it but they know what I think of Cell and why, and as a result of that it's very rare for them to try to take me on and say, "I don't care what you think of Cell, I want my paper to go there." But if they do, we send the paper there. If I think that it's a good paper, and that it's not an inappropriate place for it, despite my feeling about the way the journal runs, then we send the paper there. So now it's every few years we end up with a Cell paper.

So anyway, at that time I won. I got my little PNAS paper and Ullrich was stuck with his Cell paper, and things went along okay. I guess all of this was in the context of the way the competition plays out in laboratories and why it gets exacerbated in big laboratories. So things were going on all the time about who had primacy on a project, who was going to do which experiment, and things of that sort. And the more arms-length the relationship is between the mentor and the postdocs and students, the more those things come up. So if it's really laissez-faire, then you're really at risk for lots of battles. Either the lab has within it a lot of very strong- willed people who go off in their own directions, and power struggles get resolved internally by whoever shouts the loudest, figuratively or perhaps literally, or these little fires erupt that constantly need to be dealt with at some point.

Hughes: I imagine your own experiences have shaped how you now relate to your lab.

Yamamoto: They have. My lab is probably viewed from the outside as being run with a lot of control from the top, and I like to have a lot of say about exactly what projects are even undertaken. That's true.

[begin tape 5, side A] Oral History Center, The Bancroft Library, University of California Berkeley 72

Yamamoto: We've really kept things fairly well focused on a narrow set of things. In fact, I'm sure that there are people out there who think that it is so focused as to not be very interesting. I obviously don't agree with that, but I think that there is that point of view out there, even in this department, where people have the opportunity to know more about what to me is a tremendous variety of things that we're doing. When I look at the overall effort, things are coherent; they're focused on receptor function. They think, gee, is he ever going to get off this stupid receptor? I could go through a litany of a lot of other things that we're studying that the receptors have told us about.

I can't remember whether I've gone through my philosophy of how we do science here.

Hughes: No.

Yamamoto: It's really based on a strong feeling about how complex systems can be teased apart. I think people have very different points of view on how best to do that, and I have a strong point of view about it, and my lab runs in that way. But that's a little off the topic; we can come back to that.

So what you asked is how has that history of the way that I grew up in the Tomkins lab influenced the way that I run my own. It's really a hybrid, of course, between Tomkins and Alberts. I exercise a lot of control about the projects that get off the ground here. Bonny Mailer, my longtime technician and associate, would come in and say, after a new person has been here for a while, "Have you decided for so-and-so what they want to do yet?" I try to do it in a way that will move the person in the direction that I want, instead of just announcing, "This is what you'll work on." I never do that. But Bonny just thinks it's a game, and they're just pawns in it. [laughter]

When I was a young professor, that level of control extended to details of experiments and how things were done. That was brought home to me a few months ago when one of my students finished up, and at her going- away party, she gave a little talk about how things have changed. She had been a student for some time; I think she took six and a half or maybe seven years to finish, so she had a broad perspective on the influence that I had on her experiments at the beginning and the lack of influence I had at the end.

Now, part of that is just because students grow up and they don't care about that influence, but a part of it, she's right, is that my life has changed a lot in the last seven years. I spend much less time in the lab, in my opinion substantially less than I should, and probably in their opinion too, Oral History Center, The Bancroft Library, University of California Berkeley 73

although that's probably mixed. Other faculty members would think it's probably just about right. But it's a big change from the way that I used to do things.

Hughes: So in the past, you were very involved.

Yamamoto: Very involved, and now much less so.

Hughes: How do you feel about that?

Yamamoto: I don't like it. I'd rather have it the first way. So now long periods of time can elapse between my sitting down with a student or postdoc and going over the primary data and how the experiments are being done. Lesser amounts of time elapse between my standing around in the hall or in their bay chatting with them about their experiments. But not very often do we actually sit down and really plough through the primary data and think, how exactly are you doing this experiment, what temperature, when are you adding the DNA, how much, have you calculated the concentrations? That kind of detail is critical. Well, I think it's very important. It's an important part of the training of students, and an important part in my being able to be involved in a useful way. I think I've given up a lot of that, and I'm not happy about that.

I guess it is just something that comes with moving up in the kinds of things I'm trying to do. I believe in all of them, but they all have come at a price in how comfortable I feel with what we're trying to do in all of those endeavors. I'm too busy. I feel that it's hard for me to do things as excellently as I'd like to. There is essentially no time to savor anything. That's too bad. I very much like what I'm doing; I'm not saying I'm unhappy; I'm not. But there are elements when I look back at my past much simpler life that I miss and I'd like to have back. I just don't know how to get there.

Hughes: Well, you're putting this in the context of you as lab chief. But what about the impact on your own research? You're spending less time in the lab, which also means less time in the lab with your own projects. Consequently science is affected.

Yamamoto: Oh, yes, very much.

Hughes: In both ways: your productivity and also your productivity in terms of your students.

Yamamoto: I'm very much a science manager now, and I don't carry my own project at all. That's true for almost all the faculty members here. Not quite all. Oral History Center, The Bancroft Library, University of California Berkeley 74

Hughes: Is that the pattern across the country?

Yamamoto: Yes. It varies from place to place and person to person. There are faculty members here who work a lot in the laboratory. But most of us don't. One of the focal points for student skits [laughs] is that we couldn't do an experiment if we had to. I haven't done an experiment almost since my last sabbatical, which was a long time ago. It was 1983. I've never done a PCR [polymerase chain reaction procedure]. The predominant pattern is that successful scientists become science managers and get pulled out of the laboratory. It's an interesting irony because we all get hired on the basis of how well we do experiments. And then the faster that we rise, the faster we stop doing experiments.

Hughes: What you used to do via your own research is now done through your students.

Yamamoto: Yes.

Hughes: So if a science manager wants to have an impact on science, it makes it all the more important to maintain a close relationship with his lab. Prominent scientists in essence aren't doing science after a certain stage. What does this have to say about the scientific enterprise as a whole?

Yamamoto: That's a good question. The data are there that say that it's worked pretty well. The American science system of successful scientists becoming science managers has been true for quite some time. American science has succeeded spectacularly during that period.

It also needs to be said though that things are changing within that pattern. In particular because of the increasing breadth across which a research program could be mounted—looking at different species of organisms in the same study and using vastly different techniques in the same study, genetics to crystallography. Few if any of us have the expertise uniformly across that spectrum to be able to make valid and good judgments about what piece of data is really high quality. So we depend more and more on the expertise of others to do that.

So you then move yet another increment away in that you're at arm's length from the experiments in your own area of expertise and longer than an arm length from the other stuff. And there I think you begin to run into problems of two sorts. One is that because we're not close enough to the experiments, it's harder for us to see things that are wrong with them. The second problem is that because we have that distant relationship, it's a little bit harder to see where things should go next, what the next thing to do is. So the quality of advice that we give erodes. Oral History Center, The Bancroft Library, University of California Berkeley 75

I don't know what to do about that. I think it's a major problem. There is going to be a colloquium in San Francisco in December that's being assembled by the American Academy of Microbiology—I'm on the organizing committee—on collaborative science, which is very much focused on this issue. As things get more complex, and we depend on collaborators to tell us what is a good experiment—and we're all putting our names on these papers, of course—what does that do to the quality of our science? If it's a problem, how do we solve it?

Hughes: You said several things that really intrigue me. At the beginning of our discussion today, you talked about how doing molecular biology here is different from doing molecular biology at Berkeley. It brings up the question of institutional context. Are you aware of Kohler's work on the history of biochemistry?23

Yamamoto: [shakes head]

Hughes: Well, he traces the origin of American biochemistry back to medical chemistry. It grew up largely in a medical setting and consequently developed that orientation. He contrasts it with the case in most European settings where biochemistry was usually in a basic science setting. What I'm trying to get at is the place of the institution in shaping the science that you take on.

Yamamoto: It has a big role. I'm a little embarrassed that I keep saying this to you, but when I was a postdoc I think I was unconscious of any of that. [laughter] And so it didn't influence at all the kinds of experiments that I tried to do as a postdoc. I was aware that Gordon, in his usual way of sweeping vast numbers of people toward him, was engaged actively in conversations with clinical fellows in pharmaceutical chemistry, among them Henry Bourne, people in the physiology department—people all over the medical school. Gordon was an M.D., Ph.D. himself so he could operate in these circles, and he did so. I'm sure that one of the reasons he came here was that he could exploit in interesting ways the presence of a medical school, that it was almost the opposite of what you said, that there was an opportunity here that could be developed.

I don't know what Bill's point of view about it is. I didn't have any sense about how much he thought that [the medical school context] was going to make a big difference. I do now, because I see what he's doing, what he's

23R.E. Kohler. "Medical reform and biomedical science: Biochemistry—a case study." In: The Therapeutic Revolution: Essays in the Social History of American Medicine. M.J. Vogel and C.E. Rosenberg, eds. Philadelphia: University of Pennsylvania Press, 1979, pp. 27-66. Oral History Center, The Bancroft Library, University of California Berkeley 76

putting most of his energy into, and it's pretty clear. And that [medical interest] was probably already there. But I didn't have a sense of it at that time, and it didn't influence my work at that time, but it sure does now.

Hughes: You're saying that your perception of the context within which you were working was very much a basic science, pure research environment?

Yamamoto: That's right.

Hughes: Practical application may be somewhere down the line but it didn't really matter that you were in a medical school.

Yamamoto: That's right. It almost looked like Bill had come in here and really made a kind of a traditional, academic, non-medicine-related biochemistry department, carved it out and put it together.

Hughes: There are two things going on here. There is this basic science initiative, beginning with Comroe, but in the context of a medical school. And now the party line that you tend to get is that one of the reasons for the success of this institution is because of its collaborative nature, not only among the basic science departments, but also because there seems to have been communication back and forth between the clinical faculty and the preclinical faculty.

Yamamoto: Yes, that's interesting. I think it's a stretch to say that there has been good communication between the clinicians, that is the people who see patients, and the basic scientists. I just think that's not true. Our worlds just don't rub that closely up against each other. But there are people in the clinical departments who care about research and do research that has definitely made moves in our direction, and vice versa. I think it is a strength of this institution that probably before it was fashionable to do so, there were initiatives to really try to boot up the nature of the interaction which classically of course has been antagonistic at best.

The interaction is not without its problems here, but it really has worked very well. Some would say—and this is probably in part right—that it's just a matter of necessity. We don't have any other resources so we'd better work together because there's no room for fighting. We're just in too close quarters to be wasting our resources in that way. So if the biochemistry department or pharmacology department, for example, ever wants to be able to grow in a way that's productive, they're going to have to do so by finding another group of people around the institution to talk with.

I just last week had a conversation with people in the anesthesia department, who have developed an endowed professorship, but they want Oral History Center, The Bancroft Library, University of California Berkeley 77

to bring more basic science into their department. So we've just started some discussions on how we might be able to do that collaboratively between pharmacology and anesthesia. It could be structured in a way that is really advantageous for both departments and really does accomplish in a real way what [Anesthesia is] seeking to do. If we had a building that was full of empty labs, maybe we would never bother to talk to the anesthesia people because we wouldn't have to.

Hughes: [Dean of the School of Medicine Haile] Debas made a point in a talk he gave a month or so ago that we have this wonderful cooperative model, related to PIBS and all of that, of the preclinical sciences at UCSF. Now the clinical sciences in this institution need to do the same thing.

UCSF, which started out as a clinical institution and then rose to prominence on the wave of what was happening in the preclinical sciences, is now having to switch its focus back to the clinical sciences and bring them up to snuff, so to speak.

Yamamoto: Yes. I think that's very true, and I think that's clearly how he feels.

Hughes: Does that model really mean increased dialogue between the preclinical sciences and the clinical sciences? Or is it dean's talk?

Yamamoto: I think it does mean that. I think that institutions that are really going to make quantum moves in the coming period of biological science will be those that are able to develop such a working dialogue. The writing is very clearly on the wall that we can begin to tackle really complex physiological issues that we just couldn't do before. It's going to require a bridging of expertise in which we really get the seams out. I don't have the expertise to walk across that boundary, and the clinicians don't have the expertise to come this way directly by themselves. So we really need to start by working together.

My take on what Haile was saying is both that and that the clinical people need to begin to work out ways such that their effort is much more coherent than it is now. And that right now the clinicians spend a lot of time slugging it out with each other that ends up just being a lot of ATP going up in smoke, and that we just can't afford to do that. He's basically saying, look you guys, the basic scientists did this. They're now a really coherent force. When something goes wrong in Biochemistry, there may be a tendency for some of the other basic science departments to cheer and say, "Oh boy, did they deserve it." [laughter] There may be some of that. But in fact, it's incredibly cooperative, and people really pull together and say, "Look, we have to work on this." Oral History Center, The Bancroft Library, University of California Berkeley 78

So deans' talks are always deans' talks, but I think there is a certain measure of truth in what Haile says. That is that two things have to happen: the clinical sciences need to find some model that may not look explicitly like PIBS, but has the same end point, and that they figure out a way to define for themselves a common direction. Having done that, the hope is that both sides will see that a part of that common direction is working with each other directly, and that both of those things probably need to happen for this place to work out right now.

Oral History Center, The Bancroft Library, University of California Berkeley 79

Interview 4: November 14, 1994

[begin tape 6, side A]

Hughes: Dr. Yamamoto, as early as 1961 there was talk of founding a department of genetics at UCSF.24 I know that early history is well before your time, but do you remember any discussion in the early days of your tenure here about genetics?

Yamamoto: Only that by then there had already been a lore that had been built up around the Department or Division of Genetics or Human Genetics or whatever it was going to be. All of those things were commonly thrown around. Charlie Epstein and Shelly [Sheldon] Wolff had perhaps been chosen or potentially chosen as being key people in the development of that department or division.

Certainly by the time I came in to the faculty [1976] what was left was a bitter residue, the bitterness being that those people [potential members of a genetics division] who also had appointments in the biochemistry department felt that the new biochemistry department had wrested this thing away and was not going to develop it in the way that they saw to be the best pathway to be taken. But I don't know any of the political details that went on before that. It was clear that people perceived that opportunities had been missed or squandered.

Hughes: There was already the Center for Medical Genetics, which was NIH- funded, within the Department of Pediatrics. Epstein was interested in a clinical approach to genetics, so I can imagine him being upset not only in terms of where the division was located, namely, in the biochemistry department but also because of its molecular and basic science approach.

Yamamoto: Everything that you said is true. But Charlie also felt that he had a view of how to link his clinical work to basic work. I say that because the fellows that he was bringing in to the lab while I was a postdoc, people like David Cox and Helen Blau, both of them now at Stanford— David heads the Human Genome Center at Stanford and Helen is a professor of pharmacology at Stanford. Those are two among a group of people that Charlie brought into his division as fellows where it was clear that he was trying to pursue a cellular and molecular, more basic strategy, toward mammalian genetics.

24 Edward B. Shaw to J.B.deC.M. Saunders, April 1, 1961. (Special Collections, UCSF Library, AR 90-56, carton 10, folder 207) Oral History Center, The Bancroft Library, University of California Berkeley 80

So I think not only did he have an agenda that was more heavily weighted in the clinical direction than what he was seeing happening in Biochemistry. But I think he also felt that he could also do the other thing, and that he would be the right person to build the whole endeavor because he had a perspective of it all, whereas the biochemists didn't. So it led to some tension.

Hughes: How would Shelly Wolff have liked to have seen it go?

Yamamoto: I don't know that. Shelly was sitting [functioning] from the vantage point of the Laboratory of Radiobiology where a lot of radiation-damaged DNA, DNA repair work, the study of diseases of DNA repair, and things of that sort were going on. I think he probably would have moved in that direction. But my perception was that Charlie and Shelly always operated as a tandem and were always equivalently unhappy with the way that Biochemistry was handling things, but had been neutralized or really were not major players in the game now that Bill had taken over. So this undercurrent was just always there.

Hughes: How does the Laboratory of Radiobiology relate, if at all, to the biochemistry department?

Yamamoto: It's only tangentially related. It's largely a DOE [Department of Energy]- funded operation. It may be completely; I don't know. It's not an academic department, which means that all of its personnel also have to have academic appointments. Everyone who is a UC person has to be appointed in some academic department. So some of them have been directly appointed in Biochemistry, others have not, but their work has been closely enough related that we see them. There are appointees there in biochemistry, anatomy, and physiology, and other departments. So we see them through that route.

In addition, the biophysics program has a lot of appointees in radiobiology. That program also has been running more in parallel with the biochemistry department than really a part of it. But of course the source of things that we think about and in some cases the problems that we work on overlap substantially. So there are people in the Radiobiology Laboratory that are doing mammalian genetics, who are doing [research on] radiation damage to DNA, who are doing real hard-core cell biology and looking at how cells interact and communicate with each other and connect together to form tissues or organs—all things of interest to people in the new biology. So those relationships that have been formed between people in Biochemistry and the Laboratory of Radiobiology have been really driven by the scientific imperatives, as opposed to any Oral History Center, The Bancroft Library, University of California Berkeley 81

organizational structure. And largely organizationally the two have been separate.

Hughes: Was the mantle of molecular biology originally borne by the Laboratory of Radiobiology, and if so what was happening, if anything, in the pre- Rutter Department of Biochemistry in terms of molecular biology?

Yamamoto: That's a very good question, and I don't know the answer. Certainly my impression was that the old biochemistry department was really classical biochemistry. The senior faculty that I knew when I came as a postdoc was in that direction or in this computational biology direction— mathematics. I'm not aware of any molecular biology that was going on.

I think that Bob Painter and his colleagues in the Radiobiology Laboratory may well have been doing some molecular stuff. They were certainly concerned specifically about DNA lesions and DNA repair mechanisms, all things that could certainly lead in the direction of direct molecular studies. So you may well be right about that.

Hughes: If you envision molecular biology having to be incorporated in the existing institutional structure, where are the logical places for it to land? Or maybe I should ask it differently: where in most places did it land?

Yamamoto: In most places, it was a bleb off of the biochemistry departments, where there were biochemistry departments. That wasn't always true. There were plenty of campuses in the sixties that didn't have biochemistry departments, and then things [biochemistry] grew out of subprograms in chemistry or subprograms in biology. That's mostly where molecular biology burst forth. Molecular biology was really born of studies of how bacteria metabolize carbon sources, and how bacterial viruses attack their hosts, and seeing the connections there. So it really came out of a molecular genetic background. So I suspect that in some places molecular biology may have sprung up in genetics departments. Although I can imagine that could be a problem because there are a lot of classical geneticists that would probably disdain this [field of molecular biology].

Hughes: In 1976, after the Division of Genetics was formed in the Department of Biochemistry, Herbert Boyer was head, and listed within the division are Charles Epstein, David Martin, Brian McCarthy, Sheldon Wolff, and Chris Guthrie.25 How cohesive was this division?

25 [Grant proposal.] Project for Medical Genetics. Charles J. Epstein, investigator. July 13, 1976. (Special Collections, UCSF Library, AR 90-56, carton 2, folder 31) Oral History Center, The Bancroft Library, University of California Berkeley 82

Yamamoto: Not very. These were not people that spent a lot of time talking to each other. I think that Wolff and Epstein were included for the historical reasons that we just discussed. Both of those guys are very forthright individuals, and they have very clear convictions, and they are very willing to speak their minds, even though they were extremely aware that their views were not the popularly-held views of the rest of that group or the Department of Biochemistry. So meetings were lively, sometimes contentious.

I eventually was in the genetics program as well, as things became more programmatic in the biochemistry department, and so I attended some of those meetings. Charlie and Shelly would always say what they thought. In fact, I respected that a lot.

So you were right in your perception and the way you asked the question: this was not a group that had a natural tendency to fall together at lunchtime and talk about new issues. So it was a bit artificial.

Hughes: Was it useful for example in recruitment, in lieu of being able to say that UCSF had a flourishing department of genetics, for Biochemistry to say that within the department there was a division of genetics?

Yamamoto: I don't think it has had much impact of that sort. Because of my coming in in parallel with this rather than really knowing what the inside story is, I can only give you my perception. And my perception is—and this should certainly be corrected by someone who knows the real facts—that the division was a way finally to get something off the ground that actually had the moniker of genetics. It was a way to maybe use some money that had been sitting around waiting to be used for that purpose. So keeping it housed in a structure that we knew was stable, then we'd go ahead and put it together, even with a group of people that might not themselves be naturally cohesive, and hope that it could then grow and develop in a way that would gain its own cohesiveness.

I don't think it's really done that, to be honest with you. Even under the modern leadership of Ira Herskowitz, I don't think it's particularly had that effect. Ira, I'm sure, would disagree with me. [laughs] And so it's been sort of a little splinter off of Biochemistry that hasn't ever really been independent of it.

Hughes: I think you can only look at the division as a downgrading of the conception of a full-fledged department of genetics within the School of Medicine or the proposed "Fifth School," Human Biology.26 Has its

26 For debate on proposed locations of a department of genetics, see: W.J. Rutter to S.C. Cullen, March 25, Oral History Center, The Bancroft Library, University of California Berkeley 83

existence in a sort of quasi-form killed the drive to establish a full-blown department of genetics on this campus?

Yamamoto: Actually, that's a very good question. Well, killed the drive is a little strong maybe because this continues to come up. At the dean's executive committee a month ago, it came up. "Is human genetics going to have a real presence on this campus?" So there are still committees that are pondering this whole thing. It's very much still on the minds of people that are concerned about these issues. So I think killed is not the right word.

But has doing it this way dampened progress? I think it's probably fair to say that it has. But the question that has to follow that is whether given the situation it could have been done better a different way, or whether the dampened progress, as dampened as it might have been, was nevertheless progress. And again, I just don't know enough to be able to answer that in an informed way. But I have a feeling that it would have been hard for us to do it the other way. The Fifth School wasn't going to happen. So then the question is, how do we mount [a genetics program] in a different way?

I know that you appreciate now that many of the basic science initiatives that have come out of the modern era of UCSF have sprung from some aspect of the biochemistry department. That was what this was about. Whether it has actually gotten to a point where people can say "from", I don't know. That's kind of doubtful, as you can tell. Even now, when one looks at the PIBS [Program in Biological Sciences] programs, genetics is on a separate track from biochemistry and molecular biology. There aren't very many differences. Whereas the cell biology program, for example, which also is administered through biochemistry, is pretty clearly distinct. It really has its own identity. The cell biology community here is very strong. The cell biology students really consider themselves to be cell biology students, whereas the genetics students less so.

So yes, I think it has never really gotten off the ground, and to that extent, I guess you'd have to say that the way that it's developed has kind of hampered a full-blown development of genetics here. I don't know if it could have been done another way or not.

Hughes: Do you care to say anything about the Fifth School?

Yamamoto: [laughs] I don't think I have much to say about it. The economic priorities, and I'm sure the political ones as well that I didn't know about, made it clear early in my time here on the faculty that it just wasn't going to

1970. (Special Collections, UCSF Library, carton 2, folder 31) Oral History Center, The Bancroft Library, University of California Berkeley 84

happen, that we'd have to do it some other way. I don't know what will happen down the road.

As you know, we made a shot and a successful one, at beginning to develop basic research in human genetics here. I just mentioned Dave Cox a few minutes ago. Dave Cox and Rick Myers were able to land an NSF [National Science Foundation] National Human Genome Center here. But they eventually left, in no small part because they didn't have other colleagues to talk to. They just didn't see that was going to happen here. I think it was the major contributor to their leaving. I know David well, but Rick is a close friend, and I know that he didn't want to go but thought that scientifically he really needed to.

Hughes: The Department of Genetics at Stanford has an illustrious history.27 That was a magnet, was it not?

Yamamoto: I'm not so sure. Yes, there have been some very fine geneticists in that department. But Stanford is a very different sort of place than UCSF. Its departments tend to be small and, I think it's not unfair to say, more insular, more free-standing entities.

Hughes: Now, are you saying within the institution itself, or also in terms of how they relate to other institutions?

Yamamoto: No, within the institution itself. Very different from the UCSF strategy of getting many people engaged in a dialogue. Rather than the admittedly very good history of genetics at Stanford being the main draw, I think the more important thing to David and Rick was that the institution made it clear that they wanted to develop human genetics and were going to put resources behind it. They had just brought in a new chairman in genetics, David Botstein from MIT, who is well known to us all as a very aggressive and insightful scientist. That in itself spoke volumes about the institutional commitment. So I think that probably had more influence than the history. But you're the historian.

Hughes: I haven't done my research down there yet. [Hughes’s research and interviews with Stanley Cohen had not yet begun.]

Let's talk about the departmental retreats at Asilomar. Dr. Boyer mentioned one held at a conference center in Mill Valley,28 which you must have attended, right?

27 For a discussion of the Department of Genetics at Stanford, see the oral history in this series with Stanley N. Cohen. Oral History Center, The Bancroft Library, University of California Berkeley 85

Yamamoto: I did.

Hughes: Do you remember how that came about and who attended?

Yamamoto: A little bit. I actually cannot remember when it was.

Hughes: I think the first Asilomar conference was in 1975.

Yamamoto: Yes, that's correct.

Hughes: So the Mill Valley conference must have been either '73 or '74.

Yamamoto: I don't think so. I say that for two reasons. One is that I'm quite certain that Gordon wasn't there, and Gordon died in July of '75. The first Asilomar conference was in September of '75, right after he died. It was right when I agreed to join the faculty here. In fact, it was announced at the meeting. I went to this meeting in Mill Valley, so it leads me to believe it was actually after the first one but before the second one.

Hughes: I don't have any documentation, so I certainly don't contest.

Yamamoto: This was a faculty retreat; it was not a departmental retreat. Herb was a key player there, and I'll tell you why in a minute.

As I recall, it was organized by David Martin, who lived in Mill Valley. It was biochemistry faculty only, and I know that Dan Santi and Reg Kelly and Joe Spudich and Christine [Guthrie] and Dave Martin and Herb [Boyer] and I were there, and I'm sure there were a few others. I suspect John Watson.

What I recall being a major bone of contention was issues surrounding DNA cloning, including biosafety matters and company matters.

Hughes: So that was the impetus for the conference?

Yamamoto: Yes. And there was a lot of contentiousness about Herb, at least on my part and Christine's part. We were his opponents at that time. I was perplexed that he would try to mount a company [Genentech] even though he knew that some of his colleagues were very unhappy with the idea. The meeting was perfectly cordial. There weren't people not speaking to each other even though there were very strong feelings. I can't remember the

28 Boyer oral history in this series. Oral History Center, The Bancroft Library, University of California Berkeley 86

name of the conference center, but it was a beautiful place. It was a beautiful day. It was one-day long, all day.

I remember Herb saying to Christine and to me that somebody he was talking to had convinced him that it didn't really matter what other people said. As long as he really believed that what he was doing was right, he was just going to go ahead. That was his way of explaining to us, I think in a quite nice way, that he was going to move on with this idea [of co- founding a company]. Without saying so in so many words, it was a way of saying to us, "I'm not doing this to piss you off because I think I'm doing the right thing." So he went ahead.

I remember that exchange. So there was a lot of discussion about that. It was not long after Gordon's death, so we were still dealing with how we were going to move ahead as a department.

Hughes: Dr. Rutter wasn't there?

Yamamoto: I don't remember.

Yamamoto: I suspect he was, but I don't recall. I remember it being a quite pleasant meeting, even though the subject matter was contentious.

Hughes: The Ralston Center. Is that right?

Yamamoto: I think that's right.

Hughes: So this conference was not part of the Asilomar series. This was a special conference for a special problem.

Yamamoto: Yes. The Asilomar conference really started right up after Gordon died. I don't recall whether the first one had been planned already.

Hughes: The first one was 1975—

Yamamoto: Yes, it was. I guess there's no way I would recall because I wasn't a faculty member yet; I was still a postdoc when Gordon died of course. I spoke for the lab at that conference. I think at least one other postdoc from the lab spoke as well, but otherwise it was faculty members who spoke.

Hughes: You spoke about Gordon?

Yamamoto: No. I did at the first memorial, which was held at the de Young [Museum], and it was beautiful. People came from everywhere. But at the Asilomar Oral History Center, The Bancroft Library, University of California Berkeley 87

conference, I just spoke about the science going on at the lab, and I think at least one other postdoc did as well.

Hughes: Was that unusual?

Yamamoto: Well, it was the first meeting. Now it would be, because it's only faculty who speak. I think at the first meeting, it was not uncommon. What was uncommon, of course, was that there was no P.I. [principal investigator] to speak. But I think at the first meeting, it was a pretty loose organization, and some laboratories had postdocs as well as a professor speak, and others only had a professor speak.

Hughes: Do you know what the impetus was for the Asilomar conferences?

[begin tape 6, side B]

Yamamoto: [missing text]—to do this. I'm pretty sure we weren't the first ones. And I don't know how much of it was spurred on by Gordon's death, or if it had already been planned ahead of time. But it was a great meeting.

Hughes: It included people with joint appointments? It wasn't strictly Biochemistry?

Yamamoto: I think that that's true. I'm sure that, for example, Dan Santi was there, although he's always been treated essentially as a full appointee, even though he also splits his appointment with pharm[aceutical] chem[istry]. I don't remember if it was open to joint appointees at the time, but it certainly is now. Well, now it's different; now it's part of the PIBS umbrella of retreats.

Hughes: Why don't you for the record describe how the retreat evolved?

Yamamoto: Okay. First of all, I should just say that it's a wonderful event. It's multi- headed in the sense that it has lots of different goals, and it actually does a pretty good job of achieving them. It was situated at the beginning of the fall quarter because that's when the new students come. So it gave the new students a chance to see the whole show in a couple of days, under circumstances that were very pleasant and festive and fun. They could meet lots of people at the same time. They heard the P.I.s talk, and they saw posters from the students and postdocs. That was true I think from the first year. So I think it was nice for the students, even though now it's rather overwhelming, because it's become such a big meeting. I think maybe it was even more useful to young students then than it is now. So that was one goal. Oral History Center, The Bancroft Library, University of California Berkeley 88

A second goal was to increase communication within the department so we knew better what each of us was doing. That has always been very successful. The posters in particular I find to be fantastic. The talks are good talks, but the posters are really great because you can really go around and see that postdocs or students have figured out a technique that may help you. Then you can attach the project to a face, the data to a face. And it was fun. It really allowed us to get out of our normal milieu and see and interact with each other in a different way, even though we were still very much immersed in science. I think that was also very healthy. It was a nice release, and it gave people a more broadly-based view of the human being on the other side of the bench. It continues, I think, to do all of those things, and it's a wonderful place. So everything except the food is great about Asilomar. [laughter] It's been that way all along.

At the first one, I believe that the number was something on the order of twenty-five students, a total of twenty-five students. As we discussed last time, this was not a big student place. So if students were taking five years to get through, that means we were getting five students a year. And then the usual consortium of postdocs and a small number of faculty, and that was it. We met in the chapel. Asilomar is a converted church camp that the state took over many years ago, with some controversy now of course. And it was just great. We were kind of all lost in this big cavernous chapel.

Yamamoto: Now the meeting has grown to the point where we limit registration to 400, and many people from other programs want to come. That's been true for quite a few years now, where it's been about 400 people. People still feel more comfortable jamming into the chapel than going across the road to a bigger site for presentations. We'd rather sit on top of each other in this old room, which I certainly favor.

Until a few years ago, it was always the biochemistry department's event. We've had for a long time now to limit how often a faculty member talks, and install some very baroque rotation system for presenting talks, whether you're a full appointment or a joint appointment.

And then a few years ago, with the emergence of PIBS as the dominant graduate training vehicle here, it became one of the retreats of the PIBS programs. PIBS, which we can talk about more if you wish, is one of now two umbrella graduate training programs on this campus that is trans— Well, it's better to say it's blind to both departmental and school boundaries. Now it includes something like 150 or 175 [faculty] and 150 or 175 students. The biochemistry department administers three of the PIBS programs—biochemistry and molecular biology that I direct; genetics Herskowitz; and cell biology which now is Reg Kelly. The Oral History Center, The Bancroft Library, University of California Berkeley 89

Asilomar meeting has become the retreat of those three programs, plus a fourth, developmental biology, the newest one, which is administered out of the anatomy department. So it's now the primary retreat of those four programs.

As I was saying a few moments ago, cell biology is very coherent in its own right. Cell biology has its own retreat in addition to this one. It's only cell biology, and they're very proud of that. But at least these four programs get together once a year at the Asilomar meeting that was the old Biochemistry meeting.

[KY: Please add something re Gordon Tomkins’s jazz sessions. No one has mentioned them on tape!]

Hughes: You mentioned the social aspect of Asilomar, seeing people in a different context. I wonder what other social occasions there were in the department. I've heard for example that Howard Goodman had a Friday wine gathering, and I've seen allusions to the Chelsea Pub. I'm interested, because these are places where scientists can get to know each other's work in a more informal way.

Yamamoto: Howard was a wine fancier or is probably, so he started these Friday afternoon wine soirees. They were weekly, and I would go occasionally. Once I was on the faculty, they were right next door.

Hughes: This was only faculty?

Yamamoto: No. It was his lab plus other people that would either be invited or would wander by. This was all before the heavy biosafety regulations, so they were right in the lab. He just put some paper out on a lab bench and lay out crackers and wine, and people were smoking cigarettes, and the whole show. [laughter] It was very pleasant. You're quite right; obviously it was completely informal, and people might spend the time talking about the weather, baseball, or politics, or the newest book or movie that they'd read or seen. But just as often, it was about science. A new rumor that somebody had heard of a meeting, or a new paper that they'd read, or some quasi-science-social controversy, or some new result in a laboratory. It was very good in that sense.

The Chelsea scene was even less formal. At least the one I'm thinking of involved people going down there quite often to drink beer and play darts and—

Hughes: Late at night? Oral History Center, The Bancroft Library, University of California Berkeley 90

Yamamoto: Yes. —sit around and talk. We are all science geeks, and this is what we do. So it's going to come up in almost any context that we get together. That happened a lot.

Hughes: Were there other occasions?

Yamamoto: Well, probably. Not that I'm aware of. There was more social interaction within the department then than there is now. That may be because I don't get invited any more. [laughter]

Hughes: Which is more than just a function of department size and your seniority?

Yamamoto: Well, it seemed like it, but I could be wrong about that. But there were a lot of events like that—gatherings or parties at people's houses. There seemed to be a lot of things where a lot of the department was engaged. Whereas now my impression is there may be at least as much as before, but the place is a lot bigger, and that contributes. But it's a little bit less inclusive.

Christine Guthrie used to have this thing called a spring fling, at the spring equinox or whatever it was, a big department-wide blast in her lab, lots of food and wine and beer. Those were great. There seemed to be quite a few of those things then.

Hughes: I saw some photographs of people in the department in weird costumes. Was that a one-of-a-kind occasion?

Yamamoto: No! [laughter] We had some department-wide Halloween parties and maybe these spring parties where people would dress up. But that's in more isolated pockets, like the cell biology program has its big cross- dressers, and there's a lot of that sort of stuff. So yes, people know how to let go here. That's for sure. I think as the department has become so big, it's become harder to mount something that's really department-wide. So these little groups have popped up.

Hughes: What does that say about the cohesiveness of the department and camaraderie and working for a common goal and all those ideals?

Yamamoto: It's changed a lot. We have to be a little bit careful here about the "good old days" syndrome. But when it was small, it really was very familial. The people who remember those times, especially those who were on the faculty a few years before I was, are the ones that are very prone to become really reactionary about any further perceived growth in the department because they're very nostalgic for those times. Oral History Center, The Bancroft Library, University of California Berkeley 91

When I was a postdoc, every Tuesday the core faculty, which comprised maybe nine people, would have lunch together in the faculty lounge, which was a tiny little room with two couches in it behind the purchasing office. I'm not sure if that's what it was at that time. But it was adjacent to the library, so when I was in the library on Tuesday noons, I would hear Gordon carrying forth and everybody cracking up with his jokes, and they were having a grand old time every Tuesday.

As the department has become really big, and people have become busier and more senior, off doing lots of other different sorts of things, that's been eroded. There have been various attempts made by the people who remember and value those times to regain some familial sense, even in the midst of this much larger group. They've met with mixed success. There is a Tuesday lunch just for the primary faculty of Biochemistry.

When I became department chair in pharmacology [1994], I started a Tuesday lunch [meeting], because they didn't have ways to get together. It is a small department, and it is a chance for us to be able to do something very valuable.

So we've lost a bit of that. I think it's a natural evolution. I also valued those aspects of the biochemistry department and missed them as they would slip away from us. I think they have played a really, truly important role in giving us a perspective on where our lives sat in a bigger version of life, and how we were related to each other as human beings and not just scientists. I think it was always worth looking for ways to maintain some aspect of a familial involvement, even as we became this big powerhouse in science, as people viewed us from the outside. So it's been a struggle that I think is well worth keeping up. I don't think that the need for it goes away as one meets what may be called success.

Hughes: Well, let's broaden the view just a bit. I am hoping to hear your views on the molecular biology enterprise at institutions in this area. I am thinking of Berkeley and Stanford, but if you have other comparisons to make, I certainly am glad to hear them.

Yamamoto: Well, UCSF was the runt kid [laughs] in that family that went through a big growth spurt. Both Stanford and Berkeley had reputations and faculty and size that far exceeded those here. Famous scientists, Nobel laureates, National Academy [of Science members], household names. Both of the institutions had all of those things in biochemistry and molecular biology and genetics in overlapping fields which could be called the new biology or the modern biology. They were both terrific [institutions]. Oral History Center, The Bancroft Library, University of California Berkeley 92

As I think we've discussed before, when I came as a postdoc it was nice to find out that these names that I knew about that were somewhere "out there" were all collected together here, and that the young people that had been hired were really terrific, but they weren't widely known yet. When I looked at the quality of the faculty, it was very impressive. It's just that nobody knew about it. Even the ones that people did know about, they didn't associate with one institution. And then there were others that were going to be up and coming that we didn't know about yet.

Once I started on the faculty and others did as well, we began to enter a phase where we felt that we were doing pretty well, but no one else knew about us. It's a frustrating period for any group or institution that begins to achieve something when it's immersed in a pre-existing establishment. So the establishment resists adopting the new successful entity. We were really doing innovative things, and we had smart people, and Bill had really pulled together this amazing cadre of young people. But we weren't getting acknowledged, we weren't getting credit for it, and we weren't attracting the top students. They would come, but it wasn't due so much to us maybe as other things.

I think it was really Bill's vision of being able to recognize where the fields were going to go, and what investigators really had insight or innovation or creativity that was special. He really does have vision and a lot of self-confidence. I lay the early development squarely to him, and the later development to Bruce. It's not that others didn't play a hand; they did. But Bill and Bruce were really the big leaders that kept us on track and emphasized quality all the way through.

Bruce emphasized to me that what you always want to do is to surround yourself with people that you think are smarter than you are. I think he's always operated that way. It's not so easy for him to find [such] people. Much easier for others of us to do that. He's always paid attention to how people did their science and how people got along with each other and what their own standards were personally and scientifically. So I think we just had unerring leadership and a real tight focus on quality and doing things in a new way that didn't depend at all on seniority or power, at least within the department. Things may be different in the School [of Medicine]. That allowed this institution and this department to move at a tremendous rate.

I think there was a perception in the university that there was a big change between the Rutter years and the Alberts years with respect to the way that the department operated within the university. I would say that the perception in the Rutter era was that here was this tremendously powerful guy who would move in and take what he wanted. Whereas in the Alberts Oral History Center, The Bancroft Library, University of California Berkeley 93

era, it was much more inclusive of the whole environment of the university. So there were things done in that time [under Alberts] where Biochemistry was clearly perceived, especially by people in the department, as being too generous and too gracious with its resources. Whereas, I don't think anybody ever felt that way during the Rutter time.

But on the other hand, the times were different. [Maybe someone like] Bill was needed to pull together the resources to get things cranked up and going. And who knows, maybe Rutter was so incredibly smart that he knew that that it was time to find someone who would do it the next way. I wouldn't put it past him actually. But the combination was incredibly powerful and very nearly unique, at least amongst the science departments that I'm aware of.

Hughes: Dr. Rutter spoke in his interviews of "colonizing" other departments.29 How much of the effort and money and energy was put into the department per se, rather than into a scientific enterprise that really could no longer be run along strictly departmental lines? You had to have a strong department. But to do the science, you didn't want the department lines to be overly defined.

Yamamoto: Well, that's certainly true. I hadn't ever thought about Bill's statement of colonizing as one that was driven by the need to broaden our science base as much as it was that it was the only way we could get more positions and resources.

Hughes: That's my interpretation; I don't want to put words in his mouth. [laughter]

Yamamoto: I could be wrong about that. But it all served both purposes. A more corporate way for a power base to be developed is for a manager at whatever level to go out and make acquisitions. While that was true to some extent in Bill's case in the sense that resources tended to flow toward Biochemistry, it was also the case that because the traditional way that university departments had been set up and how respectful everyone was of the boundaries, and because of already by then limited resources, a lot of those corporate avenues weren't opened up. Bill couldn't just go out and make a deal to acquire the physiology department.

So instead, he began to become quite liberal with joint appointments, and maybe that's what he means by colonizing. So there's two kinds of colonization one could imagine that he would be referring to, and I think both of them occurred. One is the trainees from this department would go out and get faculty positions in another department, and the other is that

29 See the Rutter oral history in this series. Oral History Center, The Bancroft Library, University of California Berkeley 94

other departments would get help from Biochemistry in their recruitments and setup and access to our students.

All of those things could be regarded as intangible contributions that would be a reasonable way for a deal to be struck in which the person being recruited would have a joint appointment in Biochemistry. So we would gain a Biochemistry colleague, even though we didn't have space or positions. Bill played that card pretty liberally. He may have done that a lot more than anyone else before his time and did a great job of it.

Hughes: I think he said he had to consolidate his forces within the department to begin with, and then once that base was established, he could afford to reach out. In so doing, he both strengthened and in another sense weakened the control that he had as department chair.

Yamamoto: Yes, both things were true. As soon as you have a joint appointee, by definition, you relinquish some of the influence you have over that person. On the other hand, it was a way for him suddenly to have his fingers in all of these pies at the same time. There was really no doubt that he was the powerful guy here. I had heard said about him that when you leave his office, you shake hands with him, walk away smiling, and then count your fingers. [laughter] And try to decide just why exactly it was you were smiling.

Hughes: How much of this power was based on science?

Yamamoto: I think not much. And it's not to take anything away from Bill's science.

[begin tape 7, side A]

Yamamoto: It was just that he had real direction and other people didn't. This is a guy who really knows where he's going. He's got his headlights on, and they're on for a reason because they're pointing in a direction. So I think that frightens people that don't have as clear a sense or as much confidence about which way to point them. So they are intimidated.

His science was very good. He was incredibly famous for the three [RNA] polymerase discovery. He continued to press that biochemistry very nicely. All of that was immersed in a very nice molecular-developmental biology program that he had going [in his lab] with the pancreas and insulin in diabetes. But I always viewed his power accruing from the fact that he was an administrator who really had a reason to administer and not just somebody making sure that the deadlines were met and the reports were turned in. That was different; it wasn't the usual guy. Oral History Center, The Bancroft Library, University of California Berkeley 95

Hughes: Do you care to bring Berkeley and Stanford into this picture?

Yamamoto: They are both more classical institutions and departments than ours. They had a big history to them. The power structure was based more on classical biochemistry. Obviously, there wasn't exactly a void of modern science going on there. Stan Cohen [at Stanford] and Herb Boyer, for example, [invented recombinant DNA]. They were both big and famous places, but my opinion is that one of the things that contributed to UCSF passing them by, if we did that, was not only that Bill was moving at tremendous speed, but that they weren't. In part, it was just because they were already established, and there is inertia that gets built into a system of that sort. Their method of governance was not as efficient as ours. That's both a criticism and a compliment. Bill didn't think that democracy was all that it was cracked up to be. [laughter]

Hughes: There are other more efficient means of governing?

Yamamoto: Yes. [laughter] He wasn't a tyrant at all. But when he went into a meeting where there was going to be a vote, he knew what the vote was because he had done his homework and done his spade work and gotten out there and made sure that people knew what his point of view was and that there was a certain number of them that agreed with him. So the decisions moved along in a direction.

It was easier governance [than at Berkeley and Stanford]. The place was smaller and more mobile and didn't have the inertia of the history behind it, even though, as we've discussed before, people got pushed aside, or felt they did. So UCSF grew and changed faster than Berkeley and Stanford did and was more adaptable to the times and slowly became a very attractive place for students and postdocs and faculty to come. Certainly with faculty, we could pretty much recruit whom we wanted. There are quite a few faculty here who were offered jobs at Stanford or Berkeley or both and came here. There are at least two faculty that I'm aware of that had already agreed to go to Stanford and changed their minds. It's not that it doesn't go the other way; we were just talking about Cox and Myers. But in general, it went our way.

In general, we hired the people that we offered jobs to, and it didn't matter where else they were offered jobs, and that included Berkeley and Stanford. So we competed very well in the Bay Area. I think that we got the best young people in the world here and even in the face of offers from those places. So we were just able, from the times and the leadership, to develop in a more efficient manner.

Hughes: And the coin of the realm is the quality of the science at UCSF? Oral History Center, The Bancroft Library, University of California Berkeley 96

Yamamoto: Yes, and the way that the place is governed. There is no hierarchy that matters here. If an assistant professor comes in with ideas and wants to do things, then that will be welcomed, even if it's not in that person's department in fact. We've got plenty of examples of people whose primary appointment and space and grant administration and all that was done in Microbiology or Anatomy who just consistently made major contributions to Biochemistry.

I would say that most of the changes in the graduate program were driven by suggestions or demands or complaints from the students. We would sit down with them and really pay attention to what they said and try to respond. I don't remember two consecutive years where the graduate program has been the same. And it was okay. Nobody has ever said in a serious way, "Damn it, this year we're not going to change no matter what anybody says. Let's just try something two years in a row! Is that too much to ask?" I just don't remember that ever coming up in a serious way. People would complain about it or joke about it but it just didn't matter. If we could try to make things better, we would do it. I think that young people, maybe even students, but certainly prospective faculty of really high quality, found that attractive. And that the Berkeley and Stanford departments didn't offer. They didn't seem to have that sort of flexibility behind them.

I'll just say the obvious for the record: they're both superb places, and we all have many friends there. I think that all three institutions really work hard to try to keep science in the Bay Area at the top of their priority lists and not spend time trashing the other places. It just doesn't serve any of us well to do that. So there is rivalry and competition and almost all of it friendly, but it's there. But in the end we try to support each other.

I think that the bottom line, as you asked me a few minutes ago, comes down therefore both to the quality of the science and I think a real open feeling about the way the governance operates here. Those two things together are quite attractive.

Hughes: Anything more?

Yamamoto: Yes, there is one more thing. This can be traced to Bill's model, and that is that because of the route that UCSF took to its growth, it meant that people were talking across department boundaries very early. This was at a time when the more traditional academic model of departmental rivalries was much more the rule. At Stanford that was particularly well entrenched. The departments there tended to be small and each to have defined turf, and that turf was reasonably well staked out and guarded. So there wasn't cross-talk between departments. So it was harder to perceive Oral History Center, The Bancroft Library, University of California Berkeley 97

the collection of scientists there as a collective of scientists. People began to see where the collective idea really gave them something, an increment that you might not have otherwise. So I think Stanford in particular was prone to getting the smaller end of the comparison there. As that [collective] model began to take over, people began to find flaws in the traditional scheme. So there was a problem there.

That was less true at Berkeley, but it was still true. Berkeley had something like twenty-five or twenty-three life sciences departments that seemed to have grown by accretion. Political disagreements between any two faculty members would lead to another department. And so there was a problem for a while. But it's been quite a few years now where a big consolidation [under the Department of Molecular and Cell Biology] has been taking place incrementally at Berkeley. They are now organized quite closely paralleling our structure.

Hughes: [Daniel E.] Koshland was particularly influential in reshaping the biological sciences at Berkeley.30

Yamamoto: Yes.

Hughes: Did he look to UCSF as a model?

Yamamoto: It would be reasonable, but I don't know. We have all heard about a very critical external review that was done at Berkeley before this [reorganization] happened, which essentially gave the university the impetus that would become the Koshland consolidation model. So I think Dan probably had it all in his head, and he knew the right thing to do. How much of it was an adaptation of what he was seeing across the bay, I don't know. But yes, it was quite similar. They've done very well with it.

Hughes: What about cross-talk amongst the three institutions?

Yamamoto: They seem to be a little too far [apart] to be able to make an ongoing programmatic development work, so there's not a lot of that in a formalized way. There used to be some shared programs, as we've discussed before, between Berkeley and UCSF, and there is not much of that any more. But there is communication between investigators in a given field at the three institutions and to some extent even at Davis, and those have been very good. They're just little ad-hoc interest groups that have sprung up. Some have persisted, some have died, some have changed in their focus.

30 See the oral history, The Reorganization of Biology at the University of California, Berkeley at http://ucblib.link/OHC Oral History Center, The Bancroft Library, University of California Berkeley 98

On an institutional basis, I would say that we don't exploit the community in that sense. It's just been too hard, and there's too much going on on our own sites to be able to pay much attention to the other places. But I think that having all three institutions being as strong as they are, together with the whole biotech industry that's so strongly based in the Bay Area, makes this a remarkable target of opportunity for people that want to do this kind of thing. So it helps us all for them all to be good.

Hughes: I have learned that the department has been very quick in adopting new technology. How were resources mobilized?

Yamamoto: What you say is absolutely right. How was it done? I haven't thought about this in this way before, but let me try this out. There is kind of a frontier spirit here. A lot of what I just said about the way that department governance works and the way that it was more mobile than history-bound entities that have more inertia could be made consistent with the view that the people who come here spent more time looking outward than inward and were not just willing to listen to some crazy radical new idea but in fact were looking for it. It's not that Berkeley and Stanford didn't do that, but it's true that this place was really very attentive to technological innovation, the recombinant DNA thing being an obvious example.

Before you phrased your question in the way that you did, I would have said what I've thought in the past, which I think can also fit this model. That is that the place has always, from the entire time I've been here, had young faculty and postdocs who have been the developers of the new technology. There is almost no technique that is really gaining presence in the field that hasn't either been developed here or has a major practitioner or innovator here who's altering it in some way. It's really amazing.

So it gives people a lot of confidence that they can do any of these new techniques because they feel that if they don't understand or get into trouble midway, they really just need to go down the hall and talk to the person who invented it or the person who figured out a way to do it better. Pat O'Farrell came here as a postdoc with this new method that he'd invented of running two-dimensional gel electrophoresis that people thought was a gimmick. Most technologies are used by many, many practitioners as gimmicks and by a few people in really creative ways, and that's the way that Pat used it.

Pat came to Gordon Tomkins' lab as a postdoc having invented this method when he was a student in Colorado. He couldn't publish it. Through quite a bit of muscling on the part of Bill and Gordon Tomkins, Pat got his paper accepted in the JBC [Journal of Biological Chemistry] and off he went after a couple of rounds of rejection trying it on his own. Oral History Center, The Bancroft Library, University of California Berkeley 99

This is a paper on which he was the sole author. Bill and Gordon don't appear anywhere on the paper.

Hughes: It had been rejected because it was thought to be a—

Yamamoto: Gimmick, yes, exactly. I think this place is really open and attractive to those sorts of people.

John Sedat came to the faculty as clearly someone who was interested in pushing the technology of the microscope, of optics, being able to look at things in a way that will allow sensitivity in resolution in the light microscope that hadn't been achieved before. He hooked up with David Agard here, and they've done that. They essentially are on the new frontier of microscopy. Ron Vale, very much taking an independent tack, has done the same sort of thing.

[Tim Richardson?] has designed new molecules that will spring into activity only when he wants them to, that otherwise wouldn't allow him to do an experiment that measures the rate of a phenomenon against time or the place where something had happened. Because if you just put a chemical onto a cell or something, it will react. Well, he's worked out ways to cage things so that they wouldn't react until he wanted them to.

There is just always something going on around here that's amazing, that has been developed here. It's again the same sort of openness that attracts those people. UCSF presents itself as a terrific target for people that want to do things like that.

Hughes: Is there a point where it would be frowned on to continue to develop the technique as such, forgetting about the science to a degree?

Yamamoto: Yes, sure. Science, at least modern biology, in a way is largely technology driven. That is to say, we know the questions that we'd like to ask before we have the ability to ask them. So I've likened the progress in biology many times to a bunch of people who have reached kind of an impasse in how to approach the next question. They reach a wall, and they're feeling along a wall for an opening. There is a large fraction of those people that say, "Screw this, man. There's no hole here. I'm going to go over there and study this other problem." So a bunch of people do that, and some of them do it extremely well, and it's terrific.

Then a bunch of people keep feeling along the wall, and somebody, somebody particularly insightful often, and somebody particularly lucky sometimes, finds an opening in the wall, develops a new technique or has a new conceptual insight, and then everybody says, "Oh, here's the hole in Oral History Center, The Bancroft Library, University of California Berkeley 100

the wall." Everybody runs over and goes through the hole and it is Nirvana. It's waving grasses and warm gentle breezes, blue sky, birds singing, and an open field to run in. Everybody just has a great time. They run across this field, and then whap! They all hit another wall. Some wander off and do something else, and it starts again.

As you're feeling along a wall, and you've reached a hard stage where you really need a different way to be able to ask the question, or you need a way to ask the question where the answer will be far more accurate than any way that you know about so far, there's a period where people really admire your persistence and tenacity and willingness to kind of gut it out and stay with your question. And if you have an idea that you're dedicated to that you think is going to end up being able to carve out a gate in the wall, and you can enunciate it clearly, then people are even more enthusiastic, and they're willing to throw money at you and accolades even. But as time goes on that credit runs out. It runs out at different rates for different people. Incremental progress counts in a certain way, and your past history of being able to succeed at such things, or exactly how powerful the new answer would be if you could get this to work, makes a big difference. But then things run out.

That's true around here too for some of the people that are trying to push the envelope for developing new techniques. Most people don't do it. They bounce off the wall and go look at something else, another way that might get them over it, or a way to go over or under the wall instead of through it. Sometimes we find those things. So I think that most scientists when they reach those walls poke along for a little while and then say, "No, I can't afford this. I've got to go try something else. I'm going to try digging a tunnel." And other people say, "No, I think I've got it. I'm going to go for this." So there are people here that are really pushing the technology still on questions where other people around are saying, "Ah, it's been too long." So everybody has to define that [stopping point] for him or herself. It's hard. Oral History Center, The Bancroft Library, University of California Berkeley 101

Interview 5: November 28, 1994

[begin tape 8, side A]

Hughes: Dr. Yamamoto, did you have any role in the Cohen-Boyer experiments?

Yamamoto: No, none whatsoever. I was a very interested bystander, but I didn't have any role at all in them.

Hughes: Did you have any thoughts—the research was done in 1973—about the scientific implications of this research?

Yamamoto: There were some fairly obvious things, and I tended to think of obvious things. [laughter] If we could isolate genes, then we could begin to think about studying higher organisms, complicated organisms, in the way that we had been studying very, very simple ones—bacterial viruses and animal cell tumor viruses that have only a few genes. We were studying those really as stand-ins for studying the real thing. The stand-ins are good stand-ins, and the paradigms that have come from them have been extremely useful and very powerful. But it really meant [with the invention of recombinant DNA] that for the first time, we could start thinking about going right into the mammalian genome and studying it directly. That was one very obvious thing that emerged as the whole recombinant DNA gambit came into focus.

Hughes: The first recombinant experiment was done with plasmids.31 Was it immediately apparent to you and others that if recombination could be done in prokaryotic forms, it could be done in eukaryotes?

Yamamoto: Yes, it was. Those early experiments were followed pretty quickly by experiments from Paul Berg's laboratory with SV40 DNA [a cancer virus]. That, of course, also raised something of a stir. [laughter] But it was obvious enough at that point that DNA is DNA, and if we could do it with plasmid DNA, then we could do it with animal cell DNA. How we would find those genes to put into the plasmids wasn't at all clear yet, but we knew the principles of hybridization; we knew at least in crude outline the kinds of tricks that would have to be pulled in order to get it to work. And it seemed possible.

Hughes: What about actual function once the DNA had been transformed? That wasn't obvious either was it?

31 S.N. Cohen, A.C.Y. Chang, H.W. Boyer, R.B. Helling. Construction of biologically functional bacterial plasmids in vitro. Proceedings of the National Academy of Sciences 1973, 70: 3240-3244. Oral History Center, The Bancroft Library, University of California Berkeley 102

Yamamoto: No, not at all. At that point, we didn't have ways to move DNA into and out of animal cells. No one had any optimism that animal cell DNA would work, would function, in the bacterial cell. Just having the regulatory regions of DNA close to the gene was a very exciting prospect for those of us who were interested in regulatory proteins binding to a gene, for example. So all those things seemed possible. How we would actually move toward function wasn't immediately apparent at the time.

There was a lot of nervousness on my part and on other people's parts that eventually gave rise to the moratorium about the safety issue.

Hughes: Can you pinpoint when you began to worry?

Yamamoto: I think it was pretty much immediate—certainly when we heard word of Berg's experiments.

Hughes: Some of them had preceded the Cohen-Boyer experiment.

Yamamoto: I think that's right.

Hughes: Do you remember a graduate student in Berg's lab by the name of Janet Mertz?

Yamamoto: Sure.

Hughes: At a Cold Spring Harbor course in 1971, she alerted people to the fact that Berg was contemplating an experiment joining SV40 with lambda phage and introducing the recombinant into E. coli.32 That was before Cohen and Boyer had even begun to collaborate.

Yamamoto: Yes. It wasn't long after that then that Bob Pollack sent his letter.

Hughes: Right.

Yamamoto: So there was a substantial concern about what would happen. This was completely untested. So it wasn't that anyone of us had any direct evidence that there would be a problem, but it was easy to conjure one up. And everything else out there was unknown. So all there was was the ability to imagine that there could be a difficulty.

So yes, there was a lot of excitement because of the prospects that this research opened for us, but a lot of uncertainty and nervousness and real

32 Sheldon Krimsky. Genetic Alchemy: The Social History of the Recombinant DNA Controversy. Cambridge: MIT Press, 1985, pp. 24-38. Oral History Center, The Bancroft Library, University of California Berkeley 103

concern about safety, and a strong desire on the parts of many people to have some sort of assurance that the experiments that were being done were being done under safe conditions.

Hughes: How could risk be assessed?

Yamamoto: It was not something that was easy to assess at the time. There was nothing out there to compare anything to. So all we could do was to think about the best possible kinds of physical containment procedures to make sure things didn't escape, and—this is what eventually came out as the [NIH recombinant DNA] guidelines—to think about crippling the bugs so they couldn't go very far afterwards. So [we tried] to assess physical containment possibilities and to think about good biological containment, and then start the experiments in a prudent way and see how things went from there.

Hughes: Yes. Now, Boyer at that stage had a joint appointment, but he was not a full member of the Department of Biochemistry yet.

Yamamoto: That's right.

Hughes: Were you nonetheless as a department, and also you as Keith Yamamoto, aware of the ins and outs of the research that was going on on this frontier?

Yamamoto: Well, I don't know if I was in on the ins and outs of it, but we were all aware of the excitement of the stuff that was going on, that Howard Goodman and Herb were working on sequencing these junction points for the restriction enzymes. EcoR1 was the first one. It was pretty obvious, once the sequence was known of that restriction end, how the sticky end could be used. And then we were aware of the other experiments that were going on with plasmids in Herb's lab.

From my part as a very naive postdoc, I don't think that I was all revved up with excitement every day to see what they were doing and feeling like this was really the hot stuff that was going on on campus. But people knew about it, and I remember that Gordon Tomkins had both Herb and Howard come and talk about their work to our group meeting, for example. There was pretty lively discussions at that, although I don't remember them centering on biosafety. They were really centered on the science at that time.

Hughes: You're talking about meetings that occurred after the [Cohen and Boyer recombinant DNA] experiments had been done or leading up to them? Oral History Center, The Bancroft Library, University of California Berkeley 104

Yamamoto: I think they were after the experiments had been done. I only got here in the fall of '73, so it would be after that that those group meetings took place.

Hughes: The first recombinant DNA paper was published November of '73.

Yamamoto: Yes, PNAS. Annie Chang's paper.

Hughes: Then the Xenopus work came out in '74.33

Yamamoto: Yes, so it was pretty contemporary with the experiments—with at least the publications.

Hughes: You described last time how there wasn't a great deal of communication amongst the various universities in the Bay Area, somewhat because of institutional structure but also geography.

Yamamoto: That's true. We knew that there were experiments going on collaboratively between Herb's lab and Stan's lab on developing these plasmids and doing the experiments, but I wasn't aware of any conjoining of the institutions for this big effort or anything of that sort. It was just two scientists collaborating; that's all.

Hughes: And the same with Paul Berg's lab?

Yamamoto: It wasn't a collaboration there, but we knew what was going on.

Hughes: Was it more directly than through the literature?

Yamamoto: Well, through meetings, but not anything special about the proximity of UCSF. We were just as likely, probably more likely, to hear something at a meeting at Cold Spring Harbor [about] what was happening in Paul's lab as we were by being able to take advantage of our proximity.

Hughes: So with the exception of the Cohen-Boyer collaboration, there really was no geographic advantage?

Yamamoto: Not that I'm aware of. Yes, it's an interesting point.

Hughes: June of 1974 was the first time that the recombinant work became public knowledge. I choose that date because that's when Boyer, who was at a

33 J.F. Morrow, S.N. Cohen, A.C.Y. Chang, H.W. Boyer, H.M. Goodman, & R.B. Helling. Replication and transcription of eukaryotic DNA in Escherichia coli. Proceedings of the National Academy of Sciences 1974, 71, no.5: 1743-1747. Oral History Center, The Bancroft Library, University of California Berkeley 105

Gordon conference on nucleic acids, let out the fact that this work had been done. His remarks caused a bit of controversy because there was an agreement with Cohen, or at least Cohen understood it to be such, that the work would not be discussed before it was published.34 From those remarks flowed a lot of things—the Singer-Soll letter, the Berg letter, and eventually Asilomar and the formation of the RAC [NIH Recombinant DNA Advisory Committee].35 How closely were you following these events?

Yamamoto: I followed them very closely. I wasn't directly involved at all, but I think by then the entire community was riveted by this, and certainly I was one of those people.

Hughes: Do you mean the UCSF community or the scientific community?

Yamamoto: Certainly UCSF, but I mean the scientific community. Asilomar36 was a big event for scientists, and so everyone had at least some superficial knowledge of what was going on.

Hughes: And yet, as far as I know, there were only two representatives from UCSF who attended. Of course, Dr. Boyer, and I believe Dr. Bishop attended as well. I haven't seen the full list of participants, so it's possible that I might be missing some. Dr. Rutter in his oral history said that he made the deliberate decision not to go because he didn't think it was the proper forum for a discussion of this kind.

Yamamoto: I've heard him say that before. I don't know why he thought that, but I know that there were those in the scientific community that thought that this was a bit of a public relations ploy, kind of a throwback to the sixties, which of course was only a few years before that, where everybody would participate. What did they call it back then—be-ins or something?— where everyone would sit down and join hands and figure out the right thing to do. I know there were scientists who felt that a set of scientific decisions needed to be made, and not one that was appropriate to be covered in the press to turn into a media event, and that the decisions would be made more rationally and less sensationally if people just sat

34 For Cohen's viewpoint, see his oral history at http://ucblib.link/OHC

35 For commentary and publications of documents related to these events, see: James D. Watson and John Tooze. The DNA Story: A Documentary History of Gene Cloning. San Francisco: W.H. Freeman & Co., 1981.

36 The International Conference on Recombinant DNA Molecules met at the Asilomar Conference Center, Pacific Grove, California, February 24-27, 1975. It was sponsored by the National Academy of Sciences, with financial support from the National Cancer Institute, NIH; and the National Science Foundation. Oral History Center, The Bancroft Library, University of California Berkeley 106

down and thought through them the way that we had done before as scientists.

I didn't feel that way at all, but I wasn't subject to any of the problems. I wasn't doing those experiments and didn't have first-hand knowledge of any of it. But it seemed to me that it was an admirable thing that the scientific community would stand up and blow the whistle on itself and say so publicly and say that it's time for us to sit down and reassess this [new technology] before things go any further. So we'll have a moratorium; we'll sit down and talk about it and see where things go from there. So I liked it.

Everyone feels that it backfired on us in a way, and that we lost [research] time, and we ended up really falling behind where we could have gone if it had been done another way. I suspect that that's true. But I don't think it matters. I think that we're talking about losing time in months, and there's nothing that was done that would have been done more than a few months faster, I think, if we would have done it another way. I just don't think it made any difference in the long run.

At the time, it made a huge difference. We were in a race with Europeans; there was a sense that American science was at risk, and that we had thrown up a lot of red flags that turned out in the long run to be unnecessary. All of those things are true. But that's the nature of hindsight.

Hughes: There were things at the time of Asilomar, which already was a year and a half after the first experiments had been done, that could not have been predicted. One of them was how the Europeans and the British were going to react. Were they going to act in parallel? Well, they didn't come out with a moratorium. And secondly, as you said, there just wasn't much basis on which to do a scientific assessment of risk.

Yamamoto: Yes, we just didn't know anything.

Hughes: I suspect that nobody realized the extent of the institutional paraphernalia that would be set up, particularly as manifested through RAC.

Yamamoto: Well, maybe that's true. People who are the real critics of the process I think would say, probably rightfully so, that it's the nature of bureaucracies. This is the way that we tend to operate. Americans especially like to build these structures that seem to be seamless and to be impenetrable. So yes, maybe we could have seen it coming, and that we spent so much of our energy building this edifice [of safety guidelines], and then showing that it was unnecessary. Yes, I think that's a valid criticism. Oral History Center, The Bancroft Library, University of California Berkeley 107

I know that there are those who would say that from the very beginning, it was clear that there was no way that this [recombinant DNA research] was going to be a problem. I just didn't know enough at the time, and I think that a lot of us in my situation that were on the edge of the whole phenomenon, who saw it as something potentially very useful, surely very powerful, but also with a lot of unknowns to it, were just mostly uncertain.

I was glad that Asilomar was taking place in the way that it was, and as I said, rather proud of the scientific community for doing it in the way that it was done. What if something had emerged from those initial studies of biological physical containment that really pointed to a problem? Well, I'm confident that the mechanisms that were set up would have caught that, and everybody would have been very happy and very proud of what we had done. Well, it turned out that there wasn't that [problem].

Maybe it's the case that the really bright and thoughtful people out there could see there was never going to be a problem. That's fine. But it's also true that a lot of things that a society does are done to make sure that the majority of the people are comfortable with the sanctions that are in place. I think there was an element of that. And as I said, it's my own feeling, my own conviction, that yes, there was time lost, but not very much of it.

Hughes: There is some evidence that the scientific community considered this [safety issue] primarily a scientific matter, in fact reduced it to a question of biohazards and made it difficult for the public to participate in a meaningful way. Do you have any comment to make about the appropriateness of that argument?

Yamamoto: Yes. The way that the scientific enterprise works, especially in this country and uniquely in this country, is that almost every element of it is founded on peer review. All of us were brought up with that. Our whole livelihoods are placed in the hands of peer review. When we apply for a job, we're judged by peers. When we send in a paper, we're judged by peers. When we're promoted or fired, when we send in a grant, every element of that involves peer review.

So this is the system on which the whole [scientific] enterprise is founded, and it's worked phenomenally well. Science has moved consistently forward. Of course there have been mistakes; of course there have been episodes of outright fraud; of course there are examples of really regrettable actions taken to countermand or to avoid the forces of fair peer review. But on balance, the process works amazingly well in a way that no one who would design a system would expect it to. Our only real currency in this business is getting credit for things. Oral History Center, The Bancroft Library, University of California Berkeley 108

And yet, everything is based on telling our secrets to other people. If we don't announce what we're going to do in a grant or write what we did in a paper, then we might as well not have done it. And that's as it should be because otherwise you never really gain knowledge. You've gained knowledge individually, but the way the whole enterprise works is being able to let other people build on that knowledge. So it really means that you've got to spill the beans and tell people.

So I think that it gives us complete confidence in the process that is probably from the outside indistinguishable from arrogance and attempts to maintain the reins of power. I don't really know how one person that stands outside of the process could see it in any other way. And yet, for those of us who have grown up in this system, we know that it works.

I think that all of us as scientists tend to carry at least the risk of a dangerous double standard here in that if we hear legislators say that they'll be able to make rules to govern themselves, we become very cynical. When we hear industries say that, "No, no, let us make the rules to govern ourselves," we become very cynical. But we're completely confident that we [scientists] know how to do it ourselves completely. And I think for most of us the contradiction doesn't even occur to us, much less cause us to lose any sleep, just because we think that this process is uniquely effective. Why it works in the way that it does I don't know. But it really has worked well. My own feeling is that that's the major element that came into play there.

There's another one that probably got stated more often which is, "We have the knowledge and sophistication and the expertise to make assessments of these risks, and you don't." That's a purely elitist stance. Biology is not [perceived as] very complicated because we don't understand it very well. So we don't have such a penetrating understanding of biology that we can reduce it to a whole bunch of theorems and formulae and equations. So it's a very long way from particle physics or theoretical mathematics. So we're just kind of feeling our way, and there's a lot of intuition in biology.

The ideas are actually still rather simple. I think that we could explain the risks as well as anything else that goes on in society, but all of us, including scientists, are so bad at risk assessment and really being able to weigh the dangers of one thing against another that I think there was a real fear that we wouldn't be able to explain it in a way that people would understand, and so they would try to impose sanctions that were inappropriate. But my guess is that the bigger thing, the quicker gut response aspect to this feeling of exclusivity, was just a complete confidence in peer review. It's just worked for us. Oral History Center, The Bancroft Library, University of California Berkeley 109

Hughes: And yet, peer review is a system designed to make judgments in science. Yet the recombinant controversy involved more than science. There were social, ethical, and even religious issues. That seems to me where the peer review argument falls down. I would be quick to add that I don't think peer review operates strictly on scientific grounds.

Yamamoto: [laughs] Absolutely.

[begin tape 8, side B]

Yamamoto: What you just said is quite correct on every element. That is, that there were many issues that were raised at that time that went beyond the safety assessment question, that spiraled out into, as you said, religion, social sanctions, ethical matters. Standing if not outside of peer review, they were far more global than simple peer review. That's true. There was a feeling that other people [nonscientists] deserved to have a say about how things would proceed.

I agree with that, and on the one hand I feel that it is something that scientists have swept under the rug, and maybe it's an apt charge to say that we orchestrated things to try to keep those decisions out of the limelight and maintain as much control as possible. I think that scientists have tended to think that these are big, difficult social problems that we're not very conversant about ourselves. We have failed to communicate them well to others because we can't really say them very well to ourselves. So I would guess that there was a tremendous lack of confidence on the part of the community about how we could bring a constructive conversation to bear on these topics. Therefore, there maybe was an effort just to duck them purely on that basis, if not for other reasons.

I think it's regrettable that scientists haven't done a better job at communicating to the public what it is that we do, what we think about, and what the implications are for our actions. We are still very much at risk for really having to pay for that silence over the years. Our easy out over the years has been to say, "Well, we're working on cancer; we're working on aging; we're working on arteriosclerosis." So that all sounds fine. "Just give us our money, and we'll be on our way. Thank you very much."

I hope that the community is beginning to repair that a bit now, but only beginning. There is a mood right now to make science education of lay people real, and for us to really tell Congress what it is that basic scientists do and why, and ask for our funding on the basis of that rather than the Oral History Center, The Bancroft Library, University of California Berkeley 110

catch lines that we've used for so many years. But really, that is just beginning. I think that we've been irresponsible in that way.

Hughes: What has changed to make the scientific community wake up to the fact that it really has to make an effort in terms of public understanding of science?

Yamamoto: I think in part [due to] some enlightened leaders, people like Bruce Alberts. And in part the realization that we're going to be asked to be accountable for all this money that we've been given over the years. People are finally going to say, "Well, what about cancer? What about atherosclerosis? Why do you keep promising? What's going on in your laboratories after all these billions and billions and billions of dollars?" Some scientific societies, I think, have done a lot in this regard, the Cell Biology Society in particular. People are waking up and saying, "Well, we can say what it is that we do, and we should; we must. And that if we do it well, then people will still be behind us, and they'll still want that money to be spent." I think you've heard this line, "If you think research is expensive, try disease." [laughter] We're spending $10 billion a year in this government on research at the NIH; we're spending $1 trillion on health care. So there's a big difference there.

Well, if you then step back twenty years and ask, "Why didn't the scientific community act in a more responsible way with respect to these ethical issues?" I guess my own answer to that is, yes, wouldn't it have been nice if we had, but we didn't know what to say. We didn't have a clue about how powerful it [recombinant DNA technology] was going to be, whether it was dangerous or not, and what the real implications were versus what anybody sitting down at a typewriter could conjure up. Maybe it was all of those things that we had to speak to, and it would have been good if we had. But we just didn't know how, and as I said, we've been kind of crippled as it is, even with things that aren't controversial, about how to come clean about what it is that we're doing. So it just didn't seem like it was in the cards to be able to do it at that time. It's too bad.

Hughes: I think juxtaposed is the certainty among scientists of what this technology was going to do for science. You had uncertainties in terms of the social ramifications, yet it was clear that recombinant DNA technology opened up vistas in science.

Yamamoto: You're right. I think when you look at it that way, there was a tremendous apparent conflict of interest. We had everything to gain by making the problem go away if we could. That was apparent pretty early on; you're right. But I really do think that there were quite a few people, including some leaders in the field, that even though it was apparent to us all, even Oral History Center, The Bancroft Library, University of California Berkeley 111

those who weren't directly involved, how powerful this [technology] would be, that we were really saying, "Let's go slow here and figure this out." They got a lot of heat pretty quickly from other people, really unrelenting pressure from other people in the community that came from high places. But they stayed the course, and just said, "No, let's just take it easy here and do the right thing." I think that's great that some people were able to do that, as I said. I just don't think that we lost enough [time] to make it even worthy of debate.

Hughes: Did the RAC guidelines affect your research in any way?

Yamamoto: Well, only modestly. We started cloning a mammary tumor virus DNA at a time when it was still complicated to get the biosafety clearance and to get the MUAs [Mutual Understanding and Agreement] and all the things that were needed. So everything took a long time. You went through these multiple rounds of applications for MUAs and getting things cleared all the way to RAC, but other than that, there was no problem. So again, our work may have slowed down a little bit, but we do enough ourselves to slow it down. [laughter]

Hughes: Yet some of the research in the [biochemistry] department was jeopardized. I'm thinking of the insulin research which was eventually moved to France to escape the guidelines. I think it was as simple as that.

Yamamoto: Oh, absolutely.

Hughes: How did you feel about that, and how much discussion was there in the department?

Yamamoto: Oh, it generated a fair amount of discussion. People were polarized about it. I think by then, my own personal feeling was that the experiments were not going to be dangerous, but that the data weren't in yet. I don't remember whether I was worried about the U.S. falling behind Europe. That was talked about a lot.

Hughes: That was the flag that was raised.

Yamamoto: Oh, yes. It was a good one. This nationalistic [argument] is one that's always very effective in Congress, for example. "If we don't do this now, we're going to be—" So I don't recall where I stood on that in particular. But I was aware that there were experiments that were moving to Europe to escape the guidelines. I had some element of me feeling that that was kind of cheating. But I also was beginning to feel by then that the experiments probably were not going to turn out to be dangerous, that we're still going to need more testing to find out, but that I had confidence Oral History Center, The Bancroft Library, University of California Berkeley 112

in the way that the biosafety guidelines were being set up that if there was a problem that it would be caught and that we would be okay if we just followed these rules.

I guess it was from this feeling that, yes, I had confidence in the way the guidelines had been mapped out: [ they are] a pain, but if anything goes wrong, we're going to figure it out right away. And therefore, I probably felt that going to France to escape the guidelines was sort of cheating, that stepping around them was making everyone else do the experiments [conforming to the guidelines] while you didn't have to.

Hughes: They were called "guidelines" rather than regulations. Is that significant?

Yamamoto: Probably. I think every word that came out of RAC was debated at tremendous length. So I suspect that it probably was meaningful. I wasn't on the inside of that, so I don't know.

Hughes: The Singer-Soll letter mentions guidelines rather than regulations. And to my mind, there is a significance there. Guidelines are just that; they're to guide you in an ad lib way; they don't have the force of regulations.

Yamamoto: But they were treated very much as regulations. You really had to follow every one of them. So in that sense, they really were regulations. Everything had to be certified and signed by multiple committees, and [there were] a lot of forms and things of that sort. So except in name, they were indistinguishable from regulations. It's the old, "walks like a duck, quacks like a duck" problem. [laughter]

Hughes: Well, then there is the question of legislation at various levels. This department, of course, was critically involved. It really came to a head in 1977 when there was a series of hearings, and they happened under various aegises. But perhaps the one most relevant to the department here was the Senate subcommittee hearings under Ted Kennedy.37 The first one did not, as far as I know, involve anybody from UCSF. The second one, which occurred in November 1977, certainly did; Dr. Rutter and Dr. Boyer were called on to testify.38 There were at this point several bills pending in both the House and the Senate [related to recombinant DNA], and the state

37 The results of the hearings were published as: Recombinant DNA Research and Its Applications. Oversight Report by the Subcommittee on Science, Technology, and Space of the Senate Committee on Commerce, Science, and Transportation. Washington: U.S. Government Printing Office, August 1978.

38 For a draft of Rutter's prepared testimony (as distinguished from the text of his Senate questioning), see: Testimony before the Senate Subcommittee on Science, Technology, and Space by William J. Rutter, November 8, 1977. (W.J. Rutter papers, Special Collections, UCSF Library.) Oral History Center, The Bancroft Library, University of California Berkeley 113

legislatures were standing in the wings waiting to see what was going to happen or even moving on the issue.

It was a critical time. The federal or state governments could take away from the scientific community the power to regulate recombinant DNA technology. Was there anything happening in the department to attempt to derail these threats of legislation at various levels?

Yamamoto: I don't remember whether there were explicit things going on in the department to combat the legislation, other than letter-writing and things of this sort. There may have been other things going on besides that that I'm not aware of. There was a lot of controversy at that time in the department because of this plasmid issue. Part of the nature of the testimony that was given was about whether pBR322 [plasmid] was used after it was approved but before it was certified. And this caused a rather contentious faculty meeting and lots of contentious debate about the way that various experiments were being carried out here. We were all aware of the big race [to clone the insulin gene] going on with Wally Gilbert's laboratory [at Harvard], and I think all of us were proud of UCSF coming out on top in that one. But as the stories began to circulate about the illegal use of 322, then it raised a lot of flags around here, and we ended up having some long meetings about it.

So all of that was contemporary with all of, as you said, this huge amount of legislation that was beginning to churn through Congress about the ways that recombinant DNA would be used and who would control it. So I would guess that there was a very strong majority, of which I was certainly a part, that felt that scientists needed to keep control of the technology, and probably most of us engaged in at least signing letters, if not writing our own, to that effect. But at the same time, there was a lot of turmoil around here about how carefully the guidelines had been adhered to in these experiments. So it was an interesting irony that the things would happen right on top of each other. I'm not aware otherwise of an organized campaign to combat the legislation.

Hughes: I read that petitions were sometimes circulated at various meetings, Gordon conferences and that sort of thing.

Yamamoto: Oh, yes, that's true. There were petitions and letters that were signed, and probably some of them came around here as well. I don't recall. But yes, certainly at Gordon conferences, that's right.

Hughes: Were you more involved with the pBR322 issue than just being part of the department? Oral History Center, The Bancroft Library, University of California Berkeley 114

Yamamoto: No. I was part of the department. My lab by then was adjacent to Howard Goodman's, so a lot of those experiments, both with insulin and with growth hormone, were going on in the space right next to us or surrounding us in a way. So we knew [Axel] Ullrich and [Peter] Seeberg, and we followed their work closely. They were hard chargers who were always working all the time, so they were around to talk to all the time.

I think there was some nervousness on the part of a lot of us about how those experiments had been done. But we didn't know. So a meeting was called, probably by Bill, because he was aware of the debate that was going on. He knew that the [U.S. Senate] testimony was going to bring some of this out, so he was essentially putting us all on notice that these were things that were going to be said, so let's figure it out.

Hughes: Was there a format to the meeting?

Yamamoto: As I remember it, Bill [Rutter] presented his piece about how things had happened; gave his chronology of what had happened. People asked questions and sometimes challenged him directly about specific points, about entries in the log book and the dates that things happened and whether the plasmids were really destroyed or if they were frozen or put away or when conversations took place. So there was a lot of quizzing going on in which Bill was called upon to give answers. And in some cases Herb [Boyer] was called upon to give answers about what had happened in what way and who said what and who did what with the plasmids. So it wasn't an inquisition; you don't do that to Bill. But yes, there were serious questions that were raised.

Hughes: So this was pre-Senate testimony, which was November, 1977?

Yamamoto: Yes, I'm sure it was before that.

Hughes: The 322 episode had occurred in January of that year.

Yamamoto: Oh, yes, that's right. It [the paper on cloning the insulin gene] was published in June, I think.

Hughes: Yes. Published too fast, some people have said.39 That was another criticism.

Yamamoto: Yes. I remember sitting down, I think with Christine Guthrie, and trying to calculate how long it would take to do the experiments if they started over

39 Nicholas Wade. Recombinant DNA: NIH rules broken in insulin gene project. Science 1977, 197:1342-1345. Oral History Center, The Bancroft Library, University of California Berkeley 115

again with pMB9 [a different plasmid]. And just on the basis of how long the sedimentations would take for the plasmid runs, it didn't seem possible. It wasn't completely impossible; it was not mathematically ruled out, just like the 49ers may not win the NFC West, but they would have to lose every game. So it was one of those [situations].

Hughes: I talked with Ullrich40 after the symposium for Rutter's retirement and of course asked him that question. He said that he had done the initial experiment and it had worked; he still had enough RNA, and the paper was already in process; it was being written. He staunchly maintained that the experiment was totally doable in a short period of time.

Yamamoto: It was, as I said, not mathematically impossible, but it was tough. But Axel was a tough guy. He could really turn the crank. So if anybody could do that, those guys could do it. Seeberg and Axel were kind of legendary for being able to really get the results.

Hughes: Seeberg had no direct hand in the insulin work, did he?

Yamamoto: No, he was doing growth hormone.

Hughes: Ullrich said that he practically lived at UCSF.

Yamamoto: Oh, yes, and it's true. Those guys worked all the time. And it was great actually. I've tried to emulate that same sort of intensity in my own lab. It was a very exciting time, and they were really hard-driving guys. So yes, maybe they did it. I don't know.

Hughes: They have all been testifying for the Genentech, [Eli] Lilly, and UC suit. So maybe some new information will come out of that.

Yamamoto: I was deposed a couple of weeks ago. The case is still going on. It will never end. My best friend probably is Barry Polisky, who was first author on the original beta gal[actoside] fusion expression vector paper, which is the basis of one of the lawsuits because it's how Herb Heyneker expressed somatostatin to high levels. He's been through this courtroom scene and lawyer scene ever since—many, many, many years, and it's still going on.

Hughes: Are they getting new information?

Yamamoto: Not from me. I can't remember what I had for lunch last week. [laughter]

40 See Ullrich oral history at http://ucblib.link/OHC

Oral History Center, The Bancroft Library, University of California Berkeley 116

Hughes: So they're really pulling in everybody that was even peripherally involved.

Yamamoto: Oh, yes. They wanted to know the nature of my conversations and showed me—it's probably illegal to tell you this—people's notebooks, saying, "Do you remember this experiment?"

Hughes: Well, another factor driving the recombinant DNA controversy, particularly as time went on, was the potential commercial applications. Did you see commercial potential driving the process of deregulation?

Yamamoto: I don't think I actually did see that although, again in hindsight, it's a really obvious possibility. I was much more caught up in the issue of academic and industry relations than I was caught up in the issue of how recombinant DNA technology could be turned into new industries that would change the economy of the country. I was much more worried on a much more limited scope, because that's all I had, of how for-profit companies forming literally in our own front yard would affect our academic environment. I was very concerned about that; got very involved in it.

Hughes: I want you to talk at length about that, but maybe not right here.

Yamamoto: Yes, I will. No, I don't think I was conscious of this other thing. I would guess that for at least some people, it was a critical driving force for keeping [research] unfettered. But I hadn't thought about it that way.

Hughes: The information of successful expression of human somatostatin at Genentech was leaked to Phillip Handler who then made an announcement in the course of one of the Senate subcommittee hearings, calling it "a scientific triumph of the first order."41

Yamamoto: Phil was president of the Academy [National Academy of Sciences] at that time.

Hughes: Right.

Yamamoto: So that was very meaningful that he, the president of the Academy, would stand up and say this in Congress. I remember hearing about it, but I don't remember whether I heard about it as it occurred or whether I heard about it only later.

41 Stephen S. Hall. Invisible Frontiers: The Race to Synthesize a Human Gene. Redmond, WA: Tempus Books, 1988, p. 175. Oral History Center, The Bancroft Library, University of California Berkeley 117

Hughes: So it wasn't a big thing in the department, as far as you were concerned?

Yamamoto: Not for me.

Hughes: Well, let's go back to your interesting statement about how the scientific process in the United States works in a unique fashion.

Yamamoto: Yes, because I think this has a big influence over the development of scientists like Axel and Peter and the way that they operate. I think it's true that there is nowhere else in the world where the scientific establishment is similar to [that in] the U.S., in a couple of very important respects. The main one is that people are hired as free agents. They don't come as faculty members to work for a senior professor. In every other country—

[begin tape 10, side A]

Yamamoto: [In the U.S.] when someone is hired onto a faculty, they come as free agents. They are shown their laboratory and turned loose. I think this has had a tremendous impact on the way that American science has developed. It is said that this allows the capture of people's maximal creative periods. Maybe that's true. But I think just simply giving this level of confidence to someone just in the door means that the system can move forward. It has a flexibility to it and an adaptability to it that is really not matched anywhere else. No one is telling these people what to do.

In fairness, I should say that all of us are aware that NIH is targeting money in this direction or that direction. But this is really on a very broad scale. So in general, people can do whatever they want. Although it varies with institution and agency, it permeates every aspect of the scientific society. An assistant professor has just as much say about a paper that he or she is reviewing as a full professor. The impact of that review is the same. The paper gets rejected or not rejected. Assistant professors commonly aren't sitting permanently on grant panels, but they're sent grants for ad hoc review, and when they are invited as young associate professors, their vote is one vote, just like the Nobel laureate next to them.

So we all grow up with this attitude that we don't have to wait to have some seniority before our voices can be heard. I think it frees us to say things scientifically that we might not otherwise say or to try experiments or go in directions that we might not otherwise go. And that is the single thing that I think has driven American science the way that it has. I think the figures for Nobel prizes in medicine or physiology, 157 I think is the number, over 100 of them have been [received] by people in the American scientific enterprise. Not all of them are Americans, but people who hold Oral History Center, The Bancroft Library, University of California Berkeley 118

NIH grants and are working in U.S. institutions. I think on the one hand that's because there's a lot of money in the system, but I think it's no accident that it's worked out the way that it has.

So I think that all of these things that became issues of debate around recombinant DNA or the rate at which Peter and Axel were doing their experiments or any of these things in the end are just natural products of the system that has been developed here. There's no standing on ceremony. That's certainly the way that UCSF is, in spades. In a way, it's a quintessential example of American science. Mike Bishop [a Nobel laureate] doesn't get any more accord than the assistant professor that was hired two weeks ago. And I think that Mike would say that that's the way it should be.

Hughes: Well, two concrete things evolved from the recombinant debate. One of them was the UCSF biosafety committee, which did not preexist the controversy, and in fact began to be talked about in March of 1975. I found a letter in the archives from Brian McCarthy to Dean [Julius] Krevans suggesting that what he then called a biohazards committee be set up.42 But more than a year passed before a committee was set up. The biosafety committee first met here in October of 1976.43 Is there anything unusual in the length of time between the letter and the actuality?

Yamamoto: I wasn't on the inside of that, so I don't know. University red tape can certainly stretch that long. [laughter] There's no doubt about it. So my first impulse would be to say that it was more that, but I don't know the inside story about that at all.

Hughes: The suggestion was that the biosafety committee be modeled after the human use committee, which was already in existence.44 There were thirteen members, and David Martin was the chair, chosen in part because he was not directly involved with recombinant experiments, at least at that time.45 James Cleaver took his place within a year or two. Do you know why David Martin stepped down?

42 Brian J. McCarthy to Dean Julius Krevans, March 25, 1975. (Special Collections, UCSF Archives, School of Medicine Records, AR 90-56, carton 1, folder 18.)

43 UCSF News Services, October 5, 1976. (Special Collections, UCSF Archives, News Services Records, 1976- 86, AR 86-7, carton 2, folder 76.)

44 Leslie L. Bennett to David W. Martin, June 15, 1976. (Special Collections, UCSF Archives, UCSF News Services, AR 86-7, carton 2, folder 76.)

45 UCSF News Services, op. cit. Oral History Center, The Bancroft Library, University of California Berkeley 119

Yamamoto: No, I don't know anything about that.

Hughes: I wondered if it was because Martin became involved with recombinant research, and it was thought inappropriate for him to remain committee chairman.

Yamamoto: That's possible. I really don't know the story behind that.

Hughes: There were three scientists on the thirteen-member committee who were doing recombinant research, namely, Boyer, Goodman, and McCarthy. There were two members from the general public.46

Yamamoto: This was the original committee in '76?

Hughes: Dr. Yamamoto, you've looked at some of the documents related to the biosafety committee. Do you wish to comment?

Yamamoto: Yes. In looking at them now, it seems very notable that Brian McCarthy's letter, which was dated in March of 1975, really came hard on the heels of the Asilomar meeting in February. So I think that we were aware because of that meeting that the writing was on the wall, that we knew that there were going to be some guidelines. Something was going to be enunciated from Washington about how this technology was going to be governed— an oversight mechanism. So it was probably directly as a result of that meeting that McCarthy sent the letter to then-Dean Krevans about this, including suggestions of names to be on the committee.

Then the next thing that we saw was the fact that a vice chancellor [Leslie Bennett] was then sending out letters to prospective committee members, or essentially assigning them to the committee, and that was not until more than a year [later]. We were talking about this whole red tape issue; the distance from the second floor to the first floor was a long way. [laughter] And so at least some of that time could have been eaten up just moving things from the School of Medicine to the whole campus. It was the chancellor [Francis A. Sooy] who then appointed the biosafety committee, and then things began to operate from there.

Hughes: Did the focus on biohazards have repercussions at the level of your lab? Did you indeed change protocols as a result of this heightened focus?

Yamamoto: Oh, big, huge changes. A lot of things spilled out from the guidelines. One of them was that mouth pipetting was outlawed. Getting people to change

46 UCSF News Services, op. cit. Oral History Center, The Bancroft Library, University of California Berkeley 120

that was tough going. I became kind of a guru who would run around and invent new little pipetting devices. There are jokes in the lab about this still, about my finding yet new and more fun and better ways to pipette things other than using your mouth. [laughter] That was my way to try to get everybody to change.

And there were still pockets of resistance in my own lab that were really irritating, and I'd come in and see people mouth pipetting. By then the containment studies had shown absolutely that if you put your fingers in your mouth, that everything that you had touched that day would then be in your mouth. I mean, there was absolutely solid evidence of this. It included viruses and radioactivity and toxic chemicals and all of this stuff that you handled during the day which would end up in your mouth if you mouth pipetted. You put your finger over the tip of the pipette, let the stuff drain out; you put the pipette back in your mouth, and it was all over. In fact, there was one pipetting procedure that involved actually putting your finger in your mouth and kind of inhaling and keeping that tip partially covered at the same time. So that was one thing.

But then there was the wearing of lab coats and scrubbing things down, and no food and drink in the laboratories, no smoking in the laboratories. Those were huge changes that required all kinds of — There was a lot of grumpiness about a lot of these things—wearing lab coats, closing doors.

Hughes: Was it up to the P.I. [principal investigator] to enforce these changes?

Yamamoto: The P.I.s were ultimately responsible for enforcing them. And I think there was a mix of how stringently they were adhered to. But in general people were very responsible about it and felt that it was the right thing. We had seen published data from, I think it was, NCI's [National Cancer Institute] studies that showed this mouth pipetting thing, and it was something that I used to wave around in front of people. But there were lots of studies of that sort that rationalized why the guidelines said certain things.

Hughes: Was there any protocol established at the university or at any level for teaching safe procedure?

Yamamoto: Yes. That's a good question, of when these courses came into being. Jeez, I can't remember. The federal guidelines came around,47 and there were UC and School of Medicine guidelines as well that included local phone numbers, things of that sort. And then little lectures on handling biological materials were given. I don't remember who sponsored them or the format.

47 The Recombinant DNA Advisory Committee (RAC) released the first set of guidelines in July 1976. Oral History Center, The Bancroft Library, University of California Berkeley 121

But there was some effort at didactic instruction. But most of it was, read the guidelines and follow the rules.

You got this big book full of all this information about the various containment procedures, and one applied to having certain parts of your lab cordoned off as a P-2 or a P-1 level of physical containment. And there was all this stuff buzzing around of what your lab was outfitted to do, what they could do, and whether people were mouth pipetting. It doesn't sound like very much now, but it was really changing a culture.

Hughes: I saw reference to a UCSF manual.48 Was there a system to make sure that the members of each lab were actually following it?

Yamamoto: I don't remember that there was any kind of policing system. Was there? [laughs]

Hughes: I don't know.

Yamamoto: I think we were each called upon to just do it.

Hughes: Do you remember the Smithsonian article by a writer who spent a few months in Herb Boyer's lab?49 The article portrayed variable adherence to safety procedures and a casual attitude to the guidelines, at least as expressed by one or two of the postdocs in his lab at the time. It raised the issue of how well these rules and regulations were actually enforced.

Yamamoto: I guess they weren't. I don't remember them being enforced.

Hughes: How would you enforce them?

Yamamoto: I don't know. I wouldn't want to.

Hughes: What happens nowadays?

Yamamoto: Nowadays, the driving force behind adhering to those sorts of requirements is the radioactivity business. It's those guys that say, "You can't do any of this stuff in the lab; you can't eat, drink, mouth pipette." It is more of that than on the biosafety side. It's probably merited. So I think in general, people are very good. It took a while to get that culture turned over. Of course, the whole place is smoke-free; that's nice. But to walk

48 Regulations concerning use of P3 facility [n.d.]. (Op. cit., AR 86-7, carton 2, folder 76.)

49Janet L. Hopson. Recombinant lab for DNA and my 95 days in it. Smithsonian 1977, 8, no. 3:54-62. For Boyer's letter in response, see Ibid., 8, no. 5:10. Oral History Center, The Bancroft Library, University of California Berkeley 122

into a lab now and see somebody eating is a really jarring experience. So if there are labs where that's allowed because there's no wet experiments going on—their labs are just computers—and people are drinking coffee and eating, you think, my goodness, this is a little peculiar. And that's a big change.

Hughes: Well, another concrete outcome of the NIH guidelines was the P-3 lab. Why was it in the Department of Biochemistry?

Yamamoto: Well, everything was flowing in this direction. Rutter was here, so there was a lot of ambition to move ahead [with] the cloning of various genes. We had the space and the resources, and so it [the P-3 lab] was here. It was never questioned. It was just assumed that it would be here, and that was it.

Hughes: A small committee was set up to administer the facility, composed exclusively of members of the department. Do you have any comment?

Yamamoto: [laughs] I guess I didn't process that, and it shows what our attitudes were like back then. No, I just didn't think about it. I really was being honest when I said that it was fully our expectations that that's the way it would be, that if there was going to be a P-3, of course it would be here. And the committee, oh yeah, that's who you'd pick. So I think we were already infected with that attitude. That's a good point; I certainly hadn't thought about it at the time.

Hughes: Well, we're winding up on this subject, but I did want to bring out the issues which seem to read down from the recombinant DNA controversy. One of them is freedom of scientific inquiry and whether regulation comes in at all and if so by whom? Do you have any summary thoughts?

Yamamoto: I think that governing [scientific] inquiry basically shouldn't occur, that the direction of inquiry really is the realm of peer review. This is a tough one. So one might then ask, "Well, what if somebody decides to mount an inquiry on racial differences and intelligence? What are you going to do with the results to such an inquiry?" I guess my hope is that peer review would do the right thing at that stage. I would hope that peer review would ask, "Is the study well-founded, and if we knew the answer, would it make a difference to the way that we think about biological processes?" Both of those things should be satisfied in the affirmative if the study is going to go forward.

And so to step back from such a controversial and difficult issue: in general it's my feeling that scientific inquiry is, as I said, the realm of peer review and that it should be governed on that basis. But we have to always Oral History Center, The Bancroft Library, University of California Berkeley 123

be mindful, or more mindful than we have been in the past, that all the scientific inquiry and all of the scientific establishment is simply a little part of society, that we're just embedded in the society, and that with that comes responsibilities of being part of the society. So while the inquiry goes ahead, the way that we use the knowledge and apply it has to be done as members of society. And to do that well really demands that we make available the information that we're uncovering to people on the outside as well. So how we use scientific knowledge and how it's going to be applied or restricted or commercialized or not are all decisions that fall to the society. Society can only make those decisions well if we're free with the information.

I guess that how I think about it is that the knowledge itself is valueless, and as curious animals, we're going to go ahead and try to move ahead. But we have to be increasingly responsible about how we use it. Not that we shouldn't have been before, but that its ramifications and the rate at which it can have effects is so immediate and so profound that we need to really realize our responsibilities in a much more global sense than I think we have in the past, and do that. So it's really a parallel track that we should be following.

In a way, I think the recombinant DNA thing, while it was done in a rather cruder way at a different time when people were thinking about this in a different way, or it may be better to say not thinking about it, I guess my own judgment is that it proceeded okay, and that we basically did the right thing. We made some mistakes or didn't foresee the way that some of it would play out in the hands of the bureaucrats, that it ended up costing time, but it wasn't so much. I think it was okay.

Hughes: Is there a role for the public in the scientific process?

Yamamoto: I guess what I was trying to say was that I think there is a very definite, important, critical role for the public in making judgments about how scientific information is used. That's crucial. I'm less convinced that there is a role for the general public in making decisions about what science gets done, which particular experiments are chosen to be done. I think that these are judgments that require a lot of scientific training.

There is a debate going on right now that I've been involved with on the peer-review issue itself about how broadly based peer review committees should be in terms of their expertise. The debate stems from what I have called the breadth-versus-focus paradox, which is a very interesting one. That is that modern science is now being done in a way that is more than ever technology driven, and that to review a grant application that uses high-tech approaches requires that on that grant panel there is someone Oral History Center, The Bancroft Library, University of California Berkeley 124

who has really focused expertise into the nature of the answers that come out of such a procedure.

At the same time, biological research is more than ever very broadly based. We've begun to see connections between fields and approaches in ways that we could not see even just a few years ago. So it's not at all unusual for a single grant application to encompass experiments that have in them yeast genetics and protein biochemistry and maybe some structural work. So what that says is that for every grant that comes in to the NIH, the grant panel that reviews it has to have a great breadth of expertise. So how do you have both tremendous focus for a particular grant and great breadth of expertise that can handle a lot? It's a very interesting puzzle, and there's a big debate going on right now about how to structure peer review committees.

Well, that whole struggle is being waged by scientists that have spent their whole lives training to do this sort of thing, and we're having a hard time. It's a struggle. So when I think about that, and then try to map it against the lay public, I just think, no, that's not appropriate. You can't ask the [public] to do that. We're already questioning whether we can ask ourselves to—[

[begin tape 10, side B]

Yamamoto: But there is certainly a role, a critical role, to be played by the public at large about how the scientific knowledge is used. And it's a great fear that I have that because of the weakness of scientific education in this country in the K [kindergarten] through 12 years that the ability of the public to make those decisions in a reasonable way is really compromised. It needn't be.

Hughes: Anything more on this general subject?

Yamamoto: No, I don't think so. That was good. Oral History Center, The Bancroft Library, University of California Berkeley 125

Interview 6: December 22, 1994

[begin tape 11, side A]

Hughes: Dr. Yamamoto, we discussed last time the significant conversation you had with Dr. Tomkins, and I think there were some side issues connected with that conversation.

Yamamoto: It's true. One of the points that Gordon Tomkins made to me in that conversation that was so meaningful was, "Okay, you should just do it [research on mammary tumor virus]." It became finally apparent to me that a measure of his initial resistance came from the feeling on his part that studying mammary tumor virus was not really his idea. He didn't really have ownership of it in the way that I think he really felt ownership of the allostery idea and the genetic code idea.

I have projected out of that conversation that because of his own feelings about what had happened to his ideas in those cases, he wasn't about to stand in the way of anyone else pursuing anything. And I think that's what also permeated our conversation about my challenging him about whether he was really proud of all of his papers, when he got so angry with me.

Yamamoto: The interesting side issue that then came from that [conversation] was that as I began my own work, and after Gordon died, and I felt ownership of the [research] directions that we were pursuing, [I experienced] in fact some of those very same things that Gordon seemed to be fretting about, about ownership of ideas. They came back, not to haunt me in any way, but certainly revisited me directly with respect to the ways that others outside of my lab and outside of the UCSF community perceived, or I thought perceived, the role that I played in the work, versus the roles of Gordon Ringold and Harold [Varmus] and Mike [Bishop], with whom we were still collaborating.

[Gordon was] this super postdoc in my lab who had come from Harold's lab as a student. I was aware that as we were publishing this work, the virology community had some at best uncertainty about whose stuff this was. And I knew that Gordon Ringold was getting letters to do postdocs in "his" lab, even though he was now a postdoc in my lab.

I recall going to a meeting in Switzerland, which was attended by lots of tumor virologists, in which I sat on a bus going off to some session of the meeting with a European tumor virologist who said, "I've never been able to quite figure out whose laboratory this work is being done in. Whose work is this?" [I had] the normal feelings of uneasiness about ownership of the stuff. Oral History Center, The Bancroft Library, University of California Berkeley 126

Here I was a starting assistant professor and really proud of what we were doing. I definitely felt ownership of the ideas that we were pursuing, but the system that we were immersed in, just as Gordon Tomkins had indicated, had been established before us. So we were using it to ask this other set of questions. But the people who occupied that space, who lived in that community of tumor virology, didn't know who I was. There was no reason for them to know who I was.

I don't know how much they would have known who Gordon [Tomkins] was. Gordon was a very famous scientist, but in terms of the tumor virology community, I think that if Gordon were still alive or collaborating with Harold and Mike on this, then people would have said, "Oh, Harold and Mike are doing another thing with this RNA tumor virus." It was an interesting revisitation of that earlier conversation with Gordon.

Hughes: How did you answer the tumor virologist's question?

Yamamoto: I explained that I was an assistant professor and that Gordon had been a student with Harold and then had moved to my lab as a postdoc. It was extra confusing that we had stayed at the same institution that Harold and Mike were at. Gordon was going to go to my lab at MIT at the time that I was going to go to MIT, so then when I changed my mind, he stayed in San Francisco.

Hughes: You never discussed these issues directly with Gordon Ringold?

Yamamoto: Directly? Now, that's a very good question. I thought you were going to ask me about Harold and Mike. I don't think so. I know that it affected me, because assistant professors are, I think, filled with probably as many insecurities as full professors. [laughter] I don't remember actually sitting down with him. What would I have said, after all? He was a terrific guy. A lot of the reason that all this stuff was going so well was because of him, and so I was hardly in a position to sit down and lecture him about making sure that I got my credit. So I was in a funny position, and I don't think I ever did sit down and talk to him about it.

Hughes: Did you pick up any tension on his side?

Yamamoto: I perceived some. Here is a general issue that comes up as well: when he finished in my lab and went out and got a job at Stanford, there was a considerable amount of tension by then that already had developed over who was going to do what. Gordon felt a lot of ownership over the ideas that really got the system cranked up and working. He wanted to keep working on it. By that time that was the main thing that was going on in my laboratory, so I certainly was far from being in a position to just say to Oral History Center, The Bancroft Library, University of California Berkeley 127

Gordon, "Great, you deserve this. A lot of this was your ideas, and definitely a lot of it was your hands, and so if you want to do this, have a great time." I had cast my lot. So we were definitely going to keep going [on this project].

At the time that he was looking for and getting job offers, of which he got several and eventually chose Stanford, we had in a way the obligate conversations about who was going to do what. But the undercurrent of unspoken stuff was even stronger. I think both of us felt a fair amount of nervousness about that.

Hughes: What did he do when he arrived at Stanford?

Yamamoto: We competed for a while. The way that experiments work in the end is that you follow your results. It's a great thing about basic science. So even a little bit of difference in the way that an experiment is planned, like the cell line that you use or particular controls that you build in or how long you do something, even if you had had very similar or identical backgrounds, as soon as you separate, you would do [things] slightly differently, [and they] become key.

It's actually a nice feature of doing basic science [that] you're obligated to follow your results, even if following the results means that you decide to terminate that track of investigation. You sit down and make the decision: well, we've gone far enough; this isn't going to be fruitful. Let's back up, get back to the main trail, and start down a different branch. That happens all the time. And so it's true that we didn't reach a clear peace in terms of dividing up the spoils, and that a part of it we just agreed that we would pursue independently and just see what would happen. And over the years our results diverged.

Hughes: Which you're saying is just a natural process; it wasn't anything that was planned to avoid competition.

Yamamoto: No. Things became simpler and simpler.

Hughes: Well, that was one way of doing it. There was a race going on in the department—well, maybe one of several races—but I'm thinking of the cloning of the insulin gene.50 That work was directed at a specific goal. In such cases, it's difficult, it seems to me, to avoid competition.

50 Use of the term "race" was inspired by Stephen Hall's Invisible Frontiers: The Race to Synthesize a Human Gene (Redmond, WA: Tempus Books, 1987), which describes the competition between groups at UCSF and Harvard to clone the gene for insulin. Oral History Center, The Bancroft Library, University of California Berkeley 128

Yamamoto: Yes. The more that something is goal-oriented, then by definition things converge. You're going into the narrow end of the funnel. I felt that our work was going into the wide end of the funnel, so it was liberating. Gordon [Ringold] and I were both young at the time, and it's hard to have conviction about that perspective until later on [when] you feel more confident that your own ideas are okay and it's going to be all right. So even in the things we agreed about, I think there was a certain stand- offishness about the way that we approached the issues.

Hughes: Last time you described your general methodology as following the molecule, following the protein. Isn't that by definition an open-ended approach?

Yamamoto: Yes.

Hughes: So do I conclude from this that competition has not been a large element in your career?

Yamamoto: I don't know if you can conclude from that, but I think you're probably right, that there have been only a few points of intense, direct competition. In fact, the only two that come immediately to mind were the cloning of the glucocorticoid receptor cDNA [complementary DNA] in which we beat Brian Evans' group by two months or some completely absolutely insignificant period of time, and the demonstration of specific DNA binding by steroid receptors in general in which we didn't really know what the competition was, but we heard after we completed our work that there were competing papers in press.

Brian Payvar and I wrote that paper in no time, in less than a week. My papers in this lab usually take months to write, many months, many, many drafts, a lot of fooling around, additional experiments and things of that sort. So we whipped out that paper in no time and then found out that it was a long time before anybody else published.

Hughes: So that particular competition only affected the paper, not the way the research was conducted.

Yamamoto: [Yes].

Hughes: How about that first competition? Were you aware as you were doing the research that there were competing groups?

Yamamoto: Yes, we were. We knew that Evans was cloning, and we had heard that there were several other labs cloning. Nobody knew where anybody was. In fact, this is interesting: when we got our clone, as I did with the specific Oral History Center, The Bancroft Library, University of California Berkeley 129

binding, we were fortunate to be in a position where we had our results hammered out not long before some big meeting, a Gordon conference, a Cold Spring Harbor meeting, or something. So it was always really exciting to spring it on the community all at once, or at least I thought it was, rather than letting word dribble out or letting the paper get published. So in both of those cases, I was excited because we were able to announce [the results] at meetings before the paper had come out.

With the cloning, Ron Evans, who we were competing with—he's from the Salk Institute—was there [at the meeting]. Bert O'Malley's laboratory from Baylor was there. So we were in this nice ego-boosting position to make this announcement. Well, Evans had the same clone essentially at the same time. All these things happen this way. He published, I guess, a couple of months after we did. Essentially at the same time.

Hughes: You said that you weren't sure where he was in the cloning process, but just knowing that he was doing something did you rush?

Yamamoto: Oh, yes, we rushed. Absolutely. Both of the papers were slightly different than I would have had them if we had no competition.

Hughes: In what sense?

Yamamoto: We would have added more experiments. Not because we were worried about them being wrong, but because there were further experiments that could have been done that would have made the story fuller. But we wanted propriety.

Evans visited us before either of the papers came out; gave a seminar here. We had a very interesting conversation with him which ended in a bit of a skirmish because I let it be known that when the paper was published, we would send the clone to anyone. Ron wasn't happy with that. He felt—he made a legitimate point—that the students and postdocs in his lab and my lab that had labored so incredibly hard to get this guy [clone] should be allowed to milk it for a while, rather than having their P.I.s send it out willy-nilly to everyone.

And that's an interesting point of tension as well, and [one] that P.I.s deal with in different ways. On the one hand, it's easy and rather glib, especially these days, to say what I say. And that is, "Oh, well, if something is published, we send [the clone] to anyone." How can anybody argue with that? Well, there are people, like the people whose theses you're dealing out to other people [who object?]. So there were people in both of our laboratories that had killed themselves to get these clones, and so while it sounds nice for the P.I. to say, "We send out our material," they Oral History Center, The Bancroft Library, University of California Berkeley 130

were looking at us thinking, what the hell are you guys doing? This was a major, tremendously difficult effort, a major part of what it is that we're trying to do, and yes it's true that the clone by itself doesn't announce answers to the questions. But it's also obvious that this is a real main line to doing things that you just simply couldn't do before.

That was a tough line to define. I was determined to send it out to other people. I remember standing in the elevator in the [Medical] Sciences Building really promoting that idea with Ron, and his making the counter- arguments which I just told you about: "What about the fact that this person has killed herself for three years to do this? Are you going to just say, ‘Thank you very much. Please send out your material to everyone'?"

Hughes: So what did you do?

Yamamoto: Well, we sent it out. We do send it out. What we do is to ask everyone who requests any clone in our lab or monoclonal antibody or fragment of pure protein or whatever to send us something in writing saying what they're going to do. But then that's all we ever do. I don't even know if we keep [the requests], to be honest with you. We don't exact any more information, any promises, other than they won't distribute them [the material] without permission and they won't use them for commercial purposes. We don't say anything else in terms of restricting the experiments that they can do, or putting us on as authors of the papers, or anything of that sort. None of that happens. Every P.I. seems to treat these things slightly differently. There is no community standard to which everyone adheres.

Hughes: How do you feel about that?

Yamamoto: I think it's okay. To be honest, I have mixed feelings; I think we all do. I am comfortable enough with my version of morality that I think the whole world should follow it. [laughs] And I'll tell you a case where we got in trouble because of that in a minute. I think that I would rather have there be a diversity of behaviors and standards within a certain range in the community than to have some set of rules written down that to me would generate two risks. One is that to enforce them would require a police force of some kind, which I don't support. The other is, I think there is an insidious danger that we face in dealing with ethical issues in a bureaucracy. That is that the bureaucracy's tendency always is to make regulations, and the fear is that investigators, and especially students but all of us, will mistake written down rules for ethics. There's a very big difference. Oral History Center, The Bancroft Library, University of California Berkeley 131

So in a way I'd rather have it be the way that it is. I say that really because my experience is that the scientific community is filled with really responsive and responsible individuals. We all have anecdotes about exceptions to that, but do we want to create a society in which the laws of the land are written for those few people? Or instead, do we want to recognize the fact that by and large everyone acts really well, and there are some aberrations that are a pain in the ass to deal with? And I guess I would go for the latter. Now, maybe it's because I've never been badly burned, and I might feel really differently if something bad had happened that in my perception had affected my career or directly affected the career of somebody that worked in my lab. I don't think that's happened to us.

Now, there are middle grounds, so I'll tell you a short story about that. My standard, and the standard on which we operate in the lab, is that any inexhaustible resource that's published—DNA clone, monoclonal antibody—as opposed to an exhaustible resource, like a purified protein or a polyclonal antibody, becomes public domain.

Hughes: You make no value judgment about the type of research that's to be done with your clone?

Yamamoto: Yes. And the way you phrase that is very interesting, but we'll get back to that. But yes, that's right. So it becomes public domain and value-less in that sense. So it goes out to everyone who asks.

Then what we do, or what we have done for years, is to decorate the bald statement in two ways. One is that, because we ask for something in writing from everyone who asks for our materials, if it becomes apparent that they plan to do the same experiments that we're doing, I write back to them or call or fax and say, "Well, very interesting that you thought of these experiments. It turns out that Joe Blow, a student or postdoc in my laboratory, is doing the same experiments. So you may wish to consider this in planning your experiments. We're pretty far along, and we would prefer that you don't compete with us with our own material. However, if after thinking about this, you decide to go ahead, we'll send it to you."

Our experience has been that most of the people who request materials, upon hearing that news, then desist and they do something else. There's so much to do, it should be no problem. A few of the people press on, and we send them the clones. And I can't think of a single time when we've been burned by that. The students and postdocs can get pretty exercised by it, and I understand that.

Hughes: Well, you alluded to a case where you did get in trouble. Oral History Center, The Bancroft Library, University of California Berkeley 132

Yamamoto: Yes. The second middle ground is that people will send out a clone or a sample of an inexhaustible resource and with it will come a rider. The rider says, "Here is the clone you requested, and this clone is to be used for this experiment for which you requested it, but for no others." It basically says it's a restricted use. "You don't have permission to do anything [you wish with it]; you have permission to do what you said you were going to do, and that's it. If you want to do something else, fine, write to us. We'll talk about it. But this is what you get it for."

To be honest with you, I think I've tended to pay no attention to those riders. Not no attention, because I'm aware that people use them, but I don't have much respect for that point of view. So I think that it transferred into a lack of my cementing it into my head about what we're going to do with a given clone that gets sent to us.

So here's how we got in trouble: we got such a clone from somebody, and the somebody turned out to be a very famous and, more importantly, very powerful scientist in Europe. The clone was published, and we had a clone, we did a certain—we did something with it; I don't even remember what. A few years later, we thought of another set of experiments to do that would involve using this clone and actually would also involve our getting an antibody from the same lab.

I can say his name, right?

Hughes: Sure.

Yamamoto: Pierre Chambon, very famous guy, for whom I have lots of respect and lots of affection and regard. It became apparent in my conversation with Pierre that in fact they were thinking of a similar idea. They were using the estrogen receptor. We were using the glucocorticoid receptor, and we had his estrogen receptor clone, and we were thinking of doing a comparative analysis because the two receptors behave slightly differently in the way that we wanted to study nuclear localization.

In our conversation in the bar at this Gordon conference, it became apparent that Pierre's lab was considering similar experiments, so we planned a collaboration. It sounded like it would be fun. We had never collaborated with Pierre before, and we thought that would be fun.

We had more tools. We had mapped our localization sites in more detail, and for various reasons it made sense for the initial set of experiments to be done in San Francisco. So we said, "Great, why don't you send us your antibody, and Didier Picard in the lab will do the first set of experiments, Oral History Center, The Bancroft Library, University of California Berkeley 133

and we'll do the straight comparison between the two receptors, and we'll see where we are."

Well, we never got the antibody. We waited and waited and waited and waited, and we called; we faxed; we wrote. We never got the antibody. It was more than a little irritating. But Didier went ahead. We made our own antibody, or we bought a commercial one—I don't remember actually. His experiments worked very nicely, and we wrote a paper. We sent Pierre a preprint, because we have a policy in our lab that when we use material from another lab—we used their estrogen receptor clone—when we write a manuscript, we acknowledge them and we send out the preprint. So we did. I think I said something on the order of, "Pierre, you may remember we talked about this as a collaboration, and here is what we've learned."

We immediately get a fax back and Chambon is very irritated. At what? He's irritated both because, "I thought this was supposed to be a collaboration; we're doing these experiments too, or we're doing them better, or we're doing them faster; we're ahead," and, "You didn't have permission to use that estrogen receptor clone." Which by then had been published for four years. An entertaining set of correspondence passed back and forth in which we squabbled over this in various ways. Never once, by the way, did they ever say anything scientific about our manuscript, what they thought of our paper.

[begin tape 11, side B]

Yamamoto: [Pierre wanted us to delay] our publication until they could write a paper on a similar topic. I thought that they were behaving badly, and so I wasn't interested. So finally, out of exasperation, I sent Pierre a fax that said something like, "If you really think that someone in your lab has contributed substantively to this work, why don't you let us know that person's name, and we'll put him on the paper." It was obviously just simply a political or rhetorical device in which I assumed that the response would be embarrassment on Pierre's part—he's a very smart guy with lots of his own ideas—and he would say, "Yeah, that's a pretty good point. I think I'll just shut up now." Instead, he immediately fires back a fax with a postdoc's name and his name to be added to the paper. I was outraged, and I couldn't believe it. First of all, he's my friend, and secondly he was completely off the wall in my estimation.

So the resolution is the interesting part. I [added the two names to the paper]. I'm going to tell you why. Basically, I compromised my standards—this was clearly illegitimate honorary authorship. And then with respect to free availability of materials, it's at least an arguable case. Oral History Center, The Bancroft Library, University of California Berkeley 134

It's also the case that I'm sure I signed something that said I wouldn't use this clone. But I did. But in terms of the standards of the community, one could make an argument that such restrictions are inappropriate.

In any case, I added those two names to the paper. Why did I compromise my ethics here? The reason is interesting, and that is that Didier, who is a superb scientist, had by then found a job. He was Swiss, and he found a job at the University of Geneva and was concerned that Chambon was such a powerful scientist in Europe that if he went there under this cloud of Chambon being irritated with him that there would be political capital expended that he didn't have to expend as a new professor. So Didier appealed to me to add these names to the paper, and I did. So it was done purely on this political stance.

So here is a case of my own standards clouding my behavior with respect to using the clone, because I think when we send out a clone, as soon as it goes into the mail, it's not ours any more. It belongs to whomever gets it. And Pierre obviously didn't feel that way. And there's nothing written down that says it's one way or another. He's not an evil person because he decides to do that. He laid out a very clear standard, and I broke it. I'm sure he was irritated, so this thing happened. Well, that's not such a terrible thing in the end. Yes, honorary authorship is bad and yes, someone could haul me in front of some tribunal that would say, "Isn't it a clear violation?" and the answer is clearly yes.

Hughes: But the standards are loose, are they not?

Yamamoto: Yes, they're ill-defined.

Hughes: And perhaps also linked to nationality?

Yamamoto: Well, yes. What feels funny to me about this example is that I think honorary authorship can be a terribly damaging thing. It can really adversely affect the careers of young people, and it skews the power and attention that some senior people can garner if they abuse this practice in a general and global way. We all know of stories of people who do this, whose CVs [curricula vitae] grow to hundreds in which one has the very clear feeling that they don't really know the work represented in the papers. So it seems like a terrible thing, but here I was clearly actively participating in it and making a political decision.

I've been involved in science ethics quite a bit. I've been cast in the role of someone who has argued against having a series of very explicit rules and regulations, going out to the fourth rank of an outline, on situations that are mandated to be avoided, simply because of the complications in this Oral History Center, The Bancroft Library, University of California Berkeley 135

very simple example that I gave you. And that is, while one can write down a rule that is sterile in isolation and absolutely unchallengeable, what the rule does in its sterility is to ignore the fact that every human situation, certainly every scientific human situation, is cross-cut with lots of other circumstances that are going on that have nothing to do with the rule. So the more explicit you make the rules, the more commonly that you're going to run into situations where you say, "Well, in this case, it doesn't apply." Well, then do you really want to [make explicit rules]?

Hughes: Well, go back to your procedure of requesting to know what sort of research was to be done with the clone or whatever your lab was sending out.

Yamamoto: Okay. Bonnie Mailer [?], my specialist, spends an enormous amount of her time sending out cell lines we've made, yeast strains, receptor clones, and things of this sort. There are a lot of labs—we're in no way unique in this—that generate many more resources than we do that spend a lot of time doing this. It has always been my policy to freely send out materials, but to ask each person to say what they're going to use them for. The reason that I instituted this [policy] at the beginning was that I imagined that there could be circumstances of somebody saying, "Well, I'm in the Department of Defense, and I want to see if we can adapt your regulatory protein to activate a toxin gene at will in bacteria that we're going to drop out of an airplane over San Diego." And I would say, "Not with my stuff you don't." Well, that sounds pretty good, and in that case I guess it would be pretty easy [to say no]. But things are never that black and white, and I can't think of a single time when I've exercised an ethical standard over the ways in which our materials have been used. That's just not the way the world is cut out. In fact, I haven't thought about this for a long time until you asked the question. So we continue to ask for this [information about the use for the material].

Hughes: But you're still saying it's not for the purpose of evaluating the research?

Yamamoto: It's not for the purpose of keeping somebody from doing an experiment because we want to do it or because we are doing it.

Hughes: Or controlling the quality of research.

Yamamoto: Not to control the quality. We have certainly sent out this letter multiple times to people that want to do the same experiment we're doing, and I feel that that's my obligation as a responsible advisor to my students and postdocs. And a lot of them have been unhappy with just that. They want me to say, "No, you can't have it; we're doing that stuff." Oral History Center, The Bancroft Library, University of California Berkeley 136

Hughes: It's reciprocal, right? There must be many a time when you have written for other people's materials.

Yamamoto: That's right.

Hughes: Is it common that they too require some sort of written accounting?

Yamamoto: We always provide it because we ask for it, I guess.

Hughes: You mean even if they don't ask for it?

Yamamoto: Yes.

Hughes: Do most people ask?

Yamamoto: Yes. So I think it's not an uncommon rule, if it's not the general rule, but it's at least not an uncommon request on people's parts. People are used to it. We will always send the material. So if someone doesn't get a letter to us right away but they say, "I'll send you a letter, but could you please send this today," we would do that. What I would really do is say, "Fine, send me a fax." But we don't try to hold these things hostage.

When companies ask us for materials and we send them, we ask them for a donation to the lab of $1,000 per item. A lot of money. It's not a contingency. So we say, "The material is on the way," or "we'd be happy to provide the material. We would very much appreciate a contribution to our laboratory research in the amount of $1,000 per plasmid," or whatever. That money goes into the general lab account, and there are a few companies a year that comply with that. Some companies ignore it, and we send them the stuff, and some companies send the money, and we send them the stuff. Some companies send us one-fifth of the money, and we send them the stuff. And some companies I'm sure just say, "Screw that guy; we're never going to talk to him again," because we never hear from them again. So it really runs the whole shot.

Hughes: What is your rationale?

Yamamoto: The rationale, the excuse, is that a few [payments from] those companies a year pay for our whole mailing effort to all the scientists and academic institutions. So it allows us to distribute the materials to all of the other places, which costs us several thousand dollars a year, not at all counting Bonnie's time, which, given her salary, is a considerable amount of money. So it allows us to provide all those materials to academic laboratories for nothing, just on the basis of a few commercial companies paying up. Oral History Center, The Bancroft Library, University of California Berkeley 137

Hughes: I assume that there's another step in your thinking, namely, that these companies may possibly profit from having the use of your material and hence it's okay to ask them to pay.

Yamamoto: Yes.

Hughes: That is not, presumably, the case when it's an academic exchange.

Yamamoto: In fact, it's explicitly not. We say that it's for noncommercial use.

Hughes: That's the ethics of it?

Yamamoto: Yes. And that's worked well. I think most years a few companies pony up the money, and that covers our expenses. We can buy more shipping boxes and stuff like this. So at least we're close to breaking even because of that policy, which we've had for many years.

There are small companies I know that think that this is garbage. Here is a small company which is struggling to survive, and they've got a tiny scientific staff, one person of which has an idea for an interesting experiment to do, and I'm writing to him and saying, "Where's your thousand bucks?" [laughs] [He thinks,] What kind of a jerk is this? Does he forget where he came from [academia]? So I'm sure that [reaction's] out there. So yes, I think it's arguable that I should modify [my policy] so that if a company wants to use [my material] explicitly for commercial purposes, I would ask for money, and if they wanted to use it for basic research purposes, I wouldn't.

Hughes: Well, I pulled you way away from the chain of events that evolved from the Gordon Tomkins conversation. I think you wanted to say something about Bishop and Varmus.

Yamamoto: I did. So that was the other side of the tension. I felt I was a little bit of a sandwich here. Here's this fantastic postdoc whose work beginning as a graduate student with Harold really got this whole show off the ground. So who am I to say, "Hey, don't forget that this is my laboratory"? Without his contribution, we may well not have been working on that system. So here is that [problem]. And then [there was a problem] with Harold and Mike, who already were very famous.

Hughes: For what?

Yamamoto: For their work with tumor viruses, the Rous sarcoma virus that they were studying. I was feeling squeezed by them, that they were appearing as authors on all the papers that were coming out of our lab—not for Oral History Center, The Bancroft Library, University of California Berkeley 138

honorary authorship, because we were still collaborating. We had a couple of fights about whether I would be senior author on a given piece of work or one of them would be senior author. I can't remember any that I won in fact. [laughter] And I felt a little abused by that. I thought, jeez, you know, here's puny little me. What difference does it make to them what order the authors are on papers? And Harold disagreed about whether I was puny. He said this to me in the middle of one of our arguments: "Everywhere I go, everybody knows all about you; much more than they know about me. So forget it."

Harold, you remember, had come to UC as a postdoc just like I did. Harold came to Mike's lab. I didn't understand this at the time, but I think he was going through his own little thing about whose stuff [research] is this, [mine or Mike's]? So the last thing he needed was somebody coming in from below him [laughter], muddying the waters. And I was going through the same thing. Maybe neither of us recognized it. But there were some problems with that, and sometimes some real open battles between Harold and me. Not really between Mike and me. Mike was kind of above it all.

Hughes: Well, order of author is another area, is it not, where the rules are very ill- defined?51

Yamamoto: Yes, very much so. The only capital we have, at least before [biotech] companies [emerged], is getting credit. Another reason that I think the [science] community acts by and large incredibly responsibly is that all there is, all we can get, is credit. All we can get is acknowledgement for thinking of something or doing something before someone else or better than someone else. And yet the progress of scholarship in this field depends upon people spilling the beans over and over again, going out on the road and saying exactly what you've done, or sending something off to a journal saying exactly what you've done. Essentially you lay yourself open to someone taking it all away from you, someone bigger and better and smarter and faster.

Hughes: It's a paradox, isn't it?

Yamamoto: It's an interesting paradox. So within that paradox, I think that the community acts superbly. Yes, sure, there are jerks. But in general, I think it acts incredibly well, considering that our only currency is somebody patting us on the head and saying, "This guy was first or fastest or smartest

51 See the oral history with Stanley N. Cohen, for further discussion of order of authors on scientific papers. http://ucblib.link/OHC Oral History Center, The Bancroft Library, University of California Berkeley 139

or cleverest," or whatever. And yet, the real success of the [science] business depends absolutely on going out and telling the secrets.

So in that framework, I think I would rather have there be a lot of room and play in the way that things work because I think that things basically work. To write all these rules and regulations on the basis of the few jerks, it's better just to shame them out of business. My own experience, at least here, has been so positive, and there would be so much effort, and basically futile effort, to try to do it any other way, that we shouldn't bother. It doesn't mean that it [ethics] doesn't matter. It matters a lot.

Hughes: Has there been serious consideration given to finding a different way of ensuring ethics in science?

Yamamoto: Well, I've been on a lot of committees in Washington that want to enunciate more explicit rules to catch egregious violators of the social standard of the field. [Some say] that all we need to do is to be really explicit so it becomes really obvious that [violators] are going to get caught in the net. I've tended to argue against those [views], even though I'm certainly to the right of another group of people that say, "Don't write anything down. Why are you wasting your time going off to Washington to write anything?" And those are the people who were the strongest in saying, "Asilomar was a big mistake by the scientific community." And I think it wasn't. So I guess I'm a centrist. Good old Bill Clinton waffle- man. [laughter]

Hughes: Do you want to talk about your work on short- and long-range regulation of transcription?

Yamamoto: Yes. To give a little background: there was a paradigm that existed in bacterial gene regulation that had been well established by the time we were doing our work with mammalian cells. We thought of the glucocorticoid receptor very much as an analog, for example, of the cyclic AMP [adenosine monophosphate] binding protein in E. coli. Regulatory factors in E. coli work by binding two specific DNA sequences immediately adjacent to the promotor, the place where the RNA polymerase enzyme binds and begins to synthesize RNA. And the immediately adjacent part was absolutely critical, and beautiful experiments have shown that. If you changed the relative positions of the binding site for the regulatory protein and the RNA polymerase by a single base pair, everything changed. Basically, the regulation fell apart. So there was a paradigm which was very well founded and well grounded by then that said that regulation would work by this very short-range mechanism. That's one backdrop statement. Oral History Center, The Bancroft Library, University of California Berkeley 140

The second backdrop statement is that [Firin?] Payvar, a postdoc in the lab, succeeded in demonstrating that the glucocorticoid receptor on MTV DNA indeed bound to specific sequences, again close to the promoter. They were not that close. Instead of being immediately adjacent to where they are in the polymerase, they ranged from ten base pairs away to 200 base pairs away. But they were close. After all, the mammary tumor virus DNA was 9,000 base pairs long.

At the same time that this work was going on, several groups had discovered a strange behavior of certain pieces of tumor virus DNA. This came about because people were doing transfections. People were building vectors, plasmids, into which they could insert their favorite gene, and then that plasmid could be used as a vehicle to introduce the gene into a living cell to see how that gene expressed.

A discovery had been made in several labs essentially simultaneously that when certain pieces of the SV40 DNA were sitting on that plasmid, or other tumor viruses, like polyoma, were sitting on that plasmid, the promoter to which the gene you're trying to express was linked worked much better than if that piece of SV40 DNA was not there. Much better meaning fifty-fold better, a hundred-fold better. Really a big difference, a difference that could not be ignored.

It was mysterious, and what the hell was going on here? All you're doing is you're building a vector; you're using this SV40 base because it's a good piece of DNA—it had been cloned by Paul Berg; it was a useful piece of DNA—and suddenly your promoter is working like gangbusters if this piece of SV40 DNA is there, and it's just frumping along if it's not. So people dubbed those pieces of DNA "enhancers”. This was about 1980.

Basically, we didn't have ways to think about them. People were a little frustrated with people just throwing this word "enhancer" around and not knowing what it meant. What was clear was that, completely counter to the bacterial paradigm, it didn't matter where this piece of SV40 DNA was relative to the promoter. So many of us said, "Oh, well, it has nothing to do with standard gene regulation. We know how gene regulation works. That ain't it. It must be yet one more weird thing about viruses."

Yamamoto: This has been a standard charge that's been leveled on any research of this kind, that began back with bacterial viruses, bacteriophage, where something weird would be discovered. The first assumption was, "Well, you know those viruses; they can't be trusted. They're going to do weird things, and those weird things are absolutely irrelevant to what the cell does." Well, that's nonsense, but that was the standard thing that people said. I can't remember saying it, but I'm sure I did. Oral History Center, The Bancroft Library, University of California Berkeley 141

And the reason I say it's nonsense, aside from now having the benefit of hindsight, [laughs] is that the very simplicity of these parasites, the viruses, means that they can't be very creative. They can be opportunistic, but they can't be very creative. They can't just think of a whole new way of doing something. They have to go in and do things the way the cell does them. They can be opportunistic; they can rip off what the cell's doing, but they can't just invent something out of whole cloth because there's just not enough cloth. I think people tended to think, when they saw something weird, "Oh, you know, those tumor viruses. That's just the way it is. They're always doing something funny."

Hughes: The fact that they are stripped-down entities eliminates the likelihood of their presenting a unique circumstance.

Yamamoto: But the trouble is that there's a perfectly good logical construct that can be used for the other rationale. You just discovered the one that fits my model. There's not enough stuff there to do anything really interesting; they must simply be adapting something the cell does.

The counter argument also sounds pretty nice, if I say it to you fast, and that is, the evolutionary drive has been to get this tumor virus genome down to 3,000 base pairs, and to do it, it had to figure out ways to use these base pairs in multiple ways. No base pair goes wasted. In fact, it's going to be used for multiple things. And it was getting discovered already, the sequencing was being done, that there were overlapping genes, that there were genes within genes, things that made people feel comfortable with that idea. This is a virus that's been through many more generations than you and I have; it's had more time to fool around and think of things, and so it does. And that sounds pretty good, too.

Hughes: All right. What's wrong with that hypothesis?

Yamamoto: [laughs] I don't know! I'll have to go back and think about it.

So with that as a backdrop, we then jump to some experiments that we were doing. I read this literature, like everybody else, because we were all captivated by it, even though we didn't understand it. I didn't understand it. What I need to emphasize is that most people in the field were mostly just thinking of this as some funny aberration, and not as a regulatory protein binding site, because we knew how they [enhancers?] worked. They work right next to them [promoters?]. Oral History Center, The Bancroft Library, University of California Berkeley 142

[begin tape 12, side A]

Yamamoto: —[complete] the hardware that was responsible for specifying that a given gene would be glucocorticoid-regulated, and that this was the sole delivery system that was involved in saying, "Okay, this gene is now under hormonal control."

So the way I thought about doing this was to seize on the fact that we knew where the binding sites were and to ask, what if we took the isolated binding site and simply glued it next to a promoter that itself is never regulated by glucocorticoid, has nothing to do with glucocorticoid regulation, and now ask, is that sufficient to bring this promoter under hormonal control? If it was, it would be the simplest case. It would prove that that binding site was enough to do it.

Well, we didn't have quite the goods to be able to do exactly that experiment, but we could take a restriction fragment from MTV that included the binding sites. What we do now is synthesize the oligo[nucleotide]. We took a fragment that included the binding sites, and we—Vicki Chandler, a wonderful graduate student who's now a professor at Oregon—fused it to the thymidine kinase [TK] promoter from herpes simplex virus, a promoter that cared nothing about glucocorticoids. She showed first in controls that the promoter just couldn't care less about this hormone. She fused a restriction fragment that contained the specific binding sites that had been identified by Payvar in the laboratory, and now put—transfected—that stuff back in the cells and asked, what happens to the TK promoter, plus and minus hormone? And bingo, it was regulated. Another pretty exciting day in my life.

We had gone to great efforts in the initial construct to put the binding site in exactly the same place relative to the TK promoter [so] that it sat next to the MTV promoter. But cloning being the way that it is and was, Vicki also recovered things where the fragment had gone in backwards or where there was other DNA lying around that went in, things that were just messy. Those were also hormone regulated. We thought, wow, what the hell is going on here?

So we wrote a paper which was published in Cell in which we pointed all this out, including this funny result that it worked even if the fragment was backwards, from a distance, and pointed out the correlation between those findings and the way that those enhancer things were working. We wondered at the end of the paper whether enhancers were simply binding sites for regulatory proteins, but that in eukaryotes they have somehow figured out a way to work at a distance instead of working by the standard Oral History Center, The Bancroft Library, University of California Berkeley 143

paradigm. The enhancer phenomenon then was not anything weird; what was weird was the unexpected way that we thought regulation would work in animal cells. It's later proved to be much more global.

Then we wondered in the discussion [section] of this paper whether all gene regulation in eukaryotes would be at a distance like this, and that enhancers would be this long-range regulation, [and] would be the way that gene regulation would work in eukaryotes. Because if that were true, then it would provide a way for lots of different regulators to impose their actions on a given promoter without them having to all crowd into this little, tiny space.

The reason that I thought of that idea was because of the review article that Bruce Alberts and I had written in 197652—now we're back to this old Britton and Davidson combinatorial regulation business—in which we suggested, as Britton and Davidson had suggested, that the way for a gene to be regulated by many, many different paradigms, from situation to situation or cell type to cell type, [is that] there's a relatively small number of regulatory factors that work in combination, and that different combinations would give different patterns. We enunciated in this 1976 review a specific way that that could happen, by having multiple binding sites lying around in the neighborhood or a promoter.

Hughes: Was this combinatorial concept very much in your mind as you were looking at the results that you were getting?

Yamamoto: No, not at all. It only came as a way to try to figure out how to explain the result that the inverted fragments worked and all this other stuff, and it made us think about the enhancer phenomenon, which was all around us in the literature but that people didn't understand.

Hughes: When you invert the sequences, does that make you think of long-range regulation?

Yamamoto: No, it didn't at that time make us think about long-range regulation, but it matched a piece of phenomenology with SV40. That was that it had already been shown that not only did it not matter where the SV40 fragment was relative to the promoter, but it could face either direction. With bacterial regulatory binding sites, nothing doing. If you turn it over, you've had it. The game is over.

52 K.R. Yamamoto, B.M. Alberts. Steroid receptors: elements for modulation of eukaryotic transcription. Annual Review of Biochemistry 1976, 45:721-746. Oral History Center, The Bancroft Library, University of California Berkeley 144

Hughes: That was the first step in thinking that position wasn't key?

Yamamoto: That's right.

Hughes: Or adjacent position wasn't key.

Yamamoto: That's true.

Hughes: If I'm understanding this right, the combinatorial idea is correlated with long-range regulation—

Yamamoto: Absolutely.

Hughes: —which gives more chance for more regulatory factors to operate.

Yamamoto: Yes. This is critical, I think, for the way the basic science works: were we thinking as we were doing these experiments—in which, the experiment was to fuse a fragment of MTV DNA to the thymidine kinase promoter, and then ask whether we would see regulation. What you asked was, were we thinking about the combinatorial model, and the answer is no.

We were trying to do a sufficiency test. We were trying to ask, is the binding site for the receptor all that's needed to confer glucocorticoid regulation on any old promoter. And as I said, the precision of the sufficiency test was lousy. We didn't have just the binding site; we had this great big fragment of 100 base pairs or something, instead of the twenty base pairs to which the receptor bound. But it's all we had. We didn't have an oligo machine; there were no oligo machines. Painstakingly, Vicki could isolate this fragment and then stitch it in next to the TK promoter. We had specific, exact ways that we wanted to do the stitching, but in the end the clones gave you what they gave you.

Hughes: You phrase the question in a way that the answer could have been yes or no. But really, because of this history, the Jacob-Monod business, you're really thinking that the experiment is going to turn out one way.

Yamamoto: Oh, yes.

Hughes: That's your expectation. So that explains why you wouldn't automatically think of the Britton-Davidson stuff.

Yamamoto: Absolutely. I was not at all expecting that inverted fragment to work. I regarded that experiment that Vicki did as a control. If you look at that paper, you'll see they worked just as well. So then we thought, what in the Oral History Center, The Bancroft Library, University of California Berkeley 145

hell is going on here? So that's what then finally brought us to think, wait a minute, this is the same as what those virologists are seeing.

I got very excited about this, because people didn't have a grip on enhancers at the time. I'm not trying to portray this at all as saying that people were out bumping into walls with their noses and I was seeing things clearly. [laughter] It ain't that way.

Hughes: You’re not coming across that way.

Yamamoto: Okay. So yes, there was a lot of ferment at that time, and there were ideas flying around, and this was ours. So I started running around giving talks about whether regulation in general would run by enhancers, and enhancers would be simply regulatory factor binding sites that could somehow work over a long distance.

When we distributed the draft of our manuscript to the people in the lab, we got trashed by them for writing this. The [comment] that I remember really having an impact on me is… I came in one morning, and one of my dear postdoctoral colleagues had put up the abstract page in which we drew the analogy between enhancers and this observation [about] the receptor binding site and proposed that maybe everything worked by enhancers. Vicki Chandler was the first author, and so scrawled across this page had been written, "Earth to Vicki, Earth to Vicki, come in!" [laughter]

Hughes: And that gave you pause.

Yamamoto: Oh, yes. In fact, we toned it down. We were burned by that.

Hughes: Were you the initiator of this long-range regulation idea?

Yamamoto: Well, I guess I used the phrase a lot. By the time that our paper came out, there were people who snickered at this idea that what we had was a real enhancer. A lot of people said, "Well, it's not a real enhancer; it just kind of acts like an enhancer." And I was already by then advertising this idea—advertising isn't the right word—that this would be the way that regulation would work, which most people thought was a stupid idea. So yes, I guess I was talking a lot about it.

Hughes: Are there other examples of being misled by the paradigms that were built up around the early work on phage?

Yamamoto: What paradigms? Yes, I guess Thomas Kuhn would say they mislead people. Oral History Center, The Bancroft Library, University of California Berkeley 146

Hughes: I'm not particularly happy with the term paradigm.

Yamamoto: You're not, okay. But what they do is, they create a clear enunciation of how something is thought to work. It's the clarity that's important in a paradigm, because only in the clarity can someone lean firmly against it with another idea. As long as it's fuzzy and not well enunciated, then a counterpoising idea can't really solidify. So paradigms are critical, but what they end up doing is they establish a superhighway on which everyone begins to march, or drive, I guess. And it's only the few outliers that say, "Wait a minute, this doesn't fit." And very much as Kuhn has said, if the paradigm is really a major one, then no single outlying conclusion can knock it off track. People just shove the person aside. It's usually only under the force of multiple things that a paradigm will finally collapse and the excuses just run out. They become too forced.

So in the Jacob-Monod original thing [model] we talked about, with negative control being the answer to everything, this poor guy Ellis Englesberg, working with the rabinose operon regulatory system, showed just impeccable data for positive control, better than any of the rest of us. And it took him a decade to get the idea accepted. It wasn't only because of his amazing persistence in continuing his experiments, but also because by then several other proteins were beginning to show clear signs of being positive regulators, including those in lambda phage, which was a favorite of that crowd. Jacob after all worked on lambda. So the establishment worked on lambda, and other establishment scientists were beginning to find signs that there were proteins in lambda that worked as positive regulators.

The cyclic AMP receptor protein had been discovered in the late sixties. It was clearly showing signs of being a positive regulator. So finally the paradigm had to relax and make room for positive regulation. And Englesberg was the one that stuck with it all the way through. And I think that's the way that things work [in science].

Hughes: Did people assume that what had been worked out in phage and prokaryotes would also apply to mammalian systems? Or did you make the move to research on eukaryotes with the idea, well, these are more complicated entities. The data's not going to fit very well.

Yamamoto: Oh, no, I wasn't smart enough to think of that.

Hughes: Were most people thinking that what was true of E. coli was going to be true of— Oral History Center, The Bancroft Library, University of California Berkeley 147

Yamamoto: Well, that's the famous statement: "What's true in E. coli is true in elephants."

I bought the bacterial paradigm lock, stock, and barrel. And who didn't buy it? Well, one could say that Britton and Davidson didn't buy it. They were talking about this flaky model with multiple RNAs and this weird stuff. There was a whole chromatin community out there that didn't buy it in this simple lock, stock, and barrel sense because they thought that the proteins that were packaging the genome would make a huge difference in regulation. It was still an open question. So there were people out there that didn't go for it.

My own thinking was that proteins like the surrogate receptors would in fact behave exactly on the paradigm, and that we would first just show that, and then having shown it, we could worry about the more complex physiology of the kind that I talked about early on, that then we could get into the juicy part: gee, okay, now that we've shown that, what about the fact that the genes that are regulated differ from cell to cell? What the hell is going on here?

But I just thought, this part is a slam dunk. No problem. [laughter] We know this part. And it's why I was so proud of using this system as a starting point. [We thought:] This is going to be easy. We'll just do this first, and once we get that out of the way, then we're in. Then we can find the interesting part." I thought that this would be no problem.

Hughes: Well, in a sense, this is the way science has to work, isn't it? You have to start with a given.

Yamamoto: Yes.

Hughes: I guess the problem arises when the given becomes inflexible, and it's very difficult to move conceptually beyond those walls.

Yamamoto: Yes. So this is a different way to think about a paradigm or maybe a clearer statement about paradigms. But what the paradigm is, is the inflexible part. That's what assigns the given. People say, "Well, at least we have this to fall back on. If we don't know anything else, at least we know this." And when the paradigm begins to fall apart, things get pretty juicy. Every field goes through a period where every experiment that you do seems to be telling you only one thing, and that is that you don't know as much as you thought you did. Oral History Center, The Bancroft Library, University of California Berkeley 148

Hughes: Do you remember having an emotional reaction when you did that experiment and found that indeed things did not seem to fit this preconception?

Yamamoto: Oh, sure.

Hughes: What did you think?

Yamamoto: Well, first, I didn't believe it.

Hughes: You thought something technically had gone wrong?

Yamamoto: Yes. Vicki had to remap and repeat everything. I was just completely perplexed, and then I made the connection to enhancers. Nobody understood enhancers. What kind of connection is that? [laughs]

Hughes: So how did you do it?

Yamamoto: Well, all it did was it matched the phenomenology. It wasn't an explanation of anything. It didn't tell us how anything worked. It just said, isn't this interesting that the weird behavior of these elements is like the weird behavior of our experiment, and does this tell us something? So this is the standard trick, which is a very pleasing thing even though it's only a device, of taking two things that you don't understand and putting them together into a model that creates some order. It doesn't by any means mean that the model is right. It just is pleasing organizationally in your thinking and gives you a way to think about these two things that before just had to be facts that you memorized. Now [they become] a concept that becomes a part of the way that you think about the way that life works. So that's all we were doing.

Hughes: How did people react?

Yamamoto: Well, I told you how my lab did.

Hughes: I know, but beyond the lab. After that reaction, you toned it down a bit?

Yamamoto: We toned it down in the paper. I don't remember what we did in the talks.

Well, the reaction was mixed. It was mostly courteous. I remember getting into arguments with some good friends. Steve McKnight, a very dear friend of mine, just continually looked at our results as kind of a curiosity. He would say, "Well, these GREs [glucocorticoid response elements] could be viewed as enhancer-like." And I would say, "What are you talking about? Tell me one thing that's different between an enhancer and Oral History Center, The Bancroft Library, University of California Berkeley 149

this?" There was just this constant, "Well, this can't be an enhancer. It's not really on a virus, and it doesn't really work unless glucocorticoids are around." And I would say, "That's exactly the point. They are regulatory elements which you can switch on and off."

Englesberg had the real battle; we weren't doing anything like that. But there was a period where I just thought people weren't going to ever buy this. I don't remember thinking anything other than the fact that everything seemed consistent and gave us a very nice way to think about the way that things worked. I don't remember thinking the old "Eureka," this has to be right because it's so beautiful, or anything like that. It was just like, we don't really understand what's going on, but this is a way to explain it all. It wasn't tidy enough to be able to go out and get on a soap box about.

Hughes: I'm interested in the connection you make with evolution, and how this regulatory system might even explain Gould's idea of saltations, sudden bursts of evolutionary activity?

Yamamoto: Yes. We wrote a paper about that.53 In fact, I left out a little piece of the story. Well, let's do a little backing and filling here because it bears directly on your question.

Preceding all this enhancer nonsense, and something I should have also built into this enhancer paper because we referred to it, is something that happened when we first began to work on mammary tumor virus. I was trying to think of a reason why mammary tumor virus should be glucocorticoid-regulated, because we had shown that it was. The Beverly experiment worked.

Those initial experiments were complicated in their interpretation for a technical reason, and that is that all mice have mammary tumor proviruses in their DNA. So we can superinfect a mouse with more mammary tumor virus and it will increase its chances of getting mammary tumors, but in fact all inbred strains of mice have mammary tumor virus in their genomes. There are none that are clean.

So when we said we would do this infection, and we add hormone and the amount of RNA goes up, well, which of the proviruses is going up? Do you know that you haven't just accidentally put a provirus next to a GRE—which we didn't know about at the time—but next to a regulatory element that would make RNA that would read through an integrated

53 K.R. Yamamoto. A conceptual view of transcription regulation. American Zoologist 1989, 29:537-547. Oral History Center, The Bancroft Library, University of California Berkeley 150

provirus? There was a problem. And we swept it under the rug as best we could in the discussion and went on. But it was there as a problem.

So we decided to do the next experiment which was to ask, what would happen if we put the mammary tumor virus DNA into a cell that had no MTV DNA and then ask if it was still regulated, because that would really strengthen the case. So we infected rat cells that have no mammary tumor virus DNA and that worked.

So now we had established a paradigm, a way of thinking, that said, mammary tumor virus genome is a piece of nucleic acid that floats around represented as RNA and DNA in one case or another, that for one reason or another is glucocorticoid-regulated. Now, why is that? We didn't have a clue. In fact, I don't have a clue right now.

So I thought hard about that, and it was that bit of thinking that drew me to go talk to Ira Herskovitz, because as I pondered that, I began to wonder whether there was a relationship between this provirus, this piece of nucleic acid, that could be moved around by infection, and the work of Barbara McClintock and the corn geneticists and the bacterial geneticists who were finding insertion sequences that moved around in the DNA. Was there a relationship between tumor viruses and these pieces of DNA?

Explicitly what I was wondering was whether these tumor virus proviruses were just vehicles that existed in the normal DNA of the genome whose job it was in evolution to move regulatory elements around the genome, and that scientists have been able to visualize them, find them, because some of them have figured out ways to cause tumors.

But there were others that were just in the DNA somewhere, moving around. Just like in bacteria, insertion sequences were moving around. So there was a whole IS [insertion sequence] field that I became aware of in the mid-seventies when I was actually still a postdoc that really excited me, and this bunch of insertion sequence scientists who were studying insertion sequences in E. coli—little pieces of DNA that were just flying around the genome. I thought, wow, this is really wild.

[begin tape 12, side B]

Yamamoto: —[Insertion sequences were] really important for regulating the characteristics of the corn. That is, they carried regulatory information on them. The guys that were studying the IS sequences, the insertion sequences, in E. coli were finding promoters and terminating sequences on them, things that could be related to regulatory elements. And so I Oral History Center, The Bancroft Library, University of California Berkeley 151

thought, jeez, maybe MTV is like an insertion sequence or a transposable element of McClintock, except it's figured out how to cause a tumor in some circumstances, and so we know about them because occasionally some mouse drops dead from a mammary tumor.

So we wrote a paper in the Cold Spring Harbor Symposium in 1977 with that explicit model54: maybe MTV is a transposable element gone bad; it's fallen in with the wrong crowd, and it's causing tumors. So there's no reason that it is under glucocorticoid control with respect to forming tumors, and there's not even a reason that it's under glucocorticoid control with respect to anything it does in mammary cells.

The reason it's under glucocorticoid control is that it's in the middle of an element whose job is to fly around the genome every now and then, plop into random places, and ask, what happens if the gene next door suddenly becomes glucocorticoid regulated? And if evolution likes that, then the next generation will keep that element. If evolution doesn't care, it will also keep it, but eventually something will happen. And if evolution really hates it, you'll never see that organism again, so it doesn't matter. So we had proposed that in this theoretical paper in '77.

The growing up of the enhancer idea gave us a way to make that mechanism feasible. If one went with the bacterial paradigm, the mechanism actually wasn't very feasible. With the bacterial paradigm, the regulatory element had to be in exactly the right position. It would almost never happen. There wouldn't be any evolution. But if you want long- range regulation, you're free and clear. It doesn't matter in what direction [the regulatory element] lands, if it's upstream or downstream of the gene, if it's in the middle of the gene.

Now the target size for an effective random transposition becomes huge, whereas before by the bacterial paradigm, the target size for a random transposition is essentially zero. There's no room for error.

Hughes: So once you accept long-range regulation, there is automatically an evolutionary component to it.

Yamamoto: Absolutely. And it just explained a lot of evolution. We wrote several papers that tried to talk like that. There were several symposium papers and review articles where we clearly made the link to evolution. I really believe in that. I think that's going to be right.

54 K.R. Yamamoto, M.R. Stallcup, J. Ring, G.M. Ringold. Mammary tumor virus DNA: a glucocorticoid- responsive transposable element. Cold Spring Harbor Symposium on Quantitative Biology 1978, 42:625-638. Oral History Center, The Bancroft Library, University of California Berkeley 152

Hughes: Have you made a connection with the saltation theory?

Yamamoto: We didn't explicitly do that, but it's interesting that you raise it. I think that could be done. We didn't explicitly talk about saltation. Maybe we should do that. [laughter] We mostly talked about the fact that this would be a way to allow circuits to evolve efficiently.

I think it's not well appreciated in the field that when molecular biologists think about molecular evolution studies, what they think about are these wonderful evolutionary trees of gene families. You can show that there are seventy-five zinc finger proteins that are related—these are [related] much closer than those, and all this other business. And what we don't think about is what Allan Wilson—this wonderful biologist in Berkeley who died ten years ago—had based his whole career on. Forget about the fact that genes duplicate and diverge at a given rate. Wilson said, "That's boring. Don't pay any attention to that. The amazing thing is that the regulation of the different members of those families changes at a tremendous rate, and that regulation—"

Evolution of morphology I think is what he started looking at. Morphological evolution, [he explained], is not driven by changes in structural proteins. The globin of a whale looks just like the globin of a human, but whales don't look like humans. So forget about the fact that there's a globin family. That's not what's important. What's important is that there's a fetal globin and an adult globin; that somehow these different members [proteins] that duplicated and are evolving away from each other are regulated in completely different ways. Wilson said it's not what a protein looks like; it's where it's made, when it's made, and how much of it is made; its regulation. Forget about the other stuff. That's what he said. And it was beautiful. It was clear, and there just had to be something important behind what he was saying.

To me, that transferred the burden of explanation of evolution, and that is, how in the devil can you duplicate a gene and be able to track which Wednesday the duplication occurred ten million years ago? These genes have been in lock step with each other over all this period of time, so it's easy to recognize that they're globin genes. And yet one of them is turned on only during fetal development and then switched off completely, and the other one is turned on only in the adult. That means something about the regulatory sequences had to be changing at a tremendously different rate than the body of the sequence itself. How does that happen?

Well, when you think about it in that kind of harsh light, you know that it can't be by random single-base-pair mutations. Random single-base-pair mutations are what's happening to the members of the gene family, and Oral History Center, The Bancroft Library, University of California Berkeley 153

they're not changing at all. So that can't be it. So what it is? It must mean that there are ready-made modules that are floating around, and that there's a fetus module [laughs] that says, "You're a fetus [gene]--you're on." "You're an adult [gene]--hold your horses." They have to be able to move around intact and allow evolution to say, is it good that this gene is on in the fetus? And if it is, then okay, it will be there the next generation.

So somehow, things had to move, and that's where this transposable element driving evolution comes from. But the idea only becomes feasible if there's long-range regulation. Otherwise, you're dead.

Hughes: Has this evolutionary context always been a part of molecular thinking, or did it arise with the concept of long-range transcriptional regulation and perhaps other concepts that I'm unaware of?

Yamamoto: It's a good question. My answer is that I don't think there's a simple answer to it. It's like how we learn language; how we come to a word and use it is simply the complex sum of our experience with the word. I think that that's true about this as well, about any bit of scientific thinking. So I'm sure that there are people who eventually came to molecular biology through some very classical taxonomic, evolutionary direction that might have been thinking at the molecular level about this all along.

There were people like me that didn't come in in that way and found it a very handy way to organize thinking, and [that it was] pleasing because it seemed to be a way to explain everything. And other people that weren't there at all. So I don't think that there was a single way that it happened. There are so many entry points.

Oral History Center, The Bancroft Library, University of California Berkeley 154

Interview 7: January 24, 1995

[begin tape 13, side A]

Hughes: Dr. Yamamoto, last time we were talking about the regulation of transcription and, at the end, its tie-in with evolution. I understand that you want to talk today about what is happening at the binding site.

Yamamoto: I think that the last time we left off, we had discovered that the receptor indeed chooses the genes at which it will function by binding to specific DNA sequences. A paradigm had been built up in the field by then, which still persists I should say, that says that the function of DNA binding by regulatory factors is a simple and a singular one. And that is, to deliver the regulatory protein into the neighborhood of the promoter that's going to be controlled. This is really just a matter of local concentration of the regulator around the promoter. So the DNA just serves as a way to make sure that the protein is always close by to that promoter and not to others.

But that very finding and that very paradigm raise a question, and that is that we know that the glucocorticoid receptor and other regulatory factors, while they are very specific in the genes that they regulate, that specificity is not hard-wired. So from cell to cell or physiological condition to condition or at different developmental times, the genes that are regulated very specifically by the receptor are different.

So that says that it can't simply be that the receptor knows how to read DNA sequence, and it runs into the cell and does so, but there must be something more complicated. Well, you can imagine one very simple complication, which in fact is true, although I won't get into it in our discussion, and that is that it could be that from cell to cell sometimes the [binding] sites are covered up and sometimes they're not. So it's just an accessibility issue. In fact, that does come into play. And all I'll say about that, I think for our discussion, is that that's true. But we also know for other reasons that that can't be the whole story.

So let me just give you one trivial reason that makes it very clear, and that is that it's not just a matter of whether a gene is on or off. A gene can be on, and the hormone can regulate it positively in one cell type, or it can be on and the hormone can regulate it negatively in another cell type. That proves that it can't simply be purely a matter of accessibility. There are a lot of other reasons as well, but that's an easy one to follow. So we'll dispense with that.

So, specificity, yes: it binds with specific DNA sequences; accessibility, yes: there could be cases where the gene is simply covered up and can't Oral History Center, The Bancroft Library, University of California Berkeley 155

ever be turned on in that cell type. But those two aren't enough. So by following this principle that we discussed last time of following this one protein around, we knew that there had to be other complicating features. The philosophy, remember, was that if we want to understand those complicating features, we study the one protein that we know about in more detail, and it will tell us.

And that's what we did, and others have done as well. So we wanted to know, how is it that it does this? Well, what we knew so far, and the point that we'd reached, was that we could define specific sequences where the receptor bound. We in fact even ended up getting a crystal structure of the receptor bound to that sequence, and we knew about it in great detail: what kinds of contacts were being made, how the receptor dimerized, and all of this business.

But there was a curious thing about those sites that we and others came to realize, and that is that all that we and others could get the receptor to do at those sites was to activate transcription, to regulate positively. So that raised another puzzle: how in the devil does the receptor know how to repress transcription? We know that it does repress transcription. The physiologists and endocrinologists could point to those genes in various cell types and say, "See? There it is: the glucocorticoid receptor repressing transcription. How does it work?" And none of our sites could do that. So here we had a second unknown thing.

So here's an interesting principle of doing research, and that is that one of the most satisfying things that one can do in developing a hypothesis or a concept about how things work is to take two things that you don't understand and put them together in such a way that you end up with a notion that gives you understanding. It may be wrong but at least it allows you to understand these things.

So we had on the one hand a biological puzzle. We knew the receptor is able to regulate in ways that aren't explained by the simple rules that we knew about. And on the other hand, an experimental puzzle. We could find sites and characterize them to death, do genetics, but they only activated. So there had to be some other way to repress. So when we put those things together conceptually, they said, "Let's go find some genes that are repressed and see if the GREs look different. Maybe it will give us a different class of GREs."

Well, we did that. We first studied the prolactin gene and later on the proliferin gene. We studied a few genes where the physiologists told us, "Here's a gene that's repressed. Figure it out." And we were cocky. We thought we knew the kinds of sequences the receptor would bind to Oral History Center, The Bancroft Library, University of California Berkeley 156

because they had been found a bunch of times now, not just in our lab but by others. People could recite the sequences, what they would be. So it was actually a bit difficult to find somebody to work on this problem because they were saying, "Well, it's just going to be the same old sequence again."

But we went searching, and a postdoc found a site at which the receptor bound and repressed transcription, and amazingly enough, it didn't look like all the other sites that had been found. Then we provided a receptor to another lab where they had shown by other means that their glucocorticoids repressed transcription. We sent them the receptor protein; they found the binding site. It didn't look like the standard ones where it activates transcription, and it didn't look like our other one that it represses. So something was weird. We didn't understand what it was.

So we imported that sequence back from Dan Linzer, the investigator at Northwestern whom we provided the receptor to. Linzer had discovered this gene proliferin when he was a postdoc and was trying to understand its complex regulation. It's a very interesting protein that is made in high levels in cells that are proliferating and in the placenta, and its regulation appears to be very complicated. He's trying to understand that. We said to Dan, "Fantastic, keep doing that. Could we just take this one little smidgen of DNA where the receptor binds and look at one small question and that is, how does the receptor know how to repress transcription? We'll provide you with the information we get, and it shouldn't step on your toes in terms of understanding the complex regulation." That could well have worked out as a collaboration as well, but it turned out not to work out that way. Dan said, "Great, take the sequence." It's published anyway. "Study the sequence. Keep us posted on what's going on," and we ran from there. So that's how that worked out. It was very nice.

So we began to study it. What's emerged from those studies and studies in a bunch of different laboratories now is a surprising result. And that is that there are in fact at least three classes—not just two—of different GREs in the cell. The first one was the one that we found first, where the receptor binds and only activates transcription. At such sequences, the receptor is the only protein that's needed to bind to that sequence to get hormonal regulation. But the regulation that you get is only activation.

The second class, which turned out to be the second ones that we found, turned out to be a site at which the receptor would bind but the sequence looks different. In this class the sequences look different even between themselves. But what brings this class into a single class is that the receptor, when it binds to such sites, doesn't itself do anything. It requires another protein, a non-receptor protein, also to bind to that site in order to Oral History Center, The Bancroft Library, University of California Berkeley 157

allow the receptor to regulate transcription. And when it does that, the receptor either activates or represses, depending on the nature of the other protein that binds.

Hughes: So it's more complicated.

Yamamoto: So it's more complicated. I'll give you a few details on that in a moment.

The third class that was discovered in other laboratories simultaneously with ours is a site at which the receptor itself doesn't bind to DNA at all. Instead it binds to another protein that is itself bound to the DNA. That we call a tethering GRE because the receptor is not itself touching DNA. It can mutate the sequences on the protein that normally touch DNA, and it touches the protein. When it touches that protein, it represses. So far people have only found repression at these tethering sites. They've only found activation at the simple sites that we found first. And then at these so-called composite sites—composite because they involve more than just the receptor protein—the receptor can either activate or repress depending on the nature of the other protein.

So with those three classes, but even with just the combinatorial class, you can see how it can begin to build up a great complexity in the way the receptor could be acting, even within one nucleus. Because when you vary the sort of GRE that sits near the promoter in one sort of GRE, the receptor will just bind and activate transcription. Then it might be covered up to greater or lesser extent with these chromatin proteins or not.

In the composite class, the receptor may bind there, fine, but it won't do anything until this other protein comes along, and then it won't even decide which way to go until it looks over that other protein to see whether it will activate or repress. I'll tell you a little bit more about how that works in a minute. In the third case, the receptor doesn't even bind and doesn't do anything unless the other protein is there, but it only represses. So now you can see that even if you just take those three classes, you can begin to build up lots of ways that the receptor could be functioning, even within one cell type.

Now, the amazing thing that we discovered in the proliferin case—well, let me rephrase the observation a little bit to make it amazing. [laughter] See, I'm a real salesman here. To rephrase what I just told you about the composite class, that means that in one cell type, where let's say factor A is present as the other factor, the receptor will bind next to factor A and activate transcription. In the other cell type, factor B will bind at that sequence [and] the receptor will bind and repress transcription. So what Oral History Center, The Bancroft Library, University of California Berkeley 158

we have, then, is cell specificity in the way that the receptor is working. Cell A activates; type B represses.

Now, a lot of what biologists want to know about right now, at least those who are concerned with gene expression, is how does cell-type-specific gene expression work? What makes something cell specific? The paradigm in the field, what people think about, is that there must be some cell-specific factor that's binding to the DNA that says, I'm liver, and another one says, I'm kidney. And in liver, this gene will be activated by glucocorticoids; in kidney, it will be repressed; and in fat cells, it won't be expressed at all. If we just had the receptor, which is ubiquitous, made in every cell type, then binding next to factors that are cell-specific, we would have a way to explain all of that.

The remarkable thing that we found is that with this particular element that we looked at from proliferin, that the other factor that defines cell specificity is not cell-specific. It's also ubiquitous. Now, how does that work? Well, let me tell you how it works. The other factor, which happens to be called AP1, meaning nothing, turns out to be a dimeric factor. That is, the one binding factor is made of two subunit proteins. I'll give the subunits names because it's just easier to talk about them, but otherwise the names are meaningless. One is called Jun; the other is called Fos.

So it turns out that this factor—simplifying a little bit here—can either be made of a dimer of two Jun proteins—that's a homodimer of Jun proteins—or a heterodimer between Jun and Fos. Both of those are called AP1, both of them bind to this element, and both of them activate transcription. So Jun-Jun and Jun-Fos look indistinguishable when you look at them by themselves. But it turns out that when Jun-Jun binds to the site, the receptor activates the transcription, and when Jun-Fos binds to the site, the receptor represses transcription.

Now, I told you that the puzzle here was that AP1, that is the Jun protein and the Fos protein, are also ubiquitous. So how do you get cell specificity out of this? The answer is the way that they come together to form dimers. The form of dimers that you get depends on the relative expression levels, the relative amounts of Jun and Fos there are in the cell. So if there's more Jun, you get more Jun-Jun homodimers, and the receptor tends to activate. If there's more Fos, you get more Jun-Fos heterodimers, and the receptor tends to repress. So while it's true that Jun and Fos are made in every cell, they're made at different relative levels—or probably more subtly than that. They may even be made at the same level but they have different levels of activity or different places in the cell or all kinds of complicating things. So it's the ratio of the two proteins that becomes the determinant of Oral History Center, The Bancroft Library, University of California Berkeley 159

whether the receptor activates or represses. But they're there; the proteins are there.

So now we've been able to divine a way that a gene can achieve cell- specific expression using as its regulators non-cell-specific factors. It's like getting something for nothing. And all you do is you wiggle around the ratio of the activities of these two ubiquitous subunits, and the ratio forms a switch. So you can see the way that I'm moving my hands here, how you get a switch. It's on here and off here. And as soon as it passes, you've now defined the switch. So in defining this cell-specific switch, the cell doesn't use up a protein. It doesn't say, "Okay, this protein we can only make in liver. It's not going to be good for anything else." That's a lot of load on the genome. Instead, you can just make ubiquitous factors and decorate them in various ways, and you end up with cell specificity in this way.

So this notion has now been found in other laboratories and actually in greater complexity in our lab. We understand it better now. It's more complicated than what I've just told you. But the complications are all little decorations on the molecule that allow the receptor to act in even more specific ways. So without using up much of the genome, we now understand by this route of combinatorial gene regulation how it is that one factor can do lots of things. I shouldn't say we understand, but we're beginning to build up a view of how that could happen and some experiments that support that idea.

Hughes: Is this a universal model?

Yamamoto: I think the model is probably universal, but your question is a very good one. What we know now from work in other laboratories is that the receptor is able to interact with not just this AP1 factor but a bunch of different factors. Some of them aren't known yet; some of them are known in different genes. So there are surfaces on the receptor protein that can make contacts with not just AP1 but with other proteins as well. So again, you just crank up by a lot the level of combinatoriality.

We already have some hunches that there may be complexes of proteins, multiple proteins, at these sites. So regulatory binding sites of these types, as you know, are likely to be homing positions for what I like to call rock piles of proteins, factors that if they're present in the cell will come in and home to those positions. They essentially sort themselves out on the basis of how much protein there is in the cell, how strong the affinity for the protein is in that particular site. And they sort out and they form these little rock piles. Those regulatory machines will then be functional on the basis of what form that they've ended up taking. Oral History Center, The Bancroft Library, University of California Berkeley 160

Hughes: And each component is multi-functional.

Yamamoto: That's right.

Hughes: It really is a nice illustration of the conservatism of nature, isn't it?

Yamamoto: That's exactly right.

Well, the other demonstration of the conservatism, since you brought that up right in phase here, is something I think I mentioned already, and that is that the receptor works in yeast. So that really says that it's conservative, because the glucocorticoid receptor of course is clearly a protein that's limited to higher metazoan organisms. So it's present in frogs but not really far below amphibians. So here's this protein that has evolved relatively recently, and yet if we take that protein, that is the sequence of nucleic acids encoding it, and introduce those into yeast, Saccharomyces cerevisiae, baker's yeast, the protein works. It's an astonishing finding.

That means that all of the little surfaces that have to interact with other proteins are old surfaces, surfaces that are so old that when you take this thing two billion years out of context, or whatever it is we're separated from yeast, all the surfaces are recognized by the yeast machinery so that the interactions work correctly. It's really amazing. So it means that those surfaces really predated the formation of the glucocorticoid receptor by a lot. We don't really understand those yet.

This is really right at the edge of where we are now. We're all struggling to understand what are the surfaces that are important for the function of these proteins, and how are they important? We envision them being important because they're surfaces that interact in a complementary way with another surface in the cell of another protein, and thereby you're able to transduce this thing along, saying, I'm an activating protein; get busy.

But that surface must be used in yeast regulators that are touching their yeast machinery. Those regulators have nothing in common that we know about with the glucocorticoid receptor. But of course, they do have something in common. We just don't know what it is. [laughter]

We know for certain that yeast is not an organism that was waiting around for my lab to put the rat glucocorticoid receptor into it, and that it wasn't by chance that the receptor ended up evolving to have the surfaces that it has on it. It's locked in. The same way the genetic code is locked in: once the genetic code was settled, and we knew what the code word was for glycine, you couldn't mess with that. If you did, you'd mess with every protein that has a glycine in it. Oral History Center, The Bancroft Library, University of California Berkeley 161

Well, in somewhat less grandiose way, it can be said that once you determine a surface that can activate transcription on something, you better hang onto it because you're going to need it. So you don't get to change those very much. Factors evolve and look very different to our eyes. We talk about acidic activators and proline-rich activators, or we talk about zinc finger proteins and helix-turn-helix proteins, all these structural features that I'm naming right there that we recognize and know the crystal structures for. Even while all this evolution was going on that allowed the divergence of these different forms to take place, there must have been something saved in these surfaces that gets passed along, says, okay, you're going to be a zinc finger protein, be that way if you want, but take this with you. You're going to need this."

Hughes: Or it's not going to work.

Yamamoto: Yes, or it isn't going to work. So all the adventuresome proteins that decided to go off and make their own, they're dead. They're gone. [laughter]

Hughes: Creativity is not the thing.

Yamamoto: No, that's not the idea. [Despite] evolution's own amazing changes and the diversity that comes out of it, there's a very strong conservative force for those things that are really important.

Hughes: Yes. We can talk about saltations and evolutionary leaps and all of that, but they have to occur within a constricted framework, don't they?

Yamamoto: Yes.

Hughes: Anything isn't possible.

Yamamoto: Yes, that's right. Otherwise, nothing would work. I've often said this: the more you understand about biology, the more you'd never predict that a baby would ever be born. It doesn't seem possible. There are so many things that have to happen. Well, actually, it's a very conservative set of rules that have been laid down. This is it. Don't mess with this.

So the story on the transcriptional regulation, and I'll stop this part, has been built up really very much by following this protein, letting the mysteries emerge. Very few of them we predicted, I have to admit. Then once we finally got around to grasping what the mysteries were, then demanding of the protein that it tell us what the heck is going on. And so far I think that that [method]'s worked in a way that's been satisfying to me. Oral History Center, The Bancroft Library, University of California Berkeley 162

Hughes: Now, is there anything to be said about the growing complexity that you were working out in the eukaryotic system, as compared to that earlier model that had been worked out in phage and E. coli? That model represented a very static system; things had to stay in certain relationships or nothing worked. It would be disturbing to certain people to throw all that out.

Yamamoto: Well, it's good that you raise that [issue], and I think it's good you raise it in that way. I've thought hard about this puzzle and tried to think about why both the bacterial paradigm, what I call short-range regulation, and this other paradigm, that I call long-range, exist. So I ended up thinking about it in this evolutionary sense.

I'll tell you about that, but let me just first mention the other wing of what happened. The other wing of what happened, I think, is again instructive to us in biology. A rule began to develop that long-range regulation was eukaryotic regulation, and short-range regulation was bacterial regulation. When people studied yeast, began to dissect it hard, things were kind of in between. That satisfied people. You couldn't move very far [from the binding site].

But then, some sharp-eyed bacterial researchers discovered in bacteria that there were certain cases where long-range regulation held. And the long- range regulation looked just like the long-range regulation seen in the eukaryotes. So now we had coexisting in real time and in the same organism long- and short-range regulation. So it seemed like quite a puzzle. In one case you couldn't move the site a base pair without getting in trouble. In other cases you could move it thousands of base pairs and everything was fine. So what was going on?

My idea of what was going on was as follows: the reason that long-range regulation exists is as a driving force for evolution. I know we've talked about the idea that there are mobile pieces of DNA in the genome. So if mobile pieces of DNA carry on them long-range regulatory sites, and then move at random in the genome—this has to be in the germ line, of course—any random movement then gives evolution a chance to try out whether it likes having this promoter regulated by that regulatory site.

And if it's long-range regulation that's the rule, then the target size for an effective, random movement becomes very big. If short-range regulation is the rule, it's restrictive. So if only short-range regulation were the rule, then there would be almost no chance for further evolution because as we've discussed before the driving force for evolution is changes in regulation, not changes in the form of the protein, but changes instead in Oral History Center, The Bancroft Library, University of California Berkeley 163

when, where, and how much of it is made. So we have to change regulators efficiently to drive evolution.

So long-range regulation seems ideal for that. Any random movement, upstream, downstream, turn one way, turn another way, put it in the middle of the gene—fine, evolution will give it a try. And if it likes it, then being a long way away becomes a problem or a liability because other sorts of gene rearrangements could separate the regulator from its favorite promoter, and suddenly that organism drops dead because it's gotten used to always being regulated by glucocorticoids.

So then there becomes this conservative force of beginning to trim down the distance between that randomly dropped GRE and the promoter. What happens is long-range regulation evolves toward short-range regulation. The closer it comes, the lower the chances of separating things by change, by some sort of recombination or something. So the more hard-wired that regulatory relationship becomes with that gene.

[begin tape 13, side B]

Yamamoto: The transcription machinery is all that may differ between long-range and short-range regulation. In short-range regulation, the strength of the contacts [between regulatory factors] could be very weak, and so the only way that they'll ever work is if the DNA binding sequence makes the two proteins sit down next to each other. But if it's relatively strong, they could sit down farther apart from each other, and they'll find each other. Because even if they're farther apart, even if they're 1,000 base pairs apart, they're much closer than they would be if the protein was just floating free.

Hughes: Well, do I surmise from this that the general evolutionary trend is toward short-range regulation?

Yamamoto: Well, you can't go too far. Bacteria are not going to be evolving very well any more. They've got a few things that are still long-range.

Hughes: What's going to leave the opportunities in the eukaryote?

Yamamoto: What will leave the opportunities is that it will just be a balance between—and nature uses lots of balance points. Instead of maximizing short-range regulation, what it does is optimize survival of the organism. The organism actually doesn't care what kind of regulation it uses. It just wants to be born again next time. So any organism that draws a regulatory sequence too close freezes out its ability to evolve, and so those organisms die. The ones that have them too far apart—you got it? Oral History Center, The Bancroft Library, University of California Berkeley 164

Hughes: Yes. So it's a lovely balance.

Yamamoto: Yes. And evolution does this over and over again. We know what the error frequency is, for example, with which DNA is replicated. And we know from making mutations that we can reduce that error frequency. You'd think, gee, what's the matter? Why not? And it's the same reason— evolution. You want a few mutations to go ahead because those organisms sometimes do better instead of worse. I think that the two things coexist. I think they're evolutionarily related to each other. And it's easy to think at least of a way that the mechanisms could be the same. So I think in the end it will turn out to be that we're looking at different snapshots in evolutionary time at a given regulatory sequence.

Hughes: Is this an approach that is fairly widely accepted?

Yamamoto: I don't know. [laughter] I think it's getting to be pretty widely held. I haven't seen other models that I find compelling, and it seems like such a simple way to think about it. We've described it a few times in print, and I think that people generally think the idea is okay.

Yamamoto: So do you want to go on to signaling?

Hughes: Yes.

Yamamoto: So here's where letting the protein tell us stuff really paid off. At least in the case of the transcriptional regulation, that philosophy made sense to us. It seemed like the right thing to do. But I assumed, to be honest with you, that signaling was trivial, and that all there was to signaling was hormone finds receptor. In fact, one of the reasons that I chose glucocorticoids, or steroid receptors in general, is that I didn't want to study signaling. I could read what the struggles were with the people that were studying insulin. A peptide hits the receptor on the cell surface and then really all you could say is a miracle happens [laughter], and some genes change in the way they get expressed. I thought, Oh, god, that's too hard for me; I can't study that. I want to study transcription, all that cool stuff in the nucleus.

So I entered this thinking, to be honest with you: here's a case where I can eliminate signaling from my mind and let those people struggle, and I'll just go on with the neat stuff.

Hughes: Why did you think that signaling should be simple?

Yamamoto: I guess I didn't think it should be simple. What I thought was that I needed to reduce the complexity of the problem as much as I could and focus any Oral History Center, The Bancroft Library, University of California Berkeley 165

changes experimentally that we observed as tightly on transcription as we could because that's what I was interested in. I didn't think for a moment that— Insulin never looked simple to me. I couldn't figure it out, make head nor tails out of it. And growth factors, god knows. When I was a student and people were starting to pull growth factors out of calf serum, I thought, oh, this will never be understood. This is insanity. I was dead wrong on that as usual. But I thought, this is craziness because nobody knows what the factors are, nobody knows what the receptors are, and nobody knows what genes are regulated. You only know that this phosphocellulose fraction of calf serum makes the cells grow faster. Give me a break. And I thought that was impossibly complicated. Well, it's getting all worked out.

I didn't have a doubt that signaling would be complicated, but I didn't want to study it. I wanted to study transcription. So I thought that I had outfoxed the system, that I had a way to throw a switch without worrying about a lot of things happening in between. Because you need to be able to throw a switch to be able to look at transcriptional regulation.

So I thought, this is simple; it's simpler than Bambi Meets Godzilla. It's just like hormone/receptor, shake hands, and that's it. And it turns out that's not true. By using the very same principle for operating, the protein told us it's not true. Well, I'm overstating that a bit. I should say that other groups made a key observation that I ignored for a long time, that we eventually came back to appreciate was correct and important, and then some other things that were more in keeping with the principle that I've been talking about.

Hughes: Why did you ignore the observation?

Yamamoto: There are lots of signaling stories to be told, but [I'll tell] three that are relatively simple to describe.

One is the story of hsp90—hsp stands for heat shock protein; 90 stands for its molecular weight—and its role in signaling. The second is phosphorylation of the protein and its role in signaling. The third is a protein called LEM1, which is a cell surface protein that is involved in pumping hormone out of cells. I'll start telling them in order, and we'll see how far we get.

The observation I ignored was made in the early eighties, or maybe even '80, by several groups of investigators, not us, that in the absence of hormone, the receptor was found associated with a heat shock protein, a 90,000-molecular-weight heat shock protein, hsp90. In the presence of hormone, it was not associated. Oral History Center, The Bancroft Library, University of California Berkeley 166

I looked at those papers, read them carefully, and ignored them. The reason is that hsp90 is an enormously strongly expressed protein. It's one of the most strongly expressed proteins in all cells. It gets its name, heat shock protein, from the fact that if you suddenly shift cells to a temperature at which they're not used to normally growing, they shut off all their protein synthesis, all their RNA synthesis, all their splicing. So if you put labeled amino acids into the medium, suddenly you stop labeling proteins, except for a few. And those few that continue to be made under these shock conditions, stress conditions, are called heat shock proteins. So this is one such protein that continues to be made.

If you open up a cell, any cell—bacterial cell, plant cell, animal cell, yeast—one of the major proteins in the cell is hsp90. It's very strongly conserved and very strongly expressed, from bacteria to mammals. And nobody knows what it does. But at the time this observation was made, the main thing we knew was that this protein was very abundant.

So I read those papers and thought about what the results meant and decided they didn't mean anything. I was wrong. I decided that here was a protein that is made in 1,000 to 10,000 times excess over the receptor. And there was a clear paradigm in my head, and I think in everybody's head, that when the hormone binds to the receptor, the receptor changes its shape in some way so that now it acts differently. It goes to the nucleus; it binds DNA. Later on we found that it binds to GREs and does all these things. But it acts tremendously differently. So here is one protein that we know changes its shape. And so what if in shape one, this enormously abundant protein happens to stick to [GRE], and in shape two, it happens not to? Big deal. So I assumed it was an in-vitro artifact. And the fact that it was only bound in the absence of hormone was amusing but otherwise not informative.

The thing that gave me a little pause about the strength of my conviction was that it had been found in multiple labs—not that I didn't trust the first lab which found it. But everybody has a certain set of conditions that they use to do such experiments slightly differently. And it was found with multiple receptors. That was rather amusing, that by chance, multiple receptors would have a shape in the absence of a hormone that this protein happened to bind to, and multiple receptors, when the hormone bound, would go into a shape which it happened not to bind to. Still, 1,000- to 10,000-fold excess, anything could happen. There are such vast differences in the [stoichiometry?]. You open up a cell and you expose it to all sorts of things it doesn't normally see in real life, certainly including the buffers that you're using and everything else. It [the experimental result] couldn't be anything meaningful. Oral History Center, The Bancroft Library, University of California Berkeley 167

Besides, how in the devil do we study it? What does that suggest to you is the next experiment? It didn't suggest anything to me. I didn't go out and give public speeches about the fact that it was crazy; I just ignored it.

We cloned the receptor in '8455. Beginning in '86 and '87 we published the first paper showing that it worked in yeast. And then we thought, ah-ha! Now we have in yeast a way to ask a genetic question, to see if this old hsp observation, that was by now six or seven years old, means anything. Because in animal cells, when you're faced with this protein made at these enormous levels, and you don't have a way to mutate the gene that encodes that protein, there's not much you can say.

But in yeast, once you have the clone, it is a single experiment essentially to knock out the gene and to see what happens, because it's very easy to then pick out that gene and to go in and single it out, once you have the clone. So the facile nature of yeast genetics made this experiment accessible, where we could say, what if you mutated hsp90? Does the receptor really depend on it to work? Is there a biological correlate to this biochemical observation?

By then a group in Chicago, led by Susan Lindquist, who studies hsp proteins in yeast, had shown that if you really do that experiment, if you knock out hsp90, the cell dies. So we couldn't do that experiment; it's very hard to do experiments with dead cells. And of course, once you have that result, it's easy to say, well, that's no surprise. Here's a protein that's conserved from bacteria to mammals; it's made in these enormous amounts; why would you think anything else but that it's needed by the cell? The cell croaks. You knock out the yeast hsp90 homologues, and the cell dies.

Now interestingly, although this didn't become a crucial part of our study, we then showed in collaboration with Lindquist that if we put the human hsp90 into those cells, the cells don't die. So those cells said that the human and yeast hsp90s were sufficiently homologous that whatever the yeast hsp90 was doing to keep the yeast alive, the human gene would also do. So again it shows how enormously conservative things are.

So then a postdoc in the lab said, "All right. We can't use dead proteins. What if we just turned down the amount of hsp90 made in the cell?" So he

55 R. Miesfeld, S. Okret, A.-C. Wikstrom, O. Wrange, J.-A. Gustafsson, K.R. Yamamoto. Characterization of a steroid receptor gene and mRNA in wild-type and mutant cells. Nature 312, 779-781, 1984. Oral History Center, The Bancroft Library, University of California Berkeley 168

asked a simple question: Is there a level of hsp90, as we reduce the amount that's made, at which the cell is still alive but the receptor doesn't work? That is, does the receptor care more about hsp90 than continuing the ability of the cell to divide? It didn't have to be that way, but if it did, then we had an experiment.

So we worked out a way to tune the amount of hsp90 made in the cell, to turn it up and turn it down and turn it down and down and down. He worked this out. And then we just asked the question: Is there a level? And he found that indeed there was, that when he made one-twentieth the normal amount of hsp90, the cell continued to grow; it wasn't dead, but the receptor died. And if you turned it back up again, the receptor would jump back to life.

So that said two things. It said an experimental thing, and the experimental thing it said was that there is an experimental window which we can play between cell death down here and receptor death up here. In between we can operate; we can play with the hsp90. And the second biological thing was that this gave us the first biological experiment that said, yes, receptor function cares about hsp90. This old observation that I'd been ignoring for all these years actually means something. So we published that work.

A very bright M.D.-Ph.D. student, Shawn? Bowen, came to the lab and realized that if that observation was right, we should then be able to do genetics on hsp90 in a way that no one had been able to do before. If all you know is that a protein continues to be made in heat shock and that it's essential for life, there's not much to look at because the heat shock response affects everything. I told you that everything changes. So that phenotype is too complicated, too multifactorial, to use for a genetic assay, even though some people tried, but they failed.

The glucocorticoid receptor is something that is gratuitous in cells. Yeast doesn't care about the glucocorticoid receptor. So it doesn't care whether the receptor lives or dies or works or doesn't work. So couldn't we mutate the hsp90 gene and put the mutant genes into the yeast and then take the wild-type gene back out again? So now the yeast is depending on the mutant gene to work. So you demand that the cell continues to grow. That says you can't completely trash the hsp90. But you then look for yeast cells where the receptor is not working right, and you use the receptor as an indicator of an interesting hsp90 mutant where it's lost part of its function. Shawn did that and that works. Then we realized that we could use this system of the GRE. We hope that we'll eventually be able to use it to understand how hsp90 works in general in the cell [and begin] to build up a bank, a collection of mutations. Oral History Center, The Bancroft Library, University of California Berkeley 169

Other work [in biochemistry], that I won't describe to you in detail, went on in parallel with the genetic work. Another student, Sandra Holley, worked out ways to get this reaction to work in vitro, where she could put the hsp90 out to the receptor and now bind hormone to it and hsp90 falls off. So you get that part of the reaction to work.

We know from studies that originated in other laboratories that there are other proteins that are bound to the hsp90—so it continues to branch out— that we and others have gone off looking for and found. Some of those mutants will be normal in the way they bind to the receptor but defective in the way they bind to some of the other proteins and implicate the activity of those proteins. So by beginning with this one little observation, we're branching out into this network of other factors. I think in the end they will tell us a generally important thing about the ways that the heat shock protein works, and hopefully what the heat shock protein is doing to the receptor to allow it to function correctly.

All we know so far, just to close the loop on signaling, is that the hsp90 has to be there for the receptor even to bind to hormone. So if the receptor is made naked and there's no hsp90 around, the receptor doesn't even bind hormones. But if you put the hsp90 on, now the hormone binds. When it does bind, the hsp90 falls off. So there's this little loop that gets made that's going to be important for signaling. Precisely how that's going to be important, we don't know.

So let me tell you maybe two other stories about signaling. I'll tell you the stories, and then I'll try to draw them together. Another observation not made in our laboratory is that the receptor, like many, many, many cellular proteins, is modified by phosphate residues that are attached by enzymes called kinases to specific amino acid residues on the protein. The residues in animal cells that are most commonly phosphorylated are serines, threonines, and tyrosines. Again, nobody knew what that was for.

I should say that people were kind of exhausted by the observation, because a huge number of proteins in cells are phosphorylated, and in general people don't know what it's for. There are people who study the kinases that have written papers with titles like, "A thousand kinases in every cell." So if there are a thousand kinases, in a way it's newsworthy if your protein isn't phosphorylated. So if your protein is phosphorylated, it's not news, and so what? What does it do already? And understanding that was very hard.

This observation again was an old observation, coming at the beginning of the eighties before the [glucocorticoid] receptor was cloned. Then after we cloned the receptor, we didn't pursue the puzzle. At least in this one, I Oral History Center, The Bancroft Library, University of California Berkeley 170

always believed it would be important, but I didn't want to study it, and I didn't really have any clear idea in my head about what it could be doing. There were so many possibilities.

We eventually ended up studying it because it hadn't been sorted out yet. We were at a stage where we needed to understand something about it, and, as important as anything else, we were getting to know enough of the little nuances of this protein, all the little things that it does, that it felt to us that there were a lot of things that we could look at, a lot of assays that we had, to begin to look to see whether it really means anything.

Hughes: These are all very pragmatic reasons, aren't they?

Yamamoto: Absolutely.

Hughes: So a scientist doesn't decide, "Well, there's a question out there; let's answer it."

Yamamoto: Yes, that's quite right. I think that what is potentially confusing about the way that we present what we do to lay people is that basic scientists like to make a big deal out of this almost stochastic pathway that we follow, that we're not put into a little narrow tube and [told], "Get to the light at the end of the tunnel." Instead, we're just thrown into an open field and [told], "Find something interesting." So we can perceive problems out there, but experimentally we need to have a relatively direct route to a problem before we'll actually tackle it. So we can be enormously captivated by something, but if we're not in the position to study it, we won't try to follow it.

The harder thing and the more subtle thing about research is that every day there are decisions made about what not to do. Every experiment presents more possible ways to pursue it than you possibly can. Every day you have to decide—hopefully you're in a position every day to decide--well, I won't do this and I won't do that. Instead, I'll do a third possibility. Making that decision is challenging. I'm sure that we make the wrong ones all the time, and we just don't know it.

Hughes: And those decisions, I think you would probably admit, are certainly not made strictly on scientific grounds.

Yamamoto: Absolutely not. They're made on all sorts of grounds. You like to dress them up in as much science as you can—

Hughes: Yes. [laughter] Oral History Center, The Bancroft Library, University of California Berkeley 171

Yamamoto: So when you finally go public with them, they look pretty good. [The decision is] based on who wants to work on the problem, what kind of experiment they want to do, what you perceive the funding agencies and the journals will like, or the next place where you're going to give a seminar, who your neighbors are, what they know how to do—all kinds of ancillary things that don't really relate to the intellectual question at hand. You are moved, you are buffeted around, by those forces all the time, all the time. So the trick is that within that buffeting to still be moving in some direction.

Hughes: I thought, as I was reading and listening to you about combinatorial regulation, about the parallels between protein factors in combinatorial regulation and social factors in history.

Yamamoto: It is true that societies move in recombinatorial ways. And as you have just pointed out to me, the way that an individual research track moves is also affected, buffeted, by all of these other things. You end up taking them together, integrating them, and moving in some way. So you do the experiments that are at hand, but there are always more experiments to do than you can do. As important as doing the experiments at hand are the decisions that you made about not doing other experiments that also are at hand. So then it becomes very clear what the answer is to your question, Why don't you explore some interesting question out here? Well, you'd love to, but you're already not [exploring] the ones you can do. [laughter] So people are very busy.

When I was working on the scientific misconduct issue, there was this interesting statement from somebody, "Well, I never put into my grants or my papers my best ideas, because they'll get stolen by somebody else." And the rejoinder to that was, "Well, that's interesting. I have to club people over the head for years and years to get them to accept any of my ideas." [laughter] Most people are really focused on what it is they're trying to do, and they're very busy either promoting their own ideas or pursuing some puzzle in their labs they don't understand. And the notion of dropping everything to go pursue something that somebody else is thinking about [is impractical]. So you just don't do it. There are people who do, but most people are very much engaged in what it is that they're up to.

So what it does is that in most laboratories—not all—it makes the research relatively linear. Something usually post facto can get drawn as a leap of insight. But those things are relatively few and far between.

Hughes: Linear, except at the origin, you could never predict where the linearity was going to lead. Oral History Center, The Bancroft Library, University of California Berkeley 172

Yamamoto: Absolutely not.

Hughes: Because you're also describing a branching system.

Yamamoto: Yes, very much so. And backtracking, don't forget that. So I didn't mean linear in that it always moves forward in a predictable direction. What I meant was that there are very few quantum leaps where you end up going over here and over here.

Hughes: Well, your example of initially discounting the finding about signaling is a perfect example.

Yamamoto: Yes, completely. I'm really glad you brought that up because it's exactly right.

So we studied the phosphorylation because it was there for a long time. Other people didn't figure it out. Our problem moved to a place where it seemed like we needed to know something about it. A quick version of why is that we were getting some kind of understanding of what the various pieces of the receptor would do—this binds DNA; this binds hormone; this binds hsp90. We knew that a region upstream of the DNA binding domain was important for transcriptional regulation, both activation and repression, because when we mutated it, those things would be compromised.

[begin tape 14, side A]

Yamamoto: If we wanted to understand how activation and repression was working, and it was crowded into this same region, then it might be time for us to understand that there's a relationship to phosphorylation. So we began the study.

A quick version of where we've ended up so far is that we found that all the phosphorylation is up in that region. We mapped, we identified, the exact amino acids that are phosphorylated and found that two of the sites are phosphorylated much more strongly after the hormone is bound, whereas the other sites don't seem to care. They're always phosphorylated. And we found—this is amazing—that the sites that are phosphorylated when the receptor is introduced into yeast are the same as the sites that are phosphorylated when the receptor is normal, when it's in a rat or a mouse. So it says that all those kinases must be conserved, and that's just amazing. So it meant, again, that we could use the yeast system. Oral History Center, The Bancroft Library, University of California Berkeley 173

In a way, I have to admit, that was a little bit of a disappointing result. I thought I had a great idea; then it didn't turn out to be so great. I thought, well, there are a lot of phosphates on the receptor in the animal cell, and we don't know which ones to study.

One of the reasons I've stayed away from studying phosphorylation is that it didn't seem very scientific to me in this kind of funny sense, that what you like to do when you design a scientific experiment is to eliminate half of the universe's possibilities. It seemed to me what was happening when people studied phosphorylation was to identify, with a fair amount of pain and suffering, particular amino acid residues that are phosphorylated. Then you mutate one of those sites and ask, "Does the cell care?" If the answer is no, what have you learned? Absolutely zero after all that work.

You could say, what do you mean, zero? At least you now know that that site's not important. Ah, but you don't. All you really know is that it's not important in the particular conditions that you studied. This cell growing in this medium, on this dish, didn't care. Well, what about in a mouse, or what about a mouse in the wild, or what about in a mouse that's mating or pregnant or developing or sick or heat shocked or anything? Suddenly now it's important. So you've learned zero, absolutely zero.

So just one site at a time, I thought, who wants to do that? So I thought, Ah-ha. We know that the receptor works in yeast. So if any of these phosphorylation sites are needed, are essential for the receptor to work— that is, signal correctly, to regulate transcription correctly—then they'd better be present in yeast. Because the receptor works.

So I imagined that there would be an overlapping subset of phosphorylations, some of which would be found in animal cells only, some found in yeast only, some found in both, and that we would very shrewdly only study the ones found in both, and therefore eliminate most of them and zero in on those cool ones. They're all the same. [laughs] The conservation is amazing.

So we did the hard work, and we showed the sites were the same. I shouldn't say we did the hard work. Another group did the hard work. They mapped the sites through extremely laborious experiments in mouse cells, only in the presence of hormone, they could only do so much—it was a lot of work. And we showed in yeast that the sites that are phosphorylated are the same as what they found. They did the hard work. And then because the yeast system is easier to work with, we could do plus and minus hormone, and we found these hormone-inducible sites, and that was nice. Oral History Center, The Bancroft Library, University of California Berkeley 174

So the bottom line of what we've found so far is quite amusing, and falls into two sets of [conclusions]. One set of conclusions says that the receptor is phosphorylated by two different families of kinases. They're important and interesting families. One family is called the mitogen- activated protein kinases, MAP kinases. It has that name because it was found as a family—first it was found as an individual and then as a family of kinases—whose activity is triggered when growth factors are put onto cells. The cells begin to divide. It's now known that it's conserved from animals to yeast—same old story. There are families of them. They do different things to mediate signals coming from outside the cell into the nucleus. So the receptor happens to be a target of some member of that family.

The second family is called the cyclin-dependent protein kinases, CDKs. That family is called that because these are two subunit kinases in which one subunit is the real catalytic factor, the one that actually does the phosphate transfer, and the other is a regulatory subunit called a cyclin. It's called a cyclin because it was discovered as a protein that is made at high levels when the cells are going through the cell cycle and made at low levels when the cells are quieter. But again it's now known through some work, including some studies in Erin O'Shea's lab here, that that family is not just hard-wired for the cell cycle, but it's again involved in other cells [unclear]— So two families of kinases regulated.

And the interesting part of that is that the CDK phosphorylation events are the ones that hit the residues on the receptor that are only in the presence of hormone. If we mutate the CDK enzymes in yeast, the receptor goes way down in its activity. The MAP sites are hitting the sites that are present all the time, and if you mutate MAP kinases in yeast, the receptor activity goes up. Ah, so it says that the receptor is the target of two other signal transduction cascades, one culminating in a MAP kinase that puts phosphate on all the time and is inhibitory. So if you mutate the kinase, the activity goes up, and the other culminating in the cyclin-dependent protein kinase that puts phosphates on only in the presence of hormone. If you mutate the cyclin kinase, the activity goes down; that is, the CDKs increase receptor activity. So it says that the receptor now is not just a glucocorticoid receptor, in the sense that it's not just glucocorticoid information that it's processing, but just like your societies, it's actually integrating information coming from different places all in the same molecule. So we want to work our way back out and see what those things are.

The yeast strategy was useful because we could go right to these things. The field had made mutants in those genes; we could say, this is a CDK; this is a MAP kinase. Now we can go back to the animal cell and say, Oral History Center, The Bancroft Library, University of California Berkeley 175

what's the homologue of these genes, and what's signaling to them that's now feeding information into the receptor?

I imagine that down the road, we'll discover—and there are already hints of this from other labs—that there are ways to activate this receptor that don't even care about the steroid, that may just depend on the specific combination of phosphate residues on it, and that the steroid will make it work better or make it work worse--I don't know. In some cases, it may not affect it at all. We call them steroid receptors because that's how we recognized them at first, just like we called the cyclins the cyclins, because that's how we recognized them at first.

Hughes: But now they could be called all kinds of things.

Yamamoto: Yes.

So information processing has become really interesting to me. Of course, again it's turned out to be this combinatorial notion. So I really only have a couple of ideas; I just use them [over and over.] [laughter] So that is one kind of conclusion we can draw that we're obviously pursuing very hard.

The other kind of conclusion that we could draw is quite amusing. I forgot to tell you that the other test of what I just said to you is that you mutate the amino acid residues that are hit by those kinases. The prediction would be if you mutate the residues that are normally phosphorylated by the CDKs, the activity would go down; if you mutate the resides that are normally hit by the MAP kinases, the activity will go up, and that's what you get.

So the other general comment that I can make about our phosphorylation studies that really brings you quite up to date is that those changes in activity going down and activity going up were found by looking at GREs at which the receptor activates transcription. But if you look at GREs at which the receptor is repressing transcription, those changes in kinases and phosphorylation sites don't do anything. Phosphorylate and the repression goes right on; it doesn't care about any of that stuff. So it says again that the signals that culminate in phosphorylation are selectively affecting the receptor's function, in this case affecting the way that it activates transcription but not repressing.

I don't know whether it will turn out that the rule will end up being really that simple. Maybe if we look at other GREs or other cell types, that simple rule of activation being affected or repression not being affected may break down. It may be these promotors are affected, or these GREs are affected, and these are not; figure out what the difference is. But at Oral History Center, The Bancroft Library, University of California Berkeley 176

least what it says is that it's a differential effect. So again, phosphorylation becomes a way for the receptor to look differently and act differently in different contexts, and that's in a way what we're all trying to figure out. So those are the two things that we can come away with right now.

I'm really excited about this idea of the receptors serving as a recipient of multiple different information inputs, and then integrating those, and then having the consequences be dictated to it about how it's going to act. That's a lot of fun, I think. It will take us to a lot of different directions.

Okay, now do you want me to tell you a third story?

Hughes: Yes, I surely do.

Yamamoto: This story really is exactly in line with letting the protein tell us something we didn't expect or know about. This has to do with LEM-1, the third signaling story I said I could tell you. Here is where this observation started, and again I think it gives you an idea of how the research direction can define itself.

I told you rather glibly that we found that when we put the receptor into yeast that it worked, and that was a great day. But in fact the experiments started much simpler than that. When we got the receptor clone, we began thinking about ways to make it into a powerful genetic system. That's where the yeast idea came from. So we eventually seized on the idea of putting not the whole receptor but a part of the receptor into yeast, and the part of the receptor we decided to put in was the first two-thirds of the protein but not the last third. The last third is the signaling domain where the hormone binds and hsp90 binds and all this complicated stuff happens.

So what's left over if you cut off that signaling domain is the constituently active receptor regulatory protein that activates or represses transcription, whatever it's going to do, even without hormone, because you've eliminated this control fragment that's on it. So what we actually put into the yeast cell was this fragment of the receptor, together with a yeast gene to which we had linked a GRE. Then we just asked in a yeast strain that contains the receptor fragment, do we see a lot of activity, and in the sister strain that lacks the fragment, do we see no activity? And that's what we got.

Now, why did we do that? We did that because the simplest signal to monitor in yeast is a change in gene expression, especially if the gene that's fused to the GRE is something like beta galactosidase, which has a color marker associated with it. There are chemicals [that you can add to] the growth nutrients of the cell that will make the cells turn blue if the Oral History Center, The Bancroft Library, University of California Berkeley 177

enzyme works, whereas the yeast colony stays white if the beta galactosidase is not being made. So we can add this receptor fragment to a yeast strain and by looking at the color of the yeast cell, determine whether the receptor is working or not.

Hughes: Pretty neat.

Yamamoto: Pretty neat. So we thought when we first designed that experiment that it might actually be hard to find a yeast that would do this, and so we might have to use the genetic capability of the yeast to find a mutant yeast that would do it. So what the blue and white thing [method] does is it allows you to look through millions of yeast cells on a plate or a couple of plates and pick out the blue ones and say, "[The receptor's] working here; let's look at this [cell]."

Well, it turns out it worked in all of them. But we did the experiment explicitly to trim down the number of variables. Again, stay with our friend transcription. Also, frankly I was afraid that we would have trouble getting the dexamethasone into yeast. Yeast has this hard outer shell to it, and it's notorious for having difficult permeability characteristics. So we could also avoid all that stuff by putting in this fragment. So that experiment worked, and we were very happy.

It wasn't until about a year later that we tried putting the whole receptor in and asking, now do we get hormone-dependent transcription? So we did that, added dexamethasone, our favorite agonist, and it didn't work. I went around the lab saying, "Aren't you people lucky to be working for such a smart guy, and lucky I told you to do it this way?"

Hughes: [laughs] I know what's going to happen.

Yamamoto: All the usual PI sort of comments. So it turns out that it's not what I thought. I thought, well, dexamethasone isn't getting in. Actually, it doesn't get in very well, but it actually does get in. It just doesn't get in quite as well as [inaudible]. So [inaudible] very little of this phenotype that we were observing. We could go to a thousand-fold the normal level of dexamethasone and the yeast wouldn't activate. Well, that depressed us for a while. We thought, the yeast system is going to limit us; it's not going to be as good to us as we hoped. We can't really study the hormone- dependent reaction; we can't study signaling. Too bad.

We're helped in this field by the fact that drug companies care a lot about glucocorticoids. They are the most heavily prescribed drug and prescribed for many different applications, everything from skin rashes to use in transplantations and treatment of certain forms of leukemias, all sorts of Oral History Center, The Bancroft Library, University of California Berkeley 178

things. They have lots of side effects because the hormones work in every cell type. We had already established that. Some of the side effects are very disagreeable, but that's how it goes when you're trying to stay alive from leukemia. You don't worry about some muscle wasting. Drug companies would love to find glucocorticoids that have some of the effects of glucocorticoids but not others--to [find] an anti-inflammatory that doesn't also [cause] muscle wasting. So the chemists in those companies make all sorts of glucocorticoid-like things and say, does this do it?

Michael, a postdoc in the lab, tried a bunch of things in yeast, and lo and behold, he made an amazing observation. That is that some of the things that he tried worked just like they do in animal cells. Some were terrific agonists in animal cells and lousy in yeast. And some were really changed in their activities. RU486, a drug you've heard of, also turns out not only to be an anti-progestin, which is the way that it's used to induce abortion, but it's also an anti-glucocorticoid. It's an antagonist of the glucocorticoid receptor. In yeast it's an agonist. It works just the opposite way.

So subsequently in the lab, we have introduced the receptor into a different yeast, called Pombi, which evolutionarily is as widely separated from [Saccharomyces] cerevisiae as it is from us. And the receptor gives yet a different species-specific pattern of ligand potency. A student from here went to Stanford and put the receptor into a plant, a Rhodopsis[?], and got yet a different pattern. He put the receptor into Drosophila cells and got yet a different pattern. The same receptor is introduced into cells from different species, and in every case you get a species-specific pattern of ligand response. Amazing. So the firm conclusion we could draw from that is, it can't just be the receptor that determines ligand responsiveness. It has to be something else.

So a way to think about this would [be to] say, maybe there is some other protein present in all cells that is somehow processing the ligand signal, binding to it or whatever, and that the processing of the ligand signal gets passed along to the receptor. Let's say it modified the ligand so it binds differently to the receptor, and that ligand-modifier activity is a little bit different from species to species so the kinds of modifications you get are a little bit different. So now the ligand acts differently. That's a fine idea, and yeast gave us a way to find it.

What we know is that if we plate the yeast cells with the receptor and the beta gal gene in the presence of dexamethasone, the cells are a deathly white. If we plate those same bugs in the presence of some other drug, like one that happens to be called DAC, then the cells are very blue. The blueness of the cells says you're doing the experiment okay: the receptor Oral History Center, The Bancroft Library, University of California Berkeley 179

actually is in there; the beta gal gene is in there; they all work. But dexamethasone doesn't work. So you say, terrific, we'll take that. Now we've mutagenized the yeast genome and looked for blue colonies in the presence of dex. Let's find a mutant yeast gene that now allows dexamethasone to work correctly, and that mutant yeast gene will tell us [what] yeast is doing to the signal to make dex so screwed up.

So Shawn Bowen, as part of his rotation project when he started in the lab, and he didn't pursue this, started a project that was then pursued by a postdoc in the lab, Natasha Crowley. What Natasha found with Shawn's help is that she was able to clone a gene that encodes this protein LEM-1 that is a pump at the surface membrane of yeast that selectively pumps dexamethasone out of the cell. So when LEM-1 is wild type, normal, and you add dexamethasone to yeast, it does it fine. But LEM-1 says, forget it, and sends it right back out again. So the cell thinks there's no dexamethasone there and the receptor doesn't get activated.

So when Natasha picked the blue colonies, she found mutants in LEM-1 that don't pump right. Now the cell takes the dexamethasone, binds to the receptor, and boom, off it goes. It doesn't work with other very similar glucocorticoids, so it's very specific. And it presents a possibility to us that right now is absolute conjecture but I'll bet you is right, although you should process that with all the other bets I've made. [laughter] That is that if animal cells had on their membranes different sorts of pumps that would affect different sorts of ligands, then cell one in the presence of one circulating concentration of hormone would have hormone amount A in it, and cell two next to it would have hormone amount B in it. And cell two would look like it's responding very well to the ligand, and cell one would look like it's not doing anything. Yet a different way to make a common circulating signal, hitting a ubiquitous regulator, act differently in different cells [pl. clarify]. So I think we'll find that.

It also really flies in the face of a dogma that has been in the field as long as I've been in it, which is now gotten to be a long time, and that is that the steroid molecules are cholesterol derivatives. They are these greasy things. Cholesterol is a major component of cell membranes. So the argument, the assumption all along has been, oh, the hormones kind of grease their way through the cell membrane, no problem. They don't have to be carried on anything or anything."

I had a wonderful conversation with a scientist at Harvard named Guido Guidadi [sp?] in 1984. He's a membrane guy. He said, "That's nonsense. Steroids don't go through membranes. They have to be carried on proteins." I said, "Guido, what are you talking about? Your Nobel- prizewinning colleague next door, Conrad Bloch, won his Nobel prize by Oral History Center, The Bancroft Library, University of California Berkeley 180

looking at the role of cholesterol in membranes. These are just cholesterol derivatives. Of course they're in membranes. They don't need any stuff to get in and out of membranes." Guido gave me this wonderfully compelling argument why in fact that idea was wrong, and that these things don't float through membranes; they have to be carried. The argument is not important, but I was very impressed.

I came home, and a colleague—a kind of competitor, I should say, Suzanne Bourgeois [sp?] in San Diego—had sent me a preprint, not because she likes sending me preprints, but because I was writing a review article, and I'd asked for people to send their work. This is a great ploy to get people's work out of them. You write letters to all your competitors and say, "I'm working on a very important review article, and I'd love to include your work. But if you don't send it to me, there's no way I can do that." [laughter] So they're stuck.

So Suzanne and I were at that time kind of competing, but she sent me this preprint anyway. She had found a wonderful mutant lymphoid cell. Lymphoid cells, you may remember, are killed by glucocorticoids. She was studying that same system, a different cell type but the same idea. She like I had gotten bored with getting receptor mutants over and over again, and she was looking for other kinds of mutants. So she applied a different kind of selection, and she got a fantastic mutant of this cell line that was killed by triamcinolone but not by dexamethasone, two very, very similar chemicals. Then she did experiments that convinced me, although she interpreted the data differently, that the difference was that dexamethasone couldn't get into those cells, or wasn't retained by them, whereas triamcinolone did get in or was retained.

I got very excited by this because I had just gotten home from talking with Guidadi. I called him up and told him about it, and he said, "Ah-ha, this proves I'm right. There must be proteins in the membrane that carry specific glucocorticoids," because there's no lipid in the world that on the basis of something diffusing through the lipid biolayer could discriminate [between] dexamethasone and triamcinolone. They are too similar. So Guido said, "No lipid could distinguish. There must be carrier proteins. You should go look for them." It was 1984, and I was very impressed by that conversation but didn't do anything about it. It really changed my thinking and convinced me that there must be carriers but that people hadn't found them. Right now, if you pick up virtually any steroid paper, it will say, steroids diffuse through the membrane and encounter the receptor inside the cell.

By doing this simple experiment, simply doing blue-white screening in yeast, Natasha was able to find the carrier protein for dexamethasone that Oral History Center, The Bancroft Library, University of California Berkeley 181

affects dexamethasone selectively and not other glucocorticoids. So again, it's kind of a proof of principle [experiment]. It doesn't say, what is it doing in yeast? We don't have a clue. The yeast under our growth conditions doesn't care about it; it can kill the gene, so we can maybe do some genetics there. What's it doing in yeast normally? We don't know.

Natasha cloned the sequence of the protein, [and found] it's in a big family of carrier proteins—ATP-dependent transporting proteins—that are present from yeast to mammalian cells. So she's now looking for the version of this LEM-1 that works in animal cells. We fully expect there to be input pumps as well as export pumps, so we're looking for those. She's got some clever schemes for finding those.

[begin tape 14, side B]

Yamamoto: —[complete] to function by the receptors. How directly [were] any linked to regulation or signaling? I don't have a clue. It could be profoundly important, or it could be an adjunct that gives cells yet one more way for a variation of receptor activity. We don't know yet. But I think we can close that gap by now studying this family. So again, this is something else that the receptor is telling us we should pay attention to.

So that's a view in a nutshell of the philosophy and the ways that we've pursued it in some of these cases. There's just lots and lots of different directions all this [work] can go. It's taken us into structural studies on the protein, and crystallography, and a lot of genetics, as well as the biochemistry and molecular biology that we started with. It makes it a lot of fun because it means all these approaches can be working in tandem in the lab at the same time. It's exciting.

Hughes: Say you've been doing biochemistry, and it becomes obvious at some point you have to move into yeast genetics. How much scrambling around does that move entail?

Yamamoto: Good question. At UCSF it entails very little. This is the best place I know of for being able to move your research program where the problem takes you because there's tremendous expertise here. The ethic of the [UCSF community] is to be supportive of your colleagues and to be interactive enough that it's easy to have conversations and to share expertise and to share reagents. So our move to yeast was effortless because my lab was perched between two of the best yeast labs in the world, Ira Herskowitz's and Christine Guthrie's. We did the fly experiments effortlessly because there are terrific Drosophila labs here. Our efforts to move in the structure direction have met more fits and starts. We've developed those Oral History Center, The Bancroft Library, University of California Berkeley 182

collaborations over a long range, but we're bringing them home now, and we're collaborating. Those initial structure collaborations were with a group in Chicago, then moved to Yale, and then to another group in Utrecht in the Netherlands.

Hughes: Crystallography?

Yamamoto: Crystallography. But now we've brought those [studies] back, and there are two postdocs in my lab that are trying to grow crystals here, and we're collaborating with a group here, David Agard's. So this community is just beautifully set up to make people like me look smart when we're actually just talking to our neighbors. [laughter]

Hughes: I think probably it's a little bit more than that.

Yamamoto: Well, it's close. You'd be surprised.

Hughes: Is what techniques they bring along with them one of the factors in accepting postdocs?

Yamamoto: It is one of the factors, and different labs work this quite differently. So some labs which decide to put more eggs in that basket will actually shop for a postdoc with a given set of expertise. Other people won't do that at all. Some people will only take people who already know something about the field that they're working in, and some people say, it's nice to have some naive eyes on a problem, if they're smart eyes, so I'll take somebody from outside the field. And all those [approaches] seem to work.

Hughes: You use all those approaches?

Yamamoto: Yes, we don't really pay much attention to that [in selecting postdocs], and it's worked pretty well. Although when I'm thinking, boy, it would be wonderful to move into some structure stuff; I don't know how to make a crystal; I could go upstairs and do a mini-sabbatical in David Agard's lab or Bob Fletterick's lab and learn. So when somebody applies to me from a crystallography lab, it's true, I pay particular attention to them. We don't go shopping for them; I don't call my crystallography friends and [ask them to send me their students]. But it is one way that a lab can begin to branch out.

So when I pointed out the fantastic things about UCSF in that regard, I really do believe completely that it's much easier to move through a problem at UCSF than at other places. Other places take very different strategies. Our labs are not big, but in fact they play bigger than they look on paper because we've got collaborators here that we gain expertise from. Oral History Center, The Bancroft Library, University of California Berkeley 183

Whereas in other places, the labs actually are big because each of them becomes a free-standing operating unit. So each lab has to have a crystallographer in it and a molecular biologist in it and a yeast geneticist—you name it. That's just not true here.

Hughes: It seems a much more efficient system.

Yamamoto: Oh, I think so and more fun. It's a fantastic place to do that.

So the answer to your question is that the natural inertia of the way that humans operate makes us all hesitant to try something we haven't tried before. But to do it here, the barriers are lower than at other places. It's easier to do, and you can really get a lot of help from your friends. It's worked well.

Oral History Center, The Bancroft Library, University of California Berkeley 184

Interview 8: February 20, 1995

[begin tape 15, side A]

Hughes: Dr. Yamamoto, in 1976 Herbert Boyer and Robert Swanson founded Genentech. I'd like you to comment on what effect that had in the department.

Yamamoto: I can comment from the limited perspective that I had because at that time, in 1976, I was a brand-new assistant professor in a small department, and kind of finding my way. It wasn't a completely unknown department to me, as you know, since I was a postdoc here, but certainly being a faculty member was. Nobody, no faculty members, had experience with this sort of issue at the time.

My recollections are probably hazy, but what I recall is that we, this small group of faculty, kind of heard about the formation of this company sort of piecemeal as the rumors circulated in the department. So I as a first-year assistant professor sort of heard this, looking in from the outside, even though I was a member of the department by then, but didn't really know what to make of it, what experiences [with commercialization] elsewhere had been, what the ramifications would be.

But I had my own concerns about what it might mean for one of my faculty colleagues to form a for-profit company whose product was really the product of his laboratory research at the university. And that's what worried me. I was good friends with Christine Guthrie. I think I mentioned her faculty appointment the same week that I started my postdoctoral fellowship here in 1973. So we had kind of been friends all the way through, and we talked about this a great deal.

It wasn't for a few weeks, I guess, after I'd heard about the formation of Genentech that this was actually raised in a more formal setting of a sort, at least for our small department it was such. The faculty had a little get- together every Friday at five, or something of that sort, in a small room. It was a small group. We all sat around and had a glass of wine and chips or whatever, and just talked about things, what was going on, any department business that needed to be transacted.

So it was obvious to me by then that I had real problems with the formation of a company of this sort, and that it seemed completely clear to me, and I think to Christine, who I talked a lot about this with beforehand, that it was a bad idea, and that there must simply be a misunderstanding, or that Herb hadn't thought about these concerns that I had at the same time that I had them. That's all. So I intended to go to one of these Friday Oral History Center, The Bancroft Library, University of California Berkeley 185

meetings when Genentech was on [the agenda]. We had heard Genentech was going to be discussed, and Herb would tell us about the exciting formation of this company. I intended to go to the meeting and actually propose that we make a departmental policy against doing this, that a department member— That we will resolve as a department not to form companies whose work would be based upon our university research.

Hughes: Did you have any precedent for thinking along these lines?

Yamamoto: You know, I don't remember that. Now that I'm recounting all of this to you, in fact, I am no longer certain that it [the department meeting] was within a couple of weeks after hearing about the company. Now that I've said all of that to you, now I remember that I did some checking [of university policy] to see. Because when I first heard about this, I thought, oh, this must be illegal. There must be a university sanction that would preclude a faculty member from doing this because of what to me seemed to be obvious conflict of interest potential, and the potential for compromising academic efforts with students. I did do some checking about that, and I looked in the academic faculty manual, or whatever it was called, and also checked somewhere else that got—

Hughes: There are some documents from a UCB committee dealing with consultantships, I believe it was.

Yamamoto: Yes. And it drew me into talking with some people at Berkeley, and talking with some people at the Fair Political Practice Commission, FPPC, that you may have some of my papers about. So now I no longer recall when I actually went to the faculty meeting, or how much time transpired before I actually went to make the proposal that we don't do this [commercialization].

But it was on the basis of what to me was a surprising discovery that the university not only did not have a sanction against faculty members forming companies but seemed in fact to encourage it, and that various agreements seemed to be laid out for sharing of profits of these things, and that patent agreements seemed to be designed to rake profits back to the investigator, which is still the case. All of those things really surprised me. I was very naive—I still am. I was very taken aback by the fact that neither the university nor the NIH sanctioned these activities. So it was on the basis of those discoveries that I decided to go to the department and just say, "This is not a good idea. Let's make it a policy of our department that we won't do this."

Hughes: Well, you probably know from your friendship with Charles Weiner that there is quite a history of industry-academic associations, but not so much Oral History Center, The Bancroft Library, University of California Berkeley 186

in biology, if you discount pharmaceutical company-academic consultantships.

Yamamoto: That's right, a long history in chemistry and engineering, and physics to some extent.

Hughes: Right. But this was new for biology.

Yamamoto: Brand new, and I didn't know anything about that at the time and didn't meet Charlie until 1981, and so I just didn't have a clue. But I thought, Okay. So the university is silly. The NIH is silly. Our department won't be silly. [laughs] Christine was a strong supporter by then. If we went and simply pointed out these pitfalls and dangers, everyone would see them, and we would make an agreement.

So actually I don't know what the time window was. It was short, because it wasn't like Genentech was a big company by then. It was still barely starting. And it was still very much an issue of debate, but it probably wasn't within the first week or two.

You asked me what was going on in the department. There was a lot of discussion about the fact that this was happening, lots of pros and cons being tossed around by everyone—students, postdocs, staff, faculty—a lot of speculation about profits, speculation and jokes about the profits and prospects of profits, and who would get rich off of such an adventure, if anything would ever come of any of it, or if these whole fantasy debates about who was going to make a profit were just so much fodder for discussion and entertainment rather than anything that might actually become reality.

But I took seriously this conflict part, so whatever period of time it actually was that ensued, I went to the faculty one Friday afternoon and made this proposal and was absolutely flabbergasted—it was barely given a hearing. These meetings, I should point out, were always wonderfully informal. There was no kind of recognizing [people to speak] and there were no motions, it was just a discussion, and it always was. It was a very familial, comfortable feel. I think it was something that Rutter had always supported. It certainly was the manner in which Gordon Tomkins always operated. I never got to see him in that venue, but I knew Gordon well, and I knew that he would never go for a formal meeting anyway. So that's how they were.

So it wasn't that I made some motion or anything, but I just came ready to talk about it. I talked about it, and everybody just kind of said, "Oh, no. It's fine to do this. You've got to let people do their thing." It was barely given Oral History Center, The Bancroft Library, University of California Berkeley 187

a discussion, where I thought it would have been. Simply people would recognize it and say, "Yes, that's a good point; we didn't think of this, and let's do that." Instead, I went out of the room kind of dazed, and feeling that, gee, maybe all of them harbor their own hopes for making companies. I really didn't know. That actually occurred to me. Of course, I didn't know that, but it seemed as if there was some other agenda there that would have led everyone else so strongly to kind of swipe my idea aside. So it was dressed up sort of in this cloak of academic freedom, which was something that—

Hughes: That's sort of ironic in itself. [laughter]

Yamamoto: Yes. Well, but it was. It's true. There was a lot of that going around then. And that people had the right to do their own little thing here. And then there were a few people that pushed the technology transfer side of the argument, that this is a tremendous opportunity for us to really be able to translate some of the more theoretical, esoteric things that we do into something that will be recognized for the public good. And that was it. That was the end of the debate.

Hughes: Nobody approached the question of whether this commercialization was potentially damaging to the principles underlying the university?

Yamamoto: No. I don't remember that. Maybe it was just because I was embittered by the fact that I didn't get what I thought would be a fair hearing, but I don't remember that being a subject of debate at all. I remember it being a very short discussion. So it seemed that to me, coming out of the meeting, that I was definitely out of step with most of the rest of the faculty, and that I still felt a bit like a postdoc [rather than a faculty member], which I probably felt a bit like anyway at that point, just trying to start. But the concerns that I had and the group that I talked with about these sorts of things were talking about a whole different set of things than this group, and there was just a different value system being associated with the events.

Hughes: So then what did you do?

Yamamoto: Well, I continued to be distressed about this thing for a long time, and again my recollection of when various things happened is fuzzy, to say the least. But I continued to be involved in it, to talk about the issue, to write about the issue in the Synapse [UCSF campus newspaper] and other journals around here, and to give presentations about it, to talk with groups of young scientists about something that was a cause of great concern for me, in which my focal point was the potential damage that it could do to really a critical aspect of what I regard to be the nub of academic research Oral History Center, The Bancroft Library, University of California Berkeley 188

training, which is the open intellectual inquiry aspect. What makes this both fun and rewarding and has made the endeavor work well, is the ability, in fact responsibility, to follow the leads wherever they take you, and that the goal of a company is completely different from that. So what I tried to bring forth in things that I wrote about and talks that I gave at that time was that these are both fine goals.

What companies want to do is to define a focus, a product, a line, or some reaction they're trying to achieve, and to put on blinders and get there no matter what, and to arrive at that station at some appointed hour which closely matches the agreement made with investors and stockholders or company owners or whatever, and that nothing would let them stray away from their focus on this goal. And that's great; very admirable, and that's what companies are good for. But academic scientific training had a completely different set of goals. It was not designed for efficiency; it was designed for education and training, that students especially, and I guess all of us, needed to be able to follow the leads that the experiments provided, that there was lots of importance attached to students kind of bumbling along, and that you have to step in your own holes in this business to some extent, and that a part of mentoring is providing guidance, but a part of that is giving people freedom to operate at their own pace and make their own discoveries. Those things in fact are laudable goals as well, but they're not very consistent with this kind of steamroller, blinders-on approach that makes successful companies so successful. So it was that that I was really trying to push, and that we really had to be careful about trying to glue the two things together that don't seem to fit together.

The thing that further contaminated the whole issue for me was the money thing, and that it seemed completely improper for a public university and research that is supported by federal tax dollars to be used to set up a for- profit company. I just thought, what if the average taxpayer found out that there are two ways to go into business in this country? One is you save money and borrow money and do the best you can and find a place to rent and figure out how to put in distilled water lines, do all this stuff, and you set up shop, and if it doesn't work, you're broke.

And the other way is to get a job at the University of California, and there's already distilled water here and a huge infrastructure, huge overhead investment made by the federal government to support the infrastructure, and you set up your company and use your technicians and your students to test out the ideas, and if it doesn't work, hey, that's how it goes. You've got tenure. Nothing bad can happen. You close the operation down. You keep going. It seemed that if the average taxpayer found that Oral History Center, The Bancroft Library, University of California Berkeley 189

out, they would be very unhappy. So there was that aspect of the conflict of interest and the money.

And then the other one was this very fragile relationship of mentor and students, and faculty member and colleague, a set of relationships of those sorts. Fragile because of what academic science tries to do. It seems to me it's an amazing thing that academic science tries to achieve, and that is that it sets out a system for investigation which says to each investigator, student or faculty member, it's a wide-open field; you're on your own; good luck; we'll see you at the finish line. All you have to do is sit down and write a grant to the NIH and get some money and then do your work and we will leave you alone to operate in any way you want. So then this bell goes off, and everybody starts this race to be successful. The interesting part of that endeavor is what defines success. The only real currency that we have [in academic science] is getting credit for things from our peers. The only way we can do that is to tell people what we're doing. The only thing we have is our ideas. We don't get a million-dollar bonus for anything; we get credit. We get promotion; we get into the National Academy of Sciences; we get something, some pat on the head, for having a good idea.

The only way we can get that credit is to tell people, to spill the beans all the time. It's a very strange, interesting dichotomy. So it makes communication a very interesting phenomenon. Some people are really afraid to tell people what they're doing because their biggest ideas they've got to keep under wraps. But they're always at risk of losing credit because if they keep it [their research] too much under wraps, nobody will pay any attention to them, or somebody will think of it at the same time and publish it. So there's this whole thing about communicating what it is that you're doing. It's already very tenuous, but it's the foundation of our whole system, that kind of communication. If you layer onto that, or kind of slop onto it, this complication of the potential of one person getting rich from the idea, then it seems like it's really a complication. There's already this difficulty—let's start with between faculty members—about sharing information. And now you add onto that the fact that, well, this guy's got a company. If I say this to him, then he can make a million dollars, and I'll look like an idiot. So there's that level.

The student-faculty member [relationship] is even more complicated in that students, and here I mean generically students and postdocs, young colleagues in the laboratories, have their own kind of conflicting situation to deal with in that they are here, they're in the lab, because they choose it, because they decide this is an area that they'd like to focus on. They place a certain contract of trust with their mentor, and they set off to work. The more they're able to produce, the better it is for them, but of course, the Oral History Center, The Bancroft Library, University of California Berkeley 190

better it is for their mentor. They become, either slowly or rapidly, aware of that as they're succeeding. Their mentor is kind of climbing up the ladder on the basis of the figures from their papers. They do an experiment; suddenly it turns into a slide that the joker [the mentor] gets onto a plane and flies off to MIT to give a talk about. And pretty soon, [the students] start to think, jeez, what's going on here? I'm doing all the work, he's getting all the credit, what's happening? So there's this little deal. And then after they've been here for four or five years, they begin to add on to that, gee, when's the last time he told me something that was useful? [laughter] Let's see, when was that? A couple of years ago now, I think. And then if you layer onto that the fact that the guy [the mentor] is suddenly getting patents or has a company that's becoming enriched by some of those ideas, then it starts to feel sort of funny. I worried a lot about that. So the financial things really became a puzzle, too.

So those were the things that I was kind of running around worrying about and talking about and writing about, and there was a lot of ferment in the department in general about all of those issues, really. My own laboratory was next to Howard Goodman's at the time, as you know, so we got a chance to see some of that going on first-hand and talk with some of the principals involved, including Howard, I should say. It seemed to me that there were genuine concerns.

In fairness I have to say that a lot of the concerns that I had at the student level were not realized, didn't happen. But I think the only people who get credit for that not happening are the students.

Hughes: They just didn't buy into it.

Yamamoto: They just didn't go for it. They just didn't go for it. I was very worried that students would get exploited, that they would go to a laboratory of a faculty colleague who owned a company, and that this fuzzy line would be so fuzzy that it would be impossible to determine whether a student was working for the mentor or working for the company.

Hughes: I think it was amongst material you lent me that there was a notice at Stanford—I mean, a photocopy thereof— inviting students who felt they were being exploited—I'm not sure that that was the term used—that they could then see somebody who was named at Stanford about this problem.

Yamamoto: That's right. I think there was a lot of concern about that. I think that at UCSF, what happened was that the students simply stopped going to those laboratories. They just stopped. I just didn't realize their level of sophistication or didn't have enough respect for them. I thought a lot of students would want to be involved in this [commercialization] because Oral History Center, The Bancroft Library, University of California Berkeley 191

it's so exciting. The stuff was exciting. For all of the things it was or wasn't, it was certainly exciting.

Hughes: From the start in Dr. Boyer's lab there was real tension amongst the students themselves because two of them were included, I believe, in the initial contract between Genentech and the university that led up to the somatostatin work, although it was not labeled as such. The two postdocs were receiving a higher salary than the other postdocs in the lab, and that of course presented some tension. Plus the fact that there was a sudden cessation of the free flow of information.

Yamamoto: Oh, yes.

Hughes: There are some startling quotes made at that time about how the banter that had gone on across the lab bench was just no more.

Yamamoto: That's right. Well, that was definitely the case. For all of the fact that the students didn't end up being slaves of the company, this sort of collapse of communication within laboratories— We watched it happen in Howard's lab. I talked to many of the postdocs there and eventually talked to Howard about it, as you know. It was a serious problem that postdocs and students would come out of a group meeting and say, "They're going to get a patent on—" It would be big conversation in the hallway. "They're going to get a patent on this, and it was my idea to use the BAM site, and I remember it, and you remember it too--three weeks ago in group meeting. And now they're using it, now there's going to be a patent, and I'm not on it. So maybe next time I won't suggest the BAM site." It's as simple as that. All of our new ideas are just two old ideas put together, so it's always based on what has gone before. And as soon as you close off that form of communication, we've had it.

So communication within those labs that were doing that very competitive work was really compromised. There were just unending discussions about names being on patents and all this sort of stuff that was just ridiculous. And communication between laboratories, because of the fact that there were several labs doing this sort of thing, really became complicated, too. So it certainly had an effect at that time. When I said that a lot of the problems didn't materialize, I think the one thing I was talking about was that students didn't end up in this kind of difficult shadow area of being the slave of a company. But certainly, the price was paid, or a price was paid at that time, with respect to the problems of communication in labs.

Now, I'm sure that there will be those who will say—there are those who say—"Well, this is a shakedown period. Anything new that happens, Oral History Center, The Bancroft Library, University of California Berkeley 192

you're going to go through a period of difficulty, and if you look at the way things are now, the field has weathered it, and that we're okay again. The endeavor was strong enough that there was no lasting damage done." There's a certain point to that, but I think that the people who were weathering the situation as it was happening wouldn't be so quick to draw that conclusion. And it had a big effect.

Hughes: Your critics were, I suspect, probably saying several things, but amongst them was something along the line that one of the traditional functions of the university is to transfer information that is of use in some form to society. We now call that technology transfer; that's a relatively new term.

And the other point that I've read about was that the proponents of patenting would say that patents preserve the free flow of information by making the invention available, assuming that otherwise it would be a trade secret. I think you might be able to pick some holes in those arguments.

[begin tape 15, side B]

Yamamoto: Yes. I have pretty strongly formed views about this. I absolutely agree that universities have an opportunity and a responsibility as public trusts to transfer the information that they have, even information that they don't know to be of practical use, but certainly information that they know to be of practical use, into the public sector to be used. We're paid by taxpayer funds, the state puts up these buildings, and so I think we are accountable to the people to let them know what we're doing. In fields like the burgeoning biotechnology field, letting the public know includes providing the opportunities, and in fact pointing out the opportunities for basic research knowledge, knowledge discovered through basic research, to be applied. Okay. So I believe all of that stuff very strongly.

But I don't believe, I just can't make the transition to say that the people that can best do the information transfer side, the technology transfer side, of creating the application to make something work, are the very same people that discovered the basic knowledge. That to me doesn't follow at all. It doesn't compute for me. And so I just don't understand trying to make that direct bridge with the same person.

This isn't done in other fields. It isn't even done within fields. General Motors doesn't do the detailed design and fabrication, probably even of its motors for all I know, but certainly not of tires and locks and all of the other things that go into the components. I just don't see that that follows at all. There are huge companies and industries that are set up--the Oral History Center, The Bancroft Library, University of California Berkeley 193

pharmaceutical industry being an obvious one--to exploit the products of the discovery of basic knowledge in biology. They are certainly aware of the potential.

Now, they may not have been aware of the potential then, but I still don't believe that it's important for the professor, or that the professor is in fact even particularly uniquely equipped, to then convert his or her research findings into a company that can fabricate something. There are a lot of businessmen and a lot of business schools in this country that regard business as being actually a full-time, regular job that people actually do all the time, and work very hard at. [laughter] I certainly regard this job as being a full-time job. So I don't see that it works well to put the two things together.

So with that attitude, together with my point of view that the goals of a company and the goals of academic science are in fact at odds with each other, both perfectly supportable but not very well put together, that it seemed like this should be accomplished by having different people on the two sides of the fence, and that the technology transfer is important, but in fact should not be carried out by the same individuals. That was how I resolved that.

Hughes: What about the argument concerning patenting?

Yamamoto: I think it's true. I think that the way that laws for product use and application in this country are set up, and I guess now in the world are set up, that companies won't actually try to exploit any finding unless there's patent protection and subsequent licensing. So again, I don't have any problem with that. I think that's fine.

What I do have a problem with, but I don't see any solution for, is the policies that the government and the NIH and the institution have for sharing the profits with the inventors. Here I don't have well-formed ideas about what should be done. The naive notion, which is sort of a sixties throwback [laughs], is that what we're able to do in this institution is so inextricably intertwined with the institution itself, and all of the things that the institution does to bring people together, that anything that we do in the end could best be pointed to as a product of the institution. When a company calls me up to consult, I'm pretty sure that if I weren't here, they wouldn't call me. It's because I've been a member of this institution for a long time, I've been able to draw from its expertise in many demonstrable ways that a company might end up calling me up and saying, "Would you come out and spend half a day with us to talk about thus and so?" So my feeling is that when we are called to do such things that it is at least as much because we're in the University of California as it is because of Oral History Center, The Bancroft Library, University of California Berkeley 194

anything that I've thought of by myself. And the same goes for things that we patent.

So the sixties idea of how to deal with patent policy would be that the inventor becomes impossible to ascribe and assign, and that the invention belongs to the university, just like the grant belongs to the university. As you know, when an individual at the University of California, or any university, writes an NIH grant, the money doesn't go to the individual. It goes to the institution. It goes to the Board of Regents of the University of California. There I could certainly make a stronger case that it should be my money than any patent that comes out of it, interestingly enough. Nobody fights with the first thing because you can't go spend the money yourself. Now, I guess people could argue that that's a really unrealistic point of view, especially in today's world, to say, "Oh, well, just throw it back in the university." I guess that's what I would prefer.

Hughes: It seems to me that there's also a theoretical notion too, and that is the continuity of science. When does something really truly become new and hence attributable to an individual or a group of individuals? I think the way scientific publication gets around that is by the line of credits, that people probably abuse, but nonetheless there is a protocol that gives the reader the idea that this particular report has not just sprung from nothing. Well, when you start commercializing, it's a more circumscribed thing that doesn't clarify, at least as directly, the links that this research has, not only with the institution, which you're aptly pointing out, but also with the whole scientific tradition that made this research possible.

Yamamoto: Absolutely. That's right--tracing the origin of ideas. I don't like scientific prizes for the same reason. And that is that in fact what we should celebrate about this endeavor is that it has been able to succeed when one of its founding premises is that it's just a bunch of people sharing information, that it's really the blind Indians and the elephant, and that if each blind Indian were allowed to describe the elephant all by himself, we'd be lost. So it's just a lot of blind Indians.

Hughes: Yes, and which of those Indians should profit monetarily from it?

Yamamoto: Yes. Who's the one who finally gets to say, "I discovered what an elephant looks like"? But I don't know what the solution is. It seems to me that we could learn something here from the way that a lot of companies run their patent policies. But if you then ask me how they do run them, I don't know. But it seems to me that in a lot of companies, all the patents belong to the company, I don't know what that guy got out of inventing a Post-It, but I imagine he got something good. Maybe a lifetime supply. [laughter] Oral History Center, The Bancroft Library, University of California Berkeley 195

Hughes: I hope he got more than that.

Yamamoto: I think in most companies, the patent belongs to the company. I wish that that were true here, that the patent belongs to the University of California, and that isn't it a great thing that we're all here together so that this could come about?

Hughes: Well, how much worry is there nowadays? It's the rare biologist who does not have some sort of a link with industry. Is anybody truly concerned? To me, it seems as though the debate has very much died down.

Yamamoto: It has very much died down.

Hughes: And why?

Yamamoto: Well, I think in fairness, I guess it could be said that the scariest things didn't happen. That communication within departments didn't grind to a halt, even in departments like this one where there are multiple companies that sprang up close to the same time. So there were problems, and compromises were made, and people got kind of cut off at the pass in some cases, but the scariest things didn't happen. The more cynical view is that a lot of the stuff got pushed under the ground, under the table, under the rug, and people stopped talking about it because they were pretty excited about getting their own consulting checks.

From this perspective of the Bay Area, I'm sure it looks like most scientists are involved in companies. I don't know what it's like nationwide. I'm not so sure that it's most, but it is a lot [of scientists]. Truth in advertising here [laughs]: I'm on a scientific advisory board myself for a small company. I can tell you if it becomes relevant what kinds of concerns I went through and the conversations I had in finally making that decision, which was made two years ago. I'm not exactly a pioneer in this business.

Hughes: Well, I think now is as good a time as any if you want to go into your reasons for making that decision.

Yamamoto: Sure. This is a scientific advisory board of Tularik, a small company in South San Francisco that was founded by three friends, Bob Tjian, Steve McKnight, and David Goeddel, in which the goal of the company is to try to discover drugs that will very specifically block the function of transcription regulatory factors. My career has been about transcription regulatory factors and small molecules that affect their activities. So I've thought about this business for a while. Oral History Center, The Bancroft Library, University of California Berkeley 196

Hughes: I can assure you that your saying, "I've thought about this business" is going to look ambivalent. By business, you mean the science?

Yamamoto: Oh, yes! [laughs] Yes, I've thought about the science for a long time. So the idea that it might be possible to intervene with a biological function at that level seemed feasible to me. I and the company have no idea whether this idea will work, but it seemed feasible to me that the science had reached a stage where that was something that one could really entertain as a possibility, and that it would be potentially a much more specific target at which drugs could act. Therefore if the idea would work, one could [block?] one of many of the side effects of drugs. That's the principle.

So when those guys came to me and said they were thinking about forming such a company, I thought, wow, that is really exciting. I don't want to form the company, but that's a pretty exciting, adventurous idea. Very speculative, but very interesting. Then they subsequently came to me and asked whether I would like to join this scientific advisory board. Now, a scientific advisory board is a group of people that, to be completely honest with you, is in part a showpiece for attracting investment, investors, and in part an advisory body. I think the more established a company becomes, the less useful the board is for either of those things. [laughter]

Hughes: Now, why do you say that?

Yamamoto: Well, it's true. I think when they're first trying to coax venture capital out of people, it's nice for them to say, "We have these people." And before they have their own corral of scientists there at the company, then it's nice to have that group of people to sit around and talk with. Tularik has been going for a couple of years, and I think they're beginning to reach that point where we don't make any difference to them anymore.

In any case, they came to me and asked whether I would like to join. They showed me the list of other people that they were inviting—very exciting group of people. I like these three guys very much, and they're fun for me to talk to. The company is a few minutes away from here, and they didn't ask me to do very much. They were going to have at that time two meetings a year. It's already shrunk to one every nine months; see, they're discovering they don't need us. And then in addition, they wanted me to come down there perhaps a couple of times a year for what essentially turns out to be a research group meeting in which they invite advisors to come get associated with one particular big research project that they're doing and just sit in and give my point of view about what I think of the proceedings, and how the research is going. Oral History Center, The Bancroft Library, University of California Berkeley 197

In exchange for that, then a check gets cut for a few thousand dollars to the Board of Regents because I don't keep the money myself. There's supposed to be some sort of stock option thing, that I don't understand and never have gotten any certificates for, that is potentially more complicated, to be honest.

Hughes: You mean the stock option comes automatically or you can choose?

Yamamoto: I guess you can choose. I don't understand stock options, but I guess the idea is that for a start-up company— It's not a publicly traded company so the stock is not worth anything right now, but you can buy these stock options for a penny a share, three cents a share, some small amount of money per share, and then you have them. The complicating thing, of course, is that you have them. I guess you can give them to the regents, too. When the company goes public and the stock goes from being worth three cents a share to thirty dollars, then there's a pretty handsome [return].

Hughes: Yes.

Yamamoto: So I don't really understand it, but in a way fortunately, I've never gotten any of that stuff from them, and I haven't asked about it. [laughs] And the checks have just been converted to the university.

So where does all that money go? In my lab, I've asked the Biochemistry Department to set up a separate account. I actually have two separate accounts; I'll tell you about both of them right now. One of them is this consulting money. When I do ad hoc consultancies for various companies, all of that money, the checks, get cut to the university, and it goes into this account that then is used by my lab for research.

Unrestricted funds are almost impossible to come by, so if I want to invite a young scientist to come to do some experiments in the lab or give a talk about something that I think is exciting that would help my laboratory, then I can do that now. When postdoctoral colleagues apply to my laboratory, the ones that look the most interesting to me, I invite them to San Francisco to spend a couple of days in the lab and give a talk and to mingle with the students and postdocs to kind of see how it feels. That gets paid for by this account. So those are the kinds of things that I use it for.

Then we have another account that we use when—and this might be interesting—when nonacademic institutions request materials that we've made here: recombinant clones, organisms—

Hughes: Oh, you mentioned this. Then you ask— Oral History Center, The Bancroft Library, University of California Berkeley 198

Yamamoto: Then I ask them for money, and they occasionally make contributions, and that's where all that money goes to. I fret about the stock option thing, but it hasn't come up, so so far I haven't had to worry about it.

Okay, so why did I decide to do it? I just finished telling you I have a full- time job, so why did I decide to do it? There's two things: why did I decide to do it, and am I concerned about all of these things we've been talking about, and am I part of the group that I was just kind of implying has been bought off this crusade about there being problems simply by having my own show? Fair questions.

I decided to do it because it seemed to me to be a very stimulating thing to think about that I could hopefully do without compromising my other responsibilities here. It will be certainly one of the first things to go if I feel that that's happening. So far the burden has been light, to say the least. The meetings have shrunk to once every nine months, and then I go about twice a year to these group meetings. They're two-hour group meetings in South San Francisco. And it's been fun, stimulating. So it's a nice conversation to have. The other people on the board are superb scientists that are just lots of fun to interact with, so it's been stimulating. I have no idea if it will work, and if you ask me how the company is doing, I would have no idea about that either. I can't really tell, because I don't know enough about companies. But it seems that they're doing well. They've gained at least the attention of venture capital people to the extent that they're relatively financially secure right now.

Am I worried about these conflict issues? Yes, I am. The one level of protection that I've built into the [consulting] agreement when I signed on was that we [Yamamoto’s lab] would not collaborate with the company. This was painful for me and maybe for at least one of the founders as well because of what I've told you about our work. It's directly related to that same principle. We work with a transcriptional factor whose activity can be either activated or inhibited by small molecules, and we know that, because that's the way the molecules work. These are receptors that are built to interact with these small molecules.

So there for the company is a physiological example of something that is what they're trying to do in a commercial realm. It's easy to imagine collaborations that could spin out of this known molecule. Glucocorticoids, the receptors that we work on, are the most heavily prescribed therapeutic, I think in the country or the world or something. Space. And the reason that they're heavily used is that they work. They come with a price, and the price is side effects. So when they're used for immunosuppression for transplant operations, the price that they come with is a lot of muscle wasting, changes in bone structure, other things that Oral History Center, The Bancroft Library, University of California Berkeley 199

glucocorticoids are known to do. They're heavily used for anti- inflammatories, but they have these other side effects. They can cause mood changes when they're used systemically because they act in the brain.

So here is this enormously heavily prescribed drug, and every drug company would love to have a version of those things that doesn't have side effects. All you need to do is figure out a way to develop a derivative of the glucocorticoid that is more focused in its action than the normal hormone. It would be a great project to play with, and would lead to lots of money for the company if it would work. So that's the most obvious one, but there are many other possible ways that we could collaborate with them that would be useful for my lab.

But we just can't do it. I just can't. We had to make an agreement that we would not collaborate with them. I didn't want any pressure from them for us to collaborate, and I wanted to guard myself against going to them and saying, "Hey, let's do this experiment together." Because as soon as we make such an agreement, I think it's impossible for anyone, including me, to distinguish whether a student is working in my lab in collaborating with the company, or whether the student is working for the company.

Hughes: Did you make that an explicit tenet of your relationship with Tularik?

Yamamoto: Yes. So that's the only explicit tenet that I made. And it's been useful for me to kind of keep in my head. I can't think of right now ways that the relationship can contaminate my scientific effort here, but if it starts to happen—

There are actually several of us from UCSF that are on this board. Ira Herskovitz is on the board, Don Ganem is on the board. Ira and I at the time that we were talking about this were chairman and vice chairman, respectively, of Biochemistry, and so it seemed particularly important, if these two people were going to enter into such an agreement, that we kind of thought things through. So we actually had made it the subject of a faculty meeting, first of all to disclose that we were thinking about doing this, and both eventually joined on. And then just to raise the general issue of whether (a) the faculty had concerns about it, and (b) essentially just to get people aware and talking about the issue again. In fact, maybe just the point that you raised, that it's kind of quieted down.

I think the greater fear that I have, greater right now than my scientific research effort being contaminated by my association with a company, is that I'll just sort of piece by piece have my energy and my focus drained away from this job at the university just by having lots of these things to Oral History Center, The Bancroft Library, University of California Berkeley 200

do. I already feel like I'm torn in too many different directions. It's a wonderful aspect of this job that there are more exciting things to do than there are hours to do them. We all need to make decisions and at some point say no to things.

But it kind of happens subtly to you. The first time as an assistant professor that you're asked to review a grant, you think, wow, I've made it! This is fantastic! Somebody in Washington thought of me! [laughter] Isn't this wonderful? And that goes away real fast, and kind of dies down pretty quickly. But these things kind of grow by accretion. There is a certain nice feeling that comes from the discovery that you can do more things than you ever thought you could do. But it's like heating up the water in the fish tank a degree a day. Pretty soon you have fried fish.

Hughes: So one should be monitoring at all times?

Yamamoto: Yes. So we really held this meeting. In fact, I have to admit to you that I think we should have another one, now that we're having this discussion. But we really held this meeting in a way to kind of put ourselves on notice as a group, as a department, that we need to really pay attention to getting diverted. I think the marvelous thing about the basic science community here and the Biochemistry Department in particular has been that they've been able to maintain their focus amazingly well, and keep really the priority of making the—

[begin tape 16, side A]

Yamamoto: And so I am worried, but we're trying to watchdog it. Now that you've smoked all of that out of me, I think that—

The other answer to why it's died down has been that I guess that people aren't noticing what's happening to them. I'm very worried that this place which has been built up through really intense and careful effort by so many individuals can bring itself down without even knowing it, just by a whole bunch of little increments, any one of which could be called success. Joe Blow writes a book; Harry Smith goes to Washington—I should take that one out—and there you are. Suddenly, everybody's on the plane.

Hughes: Yes, it's insidious.

Yamamoto: Yes. So I think we have to be careful, and that includes this relationship with companies thing. Oral History Center, The Bancroft Library, University of California Berkeley 201

Hughes: One of the problems in the very beginning, wasn't it, that it wasn't clear who was doing what under what kind of arrangements? I wonder how well known it was, since Dr. Boyer so often was the target of the early criticism, how clear was it that Howard Goodman also had contractual relationships with Genentech?

Yamamoto: It was far from clear. In fact, the clearest knowledge I have of that was from what you showed me a few minutes ago. There was a lot of talk about that, but nobody had any firm information, and Howard wasn't talking. Not that he should necessarily have, but he wasn't saying what his relationship with Genentech was.

Hughes: Well, in that memo of your conversation with Dr. Goodman in 1977, I believe it was, it came up, and he maintained that he did not have a relationship or support.

Yamamoto: That's right. I forgot about that. And by then, it was clear that he already did?

Hughes: Yes.

Yamamoto: So that was the situation. It was that sort of lack of information and to some extent misinformation that was really rampant in the department. We of course weren't aware which was which. [laughter] But there was a lot of concern that members of the department were the last to know about anything, that we would find out much more in the New York Times than we would find walking down the hall and into the office of Colleague X. And that was a bad feeling.

Hughes: This seems to me doubly surprising in a department which at least at some stage was collegial and cooperative and more or less working for similar goals, or so at least it has been portrayed to me.

Yamamoto: Yes.

Hughes: What happened?

Yamamoto: I don't really— It feels like there were two distinct eras in a way even though the calendar tells the truth that there was a clear overlap. That is to say, this whole familial feeling and period in which explicit goals were defined that were at that time—unique is not the right word—but certainly forward-looking in terms of how the department would set itself up as an educational group. While they overlapped in time, somehow it seemed disconnected in how I think about the department, that this whole period of strife about the recombinant DNA stuff, the various controversies that Oral History Center, The Bancroft Library, University of California Berkeley 202

arose, the competition, the issues about patents, and the issues about company formation, seemed somehow—I really believe this—it sounds funny coming out, but it seems somehow to be sort of an encapsulated tumor.

Hughes: An aberration.

Yamamoto: Yes. While it seemed even at the time, but even still in retrospect, to be something that was definitely a part of the corpus, but kind of set aside and in its own little container and something definitely to be dealt with. But I didn't have the feeling that it really destroyed all of the other stuff that was there.

Hughes: The body continued to function.

Yamamoto: Yes. So it was putting it at risk, but it wasn't metastasizing all at once. It wasn't really wrecking the thing all at the same time. So somehow the body continued to function. So the risk was clear. If it was allowed to keep growing, then yes we would have had a real problem on our hands. But if it was contained, we had a chance to go ahead and survive anyway and fight it off. I think we were somehow able to do that.

Now, I don't know to the extent to which that analogy really works, as I back off and look at the whole thing, because of some of the other things that we've talked about: that there were clear effects on communication that people were struggling with all the time, that postdocs left laboratories to go to other laboratories during that time. There were a bunch of problems, and I think that in part Howard's leaving here probably had a lot to do with that.

Hughes: Some of the department principals seemed to have adjusted, each in different ways. I was thinking of Goodman leaving for Mass General. But I was also thinking of Boyer. Probably as a result of the tremendous furor, he very much made a separation between his university research and what he was doing for Genentech. As he describes in his oral history, he never was directly involved in research at Genentech. He was very explicit in his oral history in maintaining the research that he did—now, I'm speaking post-somatostatin and insulin and all of that—was very basic research and in fact eventually not even exactly along the same lines. In a way, Dr. Rutter made some similar adjustments, at least the cap that he was wearing changed. He did step down from the chairmanship. If you continue this analogy of the tumor, these are kind of walling offs, separations that are made between the basic enterprise of the department which is science and these other activities. Oral History Center, The Bancroft Library, University of California Berkeley 203

Yamamoto: Yes, that's a good point. There are several things that you raised that are worth pursuing. Bill clearly was sympathetic with the whole Genentech initiative of Herb’s, and I think he found it a very interesting development for science to be taking and wanted to go that way himself. There was an effort that he made early on to form a company that kind of got shoved back, and it was very much in the same way that you're talking about. And it was a real ebb and flow in where the borders of this thing would be allowed to go to and where they wouldn't, and people on both sides would make efforts to define those borders. Bill backed off with his initial effort to make a company because there was a lot of flak from other people in the department. Eventually, of course, as the world knows, he then found another way to get there.56 It's worked for him pretty well.

There was just a lot of that that was going on. And it extended, now that you bring it up, to curriculum development. Herb used to be one of the primary lecturers—I guess there were only two. Herb and Brian McCarthy used to present the molecular biology course that, I think in 1978, Christine Guthrie and I took over. At the time, I didn't think much about it in this context, but I think it was sort of the same thing, that Herb was increasingly being distracted by other stuff that he was doing.

Then there was this whole issue of, would it [commercialization] contaminate our curriculum presentation or not? And somewhere along the line without at least an explicit decision on my part that I was aware of, in a way the department kind of said, "No, it won't. We'll present this course with these people, they're kind of young and vigorous and naive, and they don't know what they're getting themselves into. And we'll give them a shot to take this thing over." In a way, it was saying, "No, the tumor stops here. We're not going to do that."

So there was a kind of ongoing recognition that the department had somewhere it wanted to go. It had this internal problem. It was a real struggle, and it was a real problem, and it had the potential of threatening every element of our operation and existence. At many of the steps along the way, we found ways to say, "No, this is it. It won't go further than this." It's an interesting question. I hadn't thought about it before, but I think that somehow we managed to do that.

And I guess it wasn't clear to me that something like that was going on. I'm not sure that we still quite have it here, don't quite have it yet, but something like that was going on. Until you asked me how these things fit together, there was this forward-looking department at the same time it

56 In 1981, Rutter co-founded Chiron Corporation. Oral History Center, The Bancroft Library, University of California Berkeley 204

was getting ripped apart by all this other stuff. It's true. It happened at the same time.

Hughes: Dr. Yamamoto, another thing that was going on at this incredibly busy time was the so-called pBR322 episode, in which I don't believe you were directly involved. But obviously as a member of the department, you were probably too much aware of what was going on. Do you have any particular comments to make?

Yamamoto: I can give you my rough recollections. Because you're such a good interviewer I'll probably set off something.

So the 322 issue was that there was a race on to clone the insulin gene in which the primary participants were Bill Rutter and some of John Baxter’s collaborators on this side of the country, and the Harvard group on the other side. It was at a time when the [NIH] recombinant DNA [research] guidelines were really just getting firmed up. Defining terms became a critical thing, about “approval” of a vector versus “certification” of a vector. Every institution was running around with their own institutional committees and their own P3 room guidelines and all of these other things.

The [insulin] race was very intense; it was known by everyone in the country in the field that the race was on. The principals on this side, the postdocs that were involved, were working virtually around the clock, and the people on my floor were very aware of that; the ninth floor was very aware of that.

So the public reconstruction of what happened was that this new vector pBR322 came on line, which grew faster and more efficiently than the ones that were available before, pMB9 and pSC101. It was a clearly superior vector and would allow the work to be done more efficiently. cDNA [complementary DNA] clones were constructed in that vector here to look for insulin, at a time when the vector had been approved but not certified.

Hughes: That's right.

Yamamoto: Then we were told that that was the case with 322 after the [insulin] clones apparently were in hand. The postdocs, Axel Ullrich and Peter Seeberg, then had this little problem: whether they would destroy the clones in the midst of this hottest race around the country right at that point and start over with pMB9, I guess.

Hughes: Right, which had been [certified]— Oral History Center, The Bancroft Library, University of California Berkeley 205

Yamamoto: [Which] had been certified, and go ahead, or not.

Eventually the paper came out in Science after a very short review process as being pMB9 clones. The controversy then boiled up about what really happened, what was behind—

So there was a big department controversy as well as a national one that eventually led to [U.S. Senate] hearings57 and a lot of other things about the course of those experiments, about which there were long and loud faculty meetings that were held. To my recollection, none of us on the outside of the issue ever felt satisfied that we knew what the real truth was. I remember sitting around and trying to calculate with some of my peers how long it would take for Ullrich to start over and recover the clones again in the new vector—the old vector actually—even if everything worked perfectly, just calculating things like how long a time it took to do a plasmid prep, and how long the spins in cesium would take, and how he could possibly have done this and still kept everything completely legal. And there were real questions that were raised.

Hughes: Was the description in Science of how the experiment was done different than actuality?

Yamamoto: Oh, yes, there was a real question about that. Were the things actually just transferred over from pBR322? And you know, the department meetings were kind of awful because they came down to questions about whether there were truthful entries in the P3 room data log book, and who actually said what to whom when, and things like this that are kind of interesting, Perry Mason-stuff, but not very useful for a department meeting. I remember them as being just sort of unpleasant, inconclusive, frustrating exercises that didn't probably leave anyone with satisfaction about whether we had accomplished anything that was useful.

Hughes: There was a larger problem as well, and that was the impending federal legislation concerning recombinant DNA. As you well know, it was the reason that both Drs. Boyer and Rutter testified before the Senate. The pBR322 problem was seen as a violation of the recombinant DNA guidelines. What you just talked about was the perturbations within the department. But was there also an external worry that pBR322 was one push towards greater certitude for some kind of federal legislative regulation?

Yamamoto: Yes. There was a real awareness that this place was very visible, and that we had to really be careful about how we operate, really stay within both

57 See the Boyer and Rutter oral histories in this series for information about the U.S. Senate hearings and the pBR322 episode. Oral History Center, The Bancroft Library, University of California Berkeley 206

the letter and the spirit of the law. Whatever could be said about the situation, it was certainly a case where it appeared that we had not done that, and that when we were sitting around in faculty meetings trying to decide whether somebody had faked an entry in the P3 room book, that things weren't really working in the way that you would like them to work, and that we were running a risk for the whole rest of the country, whole rest of the endeavor, by fooling around here. We couldn't do that. We had to do things differently.

But I certainly don't remember feeling satisfied coming out of the exercise that we would do things differently. Probably everyone on every side was frustrated and unhappy about the way all of it worked. I suspect there were feelings on the part of the principals here that the whole thing [pBR322 issue] was a ridiculous technicality. By the time we really got into the debate, 322 was certified, everybody was using it, nothing was going wrong, what's the big problem, right?

Hughes: Plus 322 was safer.

Yamamoto: Yes! It was better in every way. So there was this whole thing about, well, because the federal bureaucracy is slow at getting this thing certified is the only reason that any of this is coming up. And isn't that a little silly? So that was that point of view.

And then the countervailing one was, fine, I understand the frustrations with that, but in fact we're sitting up here very exposed, and the whole country is going to pay attention to whether UCSF is following guidelines that itself has been involved in helping to set up. If we can't do it here, then how can we expect the Congress to have confidence in the rest of the community? That was the other force.

Neither of them really gets to scientific questions that we're more used to dealing with or certainly to the heart of what the problem was in this particular case. Everybody has their own suspicions of what actually happened with those clones, and I don't know. But we certainly didn't get any satisfaction out of those discussions. It was a bad time. Oral History Center, The Bancroft Library, University of California Berkeley 207

Interview 9: March 27, 1995

[begin tape 17, side A]

Hughes: Dr. Yamamoto, I showed you some copies of correspondence related to the Biotechnology Center, which was located in HRI, the Hormone Research Institute. Do you remember how that came to be?

Yamamoto: Not in detail. But this was kind of the beginnings of what turned into what was called the Biomedical Resource Center or something of that sort. It was really just a group of us who got together to write a multiuser grant for equipment to set up a facility that I believe was meant to be campus- wide, that would be able to synthesize oligonucleotides, just to begin to make the reagents that were being used in the new molecular biology. So it was a group of people, predominantly from biochemistry and pharm[aceutical] chem[istry] and a couple of other departments, microbiology, that set out to do this. It was housed up in the Hormone Research Laboratory.

Hughes: Making it campus-wide was to enhance the chances of getting the grant?

Yamamoto: Absolutely. All of these NIH multiuser grants really encouraged this multi-use, multi-departmental facility aspect of things. And it's a facility that actually is rather well suited to that, although in those earlier days it wasn't as obvious that that was the case. We didn't really know what the user demand would be, and how well the facility would operate in terms of being able to turn out lots of material. So I'm sure there was some uncertainty about that as it was being planned.

Hughes: You did indeed end up eventually hiring staff specifically to run your center.

Yamamoto: That's right, exactly.

Hughes: And Dan Santi—

Yamamoto: Dan Santi has taken it over, and he's run it really well the whole time. He's been quite aggressive about its development and protective of keeping staffing and space up in that throughout. It became a standard agenda item at the chair and vice chair's meetings in Biochemistry to talk about some aspect of something Dan wanted to be sure that the BRC had, and so we got used to that. Dan really deserves the credit for developing it into a very effective campus-wide facility, sometimes against the better wishes of some of us who just thought that it wasn't working very well, and he really pushed to keep it going. So I think he gets a lot of credit for that. Oral History Center, The Bancroft Library, University of California Berkeley 208

In these early days, we just didn't know what it would look like, and I guess it started out in the Hormone Research Lab. Your showing me the correspondence reminded me of something that I didn't remember at all, and that was that the proportional use of the facility at that time was really weighted toward the people in the HRI, in the Hormone Research Institute. I had forgotten that. I think that probably reflected the fact that they were giving up space for it, and so they felt they had a particular call on it. Rutter's lab was extremely active at that time in cloning and sequencing large amounts of DNA, making recombinant plasmids, and so I think they felt that was a particularly important thing for them. Others on the campus were probably concerned about that, in fact were worried that it was being set up as a service arm for the Rutter lab.

Hughes: Yes. And there was talk about the equipment which had been bought under this user's grant being available to the campus for the first year, right, and then reverting?

Yamamoto: Right.

Hughes: I don't quite get the logic.

Yamamoto: [laughs] Well, I actually didn't recall it either. But as I now look at the correspondence, it looks as if Rutter, who was on that original committee to help set this thing up, perhaps has— I don't know how the original deal came about, but I'm only guessing that part of the deal of providing the space in the HRI was [that he was] able to make a deal with the rest of us that I'd forgotten—I was on that grant—such that 40 percent of the use of the hardware there would be to the HRI staff, and then the other 60 percent would be apportioned amongst a very large number of investigators.

Hughes: Did you ever have trouble getting access?

Yamamoto: Oh, we must have; I guess so. We ended up buying our own oligonucleotide synthesizer a few years later. I think the problems were both over the rate at which we got the materials and the cost. There was a debate about whether the cost really needed to be as high as it was and whether the money was going into other purposes of the BRC; not into anybody's pocket, but other purposes of the BRC, as opposed to just to pay for the oligos.

Yes, now that you bring it up, I do remember that there were some delays that were frustrating to us. I actually don't know whether those delays were reflecting this disproportionate-use formula or whether they were Oral History Center, The Bancroft Library, University of California Berkeley 209

just [due to] heavy use by all the users. I really couldn't tell you at this time.

Hughes: Well, the School of Medicine provided $350,000 originally to get the center off the ground. Do you know anything about that?

Yamamoto: No, I really don't. I really don't remember anything about that. I can't tell you.

Hughes: Well, I don't really know, but the fact that there's another letter suggesting that the departments contribute—and I think the sum was $25,000 each for the actual running of the center—shows that the $350,000 was obviously not enough to keep it operating, I suppose to pay staff et cetera. Is that indeed what happened, that departments that wanted to use the center did contribute to its support?

Yamamoto: I don't remember. I remember that discussion, as more users would come in, about we wanted to make sure that departments were kind of recognizing that this was a service to their faculty and helping to extract some running expenses for it. But I can't remember whether the assessments were actually made. I really don't know.

Hughes: In a letter from Dr. Rutter, which I presume was responding to some of the tension about access to the equipment, he suggests that because the objectives of HRI and the campus user group are divergent that perhaps two centers should be established. What came of that?

Yamamoto: Well, essentially that's what has happened. I don't know whether it was an explicit response to that or default. But the BRC is still going very strong, and they make oligonucleotide synthesized DNA and make and synthesize oligopeptides. The HRI has its own facility, and they have for some time. Many of us now have our own synthesizers, but we don't do our own DNA sequencing. Well, the HRI has its own sequencing facility.

This is something that I know that Dan for some time has been arguing is a waste of resources, essentially that the Biochemistry Department has loaned him for many years now the BRC space in which they can operate, actually on and off. And at other times, they've been up in other space. Right now, they're in Biochemistry space. His feeling is that there is actually room in the BRC's facility to put the HRI's machines, but they've chosen not to do that.

So they've still been standing alone on this, and they're very happy with the way their facility runs. I think all of us are now quite happy with the way that at least the BRC sequencing facility runs. We make our own Oral History Center, The Bancroft Library, University of California Berkeley 210

oligonucleotides, so I can't tell you about that, but I suspect it's running well. And I know that they serve a large number of investigators that don't have enough call on these machines to be having their own machine, and I'm sure it works very well for them. But it is the case that HRI has set up their own parallel facility and kind of kept it there.

Hughes: Which is available only to HRI?

Yamamoto: I don't know whether it's really structured that way or that they simply get first priority, and that other people can use it after that. We actually haven't used their sequencing facility, but I know that they are quite happy with the way that it runs. There were times when the sequencing costs or the rate at which we could get into the BRC facility made us ask questions about whether there were other available facilities around here. We never used the HRI facility, but it has been there for some time.

Hughes: All right. The next thing is to talk in a little more detail about the administration structure of the department. As you've seen, in 1985 there was quite a system of committees and subcommittees. Perhaps you'd like to talk about how indeed the day-to-day operations of the department flowed, maybe starting with the fact that you since 1985 have been vice chairman?

Yamamoto: That's right. I think '85 was my first year.

Hughes: Yes.

Yamamoto: That was when Bruce [Alberts] started his second stint as chairman. We've roped him into it twice. So at that time he decided he would do it but with a fair amount of active involvement of at least a couple of other people. So Ira Herskovitz and I were asked to be vice chairs.

We started out with a plan that we would divide the responsibilities in three ways. Bruce would take the sort of up-front jobs, a lot of the university committees that really demand that the chairman be there, appearances at dinners and things of that sort, getting up and giving little talks in the department about how things are going. That I would do various responsibilities that had to do with the faculty, promotions, space considerations, committee assignments, things of that sort. And that Ira would have things that had to do with teaching and curriculum and students.

It seemed like a good idea at that time, and so that was all set in place, and I think we even communicated that to the deans. We began to meet once a week formally, together with the MSO, the business manager in the Oral History Center, The Bancroft Library, University of California Berkeley 211

department. Happily, it became evident in the course of our meetings that in fact we didn't really need to keep this rigid a structure because we just tended to agree on almost every decision that was made. Or it was easy for us to reach agreement. Maybe that was just because Bruce is very persuasive and we just agreed with him. [laughs] But it seemed that we agreed with each other.

So as things went on, de facto we began just dividing the responsibilities of whoever was around. That seemed to work very well. We all had sign- off privileges, and so people could come and have any of us sign a document that called for the chairman. So it made it easier on the rest of the department, too, that usually one of us was in town. So there just became a division of responsibilities.

Some of the things, just because of that history that I just gave you, hung on. So the list of assignments of these many committees that you referred to was something that I did actually every year until '94. It just basically meant sitting down with the list of the faculty, and the consideration of the responsibilities of the department that were upcoming, and making sure that we had these various tasks of who was going to be graduate advisor and work on recruitment, and do the other activities and responsibilities of the department in the coming year, seminars and things of that sort.

Hughes: Did you have any rule of thumb about whom you assigned to each committee?

Yamamoto: Well, not an explicit one. It's true that you tend to ask the people that do a good job to do what you think are the most important things, and it always ends up being the same relatively small corps of people. There was no formalization of how the responsibilities would rotate. So there was a tendency to kind of move a relatively small group of people through the major committees. But I think the department is marked by a lot of cooperation, and people by and large all tend to work hard and to pull their weight in committees. There's a difference in style, a difference in the way and speed with which people execute. But I was quite happy and gratified that people really took the responsibilities quite seriously.

Hughes: Is this number of committees representative of basic science departments in this country?

Yamamoto: [laughs] It's large, isn't it?

Hughes: Yes. Oral History Center, The Bancroft Library, University of California Berkeley 212

Yamamoto: Let's see, you're looking at a list of [counts] nineteen committees. No, in fact, twenty-four committees. My goodness. [laughs] No, it's probably more than usual. Now that I'm chairman of Pharmacology, I can tell you that it has many fewer committees than that; it's a much smaller department. It's many fewer committees than that. But we don't have as many programs going on in Pharmacology as Biochemistry did by then. But it was a lot of work.

The [biochemistry] department has been throughout this period which we've been discussing a very activist place, a place that really pushes change within itself and within the campus and outside of the campus, where there are lots of people that are doing that pushing. So this [large number of committees] is more symptomatic of that, I think, and that is that people want to do things. I'm looking here now at the list from 1985, and there is a committee of four faculty that was involved in biophysics program development. Well, that program now is a first-rate program. It's a superb program. It was just getting going.

So there were just lots of things that people had in mind to try to do, and that's where all of this came from. So you're right, that it is a substantially larger number of things [committees] than most places.

Hughes: Well, Dr. Rutter stepped down as chair in 1982, right?

Yamamoto: Yes.

Hughes: After—what would that be—thirteen years of being a very strong chair. At that point, there was a co-chairman in 1982?

Yamamoto: Is that right? Who was the chairman? Didn't Bruce do a little stint?

Hughes: Oh, maybe you're right. I shouldn't ask the question without having checked my facts.

Yamamoto: And then Bob Fletterick.

Hughes: Yes. I know at some stage there is—at least on paper—a co-chairmanship. That seems quite an about-face. [laughter] From things you've said and things I've read, moving from a chairman who very much kept the reins of power in his own hands—I hope I'm right in that assessment—

Yamamoto: Yes, that's true.

Hughes: —to one where the power was obviously more diffuse. Why did that happen? Oral History Center, The Bancroft Library, University of California Berkeley 213

Yamamoto: You're right. I don't remember that little shadow period that we're discussing either. I can't quite put my finger on what was going on when.

Hughes: We can find it easily from the annual reports of the biochemistry department.

Yamamoto: Yes. But whether or not there was an explicit period of co-chairmanship, it is the case that— This is really just a matter of difference of leadership styles. Bill was chairman at a time when the group was smaller and much more of a small family unit essentially in which he kept much more of the power to himself, made many more of the decisions, would confer with the small group of people that he wanted to confer with about a given issue, and then make a decision. At the time that he was doing that, I think it was probably good for the department. It could have been done another way, but I think because of the way that he operated, it tended to be efficient, and it allowed him to use his various powers to extract things from the university, and just act relatively autonomously in doing that. He obviously did a great job at that.

By the time that Bruce took over, at least his second time here in '85, the department had grown a lot, and there were more diverse opinions around. It was a little harder to move simply by walking down the hall and talking with a few people, because you're likely to get several different opinions, strong ones. And so it was a time when it was more important for all the voices to be heard than it was to be efficient. Bruce's personality fit that extremely well. So I think we were quite lucky in not only having UCSF blessed with the leadership that it has obviously been blessed with, and the Biochemistry Department in particular, but also in a way in the order in which they came. It just worked well at the times that we needed it to have the sorts of leadership that we had.

Bruce is a very expansive leader who cares about what everyone says, and pays no attention to rank or seniority but instead what people are thinking about. He listens to anyone who has an idea. If he thinks that they have good ideas, he'll go back and ask them for more. It doesn't matter whether they're a student or a staff person or a faculty member. I think as the department began to really grow, they saw in him the sort of leadership that made most of them feel quite secure in his leadership and that they weren't going to be led astray or kind of betrayed or deceived by him in any way. It just wasn't in his character. So we were lucky, and it worked out pretty well in that way.

Hughes: It's impossible to tease out how much of this is due to personality, leadership style, wherever that comes from, and to the times. Not only are departments here larger, but there's a different sort of science being done Oral History Center, The Bancroft Library, University of California Berkeley 214

than was done in the very early days, even as late as the late sixties when Dr. Rutter arrived, where the disciplinary boundaries were much more defined. I'm wondering if things like that push leadership in certain directions. In other words, it's sort of a Darwinian thing, in order to be most effective as a departmental unit, one adopts a certain style. And if so, are there trends?

Yamamoto: I'm not quite sure I understand your question. I don't know if there are trends that cut across the context of the department personalities in terms of development of the department. I think it is quite striking that the place grew up in the way that it did, and maybe a department that didn't happen to have the wealth of leadership and the personalities of the leaders at each of those critical times wouldn't have done so well. I don't know whether it was just the force of personality or fortuitous timing or both that really allowed the place to work in the way that it did.

I think this is true that during the Rutter era there was a fair amount of distrust on the campus about the way that Biochemistry was metastasizing. Everyone acknowledged the power that Bill could wield, whether it was by charming his way to the situation that he wanted or bullying his way to the situation he wanted, he could get there. He did a great job of it. But it created some tension on the campus about how people saw the Biochemistry Department and what was happening down the line. We've referred to some things in earlier conversations about, for example, the way that human genetics was subsumed by Biochemistry during that time, and that there were certainly some strong feelings about that that weren't always benevolent to Bill's motives.

In contrast, Bruce was very much the opposite. He very much wanted to invite everybody to the party and hear what everyone had to say and show his interest in a broad range of disciplines and approaches. That was more comforting to people. Each of them got what they wanted, I think, what they wanted at the times that they were leading. At least the department clearly moved forward very strongly under both of those leaders but just in different ways. It's an interesting question to know whether there is something that forms a pattern for the success of this sort of endeavor as it goes from small to large and takes on many more things along the way.

I feel personally certain that without Bruce coming in and taking this second phase that the department would not have been as outward- reaching as it was with him and would not have been as inclusive as it was of development of other basic science departments. For example, the sorts of things that led to PIBS and all of the things that are really legendary now on this campus. So Bruce looks at these resources and thinks, how Oral History Center, The Bancroft Library, University of California Berkeley 215

can we maximize their usefulness for the whole community? And that made a huge difference.

Hughes: I suppose PIBS could be looked at as a reification of Dr. Alberts' philosophy.

Yamamoto: I think so, absolutely.

Hughes: Could PIBS be looked upon as somewhat an extension of what is happening in the biological science in that boundaries are falling, that disciplines no longer have the rigidity that they once did. That's certainly PIBS, isn't it?

Yamamoto: Oh, absolutely. I think that Bruce recognized this early on, before the rest of us did, that this was not the way to go because we were trying to serve the university by helping these other departments develop. It was the way to go because scientifically it was the way to go and that it would make us all better to be inclusive in this way. I think he saw that coming from a long way back and was really excited about inviting these other people in.

Hughes: So PIBS was Alberts' idea?

Yamamoto: Well, I don't know if it was Alberts' idea. He was certainly one of the principals in really putting the concept together. I know that Mike Bishop was also very important in that. Mike is another one of these people that really thinks hard about the context of the community and the state of science at the time. Do I'm sure that he had a big part of that as well.58 But it's those kinds of leaders, I think, that really stand out and make a difference in a place when it's at a crossroads of really being able to serve itself as opposed to serving the rest of the community.

If you think about it, it's not so obvious that the next thing to do when a department becomes really strong is to start spreading itself out all over the place. And certainly there were plenty of people in the department that were concerned about this and the way that Bruce was operating. And that if we get too big, it will just collapse on ourselves, and who are all these people anyway—questions of those sorts that were being asked a fair amount and in public. So it's not so obvious that the next thing that you should do is to start spreading out the resources.

58 See the oral history with Dr. Bishop at http://ucblib.link/OHC Oral History Center, The Bancroft Library, University of California Berkeley 216

[begin tape 17, side B]

Yamamoto: —differently, and so there was a greater opportunity there, and they capitalized on it.

Hughes: I can't cite the reference right now, but I saw something related to the graduate program that reflects what you've just said. Namely that Biochemistry had a very strong graduate program, and apparently there was some concern that that strength would be diluted by having to incorporate other departments. Do you remember that being an issue?

Yamamoto: Very much. It was very much an issue. This sharing of the students—and I'll put it that way—really began under Bill. It was his notion that a way to harvest more faculty recruits for Biochemistry would be simply to share the FTE lines of other departments, to gain a share of those FTE lines of other departments by offering joint appointments in the recruitment [process], and with the joint appointment would come access to the graduate program. In that way, Biochemistry could have this disproportionate influence, or it would have a direct influence so therefore disproportionate, on the hiring of the faculty into another department. So that was really the way that Bill was operating. I can't tell you to what degree that was simply a way to gain more, to enlarge his sphere of influence, and to what extent he also realized that this would really broaden and enrich our graduate training program, to have these other faculty involved. I'm quite confident that he had the first thing in mind. He could well have had the second [in mind]. I don't know.

Teaching was not a very high priority on Bill's list. He really wanted research excellence to be the key thing here. It's not that he didn't consider teaching a responsibility. But in my opinion, he didn't seem to put it on par with research excellence, and that was the main thing. If we could bring more really superb research to the campus and do it through this mechanism, that would be great. I think Bruce tended to put them more on equal footing with each other, and that was one of the key things that we had to sort of keep in mind. It kind of produced fertile ground on which the beginnings of PIBS could fall.

Hughes: PIBS, by the way, was very much helped along by a $13 million grant from the Markey Foundation.

Yamamoto: Yes. There's nothing like $13 million to make something look pretty good. [laughter] Yes, that had a big influence. And Bruce and the cohort of people that wrote that grant I think knew that. They knew that somehow Oral History Center, The Bancroft Library, University of California Berkeley 217

they had to get resources to help this thing get launched, and they knew that that would also give it instant credibility if it did.

Hughes: Has PIBS served as a model for other institutions?

Yamamoto: Very much. I think we've all had the experience of being sat down by somebody at someplace that we're visiting, or somebody who was calling who wants to know more about the details of the way that PIBS operates, and how they can move in that direction too. It's not that the concept was unique; there were certainly other institutions that were developing this notion of an umbrella graduate program that would encompass more than just the confines of a department. But I think in the particular way that it was done here, it was a particularly powerful concept, and when put into practice, it worked, I think, better than any of us even predicted it would. There were rough points in the beginning, but I think it has really worked out beautifully.

Hughes: Did it also serve as a model for what eventually happens at Berkeley with the consolidation of departments?59 What is the relationship there?

Yamamoto: They were very aware of what we were doing. They were also going through a difficult period. Back in the salad days when there was lots of money for the university, I think Berkeley went through a period where, as an extremely powerful and famous university, they could just form new departments at will. It almost seemed as if whenever two faculty members would have a little spat, by the next week you'd see there was a new department. [laughing] I think the number is something like on the order of twenty life sciences departments before this reorganization effort began.

So there was a lot of strength on the Berkeley campus that had gotten really fragmented, and communication was becoming a problem. So just allowing these disagreements to kind of sit around, which in the old days might not have mattered very much, was beginning to really show because limitations of resources was beginning to show up, and the melding of disciplines was definitely beginning to show up. They saw that there was going to be a real problem unless they changed their organization [of biological science at Berkeley]. In fact, they had a very strong external review that said that to them, that this [present department organization] was not working out right. It was [Daniel] Koshland and his strength of will and his judgment that was able to really drive the change. He sacrificed a lot to put this together in a way that would work in Berkeley.

59 See the oral history in this series on the reorganization of biology at Berkeley: http://ucblib.link/OHC Oral History Center, The Bancroft Library, University of California Berkeley 218

So I know that they were aware of what was happening here. By then we had become much more their equal and competitors than we'd been regarded in the past. So they couldn't afford not to pay attention to us, and a part of it was the way that the training program was working.

Hughes: Well, is there anything more you want to say about the department?

Yamamoto: I will say one more thing. It's a very interesting environment because—I said this a few minutes ago—it's so activist. There are so many people that are reaching to do a lot of things. On the one hand, it makes it a very good environment for trying out and testing new ideas, whether it's in the department, in your own lab, on campus, or at the national level, because there's someone around that's been working hard on these endeavors. You're feeling that it's not worth it, and you're exhausted, and you want to just get back into your lab and talk to someone in your lab for a while. But then you look on either side of you, and the two faculty on either side look like they're working twice as hard as you, and you think, oh, okay. There's a lot of that aspect of things in the department. It makes it feel sort of speedy, hyperkinetic, and frenetic at times.

The one criticism that could easily be laid to us is that the faculty is too busy, that they're just running around doing too many things. There's a cost paid for that, certainly by the people in the lab. That part is really true. It's very noticeable by people who simply come here to visit for a day, or certainly from us going to visit other places for a day, that the difference in the pace is really striking.

Hughes: Isn't that somewhat a function of the department being at or near the top of the heap? You're struggling to stay there.

Yamamoto: Yes, I think that's true. The other way to look at that is, when you're at or near the top of the heap, then you can kind of relax a little bit. And there's very little of that.

The other thing that happens when you're at or near the top of the heap and I think is sort of a constant danger is that, because other opportunities appear at that time, it's easy to get diverted and turn your attention to other things that don't serve the department any more, just because the opportunities are there—to edit a journal, or to run a company, or to consult a lot, go to Washington a lot. I think it's something we need to be watchful for, because it's hard to stay at or near the top, and it requires a lot of attention. There is this feeling that once you're there, that it's kind of okay, that everything will kind of take care of itself, and that just isn't true. Oral History Center, The Bancroft Library, University of California Berkeley 219

The students who are here have never been here before. It doesn't make that much difference to them that the students five years ago were fantastic and got a lot of care. When we get up in front of a class and teach that class, no one out there has heard us teach that class before. So I think it's important for us to always remind ourselves of that.

I think I mentioned in an earlier discussion that when Ira and I decided to join the board of that small company [Tularik], we actually had a faculty meeting to talk about the whole general concept of it and to remind ourselves a little bit that this was something that we should be watchful for. It's something one can slide into if you're not paying direct, explicit attention to. You begin to let your attention slide off in other directions without even really knowing it, and then suddenly the university responsibilities aren't getting taken care of.

Hughes: It seems to me that the general trend has been for the university to become more lenient in terms of its faculty's outside commitments, which puts the burden heavily on the shoulders of the individual because there isn't a monitoring force out there. The individual has to look at whether the major responsibilities of a faculty member, namely teaching, research, and administration, are being adequately carried out.

Yamamoto: That's right. And I think this is not a problem just here. I think it is true at other leading places too. You're right that institutional oversight, if it's moved at all, has gotten more lenient in the name of academic freedom. So if the department can help out a little bit just by serving as sort of a self- policing unit, then that's a lot. I think that that is a funny responsibility for a department, but it is one that can actually serve well because it's backed down to the local level of the people you run into in the hall. It allows us to check our value system every now and then. It's an easy thing to forget, to take for granted.

Hughes: Is it a subject of discussion?

Yamamoto: Oh, yes. The Biochemistry Department continues to have these annual faculty retreats of its primary faculty. We just had one last weekend. That early one that you and I talked about in the seventies up in Marin County was the first of those. We continue to have those, and very commonly the point of discussion is keeping an eye on people's outside activities.

Everyone is aware that many of the faculty are doing lots and lots of different things. I think the great thing about this faculty is that the things tend not to be really self-serving, like forming a company. I guess there would be lots of opinions about whether that's self-serving. But they're not things that are designed at least in part to garner a lot of wealth for the Oral History Center, The Bancroft Library, University of California Berkeley 220

individual but instead to do things out in the community—to write the world's greatest textbook [Molecular Biology of the Cell], as Bruce Alberts has done. Peter Walter and Sandy Johnson in the next edition will be primary authors of that book. It takes a huge investment of effort. It's something that the whole scientific community or medical community gets to enjoy subsequently and stands as a tremendous service. But for those individuals, it takes them out of the loop for a while. Or doing the stuff that I'm doing in Washington, or editing a journal; they're all intellectual endeavors that individually no one would argue with. They're all terrific. But each one of those things takes us away from here.

I guess on a larger scale one could say that Bruce being in Washington [as President, National Academy of Sciences, Harold [Varmus] being in Washington [as Director, National Institutes of Health], Zach [Hall] being in Washington [as Director, National Institute of Neurological Disorders and Stroke], and there are rumors right now about Mike [Bishop agreeing to become UCSF chancellor?].

Hughes: Oh, really?

Yamamoto: Yes. Nobody would argue with the remarkable decision in the direction of community service that those individuals have made. It's a tremendous thing that they're doing, and the fact that they've all been called out of this one little community [at UCSF] says quite a bit about the strength of it. But [their outside interests have] an impact here, believe me.

Hughes: Do you feel in the context of this discussion that it is the chairman's responsibility to pull people back when he or she feels that the university is perhaps not being as well served as it should be?

Yamamoto: Yes, I think so. I think that we have a much closer grasp of the needs of the little micro-community that we operate in, and we need to be responsive to those needs. We can't expect the university to do that. There are places, as you and I have discussed over the weeks, in which I certainly feel that the university could be doing more that would help that process. But in general, in the end that little group is one where you can actually have some influence.

I think the way that we all behave when we come in every morning, and the standards that we espouse just in casual conversation are ones that have a great influence on each other, on our peers, and on our students. It's the place where we can probably have the most political action, and where we can have our greatest and perhaps longest-standing influence. Chairmen, I think, should regard that as absolutely very much a part of their responsibilities. Oral History Center, The Bancroft Library, University of California Berkeley 221

Hughes: Well, shall we turn to the military use for recombinant technology?

Yamamoto: Great.

Hughes: As I'm sure I don't need to tell you, military application is not a new theme in biology. [Joshua] Lederberg, for one, in 1970, and I believe even before that, was talking about the dangers of using biological methodology for military purposes. I think he was particularly referring to the work that was going on in virology in the development of biological weapons. Two years later in 1972—or developed during the Nixon years—was the Biological Weapons Convention [1975] which outlawed production, development, and stockpiling of biological weapons for offensive purposes, but did not say much about defensive use. Is that true?

Yamamoto: That's correct.

Hughes: Do you want to pick it up from there and tell me how you became concerned about this area?

Yamamoto: I became active in this area because of the efforts of one person, and that is Charles Piller, who is the primary author of the book Gene Wars, for which I served as coauthor. Charles at the time was an employee of Synapse [UCSF campus newspaper] and also a freelance writer— investigative reporter, I should say—and had published articles in the New Republic and Ramparts and places like this about various political investigations that he had undertaken of various sorts. He had interviewed me on behalf of the Synapse, the campus newspaper, multiple times, usually over issues of industry-faculty relations, Howard Hughes [Medical Institute], things of that sort. So we had just talked a lot about those sorts of things.

Very often the interview would end, and then he would say, "You know, I was just doing some poking around about this biological warfare stuff. What do you know about...?"— whatever was on his mind at the time. And I would tell him what little I would know. I'm not a microbiologist, and so I'm not an expert of virology or microbes in particular at all. But I'd tell him what I knew, or I'd suggest that he call somebody. But the things that he told me had an impact, things that he'd heard that the government was doing. Charles has this kind of wonderful sort of conspiratorial tone about him. [laughter] He'd just make this amazing kind of, "Don't tell anybody; I just found this out." So he always came at me with this sort of thing that I found amusing, but in fact, they always had some impact.

So as we talked, he would say, "Well, I'm thinking about writing an article," and I would say, "Great, write an article. This is important to do." Oral History Center, The Bancroft Library, University of California Berkeley 222

And then, "You know, I'm really thinking about a book," and I said, "Great, write a book!" So by then, he was very much becoming involved in asking what it was that the Pentagon was doing, the DOD [Department of Defense] was doing, in the biological warfare area, with particular regard to this point that you've just raised about the Biological Warfare Convention, which by then had been signed by lots of countries although it wasn't until '75, I guess it was, that the United States got around to signing it.

Hughes: Is that so?

Yamamoto: Yes, after some eighty other countries had signed. Whether there was any problem with this exclusion of defensive research. The more we talked about it, the more I realized that in fact it was a gaping hole. It's easy for me to explain how that hole works. The convention was designed in such a way as to recognize that any country would lay itself open to the actions of terrorists or what have you, somebody who had no regard for the international weapons convention, if it were explicitly banned to do defensive research, to develop a new gas mask, protective clothing, diagnostics of various sorts, and treatments, vaccines.

But with recombinant DNA on the scene, that caused a substantial change. So here is how the scenario would work: let's say that you were concerned that some terrorist organization was going to put a toxin gene into E. coli, the bacteria that grows in our gut, and try to infect the whole country with this toxin and kill everyone. So you might say, "Oh, gee, what we'll do is we'll make a vaccine, an antitoxin, that will be able to specifically detect that toxin, so we'll be ready for them."

And then you say, "Well, gee, there's a problem," because you clone the gene, and they know that you'll make an antitoxin to it, and so they make a variant of the gene that's not a target of the antitoxin. So just by changing a few amino acids here and there, and they look for a variant that will remain toxic. You say, "Oh, well, gee, we're pretty good [at] recombinant DNA. We'll see your variant, and raise you one vaccine." [laughs] "So we'll make a vaccine against the variant. In fact, we'll make a vaccine against all the variants that we can think of."

So that sounds pretty good, put your mind at ease, until you think really what is going on. And there were programs like this at the DOD. What that means really is that in order to make the new vaccine, you have to make the variant yourself. So in the name of defensive research, you are making a new weapon. And if you make the new weapon, and you have a vaccine, then you really have a weapon, because you're protected. Oral History Center, The Bancroft Library, University of California Berkeley 223

Hughes: You're protected, right.

Yamamoto: Okay. So there was sort of a problem. And it meant that this distinction between offensive and defensive research was gone, absolutely gone. It just completely disappeared under this new technology. So the question that Piller was beginning to poke around with was, what is going on? Is this loophole being exploited by the Department of Defense, and if so, shouldn't everybody know about it?

So just to pick up my involvement again: I was encouraging him to yes, go write a book. This sounded like there was some bad stuff going on. He then came back and said that he was looking for a scientist to serve as coauthor. I said, "Great idea." [laughter] "Brilliant idea. That will give you—"

Hughes: Keith, sometimes you're a little slow! [laughing]

Yamamoto: Really. And unfortunately, that's not the only time.

"This will give you the kind of credibility you need and will help you open doors to places you don't have [access to]." He said, "Great. Who can you suggest?" So I suggested a few names. I don't remember who they were. But all of them were smart enough, I guess, to say no, because it wasn't very long from then that he came back and said, "Well, actually, I was kind of thinking that you would do a good job." He may have said that earlier on, I don't remember. I said, "No, no, I'm much too busy. I don't have time for this. I can't do this." He basically wouldn't take no for an answer. He just kept working on me and telling me how easy it would be, and that he would do the primary draft, which he absolutely did, and that he wanted me for all these terrific things I said would happen, for advice and for opening doors and gaining credibility, and giving him feedback on what he was writing about the science part of it, and things of that sort. Eventually, he got me to agree, and I actually did get very engaged in it, and really committed to the project. He did do the primary draft as promised. I still regard it very much as his book, with my name also on it.

Hughes: What did you contribute?

Yamamoto: Well, we worked a lot on making decisions about who to try to contact for interviews, who to try to chase down for various kinds of interviews of substance about the nature of the science that was going on, talking with various colleagues in universities who were doing DOD research, and then just fact-checking on the science that was involved, and then making evaluations of these 329 reports that we got on DOD projects that were going on to assess whether there was any potential danger, whether it Oral History Center, The Bancroft Library, University of California Berkeley 224

looked to be really kind of classically offensive research despite the international convention, and what kinds of things could come of any given project that was being described, in my opinion. So that was basically what I did.

As I said, I got really involved with it. I ended up doing some congressional testimony and going off and giving lots of talks on the topic, and things of that sort.

Hughes: I have to confess that I did not read the book. I read the introduction. But I did read some of the papers that you had written on the subject. From them I gather that you had three major arguments—and you correct me, please. The reasons that you thought that the Pentagon or DOD efforts should be opposed were first of all, it was obviously destabilizing to the Biological Warfare Convention. Secondly, it was putting the public at health risk. And thirdly—and I thought this was perhaps the most interesting reason, because the others seem fairly obvious—it was a squandering of both fiscal and intellectual resources, which of course you touched on by talking about the 329 research projects that you analyzed.

But how well did these arguments fly? Did they have any concrete results? I'm thinking specifically of the bill that I believe is in the offing at the same time, 1989, which was when your book was published.

[begin tape 18, side A]

Yamamoto: You're quite right about the conclusions. So our specific recommendation regarding the last point, that the way that this was really squandering our resources, was to transfer into the National Institutes of Health the budget for defensive biological weapons research.

It would seem a very strange thing for the National Institutes of Health to be doing anything that even had biological weapons in the name. In fact it was our point that the work at least that we had been made aware of that was going on actually did represent research that would be of great significance to public health. Mostly not public health in the United States, where the NIH obviously, or at least de facto, does put essentially all of its effort, but in developing nations in the Third World where many of the pathogens that the DOD [Department of Defense] was experimenting with represent great public health concerns.

Nobody in this country worries about getting Lassa Fever virus or Rift Valley Fever virus or all of these other terrible things. But the Third World countries do. Just malaria alone of course is a major killer. So it was our Oral History Center, The Bancroft Library, University of California Berkeley 225

view that if that work could be done under the auspices of the NIH, which really, if it knows how to do anything, it knows how to fund really good research, it would be able to carry that work faster and better and more effectively. That if all the stated goals that the DOD was espousing as rationales for this work were things that they really believed in, we knew how to do it better. The NIH could do it better. And if the information that would come from that research could be used not only to promote public health but as a byproduct for ways to better defend against the possible use of these agents as pathogens by terrorists, then that's fine. That would be fine.

In effect, there could even be, we imagined, explicit ways to make sure that some of that stuff, like protective clothing work, would continue. But it would also guard against our suspicion that some of the work was being done for more than for just defense purposes. I think we outlined actually in the book and maybe in some of the articles you read specific examples of cases where we were concerned about what the real reasons for these things were.

We only got, I should say, a tiny tip of the iceberg, and who knows how selected it was, of the total projects that the Pentagon was undertaking. So we acknowledged that we were analyzing only a small amount of data that we were given access to, even though it was all supposed to be unclassified. But we were only able to get out and [analyze] a small amount of the stuff.

So this bill, to move the budget of the Biological Defense Research Program, the BDRP, from the Department of Defense to the NIH, really came out of conversations with multiple people in Congress about how these things should be handled.

Hughes: Conversations that you were engaged in?

Yamamoto: Yes, several conversations that we were engaged in, or came from other groups that we had talked to that would then talk to their lobbyists or their congress people. The bill never passed, and the BDRP continues. The only real cracks in the Defense Department's budget for biological research have come from other lobbying forces, from the breast cancer lobby, and so you're aware that last year $250 million was kind of cleaved out of that budget and moved into breast cancer research. But the bill that would have moved this whole program over didn't pass.

Hughes: I have a note that you and David Huxsoll testified in the Senate in May of 1989, and that was in relationship to this bill? Oral History Center, The Bancroft Library, University of California Berkeley 226

Yamamoto: Yes. David Huxsoll was the director of the BDRP. He was the opponent. He and I ended up debating several times in different forums, so we were both invited to this Senate panel to discuss this, and it was in connection with that bill.

Hughes: Was that your first time testifying in the Senate?

Yamamoto: It was.

Hughes: How was that experience?

Yamamoto: It was very interesting. I learned a lot. I really learned more about where legislation comes from in that short experience than I have in any other thing I've been exposed to. It was interesting that John Glenn's staff boy had called me. John Glenn was chairman of the Government Affairs Committee which, as you can tell from the name, is a very free-ranging committee that can really look into anything they want. This bill was coming up through the ranks, and so some Glenn staffers called me one day and said they were interested in learning more about this, and that they'd read my book, and could I spare some time to talk to them. I said, "Yes. I didn't know that John Glenn was interested in such things." They gave me sort of a quizzical answer at the time that I didn't understand that basically was a non-answer. So when I interviewed with them later, I again asked them, "Is this something that Glenn has for a long time taken an interest in?" They basically kind of said, "How would we know?" They didn't say that, [but it was implied].

Glenn was chairman of the committee. So eventually there were these hearings and testimony, and the staff had put together this wonderful speech for him to give at the beginning when the cameras are going. He sounded like a real pro, like he'd been worried about biological warfare all his life. [laughter]

Hughes: So a lot of these issues are independently generated by the staff themselves?

Yamamoto: It's very much like my lab. I'm sure my lab would say this: that the staff or my lab comes up with a line of experimentation, and then they kind of parade it in front of [me]. John Glenn was using the hearing that he's chairing as a way to learn about the subject, to decide whether he's interested enough in it to really pursue it. It's very interesting. And the good ones [representatives] are smart enough that they can actually learn in that forum and then make a decision about where to go from there.

Hughes: It really makes your testimony critical, doesn't it? Oral History Center, The Bancroft Library, University of California Berkeley 227

Yamamoto: Yes. That was pretty interesting.

It was intimidating just to walk into the Senate building. I remember standing at the elevators, and there was this big brass plate with all the senators' names on it. I thought, whoa. But then to look up at the top and see Dan Quayle's name, I knew that—[laughter]

Hughes: You could stand up to that.

Had you prepared a statement?

Yamamoto: Yes. They require that. Everything has to be written down. It's all very scripted. So they have to have your statement of testimony beforehand to distribute to the committee, and they know basically what you're going to say. You usually don't say the whole thing; it all goes into the record. So you usually give a briefer synopsis because there's not enough time. They tell you how much time they want you to spend roughly, and then ask questions.

Hughes: In relationship to RAC [Recombinant DNA Advisory Committee], there apparently was some concern. I came across a letter—this is one of a historian's worries: what are we missing, what don't we come across?—it's better termed a memo, written by Richard Novick and Richard Goldstein. They were suggesting an amendment to the NIH guidelines outlawing the use of recombinant technology for the production of biological weapons. This was 1982. Do you know anything about that? Were you aware that such a move was going on?

Yamamoto: Probably. I vaguely remember that, and certainly Novick and Goldstein would be people that I would associate with that sort of action. Their politics were well known, and they were willing to try to exercise their political stance within the existing political system, so they would try to get a bill like this introduced.

The answer to it would simply have been, "There's no problem; we've already signed the convention." And of course, that was not the problem at all. [laughter] The problem was that the distinction was gone. So the problem with those sorts of bills, as I sort of obliquely implied by the way that I described the research that was going on, is that what may be weapons research to one person is the NIH finally getting around to working on the problems of poor countries as opposed to the problems of rich countries.

So I have to say that I was tremendously biased, and I was very aware of this. As I was reading, poring over these 329 reports, I was very aware that Oral History Center, The Bancroft Library, University of California Berkeley 228

many of the things that I was writing commentary on as being questionable whether it was bordering on offensive weapons research. If my colleague down the hall had been doing that project, I probably would have been cheering him on. But because it was something that was being supported by the DOD, it made me suspicious and worried. That's the problem with that sort of legislation, that learning more about the pathogenicity or toxicity of these agents in fact is well worth doing. As I said, it would be finally a step aside from the usual kind of U.S. focus of the kinds of efforts of the NIH and would begin to look at other problems around.

Hughes: Well, anything more on biological weaponry?

Yamamoto: I was just interviewed by a German reporter who wanted to know about the movie Outbreak. [laughter] Which I've not seen.

Hughes: Don't bother.

Yamamoto: Did you see it?

Hughes: Yes. It was pretty simplistic.

Yamamoto: So he just called me last week. He'd read the book and wanted to know.

Hughes: Interesting.

Yamamoto: Yes. Well, the book was translated into German, so it was easy for him to get to. So no, I don't have anything more to add about that.

Hughes: We have twenty minutes. Would you like to say something about how you go about writing a paper?

Yamamoto: Hmm.

Hughes: Do you have a set approach?

Yamamoto: Well, certainly one of the most important things about writing a paper is deciding when it's time to write the paper.

Hughes: And how do you decide?

Yamamoto: My standard for that, which I tell everyone in my lab, as I'll tell you at the end of this, all this stuff also gets colored by political considerations, so just so people don't think that I pay no attention to such things. Basically, the way that we decide is to look at the cumulative results and assess Oral History Center, The Bancroft Library, University of California Berkeley 229

whether they've reached a point where there is a general contribution there that is worth passing along to people. There are always unknowns that are left, huge, obviously. You ask whether the next obvious experiments are easy to do or hard to do. If they're easy to do, then it's not ready to write the paper yet, and you do them. If they're hard to do and they're going to take development of some new technique or building some new strain that we don't know how to make, then you write it the way it is.

It gets colored by politics, as I said, because the fields are competitive. Sometimes one ends up writing a piece of work that, if there was no one else around, you might spend another year on. There are other times when you ahead and spend the year, even though you are aware that other people are barking up the same tree, because you feel it's important enough to get the next data points, or because you're confident enough of the uniqueness of your approach or the endpoint value of getting the final result that you wait. But it's a hard thing to learn. It's something again that as usual Bruce Alberts taught me. It's a hard thing to learn, especially in the heat of battle. We're all competitive folks, and people in the lab are looking to you to kind of help them make sure that their careers move forward in this easy recognized way of being first.

Bruce impressed on me years ago something I've also told probably most of the people in my lab, and that is that it's not the object in science to convince 99 percent of the people that your work is the best work, because most of those 99 percent of the people will make that assessment just on the basis of whether you're first or not. And that what you really want to do is to impress the 3 percent or whatever, the small number of people that you hold in great esteem and whose judgments make a huge difference to you, that your work is the best work. And of course hopefully including yourself. You'd no more want to convince, put your effort into the other 90-something percent than you would trying to be well liked by 99 percent of the people in the world. Most of them you don't care about. To try to gain the respect and love or admiration of people that you yourself don't respect is sort of a wasted exercise.

So that's an important lesson in the field that tends to be itself very competitive, and it's a good thing to learn. I've passed that along to many people. So the first point is making a decision about when it's time to write.

Then after that: papers take a very long time in my lab to write. Anybody in my lab would tell you that. In fact, I'm sure that they'll all complain about how long some of them sit around. So then the next step is just deciding who's going to write the first draft. Oral History Center, The Bancroft Library, University of California Berkeley 230

Hughes: Is one person usually writing the whole thing?

Yamamoto: Usually one person writes the whole thing. It varies sometimes because of things that are very collaborative where different specialized techniques are used. In fact, we can get to that; that's a special problem. But it's usually one person writing the whole thing.

Hughes: Who is then the first author?

Yamamoto: Who then becomes the first author. So what happens is a set of conversations ensue between— Well, the first author and I sit down and have conversations about how the paper will look. Usually I ask them to make an outline with sketches of figures, and we decide how the results section will look, and what the conclusions will be.

Then, at that point, I usually tell them that there are several ways to actually write a paper. Some people start with the results. Some people start with the title and work down. I don't. I usually write the results, and I tell them that. To do that well, you have to have at least a clear idea of what the introduction is going to look like, because what the introduction does is to frame a question and to put it into perspective of the rest of the field, and then to present the answers. So you kind of have to know what the paper is going to look like at the introduction and then the results section. Write that out.

Then we go through the series of drafts: five—more than five—eight, nine, ten drafts that go over time. So it's a slow process, but I think it gives the person who's doing the writing at least the opportunity to really see how the whole process works. Scientific writing is very hard. At least, it is for me. Because in the end you're trying to do something that is almost by definition impossible. That is, you're trying to attach precise meaning to your thoughts using a medium, words, that don't have precise meanings. That's just the way words are. So words and numbers are not the same thing. There's a huge amount of subjectivity in the way that people read a sentence. If you're not there to give it intonation and inflection and to say, "Oh, no, no, what I meant was..," then there's going to be a certain fraction of people that will misread almost any sentence that you can write. So I struggle a lot with trying to think about each sentence and how each one will be read, and try to maximize the number of people that will read it the same way that I wrote it.

Hughes: Is one of your goals to try to recreate the actual experimental process, how it actually happened? Oral History Center, The Bancroft Library, University of California Berkeley 231

Yamamoto: That's a very good question. It hasn't been. In other words, I don't tell chronological stories.

Hughes: You probably don't tell wrong stories, either.

Yamamoto: I try not to.

Hughes: Almost invariably in an experiment, there are going to be some things that didn't work out.

Yamamoto: Yes.

Hughes: In most cases, are those episodes silent?

Yamamoto: Yes. There is always data select. At least in my lab, and in every lab I know of, there's data selection. This is an issue of great debate. When I was on the National Academy panel on responsible science, a moral philosopher was one of the members of the panel. He was outraged at the notion of data selection, and felt that this was just high crime, and felt that all the data should be presented, and things should be presented not necessarily I guess in a straight chronology, but at least the little miscues along the way should be presented. It's certainly not the tradition in the way that biological research is presented, and people learn early on, it has a great danger of confusion. People learn early on that data are selected, that things are not told in chronological order.

Very often, the original rationale for an experiment may not make it into a paper. It's nice when that doesn't happen, when you're a little bit straighter than that. But it means that students of the literature, graduate students who are just beginning to get into the literature, can get a very skewed idea of the way that science progresses, and get very confused about why it is that their work isn't progressing in that same way.

Hughes: Yes. It gives a very linear picture.

Yamamoto: Oh, yes. Everything looks so tidy. One thing just kind of following right after another. And it's a shame, really. But to do it the other way would make the literature such a jumble. To say, "Well, in that last figure, actually when we repeated the experiment many times, we found that that first point that's off the line is an outlier, and we think that that day it was a little bit cold in the lab."

Hughes: Yes. Where would you draw the line [in your qualifications]?

Yamamoto: Right. So instead, the point gets dropped. Oral History Center, The Bancroft Library, University of California Berkeley 232

Hughes: There is also the social-political context which almost invariably gets dropped out, too. Yet it obviously influences the course that I believe any experiment takes. Whether it's personalities or the fact that a machine is broken down or whatever it is, none of that gets into the paper, or very rarely.

Yamamoto: Yes, absolutely. So it's omission and commission: both the experiments that are there are heavily influenced by this, and the experiments that aren't there are as well. At this stage in my career, and certainly for many years now, the way that our work progresses really depends in large part by what experiments my colleagues decide that they'll actually deign to do. I've had whole projects that were my favorite things in the world not progress because I couldn't get someone in the lab to do the key experiments. Just wouldn't do it. Or they did them in ways that the answers weren't definitive, or they did them slowly, or whatever. It's incredibly frustrating sometimes, heartbreaking, to see something that you really regard as an idea that's very dear to you just not get pursued at all in your lab, or else you read it in the literature, and you think, I knew it was going to work out!

So yes, the social aspects are huge. Academic research by its nature is not optimized in any way in terms of efficiency or the kind of orderliness of the experiments that gets done. At least in the way that it's practiced around here, there's basically not a lot of bossing around of who's going to do what experiments. Certainly not in my lab, or not in labs that I'm aware of here at UCSF. There's very little prescribing of who's moving a project around to the people that can best do the experiment. You think that would be the most efficient way to do the science. Someone really knows how to do some technique, just crack dead on, and a project reaches a point where it needs that technique, why not give it to that person? They're there, real pros. Well, we don't do that. The students get to kind of fall into their own potholes, and you try to help, to let them know where they are ahead of time. But that's how they all learn. The same thing goes with whether a whole course of experimentation will be pursued. And I think that's okay. It's just something else that we have to learn. But I think it's all right.

Hughes: So writing a scientific paper is an educational activity at several levels.

Yamamoto: Oh, very much so. It really should be regarded as part of the experiment, that this whole endeavor is based upon moves forward, based upon our learning of the work of others. Unless you describe the work, it really is just about the same as not doing the experiment.

Hughes: Should a reader who has the basic scientific knowledge be able to repeat an experiment as described in your paper or anybody's? Oral History Center, The Bancroft Library, University of California Berkeley 233

Yamamoto: Yes. And it's almost impossible to do that now.

Hughes: Why is that?

Yamamoto: Because the editors of journals have— We've come upon a time in our scientific society where the journals themselves have taken on a lot of power and influence in the way the science proceeds. They've taken it on because we've given it to them. We've allowed journals to become trend- setters in our society and to really have a big influence on the kinds of experiments that we do, the kinds of things that we work on, and how we present our research.

There is a set of journals in this business—Cell, Science, and Nature—that fall into that category. They compete with each other actively for papers in an explicit way. They call investigators and solicit papers for their journals. They are willing to get hot work reported and refereed in record time. There are other journals that latch onto this and have "hot paper" sections. Figures from people's papers appear on the covers of the journals, and that becomes something that students and faculty lust after. It's taken on a life of its own that I think is entirely inappropriate. It's just a microcosm of the rest of society right now, but I think it's entirely inappropriate. So I think it's something that we have allowed them to do. If we all rejected that style of reporting—

Back to your point, materials and methods sections are boring to them. They just kind of use up pages with all these little minutiae.

[begin tape 18, side B]

Yamamoto: They think, well, if Cell is so hot, then why should I do these controls? They'll never appear in the paper. So apparently, they're not very important. There's a lot of blaming all this on students, which is just hogwash. There's a lot of this, well, my students demanded to send the paper to Cell. Well, they demand to send the paper to Cell because they watch all of us lapping after it. There's no intrinsic reason that students should just show up demanding their papers get sent to Cell. So we really need to try to change that. I'm the editor of a journal that really is explicitly trying to change that.

Hughes: What about changing it at the level of a lab director? The picture I've gotten somewhat indirectly of the way you administer the lab is as a laissez-faire endeavor, to a degree anyway.

Yamamoto: Yes. Oral History Center, The Bancroft Library, University of California Berkeley 234

Hughes: But in this regard, do you step in?

Yamamoto: There's no one probably in the department that doesn't know what I think of Cell, and that's definitely true in my lab. In general, I don't want to send papers from here to Cell. But you're quite right about your assessment of how the lab runs, and so it's also the case that I don't make explicit laws about such things. If a colleague in the lab does a piece of work in which they're first author, and they decide that the paper's going to go to Cell, then I'll send it there.

Hughes: Would you step in if a colleague used the argument, the paper is going to Cell, hence he or she did not have to perform as many control experiments? Would you allow that to pass?

Yamamoto: Oh, no. So we'll send the paper to Cell, but it will be by our own standards. And so the last paper we published in Cell I think was in 1990 or 1991. That's how often it happens.

Hughes: So the lab director does have some modicum of control.

Yamamoto: Oh, yes.

Hughes: One last question: do you have a rule of thumb about order of authors?

Yamamoto: It's a very important and touchy issue. It's a good question. I'm not sure we should try to end it on a short answer here.

Hughes: Do you want to save it?

Yamamoto: Well, the short answer is I don't have a rule of thumb, that everything gets done on sort of an ad-hoc basis. But it's a very important issue. Work is increasingly collaborative because it's increasingly technology-driven. People feel a tremendous need to make sure they get credit for things. It's the only currency we have, as I've said before. So those turn into sometimes very delicate interpersonal debates and discussions.

Hughes: Which are sometimes negotiated before the work even begins?

Yamamoto: To a certain extent. We should continue this next time.

Hughes: All right, let's stop. Oral History Center, The Bancroft Library, University of California Berkeley 235

Interview 10: April 13, 1995

[begin tape 19, side A]

Yamamoto: [Question not recorded. It concerned author order on a scientific publication.]

I guess the fact that it's a growing problem stemmed out of the fact that research projects are carried out by larger groups of people. It's true that people have larger research groups, but what I meant is that a given project has a tendency to have more investigators on it. The reason for that is good; that is to say that a given experimental question, or a given biological question, I should say, can be approached from a number of different experimental directions at once. It's nice to have several different strategies represented in a report because it helps to really bolster the notion that your ideas are correct. And so a larger number of students or postdocs may be involved in a given study that could end up actually being one paper.

And so where it used to be, and still is the case, that a paper may be the work of a single student or a single postdoc, it's become increasingly common that there are several young investigators on a paper. Maybe one doing more genetic aspects of a study, one doing more structural aspects of a study, for example. And so in earlier days or simpler times when it was just the work of a student or a postdoc, then that person would sit down and write the paper and that would be it. But now when there are several people involved, each of them feels that they make a contribution that is really critical to the work, and many times that's absolutely the case. Then it [author order] becomes much more a matter of debate.

Or a project has been begun by somebody, and maybe the initial few experiments get done by that person that say that the project is going to work. But another person comes in on the project, either because the first is leaving or is off doing other projects at the same time, and makes what is in fact the contribution that really establishes—kind of galvanizes the piece of work and really makes it clear what the paper will look like. Who has primacy there? Is it the person that really showed that the project could be a project, or the person that really established the facts that made the paper what it is? And those things really become a matter of debate.

So the question here that we're discussing is who will be the first author. So in biology, the common tradition is that the first author is the person who gets a lot of attention because it's felt by the community that that's the person that made the major contribution to the work, usually experimental, hands-on work. The last author, so-called senior author, is usually the Oral History Center, The Bancroft Library, University of California Berkeley 236

principal investigator in whose lab the work was done, who wrote the grants, who occasionally had the idea that really kind of got the experiment started. And so the issue that everybody is dueling over is who will be first author on a piece of work.

In laboratories like mine, where the conceptual focus of the lab as a whole is fairly tight, then it means that people are at the same time cooperating and competing. It's an interesting situation. It's true in any case because everybody in a group in a way is vying for the attention of the principal investigator. They all have to get letters of recommendation from the same person. They are quite aware that the person either explicitly or implicitly will be making comparisons between the people who happen to be in the lab at that time together. And yet, the work goes forward or falters on the basis of how well, in a very real sense, that people can work as a team.

It's much in the same vein because Lou Reichart is on the faculty here that I've come to understand how mountain climbing teams work. In talking with Lou and in reading the book about his climb of K2—the book is called The Last Step, by the way—that from the first step on the trail, the team members are competing with each other. But of course, they're going to go nowhere unless they cooperate. In fact, somebody will end up dying unless they cooperate. So they're all literally in that case on the same rope, but in fact, they're competing with each other to see who will be the people who get chosen to go to the top. Not everybody is going to go to the top. Here, that sort of competition isn't as explicit because several people can go to the top in that sense. Each has his own or her own project. But on projects like that where a given piece of work will turn into a paper, in a way they're competing with each other to see who's going to get primacy.

The way we resolve it— In many cases, it's clear, and that's simple. The person who makes the primary contribution writes the first drafts of the paper. It's almost always the case that the person who does the major amount of the writing ends up being first author because that in itself is a lot of work. But in other cases, it's simply not clear. There are a couple of solutions. The one that I don't like is to carve the work into multiple papers, but it's not uncommon. It's called "salami science," slicing things to the thinnest publishable unit. The other two that are commonly used are a device in which two authors are the first two on the list, and they have asterisks next to their names, and down at the bottom of the page it says that these people made equal contributions. And then the third is for me to go in the middle of the author list, and for the two primary authors, one to be the first author and one to be the last author. That device is particularly good for a postdoc who is going off to his or her own job because in the Oral History Center, The Bancroft Library, University of California Berkeley 237

literature it looks like they're the senior person that kind of came up with the idea.

Hughes: That's based on the understanding, though, that people know the Yamamoto lab.

Yamamoto: Yes, that's right.

Hughes: And can interpret what that placement means.

Yamamoto: Sure.

Hughes: Which isn't going to be known to absolutely everybody.

Yamamoto: No, it won't. Of course not. But in general, it's known, and people understand it.

The last device, I should have mentioned, is for me simply to leave my name off, which we've done. I think there are twenty-some papers published out of here in which I have not included my name. My career is not going to be made or destroyed by any single paper any more. I hope. [laughter] It certainly won't be made. It might be destroyed. [laughter] And that's a very nice thing for a person in the lab to publish a paper without me, so in the literature it's very clear that that person gets the credit for the work. And that's happened a fair number of times from here.

So there are ways to resolve it, but it's become more of a sticky issue, in a sense for a good reason: because of the way that science is done now. It's more complex, there are more directions to bear on a problem, from which a problem can be approached. But it makes this ambiguity kind of emerge, something that we just have to wrestle with.

Hughes: Is it apparent to you that this issue of author order shapes the way the science is actually pursued within the lab group in terms of choosing from parts of a problem that might bring more prominence or—

Yamamoto: Yes, it does. I think I've mentioned before that the only currency that we have in this business is the acknowledgement, credit for doing something. So the students and postdocs are pretty aware of that. At a place like this, even when they come into the lab for a ten-week rotation, they want to do a project that has kind of a clear track of significance to it, and not one that is merely exploratory, or one that is cataloguing information about a big series of mutants that we've had in the freezer for a year. In fact, those sorts of exploratory and cataloguing type of studies can be extraordinarily useful and valuable and interesting, and from that can emerge really Oral History Center, The Bancroft Library, University of California Berkeley 238

important things. But I think students and postdocs are really aware of the fact that— I guess they feel this clock ticking, and they want to be sure that they're spending their time on something that has a clear track of significance.

I think it didn't use to be that way, and it's made science more conservative. The work in the laboratory, as much leadership as we all imagine that we exert in this business, in the end is going to depend on the interest and drive and creativity and experimental skills of the people doing the work. They need to really be engaged in what they're doing, and they deserve to be. But as they have felt this crunch of competition, I think it has had an impact. It's been a conservative force in the way that things get mapped out. So they're aware of it; it definitely comes into play.

Hughes: Is there a point within a scientific career that there is license to be less conservative?

Yamamoto: Yes. Well, I've said this to every student that's come through my lab. Being a graduate student definitely is that time. It really literally doesn't make much difference if the thesis that's produced generates some sparkling answer to an important question. What matters is that the student demonstrate drive and creativity, interest, base of knowledge, experimental skills, and really on that list need not appear a full body of work, something that is recognizable as a starting question that then gets answered. It really is those other parameters that are being measured in a student, and if a student demonstrates those things, then he or she deserves and will get the sorts of letters of support that will allow the career to progress to a very good postdoctoral situation.

Hughes: Is that a common understanding in the field?

Yamamoto: No, I don't think so. Oh, you mean among investigators?

Hughes: Yes.

Yamamoto: Yes, I think it is. I've been on two postdoc grant panels. I'm on Jane Coffin Child's Foundation now, and I was on the Damon Runyon panel before. It's very clear that people pay attention to the students that have made some great discovery and have a long list of papers. But it's also the case that students that don't have that situation at all have a couple of papers in preparation in which it can really be demonstrated that they've really gone after something ambitious, and put a dent in it due to their hard work and hard thinking. Those people do fine. Oral History Center, The Bancroft Library, University of California Berkeley 239

So graduate school in fact is an opportunity to do something really daring. They're in a lab for four years, five years, actually working in a lab—that's after their coursework—in which they can get a stranglehold on a problem, even if they don't answer it, and end up knowing more about it than anybody in the world, and really exert some scholarly force on a problem. It's a real opportunity to do that. So they really don't have to be conservative at all in graduate school.

Postdocs, it's really a quite different story. They're coming into the lab for three years, or I guess more commonly a little bit more than three years now, and it means that in a couple of years, they have to have a story. They have to have a job seminar with a series of slides strung together, and hopefully a paper published, a paper in press, or more if things have gone well, which they can then use to sell themselves. So those projects in general are more conservative, and this really reflects the way that I try to mentor the people in my lab. Whereas graduate student projects need not be that way at all. They can really try something dramatically different.

There are no undergraduates at UCSF. But in institutions where there are undergraduates, and I've seen them mentored in a way that I think is really creative, those students have done the wild and crazy experiments because it absolutely makes no difference whatsoever for them. So the one window of time when somebody can really kind of let themselves go is in graduate school, and I've seen senior graduate students that are really in that situation.

There are little windows as well. Really talented and lucky postdocs who get jobs a year, year and a half, before their postdoctoral period is finished have this little window to play in, and that's really nice. And then the sabbatical years as a faculty member. Or, depending on how the group is configured, as a faculty member that has these various sorts of people coming through, sabbatical visitors, visiting scientists, students that want to do something crazy, undergrads who want to come in and explore and idea maybe first in the library. Bruce Alberts when he was at Princeton used to have a student do a junior thesis, a library thesis, just learning something together with Bruce about something that maybe neither of them really knew very well beforehand. And then some of those [theses] will flower into a wild and crazy project. Those are ways that you can kind of keep the juices flowing while you're also trying to bring in the bucks and get the papers out, and that's fine, that's fun.

So with graduate students, I really do try to do that. I think many of my colleagues allow them the freedom to kind head off in some funny direction and do something a little bit out of the norm and just see where things take them. Oral History Center, The Bancroft Library, University of California Berkeley 240

Hughes: Well, anything more on the subject of publication?

Yamamoto: I don't think so. I can't remember if we've talked about journals per se. I'm an editor of a journal.

Hughes: Well, we have and haven't. You've expressed several times your dismay over Cell.

Yamamoto: Yes. [laughter]

Hughes: But talk to me about your editorial work; that would be fine.

Yamamoto: Well, it's related to that. I'm an editor of a journal called Molecular Biology of the Cell. David Botstein, my friend at Stanford, is editor in chief, and then there's a very fine group of associate editors and an editorial board. The goal of that journal, stated now in every issue in a little paragraph, really is to encourage scientists to remember that the reporting of science is a part of the doing of science, and that this vehicle of journals is really their vehicle. And I say that in that way because I think that we've ceded that right and responsibility to editors of these various journals who are now telling us what's good science and what's not. I know we have talked about this, I remember now—but it's had a negative effect on the way that students see publications.

So what MBC, Molecular Biology of the Cell, is trying to do is to essentially regain that attitude and spirit among scientists and say, "This is your venue for reporting your work. We regard the editorial process not as an adversarial one, but as a collegial one. We're all trying to publish our work, too, and our goal in being editors is not looking for a way to make you feel bad, but instead having a conversation with you about your work. Anything that we may perceive that is an area that needs further investigation or a question that hasn't been clearly stated, we’re telling you what we think should happen in any way that two scientific colleagues sitting down together would do. You may end up disagreeing with what we have to say, and in that sense, there's only a little bit of recourse that you have."

The reviewing process really is always carried out by scientists. Every paper gets reviewed and read, and in our feedback, even in cases where the paper is being rejected, the letters are structured to really be this sort of conversation of what we think should happen. We have not yet published a single paper in which the authors haven't been asked to do something to the paper. I think that we've had, in the four years we've been operating this way, a couple of complaints about the way that the process has gone. Oral History Center, The Bancroft Library, University of California Berkeley 241

But in general, even the people who have been just kind of cleanly rejected have I think understood what it is that we're trying to do.

And what we want is to have a full explication of the [experiment’s] question, the methods by which the work was done—these things are sort of falling away from the way that papers get published now. So in most journals it's literally impossible to really reproduce an experiment on the basis of how the materials and methods are described because those things have been just truncated. They're not sexy, and so they just get squeezed out of papers. So we're trying to make sure that all of that sort of stuff appears in journals.

I think all that journals really have an important place in the fabric of the community, in part because they're written down and they're kind of an historical document. What could be more important than history, right? And so when students come to the field, one of the things that they encounter first is the literature. I think it helps set the tone of the kind of ethic of the way that the community operates. So I think it's really important in that sense as well. So we want to have things that are clear representations of the work, because that's the way the knowledge is built, but also it sets a clear standard for the way that the community operates. It's a written record of the standards by which the community operates. So that's what we're trying to do at MBC, and I think it's an interesting endeavor. I don't know whether it will work or not, but I think it's important.

Hughes: Have you as an editorial board considered the question of nonacademic affiliations of your authors? Is there any disclaimer or disclosure, I guess is what I really mean to say?

Yamamoto: Yes. That's in our instruction sheet. Explicit conflicts have to be disclosed. It's not something that we've encountered more than a couple of times, to let people know what the affiliations of the authors are. But I think it's an important thing to do.

Hughes: Is that common practice now?

Yamamoto: It's becoming a common practice, yes. I don't know if it's commonly followed, becoming a common practice in journals.

Hughes: Well, this leads into another broad topic, namely, scientific misconduct, about which you have had quite a bit to do. I thought we might start with a definition, perhaps for my benefit more than anybody else's. But can you distinguish ethics and etiquette from misconduct? Oral History Center, The Bancroft Library, University of California Berkeley 242

Yamamoto: Yes, I think so, very clearly. A line attributed to my friend Howard Schachman60 at Berkeley helps to make this clear. I don't know whether the attribution is correct, but he uses it a lot—is that what we're trying to do in talking about ethics and etiquette on the one hand, and misconduct on the other, is to separate the jerks from the crooks. [laughter] He and I have tossed that around a lot. I don't know who came up with it. It certainly wasn't me. He uses it a lot in his talks, and very effectively so. And that really is the case.

So to fill in some background, I have been active in this arena and was a member of a National Academy [of Sciences] panel that looked at this issue of responsible science, I guess it was called in the end. It published a two-volume report in 1992 after ten meetings in Washington and endless drafts of this document. And what the report does rather well, I think, is to lay out the distinctions and to make clear that misconduct in science is encompassed by this phrase FFP, fabrication, falsification, and plagiarism. What we're talking about is people making up data, reporting results that are false, or importing intellectual property of others—copying down what they write or jumping on their ideas. That's what we mean by misconduct in science.

Other issues of bad behavior, of not sending out strains, or inappropriate authorship assignment, just generally being a non-cooperative member of the society, are things that are not misconduct in science, but instead issues that really go at the heart of becoming socialized to the way the community can best operate. There's a wide spectrum. It's not good news that there are people that are out on the wrong fringe of that. But I think it is good news that the community is so diverse. It's elastic in the sense that it can accommodate many, many sorts of personalities. People discover that there's lots of ways to do science well and lots of ways to achieve things in science. Those things are not directly mapping onto each other, but they're close.

The way that we can establish ethics and etiquette standards is really simply by the way that we are when we come into our labs every day. That one-to-one contact that people are running into many times a day is the greatest political force that any of us as individuals can exert. It's a long way from voting in a national election, or a long way from working in a national election, which I've done, as you know, or even working in the academic senate of a university. But simply being around the lab and stating what you think is the right and wrong thing, how to behave, we come upon these things all the time. Decisions get made or not made every

60 See the oral history with Howard Schachman in this series. Oral History Center, The Bancroft Library, University of California Berkeley 243

day that help to form the norms of behavior and set the standards. And the students notice these things.

Hughes: You're very conscious of being a model?

Yamamoto: Oh, yes, very much so. And I think it's one of the most important things I can do. So I've often said, and only half-jokingly, that one can trace the pedigree of a scientist by how he or she behaves. People who work with jerks more often end up jerks. Who knows what the cause or effect is, but it really is the case. So again, it's not one-to-one, but it's very clear that people begin to take on not only the appearance and sense of humor of their mentors, which is sort of like dogs and their owners, but in fact they really adopt the standards of that person, and you can see this.

So it is something I'm very conscious of in that what we do and how we act make a big difference. I think we recognize that as an institution and the science community here at UCSF as well. The faculty here I think is conscious of the fact that UCSF has an important place in the community at large, and what we do and how we behave makes a difference. I think it shows in the students and postdocs that come out of here. So there is an awareness of that that's important.

Hughes: But I read into your remarks the concept that these standards are something that should be done by example rather than by some outside agency dictating how it should be.

Yamamoto: That's right.

Hughes: I can't imagine quite how that would even be possible, but—

Yamamoto: Well, there are lots of people that feel that it should be done that way, that there should be rules of behavior that get normalized at, let's say, the national level. That's one way to do it. And that these things should be written down and adhered to. Institutions rather like that, because it's easy then to find out whether someone's doing the right or the wrong thing. But I just think that there's this discontinuity in the statement that ethics are a set of rules that can be written down because then ethics are rules; they're not ethics.

[begin tape 19, side B]

Hughes: When you discover situations that you do consider to be scientific misconduct, what should then happen? Oral History Center, The Bancroft Library, University of California Berkeley 244

Yamamoto: What I think, and what we have tried to recommend, is that every institution needs to make clear to all of the members of the community what the clear road is to dealing with concerns about misconduct, who can be told what. And so whether it is a technician in a laboratory or a department chairman, there has to be a feasible avenue to deal with perceptions of misconduct. By feasible, I mean that if it was always the principal investigator in the laboratory, for example, then that would be a problem, because principal investigators can engage in misconduct just like everyone else, a department chairman, a dean. So there has to be a track around every single person and a way to go that gives protection to the person doing the reporting. That's what we on the misconduct panel call the alligator.

And the accused person of course also has rights. A career can really be stopped or derailed by a claim of misconduct that doesn't have any merit if the case isn't adjudicated promptly and properly with attention to due process and protection of the rights of the person that's accused. So it gets into all these legal considerations pretty quickly. I'm not so concerned about that, but I am concerned about doing things fairly.

My hope is that institutions will take responsibility and realize that the place where these problems will have the best chance of being dealt with fairly and promptly and correctly will be in the community where the things occur. The only hope for being able to do that is to make everyone as comfortable as possible with the idea that they can go talk to somebody about these concerns as they see them, and that many of the things will then get taken care of.

That won't always be the case, so that means that there then has to be a clear track beyond the institution as well. Institutions can make big mistakes; they have their own built-in conflicts of interest about protecting themselves from adverse publicity or protecting their donors or whatever. There are conflicts of interest there too. So there has to be a track around the institution that moves on to a higher body, and eventually all the way, as I've said, from the bench to Bethesda. So if it has to go all the way to Washington, there has to be a track for doing that. On the Academy panel, there was a proposal to actually have a board that would serve as a clearinghouse for information and concerns of this sort. You know that the NIH has its own mechanism.

Hughes: Right.

Yamamoto: One that's been subject to a lot of debate because of the way that they've operated. And there has to be a clear check all the way to Washington. Oral History Center, The Bancroft Library, University of California Berkeley 245

The important thing I think is for the institution to have a very good mechanism in place because that's the place where things should really predominantly be dealt with. If it has to go beyond, it should go on beyond. In many cases right now, the cases that have gained notoriety have gained notoriety in part not just because some people have been famous, but because we're just feeling our way as institutions and individuals of how to deal with these problems. We're not going to be able to adjudicate the end to misconduct in science any more than we can adjudicate the end to embezzlement in legal offices or Roman Catholic churches. So instead we have to try to set ethical standards in such a way that we minimize the people that have engaged in such things, and then set up mechanisms such that when such events happen, they'll be dealt with in a way that's fair. It's a difficult problem.

Hughes: Is the prominence of the misconduct question in the press a reflection of an actual increase in incidence, or something else, for example, press interest, and also the fact that some of these cases have been particularly spectacular and make very spectacular reading.

Yamamoto: There is no way that I can think of to answer that question of quantitation. It is something that there is just intense interest in. There is a broad perception within the community, and I'm sure outside of it, that there is an increasing incidence. What you're saying is actually the case, that it's increasing awareness and reporting. This is a litigious society, and so people are using this legal remedy or route very freely in this society, and much more so than in the past, and much more so than in other societies. So that's the case.

Those sorts of realizations would say, "Well, maybe not. Maybe there's always been a certain level of misconduct, and we're only now being able to perceive it because other things have pushed it into prominence." The counterweighting argument, of course, is that things are more competitive than they used to be. There is a much broader societal spectrum of individuals that are thrown together in this community than before. So it's not just highly educated people coming from highly educated families, all coming from the United States. It just isn't the case anymore. So [science is] a real world community now that has reached, has begun, t least, to reach into our broader socioeconomic spectrum. It's just only begun, unfortunately, but it has begun. So it's not as homogenous a collection of people, and you're just going to run into things [for which] people have different standards.

In fact, some of the cases of clear misconduct really reflect sociological differences, if you will. The case I'm thinking of, of absolute blatant plagiarism that was carried out by, I believe it was, a student from China Oral History Center, The Bancroft Library, University of California Berkeley 246

in which the student, when this question was [asked], said, "Well, yes. There's no higher form of honoring another person than to write down their words precisely, and this is the greatest thing that I could have done." And there it was. What do you do? So clear plagiarism, there's no doubt about that. I think that's probably the strongest statement of the fact that we're drawing from a much greater community than we drew from before, and trying to squeeze people into a common set of standards, where we assumed them before, and we really can't assume them anymore. I don't know the answer. It's an interesting question.

Hughes: The NAS panel: was its formation prompted by any specific instance or instances?

Yamamoto: Well, probably, but I think that on balance, it was prompted simply by the fact that more and more cases were appearing in the press, and that our awareness as a community of this as a real problem paralleled the awareness of that of the public, of the newspaper editors, and of Congress, and of certain committees within Congress. [John] Dingle's committee of course. Congress was really saying, "What the hell is going on here? This is our money. Are you guys spending it well or not?" I think that the Academy responded by saying, "Well, let's find out what's happening." I think that was the genesis.

Hughes: It seems to me there is an ethical question lurking there: here is the hand that's feeding you asking you to do an investigation, and you come up with an answer that if it's not colored in the right fashion, may cut off that hand that's feeding you, or at least make the case less strong. Was that a consideration?

Yamamoto: Yes, of course it was a consideration. I think that we were very aware of the fact that anything that looked like a whitewash would not serve and would in fact exacerbate the concerns. So there was a lot of struggling within the committee about how to present things. I should back up one step and say that the committee was very broadly based. It wasn't just working scientists, and it wasn't just senior scientists. There was a postdoctoral fellow on the committee, there were a couple of professors on the committee, and there were deans and chairs. There were journal editors, there were lawyers, there was a professor of moral philosophy, and there were community people. So it was broadly based in that sense. And many of them really kept calling these questions in a completely appropriate way, giving us the sort of feedback—the way that we would be viewed from the outside. There was a lot of push from that direction, saying, "How can you ignore the fact that there's this huge incidence, that the Acadia Institute in Maine does this study that says that 60 percent of the deans or department chairs in the prominent research universities know Oral History Center, The Bancroft Library, University of California Berkeley 247

personally of cases of misconduct in science, and doesn't this prove that there has to be increased incidence?" Well, not if they all know of the same case. [laughter]

So these numbers can be very deceptive, but just trying to wash over them is not going to help either. So we just tried to acknowledge the sort of argument that I just gave to you, and then to move on from there, to say, "Okay, [Scientific misconduct’s] here, it's with us. We're not going to be able to make rules that will completely eliminate it, but we have to deal with the reality that the situation is here. What do we do about it as it arises? And what do we do to minimize its incidence in the future?"

And that was where we tried to divide up this issue of etiquette, where the [scientific] community standards really have to come into play. It's really up to us as individuals in our laboratory and of departments within an institution and an institution as a whole, to say, "Look, this is the way that we do things here." And acknowledge the fact that what we do and the way that we act has a big impact on the people around us. And then at the larger level of misconduct to really have mechanisms in place to deal with it, and just try to provide assurance in that way that we're aware as a community that the problem is there, and that we're doing things as best we can to recognize it and accommodate or imagine solutions to the problem and see what we can do. Hopefully, it was recognized in that way.

Hughes: You and Howard Schachman presumably wrote and signed a dissent. What was that about?

Yamamoto: Howard and I were dissatisfied essentially throughout these many, many meetings and many, many drafts with the way that the committee seemed to be responding to suggestions for change. Not so much that our suggestions weren't being accommodated. But we felt there was a softness in the way the leadership of the committee worked that made one feel that you left a meeting with an understanding of what was going to happen and an agreement, and that it wasn't always reflected in the draft.

The specific things that we were worried about were that there wasn't a strong enough statement in the report that said the community really has operated magnificently, that it really has been remarkable, not only in its achievements, but in the way that it's gone about achieving those things. And that it's difficult to imagine a structure that could have operated better than the way that this one does. While there's an obvious self-serving component to that, I absolutely believe it. I think that it's really true that it's remarkable that things have moved the way they have, and that great progress has come out in a way that in general has just been proven over Oral History Center, The Bancroft Library, University of California Berkeley 248

and over again to be factual and correct. And that that statement should really appear in a very strong and clear way. It's important, I think, that people not in the community recognize the way that this one works and the way that it responds, the way that we talked about Asilomar [conference on recombinant DNA technology, 1975], even though a lot of scientists think Asilomar was a terrible idea. I think that acknowledgement wasn't there [in the present committee]. There was a lot of softness in it.

We also felt that the definition kept sliding. We spent an enormous amount of time on the definition of misconduct in science, and all the way up to the last draft when we decided to write a dissent, there was still softness in that definition, which ended up getting firmed up in a way that I'm rather pleased with.

Hughes: Focusing it on those three issues?

Yamamoto: Yes. By the way, there is still not a single standard definition at the federal level for misconduct in science. The irritating phrase that other agencies used is to say, "FF&P, and other practices that seriously deviate from the norms of scientific practice," or whatever it is. It's that last thing that really casts a pall onto the whole definition. As soon as you roll in this very vague [definition], then you really run into trouble, and agencies like the National Science Foundation end up getting confused between just legal misconduct, like sexual harassment, and misconduct in science. The NSF continues to mix these things up. So things where someone should just be dragged into court for doing something illegal and which there are clear sanctions in place end up getting rolled into this definition of misconduct in science. So all the way up until the very end, we were unhappy about that.

And then there wasn't a clear enough explication of this pathway notion that I described. There has to be something that people can see that is a clear path to make them feel not quite so nervous about reporting things that they see. There's a lot of problems with whistle-blowers in this society in general, and people are really afraid that by saying something, they're going to get themselves into much greater problems than they would if they didn't say anything at all.

Hughes: Are you fairly confident that you came up with mechanisms that do protect the whistle-blower?

Yamamoto: No, I'm not. I think that in the end was one of our concerns. This board that we recommended—I can't even remember the name of it, what the letters were any more—has never been implemented. So I think it still stands as a problem. Oral History Center, The Bancroft Library, University of California Berkeley 249

Hughes: The board was to monitor?

Yamamoto: Yes. Well, it was to serve as a clearinghouse and to serve as part of this track at the federal level. It's something that I know that Bruce Alberts is aware of, that it has not been implemented. He has subsequently organized an Academy meeting in which he is kind of urging the Academy to move ahead with implementing some of these suggestions from the report. There is a commission on scientific integrity, I think it is, that right now is holding hearings around the country on a more town-meeting basis to get the input of the community.

Hughes: That's through NIH?

Yamamoto: Yes.

Hughes: The underlying concern for this debate was the limitations on the scientific community’s influence?

Yamamoto: Yes, that was certainly an element of it. The counterweighting concerns were that if we didn't do something to respond to the concerns of Congress, for example, then they would do something. It's their money, it's the peoples' money, their job is to make sure that the money is spent responsibly, such as any way that they may do that job, and that's fair. I mean, we have to recognize that as a community. There's been a tendency not to recognize that: "This is our money, go away." And so if we didn't do something, and they really had these concerns, then they by all rights had a right to say, "Okay, you're not going to do anything? You will now follow these following rules." That was to be avoided. We really believed, I think correctly, that we do a better job of setting the standards. As I've already said, I think it's best done at the very local level, [better] than the feds could do. Even if it was the feds represented at NIH, we wouldn't want them to tell us how to do these things. So that had to be acknowledged.

On the other hand, if we generated a series of rules of behavior that was too constricting—and I'll give you a really good example of that in a minute that I think makes clear the issue—then we would risk making the endeavor less fun for creative people. A good example is keeping of notebooks, keeping of records. A very easy case can be made for saying that if the reporting of science is so important, then keeping the records of what you do in an experiment then becomes really crucial. Even at the level of the progress of one's own project, if you write down the lot number of the enzyme that you used for a given cleavage of a plasmid, and after a while, you begin to perceive that the plasmid is not being cut correctly, and the not being cut correctly correlates with beginning to use Oral History Center, The Bancroft Library, University of California Berkeley 250

that lot number, then you can say, "Aha." So it's easy to make the case that real scrupulous record-keeping is really important.

We know that our friends in industry have very strict rules about this for other reasons, for patent reasons. People will use this notebook. We will issue you this sort of notebook: every page is bound, and every day your supervisor has to initial every page, and they have to be dated. Unused lines have to be crossed out, so you can't be adding other entries in. And every two weeks, we'll microfilm everybody's notebooks.

Hughes: That actually happens?

Yamamoto: Yes, I think that's DuPont's policy. You'd think, gee, that sounds pretty good. What could go wrong? There's no more of this slipping something into the notebooks after the fact or changing dates or changing entries. A lot of this fabrication and falsification will go away if we simply had a mechanism like that. Well, that's not the way this [academic science] community works. So what do we do instead? Well, most of us do nothing. I don't like the way that a lot of the notebooks are kept in my laboratory. I certainly don't like the way that a lot of the benches look at the end of the day. And when I first started, I used to really try to put a clamp on those things, and I don't any more. But in the end, I'm going to be responsible if something goes wrong.

Hughes: Why don't you put a clamp on it?

Yamamoto: Well, in part because I'm too busy. But in large part because I've come to appreciate that really trying to make people behave the way that I behave is not really where it's at, and that creative people are going to rebel against those sorts of strictures. I said a little while ago that we can celebrate the fact that there's lots of ways to do science well. I know absolutely superb scientists whose record-keeping is unbelievably appalling, in my view. They just don't write things down. They don't label their films. You're sitting in their office and they're showing you a film about some exciting experiment, and then they realize, "Oh, no, that's not the right film." Sort of cast that aside and pick up some other one. "Oh, yeah, here it is; oh, no, turn it over." [laughter] It's sort of hilarious. You think, how in the hell has this person ever made any progress? But they have; it's right there; it's in the record. So there are going to be some scientists who move ahead in very, very different ways.

I think that our role as a community is to discourage that sort of thing. But if you try to make it disappear, you're going to be losing a fraction of the community that could really do something important, and that leaving room, leaving breadth, for this sort of behavior is good. And then simply, Oral History Center, The Bancroft Library, University of California Berkeley 251

as I said, saying every day what I think is the right way to be will have its little influence, and you just move on from there.

Hughes: What you seem to be saying in a nutshell is there are many ways to do productive science.

Yamamoto: That's right, and the more you try to write things down, then the more you kind of take the fun out of it for people who don't want to do it that way.

Hughes: Well, the fun and also the productivity, too.

Yamamoto: That's right. It cuts both ways. There's a postdoc in my mind right now whose record-keeping used to just drive me nuts. I mean, it just was wildly crazy-making. He just couldn't tell what he had actually done in a given experiment. I would try to read his notebooks, and I couldn't make heads nor tails out of them. Well, now he's a professor, and he really pounds on his students [laughing]. He complains to me about their notebooks. He's really on them. I don't know where that came from. Maybe a part of it came from me.

Hughes: Let me go back to the NAS committee and the dissenting opinion. I'm wondering several things. First of all, did you feel any pressure to come to a consensus, that you two were the ones that were disturbing this process? It could be argued that it was important to present a unified view from the scientific community on this incredibly complicated and important issue, and that in this case freedom of expression perhaps should be put second to the good of the community as a whole.

Yamamoto: Yes, that's fair. Well, I think that we felt our own pressure— Yes, we felt pressure, but I think we felt our own pressure to reach consensus and agreement for precisely the reasons that you just described, rather than having pressure imposed on us from the chairman of the committee or from others on the committee. I basically didn't feel that. We weren't very worried about that.

I think I should step back and tell you a little bit about how the actual writing of the dissent came about, because it will be illustrative in a sense. But let me first say that I think that our dissent served a purpose in the end and helped to move the final version of the report in a direction that was good. So having said that, I'll say that throughout the process, throughout the drafting and the meeting, it was always clear where we stood. It wasn't that we came in at the last minute and said, "We ain't gonna sign this baby; you've had it." It was always completely clear to everyone on the committee where we stood. We didn't always stand together, but— And Oral History Center, The Bancroft Library, University of California Berkeley 252

that was fine. There were clearly identifiable points of view on the committee. It was a very good committee.

We were frustrated with the fact that we didn't think that the redrafting and the course of the discussions in the meetings was really hewing to the line of agreement that we had apparently reached. So we really wanted the report better to reflect some of the comments that were made continually over and over again. It just wasn't happening. So it really was a matter of this definition, of the statement of what the scientific establishment has achieved in this country, and this clear track of reporting. Those things just weren't appearing and weren't appearing.

As we came down to this final wire, we kept making clear that there were elements of the report that we simply couldn't abide by. So at the very last minute, we were given twenty-four hours to write something down, but we weren't told it would appear in the report. We were just told, "Write something down, one page, that sums up what your concerns are, and we'll see what we can do." What came out in the end was a definition that I'm actually quite—

[begin tape 20, side A]

Yamamoto: —which in isolation is very cryptic, I think, but is there, and that was it. So we had this one day in which to generate a one-page document that we didn't really know what was going to become of it.

I think on balance, the report is good. I think it's not what it could have been, so I was disappointed in it. That in broad brush stroke is the reason that we did what we did. I'm sorry if it had a compromising effect, but I think it at least makes people aware of the fact that—what probably everyone is aware of anyway—and that is that, on complex issues like this, it's going to be very difficult to achieve a monolithic viewpoint, and that on balance, the process was undertaken with goodwill and concern and hard work, and that what came out of it is of value. It may not have been something that we all agreed on, but I don't think it compromises it unduly. I wish it didn't happen that way.

Hughes: What was the impact of the report?

Yamamoto: I don't really know how to measure that. I think that many of these reports just sort of go away, that the act of doing them and having something in a bound volume somewhere is enough to assuage a lot of the concerns, and then it just kind of goes away or people get exhausted with the issue. There was a level of exhaustion with the issue of misconduct in science, Oral History Center, The Bancroft Library, University of California Berkeley 253

that the Baltimore case had kind of blown itself out, that the Gallo case kind of blew itself out in a sense. It just kind of faded from view. John Dingle found other things that he wanted to pursue. I don't know whether some of that was the impact of the report or whether people just got exhausted. I don't know how to measure what it actually did.

In terms of the specifics of the recommendations, the most explicit one was this clearinghouse type of operation, that reform, which I said has not been executed. That hasn't had much effect. I think it was read in the community, and there may have been some things that came out of it at that level, that spun off from it at that level. But I don't know how to measure it. I don't know the answer.

Entering into endeavors like this in general is a difficult thing. I do them all the time where when the issue gets presented. After you've done a few of them, you think, I am not going to get caught again. I'm not going to let myself get roped into doing this, because I know that it won't have any impact. I participated in the strategic plan [meeting]of Bernardine Healy, which was a complete waste of time, because there was this feeling that if you don't go and you don't participate and you don't lend your voice to what you think is right in these situations, then you really have no rights to complain later. And so you do it, and too often you leave Washington or finish your report and say, "That was a waste of time. That was stupid, and it was another thing that took me out of my laboratory or out of my department, out of my institution, and I shouldn't have done that." But they're not easy to recognize. Many of them aren't. Many of them come in with this kind of high hopes and—

Hughes: At some level, there's a responsibility, too.

Yamamoto: That's right.

Hughes: You are a member of the science community, and you do have opinions, so they should be expressed.

Yamamoto: Yes, that's right. So I'm on a committee right now. It's Harold Varmus's committee to essentially provide input about how the Division of Research Grants should be organized and should function. Eighty percent of the peer review at NIH is done out of this division, and it's really on that division that our careers are hanging in the balance in a sense. So we want to give him some suggestions about how it should operate. Well, I don't know what will happen to that. But I've put a lot of time into it. We've had weekly meetings in Washington.

Hughes: It's a critical issue, isn't it? Oral History Center, The Bancroft Library, University of California Berkeley 254

Yamamoto: Yes.

Hughes: Well, from your CV, I know that you are also on the American Academy of Microbiology Colloquium on Ethics in Science. Is there anything particularly new to say about that?

Yamamoto: No, there's not. I assume that was a one-time planning board to put together a colloquium on scientific conduct.

Hughes: Ethics in science.

Yamamoto: Ethics in science. We chose an interesting issue. There was a meeting in San Francisco in December that we organized. It was chaired by Frank McCrena [?],who's written and taught on this topic. What we chose to do was to put together a small group of people who teach ethics courses in institutions, not students, not a big meeting of [inaudible]. Small group of twenty people or whatever it was that would get together in San Francisco and discuss a rather focused issue in scientific ethics. What we chose was collaborations in science and the issues that spin out of collaborations in science. Authorship is one, although we didn't spend any time on it.

The larger one, and a quite interesting one, is that as this trend continues of being able to approach a given question from a number of different experimental directions, what we're all finding is that we're ending up collaborating with other investigators who have much different expertise than we have. So yesterday, I had somebody visiting us, a collaborator [Rob Keptane?] from Utrecht in the Netherlands who is in a research group that does nuclear magnetic resonance spectroscopy.

Now, I'm pretty sure that I wouldn't know how to turn on an NMR machine. When I visited his laboratory a few years ago, his postdoc sat me down and tried to take me through the process by which they read and interpret the data, the actual data that comes out of the machine. So they just gave me a little course on what they do. They took me through it, and it was kind of, "Yes, yes, I understand, I understand," and they said, "Okay, try it." And I was terrible, terrible. It was a joke, and they probably thought it was a joke. So here we are collaborating with a group, publishing papers together with them, in an area where I really would be at sea.

But my name goes on that paper along with their name, right, and we're doing this molecular biology and genetics in which they feel the same way. So how do we take responsibility for work? When you sign a paper, this means that you're vetting that work, and you're saying that this work is right. And what do you do about that? So we had a little colloquium on Oral History Center, The Bancroft Library, University of California Berkeley 255

that issue, which is not an uninteresting one, on how do you deal with that. And it's something that's going to be on us more and more.

It was one where our goal was not to come up with solutions but to make the issues clear, to gather together materials that were useful for the teachers, and to go from there. So we were really seeding something that we hoped would go out more broadly in the community. And it was a fun thing to do. I hope it was a one-time thing, but it was one where we got together and said, "All right, here's an issue before us. The Academy wants to say something. What should we say and how should we say it?"

Hughes: Well, in one of the previous sessions, you alluded to a course in ethics. Is that your course?

Yamamoto: Well, it's not my course. It's one that I participated in several times, and I guess I was involved in the planning the first time it was taught, which I think was in 1990, or '89, or something like that. Actually, I've been involved in two such courses here. One was called “The Practice of Science,” all day on Saturday for three or four consecutive Saturdays in which we chose on consecutive days particular issues in, as the course says, the practice of science that we have to wrestle with.

One that I actually ran was called “Getting and Staying Funded”, which was essentially how the grant system works, and what goes into a grant, and what happens to a grant when it arrives in Washington, how they're judged and what matters, and how you choose a project that fits, that really looks like a grant. One was on career alternatives in science. One was on how to run a laboratory. And one was explicitly on scientific conduct.

In all of them though, as you hear that topic list read, it's very easy to see how ethics issues can be woven into each of them. So we chose, rather than saying, "Let's have a course on ethics," instead just say, "Well, what is ethics all about? Well, ethics is about how we behave in this community. So let's just do one about how the community works, and how we behave within it, and ethical questions will emerge all the way through," and it did. So in the years when I felt that the course was really successful, I felt that the people who were teaching it and leading discussions, or facilitating discussions I should say, really kept that issue near the surface so it kept poking up. Very interesting things came out.

I think some years have been very good, some haven't been so good. But I think basically it's the right way to go, rather than saying, "Okay, it's time to be ethical." [laughter] Here are the rules for being ethical. Follow these simple [rules]; watch for these warning signals. Instead, we just say, Oral History Center, The Bancroft Library, University of California Berkeley 256

"Well, how do we do our business? What kind of problems do we encounter if we try to do it in this way?" The issues are right there. They're easy to identify. What we found is that things drawn from our own experience were really the most powerful, rather than using these hypothetical test cases or case studies. Things that we pulled out of our own correspondence files and marked out names and showed transparencies of, were things that really captivated people.

Hughes: Yes, I can imagine.

I'd like to turn to your lab. I know we have discussed it, but there are a few things that I think are still outstanding. Start with a very simple—maybe not so simple—question: how would you describe the atmosphere in your laboratory?

Yamamoto: Huh, that's a good question. It's not so simple for me. [laughs] People come to my lab sort of know what they're getting into in the sense that my lab is known as one that is quite focused in what it does. Some people say overly focused in what it does. So they know when they're coming here that they're going to be working on a rather well circumscribed area. Whereas in other laboratories, I think I've mentioned to you before, "There is the bench, welcome, go find something interesting to do, and check back with me."

[The people in my lab] don't get micromanaged, at least any more. They may have felt that way before, in terms of day-to-day experimentation. Absolutely not the case now. In fact, I'm sure there are people who feel ignored now. There is always a fine line, or a not so fine line, where some people are feeling harassed, and the person next to them, who may be getting the same level of attention, would be feeling ignored. That's true. It's true. But it's undeniable that the amount of time and attention that I give to them on a daily basis about experiments is very small. So I don't think any of them feel micromanaged. I'm sure it's quite to the contrary for some of them.

Hughes: That isn't necessarily the product of your benign mood as you've gotten older?

Yamamoto: [laughs] No, no. And nobody would accuse me of a benign mood. [laughs] No, it's just that I'm too busy. So I don't like that actually. I feel that I'm not as connected to the work as I would like to be or as I should be, both. That's a disquieting feeling. So I'm very aware of that and working on various mechanisms to try to remedy that. Unfortunately, they're all [formalisms?]. They aren't things that I like to have, to have set meetings with people. Everybody has to schedule a meeting with me, even my own Oral History Center, The Bancroft Library, University of California Berkeley 257

group has to schedule a meeting with me through my secretary. Well, I don't like that. But I've come finally to realize the practicalities of the situation, that as my schedule gets completely booked every day—there's one half-hour period today where I'm not booked—and that's very common. So unless part of that booking becomes [for] people in my lab, then everything just gets filled up. So there are logistic things like that that need to change, and unfortunately part of it is formalization. But yes, you're right, I'm not putting in as much time not because I'm not interested.

Hughes: Do you expect people to report in on a defined basis?

Yamamoto: Not on a regular basis. It's not that everybody has a [inaudible] reporting. I've spent enough time out there that I've run into people, or go initiate conversations myself, just to see how things are going, and occasionally still cruise around at night and peek in notebooks. And then we have a growing number of meetings with groups or individuals that are set up now. So my own laboratory, the whole laboratory group, meets twice a week, and then there are various subgroups that meet on a regular basis. Those work very, very well, and many of those cross over to a few individuals in other laboratories as well, if they're really stimulating in that sense, because there's another PI [principal investigator]there, and some people with different points of view working on different problems.

Then I meet on a regular basis with several individuals who want to do it that way. There are others who would go crazy with that sort of thing, they would just never accommodate that. So they would much rather just be run into by me, or vice versa, and come and see me when they want to, or vice versa. And that seems to work okay. So it's really on an individual basis. But I've really learned that unless I really set things up like that, it just doesn't get done.

Hughes: You said that some people perceive your lab as being over-focused. What are they thinking when they say that?

Yamamoto: I described to you the kind of philosophy of the lab of choosing a single molecule that's involved in a lot of complicated processes, and then really bearing down on that molecule, letting us tell it what we should be studying. There is a view from at least some people in the community that think that all I've ever done in my career is to study the glucocorticoid receptor using molecular biological techniques. Well, in fact, we're studying heat shock proteins, and other transcription factors, and membrane transport, and nuclear transporter proteins, and doing structure and genetics and biochemistry. There are lots of different things going on Oral History Center, The Bancroft Library, University of California Berkeley 258

here. I can understand the point of view from the outside is that they're all bearing on this issue of how this set of receptors is working in cells.

Hughes: As long as you're finding good new information, why not do that?

Yamamoto: Sure. But it's just a difference in style. Some people don't like that style, and some people do. It's okay. But yes, I think there are people who say it's over-focused. There are people who appreciate its breadth, people who think it's just right. There's going to be the whole spectrum, and it's okay.

Hughes: You keep bringing up individual style in science, and yet you also have a lab. There must be a lab style too, is there not?

Yamamoto: Very much so.

Hughes: I mean, beyond following the molecule. When people talk of Keith's lab, more than just following the molecule I'm sure comes into their mind.

Yamamoto: Yes.

Hughes: And what might those other things be?

Yamamoto: Well, there are styles for how a question is perceived and pursued that are kind of lab-specific. We tend to be reductionists. We break things down into simple model systems and pursue them there, where other people go precisely the other way. For example, we're looking at a hormone or set of hormones that is critical in the human organ for normal human physiology and development and is involved in disease. So one way that the direct avenues are increasingly available is to study it at that level and ask, what happens in Addison's disease when there's too much glucocorticoids? Our lab is known as a lab that doesn't do that, but tends to break things down, put them into very simple systems, and crack them apart to this very little reductionist level, and then move back out again. Our science is very identifiable in that way. We do have a goal of moving back out, we do care about disease, and we're looking at systems that will move us in that direction. But our starting point almost always is to ratchet down and then figure out ways to crawl back up again. So there's that sort of style.

I think there is still a lot of cohesiveness in the lab. People kind of hang around together and hang out together in part because it is a disciplinary focus and in part because everybody who comes here gets interviewed. We don't just accept people by mail order as it were, and so we try to choose individuals that will like each other and fit together well as a little community. And they do that. They do things together, and they kind of hang out together, and that's very nice. So it does have its own little style. Oral History Center, The Bancroft Library, University of California Berkeley 259

You probably could joke about it. But I'm sure it has some reflection of my own style in it. It's just there. Many of the labs here have that sort of same persona to them, you'd say.

Hughes: So there's a selection process at the very outset on both levels.

Yamamoto: Yes.

Hughes: First, certain people wouldn't apply to begin with, and then those that aren't appropriate for whatever reason aren't going to be invited.

Yamamoto: Right.

Hughes: And then I'm sure there's an indoctrination period once they get here, too.

Yamamoto: Yes.

Hughes: Not that you sit them down and tell them what the rules are, but these are intelligent people and they pick up, I'm sure, on all kinds of things.

Yamamoto: Yes. It's very fun, actually. People come in from very different areas, and they have different viewpoints about things, and it just kind of gets woven together. When it works well, it's great fun.

Hughes: Well, I had a question about rules, spoken and unspoken, in your lab for establishing ownership of ideas and credit. But maybe you feel we've done enough in talking about how a paper is constructed. Is there more you want to say?

Yamamoto: I don't think so. Just by the way you framed the question, it's clear you understand that we don't have hard-wired rules. It really is done in my lab in this sort of informal, evolutionary way, where the thing just sort of becomes apparent who has primacy. It doesn't always become apparent, and so that's where the debates come into play, and they happen a few times a year. But I think they get resolved to people's satisfaction, and I really do step in and play a direct role right away in those cases. I think it works out okay.

Hughes: I haven't talked to anybody, and this is my fault, about the historic role of women as researchers in this department. Are you aware of any distinctive treatment or any evolution in how women in science have been regarded? If you have salient things to say about earlier experiences, Princeton for example, feel welcome to include that. Oral History Center, The Bancroft Library, University of California Berkeley 260

Yamamoto: Just like in the rest of society, women have had to do battle and have been doing battle right during the time that my career has been advancing. So I've been kind of in pace with that movement, and seeing it happen. Christine Guthrie, when she began on the faculty in '73 at the same time I started as a postdoc here, was the first woman in the department, in what was a small department. She was the only woman for a few years.

Hughes: On the faculty? Are you also including students and postdocs?

Yamamoto: No, on the faculty. There is a huge dropout rate for women as you move through the process, and so the number of women at the top of the pecking order is a very small number. Our graduate student classes are pretty consistently more than half women, so it means that there is a striking lack of role models for them. But we've been very conscious of that, recruiting and hiring women throughout the time that I've been on the faculty. We've done rather well at it here. We hire people who are almost uniformly successful. Almost everyone gets tenure here, and it's not because there aren't high standards. We really want to hire somebody that we're pretty sure will achieve well and be recognized and will be a slam dunk for tenure. And in general, that's been the case. So I think we've done rather well in hiring women. I don't know what the real numbers are.

Now that I'm in another department [Pharmacology], we're up against it again. I'm in an all-male department except for one in-residence faculty who's a woman. No tenure-track faculty that are women. We have six positions, and we'd better get some women. So I think that—

It does disservice to the cause of expanding the representation of women and minorities to hire women and minorities that aren't well qualified. So it's really important to do that. There are highly qualified women out there, there's no doubt about it. There are not as many women, and so the raw numbers are small. Because there's a lot of men who are well qualified, too. I really believe that this notion of affirmative action that is so much in front of us right now in the press and in the Congress and in the state of California is absolutely critical to maintain no matter what. I think Joe Martin has made that clear in his comments from the chancellor's office, as the affirmative action debate has begun to heat up in California. I think within science, it's absolutely critical.

The hardest thing for women right now is that virtually everyone recognizes that women have made great strides in science. The problem with that statement, which I think is true, is that there is a large fraction who now feels that the problem is solved. So in a way, it makes it extra hard for women. "You're here, there's no problem." Being a woman scientist is very tough. How do you deal with the family issues? The Oral History Center, The Bancroft Library, University of California Berkeley 261

notion of my taking nine months off for something, I just can't think about it. Do you stop the tenure clock? Does that stigmatize the woman that's involved in an unfair way?

As a minority on the faculty, women get absolutely bludgeoned for committee work by their institutions, because every committee wants their woman. In a way, that can become very detrimental to the progress of their careers. So in saying, "Gee, you're really valuable to us, and we want to get your point of view on this committee," we could be destroying them [career-wise]. So we have to be conscious of that, too, to protect them.

So there are very real problems that still exist. There are still inequities in salary and this other business, and that's all there and needs to be dealt with. But on a more day-to-day personal operations level of how to go about doing this as a woman, it's still very hard to make it. My field of studying gene expression and transcriptional regulation is horribly under- representative with women. When I organize meetings or organize sessions within meetings, it's a real struggle to make sure that women are represented.

Hughes: Is there a reason for that?

Yamamoto: I'm sure there is a reason for it. The only thing that keeps kind of cropping up as we debate that issue is that the field for a long—

[begin tape 20, side B]

Yamamoto: And we're aware of the biological clock and other issues that they have to deal with uniquely. I think that there is probably a dropout at that point. I don't really know the answer. But it really is the case that our field is really underrepresented. It's a bad problem.

Hughes: What do you think of yourself as first and foremost?

Yamamoto: This has been something that's been evolving lately. I guess I could say where I could make the greatest contribution. I think the fair thing to say is what I get my kicks out of and where I want to spend my time. A few years ago, the idea of letting my calendar fill up in the way that it does every day and taking the redeye to go to Washington for a three-hour meeting would have been completely abhorrent to me, and that meetings that took me out of my lab, even well beyond the time when I was actually doing my own experiments, were really things to be resisted. Oral History Center, The Bancroft Library, University of California Berkeley 262

Now, it's absolutely been completely integrated into my psyche and the way that I go about my days. It's in the extreme right now; I hope that will change as the chairmanship has a better fit to the rest of the things I'm trying to do. But I'm really used to it. The number of things that I'm trying to do at the same time has gotten broader. What that's done is to flatten what I think I'll actually be able to accomplish scientifically. I hate to admit that. I don't even know if I've ever said that to anybody before right now. But I think it's undoubtedly true.

I think that spending this time as chairman and doing the other things at the institution level and at the national level that I'm doing just means that I won't be able to get as much science done. I really regret that. I really want to think of myself as a scientist first, and it's been throughout my career very easy to do that. That is where I put a huge fraction of my effort. And now it's really getting evened out. I spend as much time doing other things and other elements of this career and endeavor as I do really focusing on the science that's going on in my laboratory. In many cases, the laboratory stuff has taken a back seat to other things that have deadlines waiting.

So I think that the role that I'm playing in the community has broadened a lot, and I like that. I think that there are places where I can make a contribution, certainly not a unique one, but a contribution. And I enjoy it. But I regret the fact that's meant that it's pushed down what I can do [with the] little band that's trying to figure out some questions in science.

Hughes: Knowing you, you made this decision to accept the chairmanship with your eyes wide open. What has succeeded in drawing you away from your intensity with science?

Yamamoto: I may have mentioned this, and that is that the one word that I associate with my dad is ‘responsibility’. I think that each of us has a responsibility to use our skills and talents in a way that is most effective for us. I've sort of discovered that I can work reasonably well with diverse groups of people, that I get engaged by problems within our little society, and care a lot about them, and want to see remedies to problems when they're perceived. I tend, whenever I decide to work on it, to put a lot of energy into it. As everybody that works in a bureaucratic situation knows, if somebody puts a lot of energy into something, and it sort of goes okay, then they're asked to do something else. And that's just what's happened to me.

I don't by any means say yes to everything that comes along. I'm learning that I can't do well as many things as I'm doing even now, so certainly doing more of it is not really in the cards for me. There are people who do Oral History Center, The Bancroft Library, University of California Berkeley 263

plenty more than what I'm doing, and people that do less, and so I'm kind of in there somewhere. So I think it's really this business of recognizing problems, becoming engaged by issues very strongly, and then trying to do something about them that has drawn me off into these other areas. And I enjoy the diversity of challenges and questions that are facing me.

Hughes: Within the realm of science, how do you think of yourself?

Yamamoto: I think that I think about a limited range of problems pretty well, and I think we've made substantial contributions in the area in which we work. It's a small part of this huge endeavor. Everything that we've done would have been done by somebody, so I don't harbor any self-deceptions about whether any of this stuff would be found out if I didn't come in to work anymore. But I like the style that we've achieved a lot, and I think the way that we think about problems and do science is really nice and enjoyable to me, and it's fun. So I think we've made good contributions here.

I like operating at that level within the scientific community, and working with colleagues, whether they're in my group or the rest of the scientific community. So it's a very enjoyable endeavor for me, something I take great pride and great joy in, and feel that we've operated at a high level and it's been a lot of fun. And will continue to be, I hope, for a long time.

Hughes: What difference has it made to you to be located in the Department of Biochemistry in the School of Medicine at UCSF to the way you've done your science, and to the way you've pursued your career?

Yamamoto: Oh, I think it's a nice question. It's made a huge difference. I think that I'm the sort of person that likes to be associated with a hot crowd. There are people who literally do not care about that, and I'd like to say that about myself, but it just isn't true. It was very hard for me to leave Biochemistry—not to leave Biochemistry but to kind of cleave myself off to go become chairman of this other funny little department in a field that's not really mine, because it's comfortable to be in the Biochemistry Department at UCSF. It's a great place. Everybody knows it's a great place. It's a great badge to carry around. It's a nice piece of stationery to use. And I think I like that. So there's that. There's this kind of confidence that one gains from just being associated with this group of people, and that's great. As you know, it wasn't always that way, and so I feel proud that I've been a part, even a small part, of helping to make it that way. But it is that way now. So there's that. That's at this kind of very personal ego- boosting level.

At the more profound one in terms of the contributions and the way that it's impacted on the way that we do science, it's immeasurable. It's a daily Oral History Center, The Bancroft Library, University of California Berkeley 264

contribution that literally the way that we do our science and what we can choose to do, the questions that we can choose to challenge, are colored enormously by the fact that we're here, and that around us at any moment are people that know how to do anything that we would imagine would be a fun thing to try to learn to do, and to carry into our own work. We've gained immeasurably from our colleagues in that regard. It is the best community that I know of in the world in that regard. So our ventures into yeast were made absolutely easy by the fact that we were surrounded with people who really know yeast well. So it's had a huge impact. Really talented people are around.

Bruce Alberts always told me that the way to succeed is to surround yourself with people that you think are smarter than you are. That's easy for me. And this community is full of them; it's fantastic. So superb students come here because they want to be in this community; superb postdocs show up. So it's made life easy. It really makes doing science very easy to be in this community, so it's had a tremendously strong impact in a very positive way. It's great.

And I hope that we can do the same thing in Pharmacology. We're starting from a base of a very solid community. It's changed a lot in the last couple of years because of the temporary departures of some of the great leaders here. But it's exciting for me to be participating at that level now on this campus. We really plan to make the Pharmacology Department something that will be exciting in its own right and not simply an adduct of what the community is already, but something that builds new bridges and strikes out in some new directions that will be useful to the community downstream from here.

That sort of spirit is something that I think really imbues UCSF and makes it special. You said a little while ago in a different context that once you've reached the top, you really have to kind of keep struggling to stay there. And that's true at this institutional level as well, and something that I think that the community has in their sights, not so much because we want to stay at the top as the fact that we don't want to relax. We don't want to become self-satisfied with the way that we are, because we know there's plenty out there still to be done. I think the community here has a view of that that is healthy and realistic, and one that is also in keeping with this notion of carrying out your responsibilities that I mentioned a few minutes ago.

Hughes: Lots more I could ask, but we're running out of time. Maybe I'll end with another soft question—no, two more questions.

Yamamoto: Okay. Oral History Center, The Bancroft Library, University of California Berkeley 265

Hughes: First of all, what do you do when you hang out?

Yamamoto: [laughs] Boy, that's a tough one!

Hughes: Or maybe I should ask, do you hang out, and if you do, what do you do?

Yamamoto: Well, I have a wonderful partner, Kathleen, who tries to make sure that I do a little bit of that. But not very much is the honest truth. We subscribe to the ballet and the symphony, and those are expensive enough that I don't want to miss them. They're great; they're not just expensive. We go to restaurants when we can, usually late at night because I'm working. And manage to get out and see friends. But we save most of the little tiny bit of time that I have just to spend a little bit of time with each other. If we can get away for the weekend and get onto our bikes or something, that's great. That's a real special time because there just isn't much time like that. I spend most of the time working. It means that I have to do everything kind of efficiently, that I have to play at full speed. [laughter]

Hughes: Keith, what keeps you doing all this?

Yamamoto: I think of my father. It's very important to me, I guess, just to be really passionate about what I'm doing, and to really care deeply about whatever it is that I'm doing. Once I get that feeling, then it's an automatic that I'm going to put as much energy into it as I can possibly muster at the moment. I like that. I hope that doesn't go away. I want to see that in my students and postdocs and people around me. I expect it of them, I expect it of myself, of my other colleagues. I've learned that they don't have to express their craziness in the same way that I do, but I do want them to be passionate. I like that. I think it's the way to live. It kind of reminds you that you're alive every day. So for me, that's what the real adventure is in this whole business. Life is too short to do something you don't really care about, so find some things that you care about and jump into them with everything you've got.

Hughes: I think that's a great place to end.

[End of Interview]