Cell Biologist and UC Berkeley Nobel Laureate

Home , Arthur Kornberg, Efraim Racker, Randy Schekman, Randy Wayne (biologist)

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

Randy Wayne Schekman: Cell Biologist and UC Berkeley Nobel Laureate

Interviews conducted by Sally Smith Hughes in 2014

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 Randy Wayne Schekman dated April 5, 2013. 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://bancroft.berkeley.edu/ROHO/collections/cite.html

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

Randy Wayne Schekman, “Randy Wayne Schekman: Cell Biologist and UC Berkeley Nobel Laureate” conducted by Sally Smith Hughes in 2014, Oral History Center of the Bancroft Library, The Bancroft Library, University of California, Berkeley, 2015.

iii

Randy Wayne Schekman, 2011 Photo courtesy Hadar Goren, Hadar Goren Photography

Randy Schekman has devoted his research career at UC Berkeley to working out the biochemistry, genetics, and molecular biology of the intricate system that transports proteins through the living cell. For this body of work, he was awarded the Nobel Prize in Physiology or Medicine in 2013. He is a vocal advocate of the public university and the editor-in-chief of eLife, an open-access, electronic journal in bioscience.

Table of Contents—Randy Wayne Schekman

Interview History by Sally Smith Hughes x

Randy Wayne Schekman Curriculum Vitae xiii

Interview 1: February 10, 2014

Audio File 1 1

Parents Alfred and Esther Schekman, both from Minnesota — maternal grandparents from Bessarabia, paternal grandparents from Russia — father’s post WWII engineering training at University of Minnesota on the GI Bill — Randy’s birth in 1948, nine years in Minneapolis — younger sister, two brothers — sister’s death from leukemia as a college sophomore — father’s 1959 Southern California job offer — his work in early computer science — early fascination with electron microscope images — parents were labor democrats but largely a- political — more on maternal grandparents’ 1927 immigration to Minnesota, observant but not orthodox Judaism — childhood in a Jewish enclave of Minneapolis — move to California and becoming an atheist as a teenager: “I think my interest in science overwhelmed any belief in religion.” — earliest interest in science: seventh grade — determination to save money for a professional microscope — culturing pond scum — the importance of science fairs — conducting bigger and more complex experiments at home — support from family friend who worked as a medical technician — long-time support from high school biology teacher Jack Hoskins — winning at county science fairs —starting UCLA with plans to go to medical school — choosing UCLA — freshman year: living in a co-op, chemistry instructor Kenneth Trueblood, honors chemistry with Willard Libby, working in the lab — influence of James Watson’s Molecular Biology of the Gene, recommended by Michael Konrad — summer lab project with Dan Ray exploring bacteriophage DNA — sophomore year graduate genetics class and decision to study abroad in Edinburgh with William Hayes — genetics work in 1969: limitations, new discoveries, scientists working in the field — Watson’s controversial The Double Helix

Audio File 2 18

More on the year in Edinburgh at the Medical Research Council Unit: exciting times for bacterial genetics and molecular biology — feeling the need for biochemistry, exposure to and admiration for Arthur Kornberg — completing the Edinburgh year — summer job at Harvard’s Biological Laboratories with David Denhardt — the contentious interpersonal climate at Harvard: “I knew there was another way that people could relate to each other” — return to UCLA for senior year, work with Dan Ray, focus on lab work and publication, neglecting classes and grades — leaving UCLA without completing foreign language requirement, starting Stanford — background on Kornberg’s DNA polymerase work and Nobel Prize controversy surrounding Cain’s subsequent work in 1969-1970 — vi

beginning graduate school at Stanford — socializing, youthful arrogance, meeting Costa Georgopoulous and being brought down to earth: “It didn’t diminish my passion, but I had to behave myself.” — collaboration with Doug Brutlag on M13 and then phiX174 — bringing Denhardt’s work on dnaB and Yukinori’s research into the mix — resultant publication in PNAS — working with Kornberg: “I learned a great deal from Kornberg…but that didn’t mean I got along with him.” — Kornberg’s reaction to Schekman’s thesis defense

Interview 2: February 26, 2014

Audio File 3 37

Developing an interest in biological membranes at Kornberg’s Stanford lab — discovering the electron microscopy work of S. J. Singer at UC San Diego — wife Nancy’s nursing schooling, decision to move to San Diego in 1974 — Palade’s work and Nobel Prize, attending the 1974 American Society for Cell Biology annual meeting — frustrations of switch to mammalian cells after years of E. Coli research — interest in yeast and the work of Lee [Leland] Hartwell — applying to UC Berkeley in the early months of UCSD postdoc — other notable applicants: Roger Kornberg, Keith Yamamoto, Janet E. Mertz — working in Singer’s lab — Günter Blobel’s signal hypothesis — planning work on yeast for UC Berkeley job, a rejected NIH grant proposal — job offers with UCLA and Berkeley, negotiating start-up grant money with Dan Koshland — meeting Lee Hartwell during a three week Cold Spring Harbor yeast genetics class — starting at Berkeley with small grants from the NSF and Cancer Research Coordinating Committee — later (1978) successful NIH grant — 1977 Peter Novick joins the lab to study yeast secretion — early frustrations: “So at this point I said all right, well I guess I’ve got to isolate mutants.” — investigating temperature-sensitive colonies and producing the first mutant sec1 — visit from George Palade, suggestion to Novick to examine by thin-section microscopy — eureka moment and publication in April 1979 Proceedings — skeptical Dan Koshland became an advocate — publishing in PNAS and Cell

Audio File 4 57

Seymour Benzer’s cis-trans test, gene-mapping in yeast — Novick’s 1979 Cell paper on sec1 — continued research on temperature-sensitive mutants — using Susan A. Henry’s findings on using Ludox floor polish and a centrifuge to separate cells by density — Novick’s experiments to map genes — possible tactical error in focusing lab tech Charles Field on genetic mapping of existing mutants rather than on isolating more — Novick’s continued work applying a genetic epistasis test to the mutants and findings published in 1981 in Cell — kudos from the yeast community, some skepticism from mammalian field — early method for cloning yeast genes in 1978 — 1970s recombinant DNA scare and research moratorium — Schekman’s reluctance to spend time on DNA sequencing, mid 1980s trying to convince researchers to focus on biochemistry — background with Jim Rothman — competition, similar objectives and divergent vii

approaches — “My approach is to develop a technique that will lead to discovery of the truth.” — Rothman’s work on clathrin

Interview 3: March 7, 2014

Audio File 5 73

Early to mid-1980s work on translocation engine, exceptional grad students and postdocs: Ray Deshaies, David Baker, Linda Hicke, Chris Kaiser, Greg Paine — Deshaies’ translocation study, discoveries about hsp70s — discovery of SEC61 — David Baker’s breakthroughs — “It was just a wonderful time. I just got these great people and my job was to stay out of their way.” — morale in the lab, competition and cooperation — Chris Kaiser’s SNARE hypothesis — stipulations of the Nobel: recent work, discovery vs a body of work — graduate student Michael Rexach — Linda Hicke’s discovery — Akihiko Nakano, Nancy Pryor, Nina Salama — collaboration with Lelio Orci in Geneva — Orci’s mastery of membrane morphology, electron microscopy, immunogold labeling and cryo- immunomicroscopy technique — K. T. Tokuyasu — Susan Hamomoto — COPII — early 2000s Howard Hughes Medical Institute meeting on Alzheimer’s, beginning interest — postdoc Jinoh Kim — transition from yeast to focus on cultured mammalian cells — the blurred line between basic science and practical, applicable science, biotech uses of yeast, consulting with biotech industry — postdoc Chris Fromme’s collagen work — 2003 or 2004 call from pediatric geneticist Simeon Boydjiev, his research on Bedouin families in Saudi Arabia, craniofacial disorder traced to SEC23A mutation — marveling at the complexity: “It works, it’s complex, and you know when evolution has solved a particular challenging problem it doesn’t try to reinvent the wheel, so these parts have been used ever since.” — on the known similarities between yeast and mammalian cells

Audio File 6 92

The importance of the complex system of intracellular and intercellular transportation — 2002 Lasker Award with Jim Rothman, nomination process and committee, Joe Goldstein’s leadership — winning the award, dinner with Mary Lasker, luncheon at Pierre Hotel in New York City — getting the call from Joe Goldstein — 1996 Gairdner Award with Rothman — complicated process of choosing whom to recognize for prizes, whom to leave out — the sometimes-long wait for prizes, the expectations of friends and colleagues: “Well, and you don’t have to dream. People remind you.” — Nobel Prize notification Monday, AKA “Groundhog Day” — 1:20 am call from Stockholm, news delivered by Karolinska committee secretary Göran Hansson — alerting father, children, friends, colleagues and lab — the comparable honors of receiving the Lasker and the Nobel — the secrecy of the Nobel committee — public recognition following Nobel Prize — leveraging recognition and prize money to support public higher education and an endowed chair in honor of mother and sister — media indifference to editorial on public higher education — Washington Post interview viii

with Brian Palmer, public opinion that the value of science is measurable mainly in profit and direct human health applications — the Esther and Wendy Schekman Chair in Basic Cancer Biology — additional funding from the Li Ka Shing Foundation, Robert Tjian’s brilliant fund raising — being happily busy, difficulty saying “no”

Interview 4: March 26, 2014

Audio File 7 108

The Chancellor’s Advisory Committee on Biology [CACB] started in 1982 by Dan Koshland — the reorganization of Biology at UC Berkeley — benefits of the reorganization, revitalization of several departments — the reach and limitations of the CACB — new fields of science incorporated — chairs of the committee: Dan Koshland (1982-1993) and Robert Tjian (1993-2002) — 2002 appointment by Chancellor Berdahl as chair of CACB — Berkeley’s system of voting chairs to keep the strongest scientists as leaders — assuming the CACB chair in the aftermath of the reorganization of Biology — goals for chairmanship: attempting fundraising, rethinking allocation of some donor money, working with Paul Greg — organizing departments to jointly purchase large equipment items — supporting stem cell research — CA Proposition 71 [CA Stem Cell Research and Cures Initiative] — Berkeley’s disadvantage in securing cancer and health related funding because it lacks a medical school — the tension between basic and applied science in stem cell research — Shinya Yamanaka’s stem cell research — editor-in-chief pf PNAS [Proceedings of the National Academy of Sciences] 2006- 2011 — previous editor-in-chief Nick Cozzarelli, democratizing the PNAS submission process — resistance from members of the National Academy — troublesome paper submission from Peter Duesberg — accomplishments at PNAS: moving the journal online, changing page limits, challenging abuse of member privilege — eLife origins with Robert Tjian, funding from Wellcome Trust, Max Planck Society, Howard Hughes Medical Institute — challenging the hegemony of Cell, Nature, and Science — the undeserved power of impact factor — erroneous paper, reluctance to retract — the pressure to publish papers that sell magazines

Audio File 8 127

More on eLife sponsorship by Howard Hughes Medical Institute, Wellcome Trust, Max Planck Institute — open-access promotion by PLOS [Public Library of Science] — 2011 starting as editor-in-chief at eLife — on the hegemony of Cell, Nature, and Science: “We’ve transferred our judgement and our authority to people that we wouldn’t otherwise trust to make decisions on our behalf.” — eLife innovations: consultative review approach — quicker, streamlined editorial process — paid editors vs. professional editorial staff — page limits: “pulling the guts out of the paper” — more eLife innovations: allowing updates as research advances — bad science and the pressures to publish in “luxury journals” — Guardian article of December 2013, Nobel leverage: “I’ve been arguing against ix

impact factor for years… Suddenly, I have a soapbox to stand on, and I intend to take full advantage of it.” — the dangers of having former not current scientists as the editors of Cell, Nature, and Science — hopes for eLife: to change the landscape of scientific publishing — more on rejecting impact factor — DORA [Declaration of Research Assessment] — the suffocating effect of impact factor publication on young scientists — starting out teaching, learning to enjoy it — challenges and joys of teaching freshman, learning a more interactive approach — reading Billy Collins’ poetry to freshman — passion for the public research university — middle class roots, accessibility of good public universities — media disinterest in and government divestment from public higher education — decrease in state funding over last 30-40 years places responsibility for funding on philanthropy — increasing bond between the university and business — the difficult sell of basic research over profit-generation

Appendix: Background and Focus of Laboratory, brief bibliography 147

Interview History—Randy Wayne Schekman

This oral history with Randy Schekman is one in a series documenting bioscience and biotechnology in northern California. Schekman’s research investigates fundamental cellular processes at the molecular, biochemical, and genetic levels. In the interviews, he describes the work which illuminates the mechanism and control of the complex intracellular pathways by which proteins are transported within the living cell. It was this body of research which led to the highest honors in biology, the Lasker Award in Basic Medical Research in 2002 and the Nobel Prize in Physiology or Medicine in 2013.

Schekman was destined for a career in science virtually from the start. As a youngster, he sequestered himself in his bedroom for countless hours, examining random material with a microscope purchased with hard-earned cash. Aiming initially to enter medical school—“Well, that was, for a Jewish family, my god, that was [what you do]”—his experience with hands-on molecular research as a UCLA undergraduate totally captured his fancy. That unwaveringly was what he fixed upon. In the mid-to-late sixties, it was the expanding field of molecular biology that began to dominate much of biological thought. Like so many of his scientific generation, young Schekman was turned on by James Watson’s Molecular Biology of the Gene and The Double Helix to the exciting possibilities opened up in investigating biological processes at the most basic level. After graduate school at Stanford and a postdoc at UC San Diego, Schekman in 1976 accepted an assistant professorship at UC Berkeley. It was here over the years that he and a remarkable group of graduate students and postdocs, to whom he gives specific credit in the oral history, revealed the vesicle-mediated, step-by-step secretory trajectory of amino acids, the building blocks of proteins, through the cell. Through a consummate teacher’s clear descriptions, he details the highlights of his research, allowing even the non-scientist to grasp its significance and the ingenious biochemical and genetic tools he and his laboratory invented and employed.

But the oral history is not only an account of stellar science; it also describes Schekman’s extensive contributions to the scientific community at large and to the university he loves. He served, for instance, as editor-in-chief of the Proceedings of the National Academy of Sciences (2006-2011), where he successfully raised the journal’s prestige and simplified the manuscript-submittal process. He stepped down in 2011 to become founding editor-in-chief of eLife, an electronic, open-access bioscience journal providing a new avenue for publication in the field. A prime intention is to compete with Nature, Cell, and Science, which Schekman provocatively dubs “luxury journals” publishing trendy scientific fields to the detriment, he maintains, of more important but less flashy research. Using the prestige of the Nobel Prize to capture attention, he bluntly declared that leading academic journals distort the scientific process and represent a “tyranny” that must be broken.1 Predictably, the stir created in the bioscience community

1 “Nobel winner declares boycott of top science journals,” The Guardian, December 9, 2013. xi

was and remains considerable. Unfazed, Schekman continues to stick to his philosophical and editorial guns.

Aside from his teaching and research responsibilities at Berkeley, he has served in leadership positions as Co-Chair of the Department of Molecular and Cell Biology (1997-2000) and Chair of the Chancellor’s Advisory Council on Biology (2002-2012). The latter represents Berkeley’s biology faculty and reports directly to the chancellor on the status and standing of biological science at Berkeley. In 2004, Schekman stepped into the political arena as a vocal advocate of California Proposition 71, the stem cell initiative. After the proposition passed overwhelmingly that year, Schekman led the campus effort to establish the UC Berkeley Stem Cell Center and was program director of the accompanying training grant.

Behind the focus on science and science-related activities, the interviews reveal a very human and humane individual: in the fact that he is “Randy” to all and sundry, in the class he continues to teach for freshman students, in his careful attribution of credit to and pride in his students, in his emotional retelling of his phone call to his father reporting that he had received the Nobel. But one seldom rises to scientific heights without considerable self-confidence and competitiveness. Schekman is no exception. His account of confrontations as a graduate student with the formidable Arthur Kornberg, his dissertation advisor at Stanford and a Nobel laureate, reveals a young man of striking self-assurance who survived the encounters, one might guess, because of undeniable brilliance. His competitive streak is evident in his description of encounters with James Rothman, sometime collaborator on cellular protein transport with whom decades later he was to share the Nobel Prize. As Schekman recounts in the oral history, “…we had a job opening [at Berkeley] at the time, so Rothman came for a visit, and I was his host. He was incredibly impressive, I mean really. I started to talk about my ideas, and he just completed my sentences for me.” Despite Rothman’s intellect, the department decided that his domineering personality was not the right fit and turned him down. Imagining the tensions that would inevitably have arisen between two ambitious competitors in the same field, Schekman frankly states that it was just as well that they didn’t end up in the same department: “That wouldn’t have worked, that wouldn’t have worked.”

His own roots in public education lengthy and deep, Schekman, honored as he deeply was by the Nobel award, nonetheless pointedly noted that in 2013 he was the only U.S. laureate in the sciences from a public institution. He lost no time in using the stature and visibility accompanying the Nobel to advocate for support of the public university, especially his beloved University of California. To underline where his academic heart lies, he donated his share of the Prize money to endow a chair in basic cancer research at Berkeley, which he named after his mother and sister, both victims of cancer.

Four two-hour interviews were videotaped between February 10 and March 26, 2014 in Schekman’s correspondence-littered office in the new Li Ka Shing Center xii

for Biomedical and Health Sciences at Berkeley. Not one to waste a minute, he cordially greeted the interviewer and videographer each time and then immediately returned to his computer screen until we were ready to roll. The lightly edited transcript was sent to him and returned, all queries answered and with no substantial changes. The oral history documents the story of a man passionate about the research at the core of his professional life and dedicated to the science community he continues to serve as researcher, teacher, publisher, and advocate for the public university.

This oral history joins over one hundred on bioscience and biotechnology available online at http://bancroft.berkeley.edu/ROHO/projects/biosci/oh_list.html. The Oral History Center of The Bancroft Library is under the direction of Neil Henry. Special thanks to Paul Burnett and Julie Allen for videotaping the interview sessions, to Julie Allen for finalizing the interview transcript, and to David Dunham for web presentation.

Sally Smith Hughes Historian of Science and Interviewer University of California, Berkeley May 2015

xiii xiv

Interview #1: February 10, 2014 [Audio File 1]

01-00:00:00 Hughes: It’s February 10, 2014, and we are in the office of Dr. Randy Schekman. There is a previous short interview with you in the Daniel E. Koshland, Jr. Retrospective series, but we’re going to starting from year one today—or before year one! Because I want to start with your parents and where they came from and what they did for a living.

01-00:00:37 Schekman: Sure. My parents were Alfred and Esther Schekman. They grew up in Minnesota. My mother’s parents had emigrated to the U.S. from what used to be Eastern Romania, an enclave called Bessarabia. My father’s parents came from Russia, probably after the revolution. Both families migrated independently; they didn’t know each other until the children met in Minneapolis and St. Paul. My father was an engineer. He was on the GI Bill near the end of World War II at the University of Minnesota, and they met through some mutual acquaintance, I guess. They didn’t go to the same high school. They fell in love; they married. My father was twenty-two; my mother was eighteen. My mother finished high school but did not go to college. My father graduated from the University of Minnesota.

01-00:01:38 Hughes: In what?

01-00:01:40 Schekman: In engineering. He was a mechanical engineer by training, and for several years he worked at General Mills doing, I don’t know, particle analysis of some sort. They lived, initially, in St. Paul for a year. I was born [1948], just shortly after the first year they were married. We moved to Minneapolis, in probably 1949, first to an apartment and then to a home that my father designed and was built for him, a small home on the north side of Minneapolis. We lived there for the next nine years, where my mother was a homemaker, and subsequently there were three more children born, one daughter and two other brothers. My youngest brother was born in Orange county seven years after we moved to California.

01-00:02:41 Hughes: Were any of them eventually scientists?

01-00:02:44 Schekman: No. My sister tragically died of leukemia after we moved to California when she was just a second-year college student. I’m not sure what she would have done. She had a boyfriend; they were engaged. She probably would have had a family, is my guess. She was the next one. She was twenty months younger than me, so she was born in Minneapolis also. The next brother is an educator. He was a high school principal. Now he’s an assistant superintendent of the Watsonville School District. And the next brother has emotional problems, 2

let’s say, and he hasn’t really done much. The last brother, who was born one week before I left for college, is kind of in PR and computer graphics and works for an advertising company, I think. No, no science.

My father, I think, had some rudimentary interest in science but it wasn’t that well-developed. Anyway, so he worked at General Mills, and then he answered an ad for a computer company in Southern California in the fall of 1959. He came out to California for an interview and realized there was life outside of the frigid Midwest. He came home and he said he had a job offer, and he said, “We’re out of here.” So we left—

01-00:04:34 Hughes: Excuse me, but did he have a background in computer science?

01-00:04:38 Schekman: Not really, not that I know of. No, this was 1959. I don’t actually know what he was first doing, but I think it was an early computer company of some sort, and he became a systems analyst and learned software design. I think what he did with most of his career here in California is work on software design in a series of companies in Southern California. Finally, I think with the last company he worked for, he actually designed the first stock quotation system that was active online across the country. It was a company called Quotron, so it was a really very early in that field. He never wanted to do management. He wanted to just be an engineer and work with a small group of people. They wanted him to become an executive in this firm, but he said no way, and then he proceeded to retire just to avoid it. [laughing]

01-00:05:52 Hughes: Did he bring his work home?

01-00:05:55 Schekman: Not really. He would bring things home from General Mills, samples of metal that they had laying around, and that kind of piqued my interest. I remember also at one point very early on, still in Minnesota, he brought home some electron micrograph pictures of bacterial viruses that they were using simply to gauge the size of particles. These were virus particles. I may even still have those pictures. That is vivid in my mind.

01-00:06:30 Hughes: What year would that have been? Or approximately.

01-00:06:33 Schekman: Oh, probably ’57-’58, something like that.

01-00:06:36 Hughes: So electron microscopy was—

01-00:06:40 Schekman: Oh yes. People were using it to look at things, sure. It wasn’t that sophisticated then. He was just looking at a sample without much processing. 3

01-00:06:51 Hughes: It seems a strange choice. You wonder where he got bacteriophage.

01-00:06:58 Schekman: Well, I think it was a standard size.

01-00:07:02 Hughes: Oh, I see. He was calibrating.

01-00:07:03 Schekman: He was calibrating some particles that they were looking at. He didn’t care about the viruses.

01-00:07:15 Hughes: Imagine yourself sitting around the dinner table with all your siblings and your parents. Can you give me an idea of the flavor of conversation?

01-00:07:27 Schekman: Well, at what point? [laughing] I don’t remember the conversations around the dinner table when we were still in Minneapolis. I was a kid.

01-00:07:39 Hughes: Yes, you were ten when you moved, right?

01-00:07:40 Schekman: We drove from Minneapolis during the last week of December, 1959, just as I was turning 10 years old. I have only vague recollections. I remember once for my birthday they got me a military uniform, and I hated it. [laughter] And I expressed my displeasure with it. I remember actually in those early days also being interested in astronomy and thinking about the planets. Kind of rudimentary stuff. But dinner conversation? Gosh, I don’t know.

01-00:08:23 Hughes: I was just wondering if there was political discussion.

01-00:08:26 Schekman: Oh no, no, no. My father was a labor Democrat, but not terribly political. No, I have no political sensibility from that time. My mother’s parents, we were very close to them, and we would have Friday dinners with them to celebrate the Sabbath. My grandfather Raymond was a labor Democrat, not a radical at all. He escaped the Communists in Romania, and he had nothing but virulent things to say about the Communists all the time, I remember.

01-00:09:13 Hughes: And is that why they emigrated?

01-00:09:15 Schekman: Yes, well, it was. My mother’s parents emigrated in 1927. He was in the Romanian army, and there was a lot of prejudice against Jews. They, I think, entered some kind of a lottery, and he and his new wife both managed to win the lottery, and they got out as quickly as they could. They took a ship to New 4

York. They entered the country through Providence, not through Ellis Island, which I found odd. I don’t know why that was. But anyway, they came in through Providence, Rhode Island, and then they went briefly to New York, and my grandmother Ida hated it. She couldn’t stand so many people. They had a kind of a cousin, an adopted cousin, who had already set up, moved to Minneapolis, and so they moved to Minneapolis. My grandfather had been a tailor in the Romanian army, and so he got a job tailoring men’s suits and coats, in the clothing business, in Minneapolis and did his whole career there. His high moment was fashioning a coat for then Senator Hubert Humphrey.

01-00:10:32 Hughes: Was religion a big part of life?

01-00:10:33 Schekman: Oh yes, oh yes. I think particularly on my mother’s side they were quite religious. Not orthodox. I would say they belonged to a conservative congregation, but very observant. The Sabbath was special; all the major holidays were very special.

01-00:10:52 Hughes: Was there quite a Jewish community in Minneapolis?

01-00:10:56 Schekman: Yes, believe it or not, yes. In fact, I tell a joke: when we moved to California and people said, “Gee, you don’t seem Scandinavian.” I said, “Gee, I only knew Jews in Minnesota. I didn’t know there were any Scandinavians.” So we grew up in a part of Minneapolis which then was almost a Jewish ghetto.

01-00:11:17 Hughes: Was there prejudice?

01-00:11:21 Schekman: I first experienced anti-Semitism when I was a kid. I remember walking to school. I was somehow late to school, and some larger kid came up to me and said, “Do you go to the Jewish Community Center?” Which I did, after school. I said yes, and then he punched me in the stomach and then walked off. [laughing] I didn’t know what the hell he was talking about. I had no experience with that. But that was it. I don’t remember anything more than that. I quickly got over that, but realized yes, there’s such a thing as anti- Semitism. But it was otherwise a pretty insular community. Certainly all my friends and my parents’ friends, not all the neighbors, but most of the people I acquainted myself with, were Jewish. We belonged to a synagogue, and I went to Hebrew school, which I hated, I hated with a passion. [laughing] The only phrase of Hebrew that I remember is roughly translated, where the teacher would say, “Why did you leave your head at home today?” [laughter] Once when I was going to Israel on a scientific trip, and they saw that I was Jewish or had Jewish heritage, they asked me as part of their security if I knew any Hebrew, and I recited this in Hebrew, and they laughed and said okay, get out of here. [laughter] 5

01-00:12:58 Hughes: You never can tell when Hebrew comes in handy.

Well, when you moved to LA, did your parents select a Jewish community?

01-00:13:08 Schekman: No, I think at the time we then moved to Los Angeles their religion started to, let’s say, liberalize. I think we belonged to a Reform congregation for the rest of the time that I lived at home. I didn’t go to Hebrew school once we moved to California, but I did occasionally go to a religious school in the late afternoons. And then certainly for my bar mitzvah preparation, which was at a synagogue not too far from where we lived, probably there was a year or two of preparation for the ceremony. And then maybe a year later I continued in a religious school where I would go once a week—it wasn’t a Hebrew school per se, but it was religious—until I was confirmed, which I think is a confirmation ceremony that occurs when you’re in tenth grade or roughly at that age, fifteen or so, which was a year or so after my bar mitzvah, maybe a year and a half. And shortly after that I decided I was an atheist. [laughing] I told my parents that, and my mother said, “Oh yes, well, until you have kids.” And that was it. There was no further conversation on the subject.

01-00:14:39 Hughes: [laughing] Really! That’s amazing.

01-00:14:41 Schekman: Yes. I think my interest in science sort of completely overwhelmed any belief in religion.

01-00:14:54 Hughes: Well, tell me when you first became as passionate about science as you still are.

01-00:15:01 Schekman: I think that happened in junior high school. The earliest moments I recall are when I went to a science fair—I think it was at my junior high school. It was probably seventh grade. Going into the science fair was to me a revelation, seeing all these kids doing independent projects. Frankly, I liked the sense of competition. I was always small in stature, and I was never terribly coordinated, and so I wasn’t going to be an athlete. I was a pretty good student, not great, but a pretty good student. But this immediately somehow resonated with me.

Around that time I think I’d gotten a toy microscope, and I started looking at protozoa swimming around in pond scum. That was my first real immersion in science, and the realization that there was a world beneath the visible range that was just as amazing as the visible world. That to me was a revelation. So I spent hours in my room looking through these toy microscopes. [laughing] I remember I had one that projected a light image onto a scintered glass plate, and, you know, it was just endlessly fascinating. 6

At a certain point I think I had different jars of stuff that I’d picked up in the gutter or from some pond, and I was culturing them in a cabinet in the bathroom and looking at the different life that one could see. I don’t remember exactly when this was, but I remember that at a certain point I was discussing this at the dinner table, since you asked, and I don’t know why, but my father said, “Well, you know it’s just a toy microscope.” And I remember being kind of wounded by that. [laughter]

So at the time I started making money babysitting and mowing lawns for neighbors, so I resolved at that point that I was going to get a professional microscope. So I did over a period of time, and I’ve lost track of how much time it was that I was collecting money. But my mother kept borrowing. I had an envelope that I kept in the closet of my bedroom, and my mother kept borrowing the money for groceries, and I got more and more upset. I don’t know, again, over what period of time this was, but I got upset. At a certain point when I finished mowing a lawn, instead of riding home on my bicycle— oh, and I had a paper route too, so I’d get up early and that was pretty exerting. This I remember vividly: instead of bicycling home, I bicycled to the police station. I told them that I was running away from home because my parents were stealing my money, and I couldn’t get my microscope. [laughter] I don’t remember them laughing, but I think they took it seriously, and they called my dad. He came in very stern-faced, and one of the policemen took him back into his office, and they chatted for a while. I don’t know if my father even remembers what they talked about. I should ask him! He came out, again looking very serious, and that afternoon we went to a pawn shop, and I got a hundred-dollar microscope.

01-00:19:05 Hughes: That he bought, right?

01-00:19:05 Schekman: No, it was my money! What do you mean they bought it? It was my money!

01-00:19:08 Hughes: I thought there wasn’t enough left.

01-00:19:10 Schekman: No, I’d saved up enough, I think. Well, that’s my memory anyway. Maybe my father has a different memory. He does have different memories. [laughing] So I got a Bausch & Lomb monocular microscope, a serious high school kind of microscope at a pawn shop, and it became my prized possession. I was constantly looking through that thing all throughout high school. It was just my obsession. I was a typical nerdy kid, I know the type now, but I thought I was unique in high school. No one else was quite like me.

01-00:19:58 Hughes: And that was all right with you? You weren’t feeling left out? 7

01-00:20:00 Schekman: Yes! It was my special mark. I was unique. That was my way of showing my independence. I didn’t go out with girls, for sure. I spent all of the day and night looking through my microscope, just marveling at the microbial world.

01-00:20:23 Hughes: And you entered science fairs, right?

01-00:20:23 Schekman: Yes, oh yes. That became my passion for the year. My annual cycle was geared around getting ready for the science fair project. As time went on, after the initial project in eighth grade where I was just looking at pond-scum organisms, we hooked up with— One of my parent’s friends was a medical technician in a hospital in Long Beach. She took an interest in me, and she would get me stuff. I don’t again [know] the time when this was, but I got some scientific equipment, some glass Petri plates. At a certain point I constructed an incubator in my room that was a rheostat hooked up to a light bulb, and it was just keeping a constant temperature. I was growing some bacteria on Petri plates. I realized that one cheap source of nutrient for growing bacteria on Petri plates was blood, human blood, and so there was outdated human blood [at the hospital in Long beach] and I would get pints of this outdated blood and keep it in my mother’s refrigerator at home. And I would use her pressure cooker to heat up the agar. I bought agar from some scientific supply house, and so I would pour my Petri plates in her kitchen with blood, which worked really well. [laughing]

01-00:22:07 Hughes: She was all right with all of this?

01-00:22:08 Schekman: Well, no, not really, but I was an odd duck, and I think she tolerated me. [laughing] In high school, at a certain point, I did an experiment where I was looking at small molecules that were produced by bacteria that I was growing in my room. I used paper chromatography to separate these small molecules, and I used a solvent—this I probably got from the high school chemistry lab, a solvent that included pyridine, which is a noxious, really noxious organic solvent. I was doing this paper chromatography in my bedroom, and the room—and indeed the whole house—got really stunk up, and I couldn’t sleep in my room for the next several nights.

01-00:22:59 Hughes: Now, how did you know how to do that? Were you learning this kind of thing in science class?

01-00:23:04 Schekman: I read a lot. I’d go to the library, and that was another passion. I’d spend hours and hours poring through the stacks in the main library in Long Beach or the library in our local community. If I wasn’t in my bedroom looking through my microscope, I was in the library reading anything that I could. I had some 8

influence from this medical technician in the hospital, and then briefly there was a biology professor at Long Beach State that I think was helpful, just briefly. But mainly it was my high school biology teacher Jack Hoskins who took a great interest in me. He actually introduced himself to me when I was still in junior high at I think the county science fair. He asked if I knew him, and I said no. I thought he was a friend of my parents, and he said, “No, I’m going to be your biology teacher next year. And he’s been there all the time. In fact, we still communicate, and he sent me a congratulatory note [for the award of the Nobel Prize].

01-00:24:20 Hughes: He recognized your budding passion?

01-00:24:21 Schekman: Oh yes, oh yes, and he was very supportive. I don’t think he was terribly knowledgeable about microbiology or anything molecular, but he was very supportive and he was my informal advisor. Of course I took several classes from him as well, and then we’ve kept in touch over the years from time to time. We reconnected early last year before the Nobel. We’d lost touch. I’d tried to get in touch with him when I won the Lasker Award in 2002, so I called the district, I called the school. He’d long since retired, and they had no forwarding address for him, so I gave up. But then early last year I guess he just Googled me and then he got in touch. So we exchanged messages, and I sent him a clip of an online video that I’d done describing my general area of science, and then on the day of the Nobel Prize he sent me a note that morning. Actually, I’ll see him next week.

01-00:25:39 Hughes: Oh really?

01-00:25:40 Schekman: I’m going back to my high school. They’re having a science day, and I’m their featured guest, so he’s going to come over. I haven’t been back to my high school since I graduated almost fifty years ago. I barely recognize it. Once he came to my office in Barker Hall, just showed up, and I was stunned. So he’d been following me a little bit. And then he came to one of the high school reunions we had, on the occasion of the twentieth or twenty-fifth high school reunion. But I haven’t seen him since then, and he retired a long time ago. He’s in his eighties, but he’s still alive, and I’m really eager to see him.

01-00:26:24 Hughes: So he was the first of what would be several mentors, would you say?

01-00:26:28 Schekman: Yes, oh yes. I went to the state science fair a few times because I’d win first prize in the county science fair. So I’d go to that state, so that was really my big moment. But I noticed that some of the other kids had very sophisticated projects, and they were clearly working in a university laboratory to do this. They weren’t working in their garage like I was. [laughter] So I think some of 9

them had parents who were faculty members. I didn’t have that kind of thing, but it’s fine; it was a great experience. But I didn’t really learn science until I got to college. I read a lot, and I was knowledgeable superficially.

When I started at UCLA as an undergraduate, I was determined to go to medical school. I didn’t really appreciate that there was a career track where you could actually be a scientist. Somehow, I don’t know why, it hadn’t dawned on me. And I think partly it was—it was certainly parental pressure. At a certain point my dad was concerned about what I was growing in my incubator in my bedroom, and so he asked a physician family friend who looked at it, and it didn’t look like anything—and what would he know? He said he wasn’t too worried about it, but he told my dad that, “You want to try to discourage him from going into microbiology. There’s no money in microbiology.” [laughter] So of course when I was in [high] school I thought okay, I’ll go to medical school. Well, that was, for a Jewish family, my God, that was—

01-00:28:23 Hughes: Yes, that’s what you do.

01-00:28:26 Schekman: That was perfect. Now it’s for an Asian family, but then it was a Jewish family. So I was raring to go, and I went to UCLA. But I very quickly realized that there was this world of science, and in contrast my classmates, most of whom were pre-meds and weren’t interested in science. They wanted to go to medical school and be comfortable. So very quickly, in probably my freshman year, I turned off to that and decided and told my parents.

01-00:29:02 Hughes: Well, step back a minute. Was UCLA always it? Did you apply anywhere else?

01-00:29:08 Schekman: Yes, that was it. My parents wanted me to go to Long Beach State because they just didn’t see how they could afford to send me to college, even though it didn’t cost anything back then. But I would have to live away from home, and that cost something. If I’d gone to Long Beach State, I could have lived at home, and it would have been less expensive. My father went to the University of Minnesota on the GI Bill, so he had everything paid for him. There was no question that I’d go to college. That was always—you’ll go to college. There wasn’t this hierarchy. I didn’t realize there was a hierarchy until I was in high school, and some of my classmates applied to Stanford, and that seemed kind of exotic to me. I just didn’t see going far away.

In fact, I thought about Berkeley. I had the Berkeley catalog, and I even read a book by Gunther Stent on bacterial viruses when I was in high school, and I dreamed about what it would be like to be at Berkeley, because it seemed pretty advanced. But Berkeley was also at that point quite radical, and 10

although I wasn’t politically conservative it just seemed too radical to me, too distracting, and too far away from home. Why didn’t it occur to me to think about some place like Caltech, I just don’t know. It just didn’t dawn on me. It was, I’ll go to college, and UCLA was practically free.

01-00:30:49 Hughes: Well, Caltech is a private school. Where would you have come up with the tuition?

01-00:30:54 Schekman: Of course. Yes, well, back then I bet it wasn’t that expensive. Of course it was more expensive than UCLA, and money was an object. There were at that point four, and then five, kids in the family. One thinks about higher education differently. Then it was a common good. It was well supported by the state. And so I could work a summer job and pay the small fees and the room and board at the student coop and books. It was virtually free for all five kids, virtually free.

01-00:31:45 Hughes: So it wasn’t a decision around science. It wasn’t as though you had singled out somebody that you admired and wanted to learn from?

01-00:31:54 Schekman: No, not at that point. I had the UCLA catalog, and it looked like there were all kinds of cool courses there. Actually, I do remember there was another connection I had to UCLA. Probably when I was very early in high school, I wanted to get some scientific equipment, and I didn’t know how to go about doing that. So I wrote to a professor in the microbiology department in the medical school at UCLA, and he very kindly sent me a huge scientific supply catalog, and then he invited me to come to a microbiology symposium at UCLA. [laughing] So my father drove me; I couldn’t drive yet. I sat in the audience, not knowing anything about what was being discussed. But I used the catalog, and I bought some glassware and glass Petri plates. So that was my first connection to UCLA. It seemed like a large, very sophisticated place, compared to where I was in Orange County, and it was perfect. So I got on my motorcycle when I graduated from high school, and I rode the thirty miles to UCLA.

01-00:33:07 Hughes: And lived there?

01-00:33:11 Schekman: Yes, I lived in a student coop. It was the cheapest option, and you work a few hours a week. I think I paid no more than $400 a term for room and board. It was really crowded, but I didn’t spend much time there. I spent all my time in the library. I planted myself in a study carrel in one of the libraries and just spent all my hours there. I did well in my freshman chemistry class. 11

01-00:33:44 Hughes: I read your interview with UCLA. There I learned that you had taken an honors course with Willard Libby.

01-00:33:59 Schekman: Willard Libby, yes, who’d gotten his PhD here at Berkeley, I only recently realized.

01-00:34:02 Hughes: Oh really! I guess I should have known that. Now, is that what you were referring to when you mentioned the chemistry class?

01-00:34:19 Schekman: I’m not sure what I said. I was in freshman chemistry; that was an amazing, amazing class. The first-term instructor Kenneth Trueblood was a fantastic teacher. I remember being awestruck because at the end of the term he got a standing ovation, which I have never seen since! [laughing] So that was great, and I did well. I really enjoyed the class, and as a result of doing very well in the class I got admitted to an honors section, for I think the third term. UCLA was, and still is, on the quarter system. And the third term was taught by this guy Willard Libby, to a select group of the students. And the special thing about that term was that you had to work in a lab in the chemistry department. Libby himself was actually not a good teacher, I have to say. I don’t think he knew how to teach freshmen, and I don’t know if I did that well, but I loved working in the lab.

I got assigned, just by chance, to a lab of a beginning assistant professor, a molecular biologist, who had himself been a postdoctoral fellow here with Gunther Stent. This guy—Michael Konrad was his name—said, “Well, the first thing is you have to read this book.” And he gave me a copy of what was James Watson’s first edition of a really very important book called Molecular Biology of the Gene. It was a revolutionary textbook because it introduced the field of molecular biology, much to the resentment of the dominant biochemists at the time. He was, Watson, always a very strongly opinionated guy. This book was written in a beautiful style and really was very influential for me. I remember going to a park and just sitting there and reading it.

01-00:36:45 Hughes: It wasn’t above your head?

01-00:36:46 Schekman: I suppose it was, but I persisted. I think maybe I went to this fellow’s office, and we talked a little bit about it. I just read it over a long period of time and just had a sense of what this emerging field was. Actually, I’m trying to recall. That’s a good question. I don’t know that it was over my head. Maybe some of the details. But I’d read about DNA before, and the little project that this faculty member had me working on was to take DNA and hydrolyze it in acid and do a paper chromatographic separation of the four bases. So that was my project. It was just a little trivial make-work project. 12

01-00:37:37 Hughes: And that was at UCLA?

01-00:37:38 Schekman: Oh yes.

01-00:37:40 Hughes: So you had been exposed to DNA.

01-00:37:41 Schekman: Oh absolutely. Of course, of course.

01-00:37:45 Hughes: You were too young for the Watson-Crick discovery [1953].

01-00:37:49 Schekman: Oh yes, I was four or five years old. But I’d read about DNA. I didn’t know a lot about it until I read this book by Watson.

01-00:38:00 Hughes: Did that galvanize you?

01-00:38:03 Schekman: Yes. I became really keenly interested in molecular biology through that exposure.

01-00:38:13 Hughes: Now, do you think that Konrad had that in the back of his mind? Or maybe in the front of his mind.

01-00:38:16 Schekman: What?

01-00:38:15 Hughes: That here was a bright student, and let’s draw him away from chemistry and into molecular biology?

01-00:38:20 Schekman: No, he was himself a kind of a geneticist. He was not a chemist, really. He ended up not even getting tenure there.

01-00:38:27 Hughes: Oh really.

01-00:38:28 Schekman: Yes, he was a molecular biologist. I think the chemistry department was going to branch out, and they hired him, although I don’t think he was really a chemist. So no, I was just doing stuff. If I’d done stuff that was going on in his lab, I would have done bacteriophage genetics. I guess he just decided here’s a simple thing that I can give this guy to do. I don’t know that he put much thought into it or really evaluated me all that much. I lost touch with him over many years. But as a result of the Nobel, he got in touch with me. I’d seen him 13

once—he came up here and he worked in a biotech company. He’d actually worked at Berkeley with Donald Glaser, and worked at Cetus, the company that Glaser founded. And then I think he retired, and he now lives in Sausalito with his wife. He’s written a book about life on the docks, and he sent it to me—I don’t know what I did with it. Anyway, I’ve corresponded with him. And he remembered! I was amazed. He remembered the very experiment that he’d sent me out to do, forty years later, forty-five years later. When he sent me an e-mail, he said, “I don’t know if you remember me.” Of course I remembered him, and I sent him the link to the UCLA story. I said of course, not only did I remember the experiment that he had me do, but more importantly, I reminded him about this Watson textbook, which he said he didn’t remember that he had referred to me. But both things were crucial.

My father got me a job at his engineering firm that summer. He was hoping that I would become interested in computer science, but I found it really boring, writing code. So over that summer after my freshman year I thought about what would I like to do in the laboratory, and I cooked up some crazy idea, and I went shopping around to find a faculty member. And curiously, I didn’t go back to this fellow in the chemistry department. I’m not sure why. But I went around to various other faculty and asked if they would be interested in having me work in their lab on a kind of an odd-duck idea I had about how to improve the way naked DNA molecules could be taken up into bacteria.

Normally if you’re studying a bacterial virus, it has a protein coat and has a way of injecting DNA into the bug so that the viral chromosome can replicate. But if you take away the cell wall that surrounds the bacterium and you mix it with naked DNA, at very low efficiency the DNA molecule will somehow get into the cell. I had some crazy idea about using an organic solvent to somehow facilitate this process. I remember this. And I went shopping around with this idea and finally I found a guy who was another beginning assistant professor in the zoology department at the time. He said, “Okay, well sure. Come on and try it.” And I think he could see that I had the special spark, and so he got me really much more deeply involved in the work that was going on in his lab, not just this crazy idea.

01-00:42:09 Hughes: And that was Dan Ray.

01-00:42:11 Schekman: Dan Ray, yes.

01-00:42:13 Hughes: Do you think there was some association with the fact that he was a junior member of the faculty? 14

01-00:42:26 Schekman: Yes, I remember visiting with at least another person who was in the medical school/biochemistry department, and he said he had no room. Did I think to go to a senior person? I think that probably the kind of inexperienced punk like me probably wouldn’t have had much of an audience with a more senior established person. I didn’t really know the faculty, so I just went shopping around. The brand-new guy has empty space, and he’s in the lab himself so he can show me stuff.

01-00:43:07 Hughes: So what did you do with the naked DNA?

01-00:43:13 Schekman: Well, I did try the experiment. I don’t think it did anything. It smelled up his incubator, but it didn’t do anything. But he got me involved in actually what he was doing, which was studying how small viruses replicate, how their chromosomes replicate. He taught me the techniques that he used to manipulate chromosomes in these cells and to evaluate them using the ultracentrifuge and gradients and things.

01-00:43:42 Hughes: Now all that was probably new to you, wasn’t it?

01-00:43:45 Schekman: Oh yes, of course. It was all completely new. And then he offered me a summer job, which was great. That was the summer after my sophomore year. At that point obviously it had already clicked, and I knew I wanted to do this.

But also, at UCLA I was actually doing really well. My grades were really good, and I was getting into the science. Since I’d sort of given up on the idea of medical school, I continued to be, frankly, disgusted with my classmates who weren’t that interested in science. They were mainly interested in getting good grades. And I felt, frankly, in my sophomore year that it wasn’t a terribly intellectual environment. So I decided, probably in my first semester of my sophomore year, that I would think about transferring to another university where the students were more serious about scholarship. I don’t know why, but I focused on the University of Chicago, and I decided I was going to apply there. I’m sure my parents didn’t think that was a very good idea, going away and more expensive.

At around that time I learned about the Education Abroad Program, which was still fairly new in the UC system, and this was very appealing. I was taking—I think I was doing this in the first or second term of my sophomore year—I was taking a graduate-level genetics class.

01-00:45:25 Hughes: Whoa! 15

01-00:45:29 Schekman: It was wonderful. I really loved it. The professor of that class took an interest in me. Somehow the subject of this Education Abroad Program came up. I had already decided I wanted to go to Britain, because I didn’t want to have to challenge myself with a foreign language. So he said, “Oh, well you should contact a fellow named William Hayes,” who was a professor of a new Medical Research Council unit that was being established at the University of Edinburgh. One of the options was to go to Edinburgh, because there was a UC systemwide program that included Edinburgh and maybe a half a dozen other British universities. So I applied for the Education Abroad Program and I got in. I wrote away to Hayes, this guy Hayes in Edinburgh, and somehow he thought that I was coming to Edinburgh as a sabbatical visitor. [laughter] So I spent that next summer working in Dan Ray’s laboratory and really getting into this bacteriophage DNA replication.

The Education Abroad Program back then was quite lavish compared to what it is now. Basically, there was more money for the university. And so I got a Regents Scholarship to help pay, and they took us all on an ocean liner from New York to Europe. All of the EAP students who were going to Europe were all together. We all met in New York and took this three- or four-day trip in the SS United States. So I got to Edinburgh, and I stayed in a flat that I’d rented from some landlord, a very nice woman. I showed up in the buildings where Bill Hayes is, and I think he pretty quickly figured out that I wasn’t a sabbatical visitor. But they’d already set me up with my own office and my own laboratory with a name tag on the door, listed as a visiting professor from UCLA for the opening of this MRC unit. [laughter]

01-00:48:04 Hughes: Did you find this a little intimidating?

01-00:48:04 Schekman: Yes! Oh yes! It was very intimidating. I was nervous meeting these guys. At the opening ceremony there was one of the great geneticists; Jacques Monod was there, and I shook hands with Jacques Monod. But they quickly realized that I was just an undergraduate, and so they put me under the wing of one of the more junior staff members John Scaife with whom I worked. But I continued to work on a project related to what I was doing back at UCLA.

01-00:48:40 Hughes: The bacteriophage.

01-00:48:42 Schekman: Yes, sort of on my own.

01-00:48:46 Hughes: What were you supposed to be doing? 16

01-00:48:47 Schekman: I was supposed to be working on bacterial genetics, but I found it kind of boring, and I wanted to actually do something that was more physical.

01-00:48:56 Hughes: But you were picking up genetic techniques? I’m thinking ahead to your future genetic approach to your research at Berkeley.

01-00:48:59 Schekman: Oh yes, it was a wonderful influence. The year was a spectacular year.

01-00:49:06 Hughes: Where are we? We’re getting to the early seventies?

01-00:49:16 Schekman: This is 1969.

01-00:49:17 Hughes: So say something about the state of genetics at that point, what you could do and what you couldn’t do.

01-00:49:27 Schekman: Yes, well, bacteria were the dominant theme of molecular biology. If you read Watson’s first book, Molecular Biology of the Gene, it was more about bacterial genetics than bacterial biochemistry, but there was some physical chemistry on the properties of proteins and nucleic acids Phage, bacteriophage was the dominant, really by far, the dominant experimental system.

01-00:49:53 Hughes: Not E. coli yet?

01-00:49:57 Schekman: Well, yes, bacteriophage infecting E. coli. Oh, absolutely. It was all E. coli or its bacterial viruses. Everybody worked on them. There were a few other things, but mainly it was that. Genetics was seemingly very powerful, and the viruses were particularly powerful because you could map the genes. But it wasn’t yet possible to do physical mapping of genes. That really came just about with the first efforts to clone genes [early 1970s]. But this was before the advent of recombinant DNA, of using these enzymes called restriction enzymes to break DNA. They had not been applied yet. I think Stanley Cohen, Herb Boyer, were maybe beginning to work on the first restriction enzyme that could make a clean cut. But that was still, I think that was still in the future.

01-00:51:08 Hughes: Well, Herb had been working on restriction enzymes for a long time and not getting very far.

01-00:51:13 Schekman: Yes, well there were restriction enzymes that had been discovered years earlier, but of a different class, that didn’t make a neat cut. They would bind 17

and then cut somewhere later. Werner Arber in Basel, Switzerland won a Nobel Prize for really the first site-specific DNA endonucleases. But they weren’t a tool. They couldn’t be used as a tool until the early 1970s, and this period I’m talking about was before then.

01-00:51:41 Hughes: Because the restriction enzymes weren’t specific?

01-00:51:44 Schekman: Well, they hadn’t been purified and characterized, because one couldn’t sequence DNA really, yet.

01-00:51:52 Hughes: So how were you mapping genes before the advent of site-specific restriction enzymes?

01-00:51:53 Schekman: Well, you would do genetic crosses. That’s how people mapped genes.

01-00:51:56 Hughes: Oh, I see.

01-00:51:59 Schekman: You would map genetic traits and use bacterial mating, conjugation, to map the traits by what now seem very crude experiments. And likewise, bacteriophage, which would recombine when they were co-infected in a bacterial cell would— You could measure the genetic linkage between different traits, and that would be roughly reflecting the physical linkage, but not exactly. Physical mapping of mutations and genes hadn’t yet been developed at all.

01-00:52:40 Hughes: And of course no genetic sequencing yet either.

01-00:52:43 Schekman: No, not really. It was just the beginnings of— You could get a PhD sequencing the last nucleotide on the end of a bacterial virus chromosome, back in the late sixties. That was going on at Harvard in Cambridge in Watson’s team.

01-00:53:01 Hughes: Were you paying attention to all this?

01-00:53:03 Schekman: Yes, yes. I was certainly aware of it.

01-00:53:11 Hughes: Reading the journals? 18

01-00:53:10 Schekman: What journals did I read? I was pretty assiduous in reading. I remember even before then, when I was at UCLA, probably in my sophomore year, I would pore over the journal titles. I remember being captivated by the Proceedings [of the National Academy of Sciences], the PNAS, trying to read articles. It was pretty advanced compared to my knowledge. But reading Watson’s book really helped, and I learned a lot on my own. I took a genetics class in my sophomore year at UCLA, before I went to Edinburgh. I remember the professor encouraging students to go look at this new book of Watson’s, The Double Helix, which was coming out serialized in The Atlantic Monthly. It was the fall of 1967, and I remember going to the main library and checking out The Atlantic Monthly.

01-00:54:15 Hughes: As you well know, anybody who’s read that book knows, it’s hardly a story of pure science going on in a vacuum.

01-00:54:26 Schekman: Yes, I didn’t understand the controversy. It didn’t dawn on me that it’d be controversial when I was reading it. To me it was just exciting!

01-00:54:36 Hughes: You didn’t have a vision of science as being a pure enterprise with stellar people with no human needs pursuing their objectives?

01-00:54:54 Schekman: That’s a good question. I don’t know what I thought about how science was pursued, whether there were personalities involved. I just remember feeling that this was exciting. Yes, okay, there are people, they did strange things. They were nerds after all; they did strange things. [laughter] Nerds are weird, so all the controversy about it just went right over my head. I was just excited.

[Audio File 2]

02-00:00:00 Hughes: You mentioned shaking hands with Jacques Monod. Is that about as far as it went?

02-00:00:15 Schekman: He was polite, and he could see I was trembling. [laughter] So he was very nice. I met other people that year. It was a great year in many ways.

02-00:00:30 Hughes: There were a lot of people coming through the department?

02-00:00:32 Schekman: Yes, it was exciting. Bacterial genetics and molecular biology were really taking off. This was still before recombinant DNA. It was a brand new Medical Research Council unit. But shockingly, several years later they closed it down because they thought it was old-fashioned to have a bacterial genetics 19

MRC unit. They closed it down, and then the recombinant DNA revolution hit. It was just really stupidity, administrative stupidity.

02-00:01:06 Hughes: When it came to Randy Schekman, how were you defining yourself at that point? In terms of science I mean.

02-00:01:18 Schekman: I could see myself increasingly going down this very specific road. Sometimes I thought I was somehow confining myself too much. But it was a path that I was simply driven to, and it just resonated with me, and I knew this was going to be my life.

02-00:01:40 Hughes: Meaning molecular genetics?

02-00:01:43 Schekman: Oh, you mean what discipline I defined myself as? Well, I think at the time I did not see myself becoming a strict geneticist. I did have, I think, an abiding interest in molecules. I remember feeling as though what I really needed was more biochemistry, where I could really dig in and understand molecules.

When I was in Edinburgh that year, my lab mate next door to where I was working was a fellow named Len [Leonard E.] Kelly, who years later subsequently became a faculty member here in the genetics department at Berkeley. He did not get tenure. But his older brother was a fellow named Reg[is] Kelly who was at the time a postdoctoral fellow in Arthur Kornberg’s lab. So I remember Len. We were talking about DNA replication because that was my interest, and he even gave me papers from his brother, reprints of papers that he had written with Kornberg on using the enzyme that Kornberg had discovered and showing that it looked like it was pretty good at DNA repair, which was not what Kornberg wanted, but still there it was. I think at that moment I resolved that Kornberg was the kind of master that I really needed to learn from if I wanted to move along the path from more physiologic experiments to more molecular experiments.

During the year I took the biochemistry course, which was in the medical school, but spent all my time in the lab which was on the other side of town in Edinburgh. I think the professors in the biochemistry course were pretty upset with me. They had this kind of a hazing ritual at the very end, where you take a comprehensive exam covering the whole year, which was really so different than anything I’d experienced here. So I worked very hard. I read the whole textbook, and I don’t even know how I did on the exam. But the memorable thing is at the end they give you an exit interview, where they picked me out as some American punk, and they really verbally hazed me during this thing. It was really humiliating. [laughing] But somehow the grade translated well, and I did well. 20

02-00:04:18 Hughes: Why did they haze you?

02-00:04:24 Schekman: I was an arrogant little jerk. I remember getting into arguments with them. I was ill-behaved, by British standards certainly.

02-00:04:44 Hughes: Well, it’s a more hierarchical system in British academia.

02-00:04:47 Schekman: Oh, yes. I think where I was working in a lab they liked me, but where I was supposed to be doing my coursework, I don’t think they appreciated what I was doing.

Rather than staying in Europe that summer— I had traveled during the two breaks, the winter and spring break, extensively on the Continent. I really loved that. But I decided I had to make some money. So in thinking about what I would do that summer after my junior year there were two options. I didn’t want to just go back to UCLA. I wanted to do something a little more exotic. So there’s an undergraduate research program at Cold Spring Harbor, which is really an important program. Lots of people really launch their career by being undergraduates at Cold Spring Harbor. So I looked into that program. They paid you enough to sustain you for the summer, but I needed to make some money for the school year, so I didn’t apply.

Instead, I learned of a friend of Dan Ray’s who was working on small phages as an assistant professor at Harvard in the Biological Laboratories, like right next door to Jim Watson who was still there and Walter Gilbert who was also there. That department was really sort of the epicenter of molecular biology at the time, in the late sixties. It was just in such ferment there they attracted the best graduate students, and from a distance it looked to be incredibly exciting. So I corresponded with the fellow, the assistant professor, whose name was Denhardt, David Denhardt. And he said sure, come on, and he offered me a summer job.

I took another boat over from England, now to New York, and my father met me, surprised me at the dock. We drove up to Boston, and he dropped me off, and I spent the summer there. It was indeed a revelation, but in a way that I hadn’t anticipated. What I realized from the summer there was that I could never go to a place like Harvard. It was so competitive, and people were so personally obnoxious to each other. Everything was maximized for contentiousness, and it seemed to me it was antithetical to the way I wanted to do science. So although it was an intense experience, and I learned a lot— I even got to go to the Cold Spring Harbor bacterial virus meeting that summer, which was fantastic. And I met Watson, I met Gilbert, I met all these people. Although it certainly confirmed my interest in the subject, it was just so 21

distasteful to me that I didn’t apply there, at least in Cambridge for graduate school.

02-00:07:44 Hughes: Well, Watson is hardly an uncontroversial figure, and we’ve since heard about the static, if you want to call it that, in the biological community at Harvard. I think of E.O. Wilson, who certainly has written with frankness about his tension specifically with Watson.

02-00:08:05 Schekman: Sure, sure, sure.

02-00:08:07 Hughes: And because they were the people they were, I’m sure that trickled down to—

02-00:08:12 Schekman: Yes, to his people, yes. But okay, it’s true. It’s all true. But on the other hand, they were doing fantastic work.

02-00:08:20 Hughes: Oh, of course they were.

02-00:08:23 Schekman: They were making really important discoveries at the time.

02-00:08:26 Hughes: You said early on in this interview that you liked the competitiveness of the science fairs. But you didn’t like the interpersonal part of it?

02-00:08:40 Schekman: Yes, it was personally obnoxious. They would do nasty things. There was some sabotaging going on even. People were so competitive—it was too much. I remember there was a room in the Bio Labs where everyone had their instruments called a scintillation counter to measure radioactivity. And that was the key instrument that everyone used, for all of one’s experiments were measuring/quantifying radioactivity in individual samples. These were expensive instruments, and so an assistant professor couldn’t necessarily have his own instrument. So all the senior faculty had their instruments in a common room, ostensibly to be there to share. So you had this big room with all these instruments, and I was in there all the time. But each instrument had its own sign-up rules about when you could sign up and how far in advance and this kind of nonsense—optimized for the lab that owned the instrument. So if you didn’t observe that they’d kick you out of the machine.

And I remember vividly one day that Denhardt was doing an experiment, and he left a set of samples for me, and he said, “Please put this in this scintillation counter at ten o’clock tonight,” because that’s when he’d signed up for. So, fine. Sometime before then one of Watson’s or Gilbert’s graduate students came marching into the lab and said, “Denhardt signed up illegally. I’m going in.” [laughter] I went up there at ten o’clock with my tray and started arguing 22

with this guy, and he was standing there putting the samples in one at a time. It was just, “Go away, punk.” No way. Having experienced UCLA and a little bit of Edinburgh, I knew that there was another way that people could relate to each other. Over the years I’ve had many job offers at Harvard, and every time I go back there I have a taste of that, and I find it so unpleasant. There are some great people there, and there are even some nice people there, but there’s something about the place that just gives me the shivers.

02-00:11:13 Hughes: So then you came back to UCLA and you still had your senior year.

02-00:11:15 Schekman: I came back to my senior year, yes, and went back to working with Dan Ray on some observations that I’d actually made in Edinburgh and I continued to work on. I’d had the good fortune of being able to publish several papers as an undergraduate. Two papers Dan had put me on as co-author when I was in his lab just after my sophomore year, which were published while I was in Edinburgh, and then one when I was in Denhardt’s lab. I was a first author on a paper in the Journal of Molecular Biology from work that I did in that summer, and then another one on work that I did in Dan Ray’s lab that I finished in my senior year.

02-00:11:58 Hughes: Highly unusual for an undergraduate.

02-00:11:59 Schekman: Yes, but that’s what science is about. You publish your work, and I was spending so much of my time [in the lab] it really got to an extreme situation in my senior year. I had classes that I had to take, but I stopped going. [laughing]

02-00:12:14 Hughes: Oh really?

02-00:12:15 Schekman: Oh yes. I said all this stuff is irrelevant. What matters is my experiments.

02-00:12:25 Hughes: You’d picked up the biochemistry in Edinburgh?

02-00:12:27 Schekman: A little bit, a little bit.

02-00:12:30 Hughes: You felt that you had enough of the basics, in science I mean, to get ahead?

02-00:12:36 Schekman: Yes., Well, if you’re passionate about something, if you don’t know something, you go and read it. I spent a lot of time in the library. I’d read papers. I’d pick stuff up. I think I realized around then that I was actually 23

pretty creative in designing experiments that others hadn’t really thought about, and that kept me going. I think being creative in that way is more important than just learning basics. [laughing]

02-00:13:03 Hughes: Where did that come from? Was there any model for that in any of the people that you’d encountered, or was it just Randy Schekman?

02-00:13:12 Schekman: The creative aspect?

02-00:13:13 Hughes: Well, the looking at things in a different way, is what you’re saying, isn’t it?

02-00:13:18 Schekman: Yes. No, I think that just came from me. How do you teach that to somebody?

02-00:13:25 Hughes: Yes, I don’t know how you do. I don’t think you do.

02-00:13:25 Schekman: I was so obsessed about it that I would always be turning things over in my mind, constantly, constantly.

02-00:13:31 Hughes: What was your social life?

02-00:13:34 Schekman: Well, let’s see—at UCLA not much. I had a girlfriend in my senior year, and I lived with her that summer. But before that, I dated a little bit but not much, and not at all when I was abroad. No, I was still pretty much the nerd. [laughing] So when I got back to UCLA— Well, this fellow Denhardt from Harvard tried to convince me to stay on and work in his lab for the next year, but I knew I had to go back and graduate. But my grades started to suffer, actually to the point where I think by the second term of my senior year I was put on academic probation. Before then I’d had mostly As. But [my grades] really sunk, particularly in my senior year because I knew what I wanted to do, and other stuff didn’t matter.

02-00:14:39 Hughes: I’m sure there were requirements in the humanities.

02-00:14:43 Schekman: Oh yes. I did as little as possible, and the one real sore point was foreign language. I had never had much facility in foreign language. I’d taken French in high school, did okay, and then I took German to finish my foreign language requirement at UCLA in my senior year. I failed the class, and I said, okay, I’ll have to take it during the summer session—and I didn’t go! I left UCLA after that last summer without actually having satisfied my foreign language requirement. When you’re young and stupid… I also left UCLA 24

having been selected number three in the draft, which was the first year of the lottery system. And so I left with two things over my head, but I was completely oblivious. I still can’t imagine now; if one of my kids had this problem I wouldn’t sleep! But I was completely oblivious. I’d gotten into Stanford even though I actually hadn’t graduated.

02-00:16:03 Hughes: Did UCLA give you a diploma?

02-00:16:04 Schekman: No, they didn’t.

So I’m at Stanford— I should take a step back. So this fellow Kornberg was at Stanford, and it was a great department. It was certainly the best biochemistry department in the country, if not the world at the time. And it was incredibly selective. They had an entering class of five students for graduate school. At the point that I was admitted to the program, I think everyone who was offered a position accepted. I don’t think they’d ever had anybody turn them down, because it was really quite a unique department, really close-knit and the opposite of Harvard in my estimation, going in. Everybody worked together, although I realized when I got there that Kornberg was a person apart, even within that department.

02-00:17:07 Hughes: Were you admitted solely on the basis of your work?

02-00:17:20 Schekman: Yes.

02-00:17:20 Hughes: Nobody paid attention to the fact that you didn’t even have a diploma?

02-00:17:26 Schekman: Well, you see, when I interviewed for the position at graduate school it was long before I’d finished.

02-00:17:31 Hughes: I see, and so you didn’t bother to mention—

02-00:17:33 Schekman: Yes, so they didn’t know about it. But they’d already noted that I had some lousy grades. [laughing] I also had several publications, which is a little unusual.

02-00:17:44 Hughes: Well, obviously, your science for an undergraduate was stellar.

02-00:17:47 Schekman: But I was also pretty obnoxious, and I think there was some hesitation, but they let me in. 25

02-00:17:58 Hughes: Now, was that largely Kornberg’s decision?

02-00:18:04 Schekman: No. In fact, taking a step back, he was on sabbatical. So here’s a bit of science that’s really relevant. Kornberg had become famous and won his Nobel Prize on the basis of an enzyme that he discovered when he was a faculty member in St. Louis at Washington University, the enzyme called DNA polymerase, which he of course thought was the replication enzyme. He did everything he could for the next ten years or so to try to prove that it was a replication enzyme. The summer that I was at Harvard, that crucial summer, a fellow named John Cairns, a scientist, actually the former director of the Cold Spring Harbor Laboratory before Watson took over, had done— He was always kind of an iconoclastic guy and was very skeptical that DNA polymerase was the replication enzyme because, well, it didn’t seem to work fast enough. It couldn’t polymerize fast enough, and I think he just probably personally didn’t like Kornberg. So he did an experiment himself with a technician where they took bacteria, and they exposed the bacteria to a chemical mutagen. They’d just screen lots of colonies using the Kornberg enzyme assay in little lysates of thousands of mutagenized bacteria. And they found a mutant clone that when they made a lysate had no DNA polymerase activity. He was able to show eventually that it was a mutation that really did kill the enzyme. It didn’t make the protein, and yet the bacteria grew fine. So this was published in Nature in 1969, that year that I was going from Edinburgh back to Harvard and then back to UCLA.

02-00:20:02 Hughes: And ten years after Kornberg’s—

02-00:20:02 Schekman: Nobel Prize.

02-00:20:03 Hughes: Nobel Prize, yes.

02-00:20:05 Schekman: And maybe fifteen years after he’d first discovered DNA polymerase. So this was really kind of an earth-shattering discovery. Cairns found that this mutant bacterium was deficient in DNA repair. If you exposed it to ultraviolet light it died much more rapidly and completely than a normal bacterium. So he concluded on this basis, which others had already suggested—indeed, Reg Kelly had evidence to support this just based on the properties of the enzyme—that this enzyme, DNA polymerase, was involved in DNA repair, not in chromosome replication. That was just earth-shattering. Kornberg was criticized and almost humiliated. He of course was unbowed himself. [laughing] 26

02-00:21:08 Hughes: It’s particularly ironic, to my mind anyway, in that he was such an advocate of pure enzymes, and yet he had the wrong one!

02-00:21:21 Schekman: Well, okay. So you said it’s the wrong one. It was the prototype replication enzyme, and the real one works by the same principle. He shared the Nobel Prize with a guy named Severo Ochoa, who discovered what he thought was the RNA synthesis enzyme. Actually the enzyme that Ochoa discovered, for which he shared the Nobel Prize, had absolutely nothing to do with RNA synthesis. So Kornberg’s discovery was more well supported than Ochoa’s discovery, at least insofar as the Nobel Prize is concerned.

So this to me was fantastic, because it was the importance of genetics. And the Cairns mutant lacked the enzyme thought to be the replication enzyme. Obviously there was a replication enzyme that was just missing. In fact, it turned out that one of Arthur’s sons, Tom Kornberg, who was a Juilliard musician but who injured his little finger and could no longer play the cello, but because Arthur had insisted was also enrolled at Columbia University. In a summer project the following summer after the Cairns mutant was published, he went into a lab in the biology department at Columbia and discovered the other replication enzyme. In making a lysate of this mutant bacterium, he discovered the other enzymes. So it was dubbed by Nature magazine Kornberg junior enzyme. [laughter] It was a more complicated enzyme, but it worked by similar principles. And so the principle, I think, is intact.

02-00:23:02 Hughes: An amazing story!

02-00:23:02 Schekman: Yes, it is an amazing story.

02-00:23:04 Hughes: All of that happened soon after you arrived at Stanford?

02-00:23:12 Schekman: No, this was the year [1969-70] before I arrived. It was going on all that summer when I was at Harvard. I remember going to this Cold Spring Harbor meeting and talking about the Cairns mutant even before it was published. Everybody was abuzz about this. So the field was really in ferment at the time. To me, it was the perfect time to now really delve into the biochemistry even more deeply, and we’ll get to that when I talk about what I did in Arthur’s lab.

But in the meantime, I got into the [biochemistry graduate] program, which was really great. Even before I was admitted to the program, I made a point of coming up to Palo Alto to meet Kornberg, who was then on sabbatical. He had decided to do a series of little mini-sabbaticals, working first in a chemistry laboratory, Harden McConnell’s, in the chemistry department at Stanford. Arthur had decided, maybe because of the Cairns mutant, that somehow he 27

was missing action at a membrane’s surface. People knew that chromosomes were replicated on a membrane’s surface in bacteria, and so maybe he had to immerse himself in membrane biochemistry. And so he decided to do a series of little mini-sabbaticals in all the great membrane labs in the world. I met him on the first step, which was just across the street there in the chemistry building, and I arranged to interview him, and he was gracious to meet with me. I made some comment about the Cairns mutant, and I could see he wasn’t happy about that. I said that I thought this was really exciting, and the field was shaken up, and now it’s time to go in and really—really understand what the replication enzymes were.

So I got into the program, and he came back from sabbatical. Back then people didn’t rotate in different laboratories before they chose a thesis. So I arrived at Stanford, and I was full of myself. All the first-year students were sitting and reading and thinking about what they would do, and I was already busy doing my own experiments and continuing with the work that I’d done at UCLA. [laughing]

02-00:25:32 Hughes: Which probably impressed Arthur.

02-00:25:33 Schekman: Well, it may have, but I think I was so ill-behaved that they were really worried what they had on their hands there. I was so defensive. I’m really embarrassed thinking back on how I behaved back then. I was the only student in that program, certainly that year, that came from a public institution. They all came from Harvard, Yale, and University of Chicago, and they probably all had superior coursework exposure. Well, I was only working in the laboratory; I wasn’t going to classes. So I was very defensive, I think, and I overcompensated by being really aggressive. Kornberg said, okay, come in my lab. But after that they put me in a lab room all by myself. [laughter] I had my own little lab room to myself so I could cool off.

02-00:26:43 Hughes: But you probably loved that.

02-00:26:45 Schekman: Yes, I suppose. Was I even enough self-aware that I’d been putting people off? You know what happened early on? I think people actually pushed me away. I knew that, and so I was feeling isolated. But one of the postdoctoral fellows in one of the labs invited me to join a group on a camping trip. It was really a good experience because I was away from the laboratory and I had to just interact socially. The host, Costa Georgopoulos, of this trip is still a good friend. He was merciless. He was poking fun at me and puncturing my ego. [laughing] It was probably the best thing that ever happened, and I think after that I realized that I had to actually be a human being. It didn’t diminish my passion, but I had to behave myself. These were all smart people. 28

02-00:27:47 Hughes: Now, was Arthur your advisor?

02-00:27:51 Schekman: Yes, he was my advisor.

02-00:27:55 Hughes: You were seeing him enough to suit you even though he was on these mini- sabbaticals?

02-00:27:57 Schekman: No. He was on the sabbatical the year before I started. He’d come back and was raring to go.

02-00:28:06 Hughes: I think of him as a strict biochemist, or enzymologist really. Was he picking up more about membranes once he had finished his sabbatical year?

02-00:28:30 Schekman: Well, he was picking up membrane biochemistry, not genetics or molecular biology. I think he decided that perhaps what they (his lab group) were missing was that the real replication enzymes were organized on the membrane’s surface. Of course when you make an extract and you purify DNA polymerase, the first thing you do is you centrifuge away the membranes. And so he thought that maybe that was what was missing, and they had to somehow focus on biochemistry at the membrane interface.

02-00:28:58 Hughes: And did he?

02-00:29:00 Schekman: Yes. I had some of my own ideas initially that I was pursuing, and he was sort of supportive, but I was just probing. I was the one who came to the lab with some actual significant experience with small bacteriophages. He had worked on these before, but I actually had more experience on these small bacteriophages than anyone then in the lab. So I think he was interested in having me pursue things, thinking about how one might study replication of these small viral chromosomes.

I was poking around and not doing much of any value, I think, until I went away to a DNA replication meeting in Colorado. I came back, and his star graduate student, Doug Brutlag, who was two years my senior, told me that while I was away they’d cooked up this great idea. So here’s the scientific challenge: viruses very often start off as circles. In the case of these two small viruses that I’d studied, they’re single-stranded circles, not a double strand. And so when the virus infects the cell, the first thing that happens is that the host machinery converts them from a single strand to a double-strand circle. And then the double-strand circle replicates and makes more viruses and peels off a single strand and that gets packaged into the virus particle. I’d been 29

studying the mechanics of that using physiologic experiments on intact cells, but I realized that the action would have to be at a more biochemical level.

Kornberg, in a really amazing triumph that I remember vividly when I was an undergraduate, had published two crucial papers in the Proceedings, in the PNAS, in 1967—where a postdoctoral fellow in his lab had taken the polymerase I and found conditions where he could copy the circle and make a copy that was infectious, which meant that the enzyme had faithfully reproduced all of the genetic information of all the genes on this small virus. And then he took the copy and he was able to make the complement of that. So he had actually reproduced the authentic viral DNA, which was, Arthur argued, a strong argument that this was a replication enzyme. Well, all it said is that it was capable of doing that; it didn’t say that it was actually the enzyme doing it.

02-00:32:10 Hughes: Now, is that the work that got the media all excited about the so-called “creation of life”?

02-00:32:16 Schekman: Yes, I remember that newspaper article. I think I had that framed in my bedroom at UCLA. [laughter] Yes, it was beautiful, two beautiful papers in — I don’t know if it was back-to-back issues of the Proceedings. This was before I got to Stanford.

Now, the crucial thing about the paper was the enzyme that he had discovered, DNA polymerase, was unable to start a DNA chain de novo. That is, it needed a starting block, if you will. And the starting block that was provided, which was entirely artificial, was a boiled extract of bacteria, which provided some small pieces of DNA that could hydrogen bond to the viral single-strand DNA, and that would be the starting block that DNA polymerase would use. So the completely open question after those papers was, how does the DNA chain actually initiate? Are these things that are being provided by the boiled extract? Does it have any physiologic meaning? Well, people who are skeptics say no. That was another criticism of the enzyme. Unlike the enzyme that makes messenger RNA, RNA polymerase, which by itself can initiate de novo the DNA polymerase, Kornberg’s enzyme could never start on its own, which supported other people’s argument that it was a repair enzyme, because if it were repairing DNA, it would have an end that it could use as a starting block to stitch in a new piece of DNA. Okay, so then the question is where does the primer come from? That was a big question that Kornberg posed, where does the primer come from?

During a crucial week when I was away at this meeting, Arthur and this fellow, Doug Brutlag, cooked up an idea which was really quite an amazing idea when I came back to hear it, that maybe the enzyme that makes RNA would actually make this primer. After all, RNA polymerase was capable of 30

copying the genes on the chromosome of these viruses. Therefore maybe in special circumstances it would be deployed to make the starting block, the RNA primer, and that predicted that RNA would initiate DNA chains by DNA polymerase.

02-00:35:06 Hughes: But this was all hypothesis.

02-00:35:06 Schekman: It was a hypothesis, absolutely, but it was simple to test. When I came back I think Brutlag had not even started the experiments. But the first experiment was really trivial because the enzyme that makes RNA in E. coli is sensitive to a drug, an antibiotic called Rifampicin. And so the simple, trivial experiment was to take bacterial cells and infect them with a virus in the presence of this drug which should not affect DNA polymerase. It does not affect DNA polymerase. But if this was the first thing that had to happen for a single strand to be converted to a double strand, and if it used the host RNA polymerase, then you would interrupt replication right from the start. And it worked, amazingly it worked.

02-00:35:57 Hughes: Now, did you do that experiment?

02-00:36:01 Schekman: No, I didn’t do that. I didn’t do that. That’ll be the subject of another story I’ll tell you. [laughter] I didn’t do that experiment, although I don’t know, maybe if I’d been there at the time— I would have been the obvious person to do that experiment because I was the one who knew how to do that experiment. To me it was the same kind of thing that I’d done in Dan Ray’s lab. Of course it was not my idea, not my idea. So Brutlag did the experiment, and it worked in one particular setting with the virus that I’d worked on and which I had brought to the lab, a virus called M13 which infects bacteria, E. coli. And so it was really exciting. I remember thinking—why didn’t I think of that? So I was very interested.

The next question to pose—well, there are two questions to pose. The next question that I posed was well, once you make the double-stranded circle, then the next stage in the replication cycle is that you make more and more copies of the double-stranded circle, like you do [in] chromosome replication. And I said, well, there’s a way to test— The subsequent replication requires a viral gene and therefore RNA polymerase. I’m foggy on the details. Anyway, it requires transcription of the viral double-stranded genome. And so if you added the drug and it blocked replication, you couldn’t know that it wasn’t because you hadn’t manufactured some of the viral proteins.

I won’t bore you with the details, but knowing the literature better than they did, I said, well, there’s a way to actually distinguish this by using the drug at a certain concentration, or something like that. And so I did the next 31

experiment, which then demonstrated that ongoing double-strand chromosome replication also required the action of RNA polymerase to facilitate the replication reaction and not merely to transcribe genes. That was an important observation because it suggested that chromosome replication in E. coli might also invoke this RNA primer mechanism. At the same time, crucially, Brutlag devised a way of breaking open E. coli cells and adding naked DNA template to this crude extract. He could show that sure enough that very same initial step where you take the single strand and make its complement, that was also exquisitely sensitive to this inhibitor of RNA polymerase. So that was really spectacular.

02-00:39:20 Hughes: You were proving yourself.

02-00:39:22 Schekman: Well, yes, okay—they knew I had knowledge and skills. I was part of the team then, and so it was really exciting.

02-00:39:35 Hughes: You were building on the work that you did in Ray’s lab, but of course moving it to a higher level. There’s so much talked about in the history-of- science literature—well, the stuff that I read anyway—about the tremendous advantage of being in Kornberg’s department at that point because of what was available from his very own refrigerator in terms of exotic enzymes that nobody else had.

02-00:40:07 Schekman: Yes, but that didn’t come into play in these experiments, because these were all—

02-00:40:13 Hughes: Commonplace.

02-00:40:15 Schekman: The techniques that I used in my experiments in those early days were things that I learned as an undergraduate at UCLA and the reagents were commercial reagents. No, what was crucial was the intellectual ferment. It wasn’t the reagents; it was the ideas! It’s always the ideas really. At that point I was launched into this new path and it was very exciting.

This fellow Brutlag was then starting to look at the enzymes further, the enzymes that were involved in this initial single strand to double strand reaction. Because of the experiment that I had done, I tried to set up a replication reaction in the extract that reproduced the ongoing double-strand chromosome replication. That didn’t work and it was frustrating. At a certain point—well, it was probably after just a few months—Kornberg said, “Let’s try this other virus called phiX174.” The virus that I mentioned that we had worked with was M13. But there’s another one, a very different virus but still a single-stranded circle superficially similar but genetically very different, 32

called phiX174. PhiX174 was the better known of the two viruses. It was the one whose DNA was copied in this famous 1966-67 work of Kornberg’s that led to this news release about life in the test tube and this kind of thing. But for reasons that I can’t really recount, the initial experiments that Brutlag did were with M13, which showed this requirement for RNA polymerase.

Well, I did the experiment with phiX because I had experience with that, and the result was completely different. PhiX was not sensitive to this drug Rifampicin in that initial step, nor in subsequent steps. So that was troubling at first. Why would there be such a difference? And still I couldn’t explain why this would be. But then I went to Brutlag’s in vitro reaction, this extract of E. coli. And having purified the phiX174 DNA and also the M13 DNA I found—and this was my really most important initial observation—I found that one could reproduce the difference between these two templates in vitro. You could show that the M13 template was sensitive to the drug, and at the same time that the phiX was not sensitive to the drug, so it eliminated any kind of indirect effects. Oh, and by the way, already at that point it was clear that ongoing chromosome replication of E. coli was not sensitive to this drug Rifampicin, so M13 was already seeming like the odd-man out. It was an instructive discovery, and indeed it led to subsequent discoveries about a role for RNA in initiating a DNA chain. M13 was exploiting the transcription enzyme of E. coli and phiX was not. Importantly, the hunch was that phiX would be a more faithful replica of what the chromosome was doing, the requirements for ongoing chromosome replication.

What I was able to reproduce in this crude extract was the distinction between the two. That was to become my thesis project. I would now have a whole new opportunity—by exploring phiX one might actually find more of the machinery that the host cell actually uses. I was aware, and the others were not, of a crucial background piece of information relevant to this, which was that my advisor at Harvard, this fellow Denhardt, had already published a paper in the Journal of Molecular Biology that showed that that initial step in phiX, the single strand to double-strand reaction in vivo, was dependent upon a gene called the dnaB gene, which geneticists had identified as a gene required for ongoing chromosome replication in E. coli.

So there was a whole path of discovery that Kornberg had been probably ignorant of, and certainly would have been dismissive of, that involved genetics. There was a Japanese scientist who was working in Paris named [Yukinori] Hirota who made mutants of E. coli which, unlike the Cairns mutant which was perfectly viable, now stopped chromosome replication at a temperature that was incompatible with viability for this mutant. These are these temperature-sensitive lethal mutations. So if you want to study essential genes in a microorganism, then you can study them by introducing the mutation that causes the protein to be thermally unstable, temperature sensitive, a classic way of looking at essential genes which we exploited in my lab here. These groups actually had already identified about a half a dozen 33

genes—they called them DNA genes, dnaA, B, C, D, et cetera—which when cells were shifted to human body temperature, ongoing chromosome replication ceased very rapidly. I was aware of this literature. Kornberg, I don’t think was. And I was specifically aware that this guy Denhardt had demonstrated that this mutant called dnaB was defective in this very initial step that I could now reproduce in the test tube, in vitro.

So I went over to a lab in the biology department at Stanford, because those mutants weren’t in Kornberg’s collection, and contacted a fellow named Phil Hanawalt, who interestingly was the graduate advisor of this fellow Dan Ray, so I sort of knew him. They had these mutants from this Parisian group. And I got the set of them, and the one that my advisor from Harvard had published, dnaB. Another crucial experiment was I demonstrated, in the extracts of bacteria, that the dnaB mutant was temperature sensitive in vitro, just as it was in vivo, for phiX, the one that didn’t use RNA polymerase. But not for M13, the one that did use RNA polymerase. So that was my first real big discovery.

02-00:47:53 Hughes: And you published that.

02-00:47:55 Schekman: Yes. So we published that in PNAS. Back then, everyone had to have their best papers in the PNAS, so that was very exciting. The rest of my graduate career was trying to go after the enzymes that phiX exploited. It led eventually, after I left, to Kornberg’s lab purifying all of the real enzymes that were involved in making the authentic RNA primer for DNA replication.

All this was going on as I developed a very close friendship with a postdoc in Arthur’s lab by the name of Bill Wickner, who is still my best friend, all these years later. He introduced me to my wife, Nancy Walls, whom he had dated when he was a medical student at Harvard. So he and I were close collaborators, and at least initially even competitors, but close collaborators on all this work.

So I learned a great deal from Kornberg.

02-00:49:06 Hughes: Is he on the paper?

02-00:49:07 Schekman: Oh yes. He was not on that very first paper, but he was on several subsequent papers. So I learned a great deal from Kornberg. It’s indisputable. He was just sort of imprinted on me, but with my own style. But that didn’t mean I got along with him. [laughing] I didn’t really get along with him. He was tough, just unrelenting. It was never good enough. But to be fair, he was demanding of himself just as he was of everyone in his lab. But he could be verbally brutal. It wasn’t like the experience that I had at Harvard, which was just personally obnoxious. Kornberg was just psychologically brutal. 34

02-00:49:57 Hughes: I did quite a number of interviews with Arthur and got along with him fine, but of course I was in no way a competitor.

02-00:50:08 Schekman: Yes, I read some of your interviews with him.2 Some of the passages I was so put off. He was so dismissive of this guy [Severo] Ochoa, for instance. I couldn’t believe the chutzpah of his remarks.

02-00:50:26 Hughes: Paul Berg also had a tough time with him when he dared to—

02-00:50:41 Schekman: Move away from—

02-00:50:42 Hughes: —abandon E. coli.

02-00:50:45 Schekman: Yes, I know, I read that whole interview. I probably shouldn’t have because it was a little too close to home for me.

I was probably continuing to have my own ideas. I challenged Kornberg in front of other people, and he didn’t like that.

02-00:51:07 Hughes: No, I bet.

02-00:51:07 Schekman: We would poke fun at each other at the annual department Asilomar retreats, and he didn’t like that. He was just tough.

The most amazing experience I had was at the very end. I’d been actually pretty successful, right? I’d published really important work, and okay, I knew I had, so maybe that was part of the problem. But I didn’t do things the way he wanted me to do. His idea was that I would work on one of the proteins, and I would purify it to homogeneity and study it, and other people would purify the other components. At a certain point, my work was going nowhere, and I was struggling with the fractionation of these components. It was because there are many different proteins required.

Fortunately, at that time I got married, and I went on my honeymoon, and I was away for a month. I can’t believe Kornberg allowed me to be away for a month, but I was away for a month, and I had time to reflect. When I came back, I had a new approach to what I was doing, which he thought was reasonable. I went about doing it, which was to break things down into subgroups without purifying any one thing, to just resolve things in large fractions and to get a sense of the complexity of it. That worked really well,

2 http://content.cdlib.org/ark:/13030/kt6q2nb1tg/ 35

and we actually published a Science paper on that. But I wasn’t doing things according to his dictates. My style was not his. My notebook wasn’t kept up to his standards. So he got really sort of nasty at the end. I think he was happy to see me go.

And then it really fell apart on the day that I was to give my thesis defense. Everyone gave a thesis presentation in the library in the biochemistry building, which held maybe fifty people, but it was packed. That day was special because his really close friend by the name of Efraim Racker was there. I don’t know if I’d met Racker before, but I knew of him. He was another classical biochemist. He had a good sense of humor, and he was called in by the biochemistry department to give some lectures in their biochemistry course. He was there on the day of my thesis presentation, and he attended my lecture. He got up near the end, before I finished—oops, oh my, look at the time. [brief interruption about lunch plans] Look at the time! I’ll finish this story. So Racker got up in front of everyone and congratulated me. It was his kind of biochemistry.

But if I go back to the beginning of that hour, Kornberg stood up and introduced me, and I got up, and I gave a historical perspective on my work, which was, in reflecting back a few years, there were other observations out in the literature that suggested that RNA may have a role in DNA replication at the origin of DNA replication. There were some genetic experiments. And I think by then David Baltimore had already shown that retrovirus reverse transcriptase uses an RNA primer to make DNA. So I mentioned these things. Kornberg always took assiduous notes. I swear when he was sitting on the toilet he would take notes. So he had his notebook open, and he was taking notes on my lecture, and then I mentioned this historical perspective. [imitating sound] He closes his book. I could see he was getting agitated during the hour. At the end Racker congratulated me, he walked out to prepare for his lecture, and Arthur stands up in front of the room and he says, “Well, that’s it for this part of the exam.” Now, it had never been referred to as an exam. It was a last presentation. You would adjourn to Arthur’s office, there’d be a round of sherry, and you’d be on your way. So I knew I was in trouble for some reason, but I still didn’t appreciate what I had done that was wrong.

So we adjourned to his office. Fortunately I had witnesses. There was Bob Lehman, Dale Kaiser, a guy Gan Ganesan in the genetics department, and then the poor assistant professor Peter Day who was ostensibly the chair of the committee from the biology department. And Arthur. He was starting to really get agitated. I think someone asked me a polite question. Then Arthur turned to me, and his hand was trembling, and pointing a finger at me, he said, “I want to take you to task for your historical perspective. God damn it—it was my idea. I don’t care what anybody else did. It was my idea, and I told Brutlag to do that experiment. And you—you just jumped in on this.” 36

02-00:56:44 Hughes: Ooh!

02-00:56:45 Schekman: [laughing] Yes, I was a first-year graduate student. And he was just like—he erupted! I looked at the other people in the room, who were already well- established scientists, and they were turning shades of pink and looking for an escape hatch. They didn’t say a thing. And then I was dismissed from the room, before any resolution. I was wandering up and down the hallway outside of the office, wondering what my fate was. Racker, who had finished his preparations, came up to me. He could see how distraught I was. He put his arm around me, and he said, “Randy, I know how you feel. Arthur yelled at me today too.” [laughter] 37

Interview #2: February 26, 2014 [Audio File 3]

03-00:00:00 Hughes: It’s February 26, 2014, and Paul Burnett and I are in the office of Dr. Randy Schekman. Dr. Schekman, last time we raced through your time at Stanford, and now I think we should move on to UC San Diego. Perhaps you would tell me, why did you choose San Diego?

03-00:00:39 Schekman: As my career developed at Stanford, I became interested in biological membranes, through two influences. One, Kornberg himself discovered a year before I started in graduate school that biological membranes may be involved in organizing chromosome replication, and so he felt he had to learn about membranes. He did a series of sabbatical visits with different laboratories, including the laboratory of George Palade at Rockefeller University. When I joined Kornberg’s lab, he was just that first semester teaching a new graduate course in membranes, so I took the class. But my interest blossomed when a year later what turned out to be my best friend, Bill Wickner, joined Kornberg’s lab as a postdoctoral fellow. He had come from doing graduate work with Eugene Kennedy at Harvard Medical School. Kennedy was a very important biochemist who discovered the pathways of lipid biosynthesis in bacteria. So Bill had a real passion for membranes, and we talked endlessly about membranes and what was known or not known.

The replication reaction that reproduced all the authentic requirements for chromosome duplication that we talked about last time, when Bill discovered that membranes were not required for that reaction, at that point Kornberg almost lost his interest, not quite. But my interest persisted, because I felt as time went on that I did not wish to compete with Kornberg in the field of replication. He was such a dominant influence, such a powerful personality, and I somehow felt that I wanted the freedom to pursue things in my own way and to have my own identity. And so I started reading more widely in the cell biology of membranes, and I became aware of the work of S.J. Singer, John Singer, in the Department of Biology at UC San Diego. He had trained as a physical chemist. Kornberg and the people in the biochemistry department at Stanford knew him from that work in physical chemistry. But in the time since they knew of him he had become a cell biologist and used visual techniques, principally electron microscopy, to visualize membranes. And in 1972, I believe it was, he published a very important paper called “The Fluid Mosaic Model of Membrane Structure,” which crystallized the views on how membranes were organized.

03-00:03:43 Hughes: What was the model? 38

03-00:03:45 Schekman: The idea is that membranes are two-dimensional fluids where the long-range lateral movement of proteins and lipids is dictated by the lipid matrix of the membrane. So the lipid constituted the fabric, if you will, of a membrane, but it’s a two-dimensional fluid, so things should be free to move around laterally over long ranges, and with two degrees of freedom of movement, either lateral diffusion or spinning about an axis perpendicular to the plane of the membrane, but without transbilayer rotation, which would be thermodynamically unfavorable.

03-00:04:28 Hughes: Now had Singer worked that out, or was that already known?

03-00:04:32 Schekman: Well, Singer popularized it and crystallized the ideas. Others claim that they did the experiments that actually led to that [model]. Indeed, there were experiments that preceded this paper of his, which was a review article that established the mobility of proteins in membranes. But he put it together in the context of physical chemistry, which to my way of thinking looked like a unique contribution. So anyway, it influenced me. He had other papers that I found intriguing about how membranes may be put together, how there may be an assembly line.

My wife, Nancy Walls, who was then a nurse at Stanford, had not actually gotten her undergraduate degree in nursing. She [eventually] got an RN degree. She wanted to continue and get a bachelor’s degree, and she had taken credits at a local junior college, so she thought that it would be better if we were to stay in California because she would then be able to transfer her credits. So I restricted my search to California, not that I had to be persuaded to remain in California. [laughter] And so we focused on San Diego. In the end, she took her degree at the University of San Diego, a private school, which really didn’t transfer credits, so it really didn’t matter. But anyway, we were happy to go there and get away from Stanford. My relations with Kornberg had soured near the end, as we discussed last time, so I was happy to get away and start my life.

03-00:06:20 Hughes: You mentioned Palade, and I can remember seeing electron micrographs of what looked like a very static membrane. What happened between Palade’s work showing how a membrane is constituted and what seems to me a very dynamic model?

03-00:06:50 Schekman: Well, Palade devised techniques to probe the movement of things within the cell, but relying on electron microscopy as an output. In fact, his really most brilliant experiment, and the one for which he won the Nobel Prize, was using a combination of autoradiography and thin-section electron microscopy to visualize the movement of newly synthesized radioactive proteins from station 39

to station within a cell. So it’s not a real-time technique, and it’s almost primitive by what we can do now. But in the 1960s and seventies, it was the way that he was able to deduce the sequence of events in the transport of proteins in the secretory pathway. He came to Stanford because he was good friends with Kornberg and gave lectures. I have to say I wasn’t too taken with the work at the time because it was not particularly molecular.

Palade won the Nobel Prize in 1974, and the American Society for Cell Biology had its annual meeting in San Diego that year, just literally a month after I moved from Stanford to San Diego, and so I went to the meeting. The society now is a very large organization. It was more of a cottage industry back then. But he had a special reception and a packed audience, and he talked about— Basically, he gave his Nobel lecture and received a standing ovation. He’s a hero in the field of cell biology. Again, maybe it was my youthful arrogance, but I felt in listening to him that there was so much that he didn’t know. You could use these techniques and see how things moved within the cell, but there was no molecular appreciation. In fact, I found the whole field seemed to be very descriptive and without any molecular foundation. I guess I was spoiled by having just been in Kornberg’s lab and being able to probe things at a molecular level. So that’s where I began.

What I learned early on was that John Singer was also more or less in that mold of descriptive cell biology, and so we had lots of discussions, arguments about what I would do while I was in his lab. In the end he persuaded me to do a project looking at the process called endocytosis, the internalization of molecules into cells, in this case into cells of human neonatal erythrocytes. They had been described in the literature to be capable of endocytosis, whereas adult human erythrocytes are not capable of endocytosis. So I spent two years looking at that and learning to do electron microscopy But I have to say, I continued to be very frustrated with the tools then available to study human cells.

03-00:10:14 Hughes: Now, was your major technique electron microscopy?

03-00:10:17 Schekman: Yes, that was what I did.

03-00:10:18 Hughes: So that would tell you visually about the assembly but nothing about the molecular constitution?

03-00:10:24 Schekman: Yes, well, one could do some molecular experiments, but the scope was limited. I was learning a new discipline, and I was learning about membranes, and I was learning from somebody who had a broad knowledge of cell biology. 40

03-00:10:37 Hughes: Your work, as I remember, at Stanford, was all in E. coli.

03-00:10:41 Schekman: Yes.

03-00:10:45 Hughes: And now you were working in mammalian cells.

03-00:10:46 Schekman: Yes.

03-00:10:47 Hughes: What cell biology did you have to pick up on, if any?

03-00:10:52 Schekman: Well, I think I learned more of the literature and some of the techniques. But I also learned and was frustrated by the limitations of what one could do, particularly in this case, where I was reliant on cord blood from a local labor and delivery ward in a hospital. So I lived for those phone calls from the nurses to say that they’d have more samples for me. They didn’t seem to appreciate that my work was more important than delivering these babies. [laughter] So that was frustrating, and I have to say during that two-year period I really longed for the possibilities that came with studying microorganisms.

I resolved, even as I just started to work on these mammalian cells, that I wanted to work on yeast, because I was taken by the work of a yeast geneticist by the name of Lee Hartwell, Leland Hartwell at the University of Washington, who during the time I was a graduate student was dissecting the process of cell division in yeast using genetics. In fact, I remember meeting him. We had invited him to give a symposium presentation at Stanford when I was a student, and I remember reading that literature. I might have even considered postdocing with someone like him, but I decided against it.

03-00:12:29 Hughes: Was yeast being looked at now as a way of looking at mechanisms in higher organisms, that that was a good step to take from all the work in E. coli?

03-00:12:38 Schekman: Yes. I think increasingly people were. Molecular biologists who had worked on E. coli were moving into yeast because of the application of genetics.

03-00:12:48 Hughes: Was there the certainty, or at least a strong suspicion, that what happened in yeast would be true of even higher organisms?

03-00:13:00 Schekman: Yes, I think so. It’s a eukaryote, it has a nucleus, it has organelles, it has mitochondria. There were prominent investigators already studying 41

organelles. Gottfried Schatz, first at Cornell and then in Basel, Walter Neupert in Munich, were studying mitochondrial biogenesis in yeast.

03-00:13:27 Hughes: Using molecular techniques?

03-00:13:27 Schekman: Using molecular techniques, not necessarily genetic techniques. Fred Sherman at Rochester University was doing yeast genetics on mitochondrial respiratory function.

03-00:13:42 Hughes: So it was a reputable line of inquiry.

03-00:13:44 Schekman: I think people in the traditional cell biology community probably would have dismissed it, and did dismiss it as a model for mammals. I think in that 1974 meeting that I attended of the Cell Biology Society, I doubt that you would have seen very many papers from yeast people. The yeast people would have gone to more of a molecular biology meeting.

03-00:14:10 Hughes: Was it a practical choice to use yeast cells? You didn’t have to rely on people to give you cord blood? Why did you choose yeast?

03-00:14:21 Schekman: Oh well, it’s practical in many senses. Obviously, you can control the growth and genetic composition of a yeast strain. It’s an organism. See, you work with cells from a mammal [as] tissue culture cells. It’s not an intact organism; it’s somehow artificial, whereas yeast is an organism. And the genetics were and are powerful. In some ways, it was easier to do yeast genetics than bacterial genetics because yeast can grow in a haploid or a diploid life cycle. So you can make mutations in a haploid strain, and then you can mate the two mating types and establish genetic relations by genetic complementation. It’s actually technically much easier to do that with yeast than with coli, at least back then.

03-00:15:20 Hughes: Were you doing that already?

03-00:15:23 Schekman: No, I wasn’t; I was not a geneticist. I was certainly familiar with the language, and I’d done some simple genetic manipulations, but I was not a geneticist by any stretch of the imagination. But I was deeply appreciative of Hartwell’s work. I was also influenced in my graduate work by the availability of mutants in DNA replication, which I think we discussed last time, and was influenced by the work of bacteriophage geneticists who were able to study bacteriophage particle assembly and to use a combination of genetics and biochemistry to reproduce the assembly of a bacterial virus in a cell extract. 42

03-00:16:11 Hughes: Did that ring a bell with you, that the conjunction of those two approaches was useful?

03-00:16:16 Schekman: Yes, oh yes, that certainly influenced me very early in my graduate work.

03-00:16:22 Hughes: Were you unusual at the time?

03-00:16:23 Schekman: Was I—?

03-00:16:25 Hughes: Your training was biochemistry and molecular biology. It was not a given that you were going to segue into genetics.

03-00:16:35 Schekman: Well, because of what I did as an undergraduate, I was aware of genetic studies on DNA replication, and although Kornberg was almost antagonistic to genetics, he himself in his lab, before I was there, had used bacteriophage mutants to understand bacteriophage replication to some extent. He just didn’t see the use of it in the kind of enzymology that he wanted to do. I introduced that into the laboratory when I went across the way to the laboratory of Phil Hanawalt in the biology department at Stanford and picked up the temperature-sensitive DNA replication mutants of E. coli and brought them into the Kornberg lab. Because I was aware of the literature on this, I was able to do an experiment that no one else in the lab would have even thought of doing, and that led to my being able to develop biochemical assays for the gene products that actually are required for replication. That experience—I think I mentioned this last time—powerfully imprinted on me and set the stage for what I was going to eventually do on my own here at Berkeley. But the contour of that, the ideas, had not gelled yet.

But the time that I had in San Diego was really valuable. I have to say, I wasn’t so engaged in what I was doing there experimentally, but I was really keenly interested in what I was going to do on my own when I got to Berkeley. In fact, maybe it was a reflection of the times, when I interviewed for the job here at Berkeley, it was very early, like in the first few months that I was a postdoc, and my interview seminar was my graduate work. It wasn’t anything to do with my postdoctoral work.

03-00:18:29 Hughes: Oh really?

03-00:18:31 Schekman: Yes, that would be kind of unheard of now, but it wasn’t so unusual then. Postdocs tended to be shorter in term, and my graduate work had been very successful. I wasn’t as confident that my postdoc work would be as 43

productive, and so I wanted to apply early on, and I did, and I got the job here at Berkeley.

03-00:18:54 Hughes: Right then?

03-00:18:54 Schekman: Pretty much at the beginning of my postdoc.

03-00:18:57 Hughes: Was it a given that your graduate work would not be exactly what you would be coming to Berkeley with?

03-00:19:11 Schekman: There was, I think, very much less attention paid to having detailed plans. I remember writing a prospectus on what I was thinking about doing here. There were two very different possibilities, one having to do with E. coli cell division and the other having to do with yeast cell division.

03-00:19:31 Hughes: Why did the biochemistry department want you to come?

03-00:19:35 Schekman: Well, I’d been very productive as a graduate student. I’d been very successful. I was not their first choice.

03-00:19:46 Hughes: Oh really?

03-00:19:49 Schekman: Oh, yes. If you look at the people who applied that year, it’s quite remarkable. Roger Kornberg was one of the applicants for that job. And a fellow named Keith Yamamoto, a very successful scientist at UCSF.

03-00:20:00 Hughes: Oh yes.

03-00:20:01 Schekman: He was also a candidate for that job. But the first offer was given to a peer of mine from Stanford, a woman named Janet [E.] Mertz, who had been a graduate student with Paul Berg and who had been very successful as a graduate student. They had no women in the department here, and so they felt pressure even back then to hire a woman, so I think that was part of the reason. But she was really not interested in being in what at the time was a traditional biochemistry department, so she turned the job down.

03-00:20:41 Hughes: Maybe like you she wanted some independence. 44

03-00:20:45 Schekman: Yes, maybe that was it. She got the job here, I think, before she started her postdoc.

03-00:20:53 Hughes: I’m wrong. She had been at Stanford.

03-00:20:56 Schekman: She had been at Stanford. Yes, she hadn’t been here. She was on her way to MRC [Medical Research Council] Cambridge for her postdoc with John Gurdon. Anyway, she was offered the job here, but fortunately turned it down and decided to accept a position in a molecular biology department at Madison, Wisconsin. And so then they went to me, and I accepted the job over the phone. [laughter] I was a very foolish negotiator. Mike Chamberlin, who was the chair of the search committee, called to offer me the job, and I think I more or less said, “Great, I’m coming!” [laughing]

03-00:21:36 Hughes: Without any discussion of salary or space.

03-00:21:43 Schekman: Yes. I was naïve, very naïve. Anyway, the San Diego period was crucial. It gave me a lot of time really to think about what I wanted to do. So I read the literature on yeast and what little was known about yeast membranes and vesicular traffic in yeast. There was really very little, very little.

03-00:22:11 Hughes: Did Singer leave you alone? He could see that you would run with it?

03-00:22:15 Schekman: Yes. He was almost the exact opposite of Kornberg, who was very hands-on and very demanding. Singer was laid back and—ambitious. But his approach to science was to think of creative ideas that conformed to his view about how membranes were constituted. Then he’d suggest a broad investigation, and then he’d say what you should expect to find, and as soon as you validated his views with one experiment he was ready to write the paper. [laughter] It was so different from Kornberg. Frankly, it didn’t suit my personality either, and so we didn’t really see eye to eye.

03-00:23:04 Hughes: You were leaning more towards Kornberg’s approach in that particular area?

03-00:23:07 Schekman: Oh yes, oh yes. I wanted a molecular/mechanistic approach, and it just didn’t seem feasible to do that while I was in Singer’s lab.

I’ll never forget the first year I was there, probably after Palade’s lecture, two very important papers came out in the Journal of Cell Biology by Günter Blobel, a protégé of Palade’s at the Rockefeller University, which described a biochemical reaction that allowed him to reconstitute the translocation of a 45

protein across the membrane of the endoplasmic reticulum. It led to what he proposed, called the signal hypothesis, which years later led to his Nobel Prize.

03-00:23:57 Hughes: Please explain the signal hypothesis.

03-00:24:00 Schekman: Yes. What Palade had done in his work at the Rockefeller, among other things, was he found a way of isolating pieces of the endoplasmic reticulum (ER) membrane with a ribosome still stuck on. Palade could show in the test tube that if you allowed the ribosomes to continue to elongate protein chains that they were caught in the act of making when the tissue was homogenized, they would progress until the end of the polypeptide, and the remaining polypeptide would thread across the membrane to which this ribosome was bound and would come to rest in the interior, the luminal space of the ER. What Palade could do was to capture the event and then complete the event in vitro. So that was the extent of his biochemical analysis. It was really important stuff. It was done actually by another protégé in his lab named David [D.] Sabatini, who was a peer of Blobel’s in the Palade laboratory.

03-00:25:04 Hughes: I realize that you were fine-tuning what must have been a very rough model of how protein trafficking occurs. People knew that it had to come from the ribosome to the ER [endoplasmic reticulum] and then onto the Golgi, but nobody knew how.

03-00:25:33 Schekman: No, the molecular aspects of this were obscure.

03-00:25:36 Hughes: Unknown.

03-00:25:37 Schekman: Obscure, obscure. What Palade’s experiment suggested but didn’t prove was the existence of some channel in the ER membrane to which the ribosome would adhere and through which polypeptide chains would progress across the membrane of the ER into the interior of the luminal space. Palade’s experiments allowed one to study the completion of that reaction, which didn’t lead inevitably to the discovery of the channel but at least allowed one to think about studying this biochemically.

The independent work of Blobel was to dissect that reaction further. Blobel found a way of taking these membranes with ribosomes on them and stripping the ribosome off. Then he could take ribosomes and mix the ribosomes with messenger RNA that encodes a secretory protein and all the goodies necessary for protein synthesis, and mix those ribosomes’ messenger RNA nascent chains with stripped ER vesicles and initiate as well as complete the process. So whereas Palade was only following the tail end of it, Blobel was able to 46

initiate the process and study all aspects of that from beginning to end. He discovered in the course of doing this that the newly synthesized secretory protein has a piece of information at its amino-terminus called the signal peptide, which is cleaved, clipped off of the polypeptide as it pokes its way across the membrane; a step that precedes anything that Palade could have seen. From that he extrapolated the theory that that piece of information was the signal that directed the nascent polypeptide ribosome complex to a special site on the ER membrane. He predicted that site would be a channel that specialized for the translocation of proteins.

03-00:27:55 Hughes: But nobody was figuring out what the genetic basis of all this is?

03-00:28:00 Schekman: No, not in eukaryotic cells. Now, around the time of those two papers by Blobel, Jon Beckwith at Harvard Medical School and a postdoctoral fellow in his lab named Tom Silhavy started doing genetics in E. coli on protein secretion and developed a genetic approach to identifying gene products that interacted with a signal peptide that’s involved in the translocation of proteins from the inside of an E. coli cell across the cytoplasmic membrane of the bacterium. They [identified] genes which eventually turned out to constitute the channel in the E. coli inner membrane that subsequently turns out, years later, to be formally equivalent to the channel proteins in yeast and in mammalian cells. But those were early days, and they hadn’t actually identified the channel protein just yet, at around the time Blobel was doing this.

These two papers came out in 1975 in the Journal of Cell Biology, and I remember Singer being quite taken with the conclusion about the signal peptide because it conformed to his ideas about membranes being thermodynamic barriers that would preclude the passage of large polar groups unless facilitated by some kind of a channel. So he liked the idea of the signal hypothesis. But then, as I drew him out on the approach that Blobel was taking, he said something memorable which has stuck with me all these years. He said, “Well Randy, you’re never going to learn anything about how membranes are put together if the first thing you do is make a homogenate,” which is antithetical to the principle of Arthur Kornberg. [laughing] So I thought oh God, now I’m in for it! [laughter]

03-00:30:25 Hughes: So what did you do with it?

03-00:30:29 Schekman: Well, I wasn’t doing anything of that sort in his lab, so it just struck me that someone would say such a thing. And it’s actually not an unusual comment. Basically, people who are biologists or geneticists share that view. They’re suspicious. Anytime you break a cell open they’ll say— We have this notable colleague, Harry Rubin, here at Berkeley, who is almost a vitalist in his view 47

on whether molecules are relevant to life. [laughter] Frankly, it’s a silly attitude. It’s a completely silly attitude because pathways have been established through biochemical analysis since the beginning of the twentieth century. It’s almost as bad as arguing against evolution, but it’s an attitude that too many biologists share.

Anyway, the important thing in terms of my career was that it was a good time to reflect on what I wanted to do and how I wanted to go after things. I spent months near the end of my time—when we knew we were moving up here— preparing a research grant for federal funding based on ideas that I had at the time about how one might study how yeast cells divide physically, how they pinch at the division cleavage plane. I was really interested in that. There was some evidence for vesicular traffic feeding that division plane, and so I had these grandiose ideas about isolating secretory vesicles from yeast and isolating the division septum. I was proposing a career worth of work for a few years of support, and I had the grant read by lots of people, including Dan Koshland. Most of them said great, really original, looks terrific. Mike Chamberlin, who was here at the time, read it and said, you know, you really need some meat-and-potato projects too that are going to work. I had all these pie-in-the-sky things for which I had no preliminary results. And so there was a note of skepticism in some people, but most people thought this is really original. Of course I submitted it to the NIH, and it was trashed shortly after I got to Berkeley. The grant came back with very critical remarks.

03-00:33:15 Hughes: What were the specific criticisms?

03-00:33:17 Schekman: Well, I had no relevant experience with yeast. My one experience was that in the summer before I came to Berkeley I took a three-week Cold Spring Harbor course on yeast genetics. It wasn’t really any kind of an immersion in the field, and the committee was dismissive of that. I had no experience working on vesicular traffic. I had no preliminary results, because I hadn’t worked on yeast. [laughing] But the thing that really hurt was that, “He’s proposing things that haven’t been done before.” This was levied as a criticism! [laughter] I thought that’s what it was all about.

03-00:34:09 Hughes: Yes, but you were a young thing, just starting out.

03-00:34:09 Schekman: Well, looking back now—I probably have that grant somewhere—of course I was naïve; I was naïve at many levels. I was naïve in the breathtaking scope of things that I was proposing to do with my own two hands. I had no experience.

03-00:34:35 Hughes: So there you were without funding. 48

03-00:34:38 Schekman: Yes, well so I got— In my negotiation to come to Berkeley, Dan Koshland was the chair of the biochemistry department. Since they gave me the offer so much before I was actually going to be here, I had an offer at UCLA. A man named Paul Boyer, who started the Molecular Biology Institute there, had invited me to join their faculty. The offer at the time was, I think, a set-up fund of $50,000, which seemed like a king’s ransom, and Berkeley was offering me nothing. Koshland said, “Well, you know, it’s so much in advance, you’ll write a grant and put in the equipment that you need in the grant, and you’ll get the money.” I said, okay. At UCLA, Boyer offered me assistant professor step III. You know there are all these steps. Koshland offered me step II. So in one of the meetings I had when I came up here I said, “How come, since it’s all the University of California, that I would be offered step III there and only step II here? It amounted to maybe $500 a year difference in salary. And Koshland—I’ll never forgive him for this—said, “Well, each step means an additional two years, and so if you take a step III you’ll have two fewer years in which to be considered for tenure. I said, “Oh my God, that’s terrible. Well gee, maybe I should take a step I.” [laughter] Why would he lie to me? It’s not true. It’s just not true. He probably didn’t even know. He was looking for some excuse.

03-00:36:28 Hughes: He wanted you to come.

03-00:36:29 Schekman: He wanted me to come, but there was a certain insensitivity. When we negotiate with an assistant professor now, it’s a different game. Back then I think the feeling was, listen young man, we’re doing you a favor.

03-00:36:50 Hughes: Well, that’s Berkeley isn’t it? That’s the image.

03-00:36:52 Schekman: Well, not anymore. It hasn’t been that way for a long time.

03-00:36:57 Hughes: Was it in your thinking that if I’m going to choose between the two, Berkeley has more prestige? You’d had a great time as an undergraduate at UCLA. Why weren’t you more interested?

03-00:37:14 Schekman: The biochemistry department was really very strong. It had really outstanding people in it.

03-00:37:22 Hughes: Here.

03-00:37:21 Schekman: Here. More so than at UCLA. With Bruce Ames and Dan Koshland and Howard Schachman and Mike Chamberlin and Stuart Linn. I remember 49

vividly my interview here in what was then called the Biochemistry Building, subsequently called Barker Hall. It felt good, it was a unit, everyone was in this building, there was a good spirit. It just felt right to me, and UCLA was still not well formed. The Molecular Biology Institute didn’t have a real home yet. There was no immediate prospect of a building. And all along I had this image of Berkeley and the strength of Berkeley. I do remember thinking though, when I was at Stanford and first applying for the job to Berkeley, that oh God, it’s a public institution, and there are going to be problems with it that I remembered when Ronald Reagan was governor. But that all melted away when I visited here and I saw this good, really excellent spirit in that department. The fact that it was a classic biochemistry department just didn’t detract from it at all as far as I was concerned, quite unlike what Janet Mertz felt. I thought that was a very appealing thing. I wanted to do this. I wanted that influence, even though I was thinking about doing something more biological. My goal was inevitably to do biochemistry.

03-00:39:00 Hughes: More biological, but more genetical.

03-00:39:05 Schekman: Well, okay. My first NIH grant application— My first thoughts when I started at Berkeley were not really genetics. I wasn’t proposing to do genetics. In fact, I remember my undergraduate advisor at UCLA said, “Well, are you going to actually do genetics?” And I remember saying, “No, probably not. But it’s going to be available like it was when I was a graduate student, and I’ll avail myself of it as I need it.” And that was naïve. I think probably I’d been infected a bit with the Kornberg antipathy to the genetic approach. Curious that I would have such an attitude considering how I used it.

During this really intense period when I was in San Diego thinking about what I wanted to do, I had a little card catalog. Every time I’d have a fresh idea, I’d write out more ideas on a three-by-five card. I remember one of those cards was yeast secretion mutants and how one might go about isolating yeast secretion mutants.

03-00:40:26 Hughes: Were those naturally occurring mutants or were people inducing them?

03-00:40:32 Schekman: Well, you know, mutations arise spontaneously at a low frequency, and you could screen for naturally occurring mutations. But typically you actually use a chemical mutagen to enhance the process and allow you to look through more colonies to find mutations in greater frequency. Anyway, so that was one of many thoughts that actually didn’t even find its way into my first NIH grant, not that it would have helped, I don’t think. 50

03-00:41:03 Hughes: So obviously, you weren’t worrying about the status of genetics on this campus.

03-00:41:09 Schekman: No.

03-00:41:11 Hughes: It wasn’t a particularly strong field here, was it?

03-00:41:14 Schekman: Yeast genetics was actually very strong, not in the biochemistry department, but there were two prominent yeast geneticists on campus, Bob [Robert K.] Mortimer and Seymour Fogel.

03-00:41:28 Hughes: What about [Clinton] Ballou?

03-00:41:30 Schekman: And Ballou. Well, okay. So Ballou also was in the biochemistry department, and he was actually studying things that were very relevant to what I was proposing, although he’s a chemist. He’s a carbohydrate chemist by training. He had isolated yeast mutants defective in glycoprotein/glycan biosynthesis. I became aware of his work. I didn’t quite see the point of it. [laughter] It wasn’t really the sort of thing that I was thinking about. But anyway, he was here. And so yes, he was certainly doing some yeast genetics, and he was isolating mutants, but no one would call him a geneticist.

03-00:42:17 Hughes: Okay. We’re left with you lacking a grant.

03-00:42:22 Schekman: Lacking a grant. Okay, well I had also applied more or less simultaneously to the NSF.

03-00:42:29 Hughes: The other application was to the NIH?

03-00:42:31 Schekman: Yes, but the NSF [awards] smaller grants. When I was at Cold Spring Harbor for that three-week period doing this yeast genetics course, Lee Hartwell came to give a lecture, and he told me that he was one of the referees on the NSF grant, and he said he really liked it. In fact, I remember he said it was really good to read a yeast grant that didn’t involve isolating more mutants. [laughter] And it’s true, I wasn’t [planning to]. But he liked it, and I heard from someone else that they had reviewed it. So it was reviewed favorably and I got $35,000 for two years from the NSF.

03-00:43:13 Hughes: Oh my God. 51

03-00:43:14 Schekman: A pittance. And then there was a small grant that I got from the Cancer [Research] Coordinating Committee in the UC System, and so I got $10,000. So I had a few thousand dollars to begin with. Of course the graduate students that joined my lab were supported on training grants, and the department gave me some used equipment, some of which worked. [laughter] Everyone said if you need stuff come and use it in my lab.

03-00:43:48 Hughes: So it sounds like a friendly place.

03-00:43:50 Schekman: It was very friendly, very friendly, yes. So we started, and I was constantly struggling for money. I didn’t even bother to apply to the NIH for a couple of years, until we isolated the first secretion mutant. And then it was clear, at that point, that we had a lot of things that we could do. Then two years later the NIH gave me a grant, so I had support.

03-00:44:25 Hughes: So that was about 1978?

03-00:44:28 Schekman: Probably ’78.

03-00:44:33 Hughes: I know from looking at least at the synopses of your papers that Peter—is it Peter Novick?

03-00:44:37 Schekman: Peter Novick, yes.

03-00:44:39 Hughes: Did he come right away?

03-00:44:42 Schekman: He was the first year, yes. I think he rotated in my lab in the spring semester, so that would have been early 1977. He had been an undergraduate at MIT, and he’d worked in a lab in the medical school at Columbia. His father was a physics professor at Columbia. [Peter] was very smart but very quiet, very quiet, and so it was really hard to get much out of him. [laughing] But he wanted to join the lab, and he seemed bright. We started in in the summer of 1977, I would say. He was going to study secretion. The objective, I think initially, was to get a way of isolating secretory vesicles from yeast cells. One of the ideas that I had that was a foundational idea was that the secretory vesicles in the bud portion of the dividing cell would be responsible not only for secretion but for assembly of the cell surface. That is, the membrane of the vesicle would be the building block for the plasma membrane in the cell. That was not a given, and certainly no one else had really done anything to test, to even talk about that idea, at least not in yeast. 52

03-00:46:15 Hughes: Why would you think that?

03-00:46:19 Schekman: Well, you have these packets of secretory proteins. The membrane of the vesicle obviously is going to have not only lipids but proteins. Why not consume the container as an act of allowing a quantal growth of the plasma membrane? Why just use it to discharge proteins into the cell wall and then resorb the vesicle to be recycled? Yeast cells, unlike mammalian cells, can go quiescent but continue to make and transport macromolecules. Yeast cells are continuously growing and secreting when they’re on a rich growth medium.

03-00:47:03 Hughes: It’s also kind of conservation of energy, is it not?

03-00:47:06 Schekman: Okay, but that’s a dicey argument when it comes to cells.

03-00:47:10 Hughes: Is it?

03-00:47:11 Schekman: They expend energy for all kinds of things that you might consider wasteful.

I don’t know, it was sort of a no-brainer to me. Maybe it was that others had not really thought about it. But to me it was a no-brainer that these vesicles would be the building block of the plasma membrane. So my initial thought to test that was to have a way of isolating these vesicles and studying their composition. But they’re so few in number in a normal yeast cell because the process of secretion is so efficient. Novick and I initially thought to interfere with this not by mutants but by drugs, by some kinds of chemical inhibitors. There were some things that were used back then to study secretion. They were pretty crude, blunt inhibitors. So we tried a few of them, and fortunately nothing worked. [laughter] So at that point I said all right, well I guess we’ve got to isolate mutants. It was almost sort of in frustration.

03-00:48:08 Hughes: Then you got into the temperature-sensitive stuff.

03-00:48:11 Schekman: Well yes. So then the obvious prediction would be that if these things are essential for allowing the cell surface to grow, you’d have to have conditional mutants because a deletion would be lethal. And that would be a traditional approach that had been used in bacteria and also used in yeast over many years, so that was nothing terribly novel. But initially, again influenced indirectly by genetics, we thought, I thought, we would need some clever selection procedure for the mutants, not merely a screening. See, what Hartwell did, which was almost trivial but really elegant, was he took cultures of yeast and exposed them to a chemical mutagen and then just plated them out and looked for temperature-sensitive colonies, and then inspected cells 53

from each ts colony for the appearance of the cell in the light microscope. You could tell when mutation was specifically affecting a particular stage in the cell division cycle because the cells would arrest with a unique, what he called terminal morphology that was characteristic of the event that was blocked. So his was just a pure visual screen.

03-00:49:34 Hughes: I see. But this procedure doesn’t halt the process in a specific area of the cell, does it? You’re not finding that only the very beginning stage has been blocked.

03-00:49:46 Schekman: No, that’s what it was.

03-00:49:47 Hughes: Oh.

03-00:49:48 Schekman: But in his case, the cells continued to get bigger. But they arrest without a bud or in a dumbbell shape, or sometimes the multiple buds would come out. They were affecting cell morphology in a way that he could somehow understand. So it was just a very elegant, simple screen.

But most geneticists operate by a different principle. They think that they have to have some selection procedure where you actually impose conditions that would allow a mutant to survive, whereas a wild-type cell would die. That’s called a genetic selection, and it’s powerful in an organism like yeast or E. coli because you could mutagenize millions of cells, and if you had a really powerful selection the mutant would survive on a Petri plate, whereas everything else would die.

03-00:50:41 Hughes: So it was a no-brainer that you were going to go in that direction.

03-00:50:43 Schekman: Yes, that was the obvious thing to do. But how to do it? The devil’s in the details. So the idea I cooked up was the following. It was known at the time that yeast cells will take up sulfate from the growth medium.

03-00:51:01 Hughes: Sulfate?

03-00:51:01 Schekman: Sulfate, the oxidized form of sulfur. It’s used for biosynthetic purposes to make the amino acids cysteine and methionine. Someone showed in the literature that when you starve cells for sulfate, the sulfate permease is induced, and you can measurably detect the increased ability of a cell to take up radioactive sulfate. They also found that these cells that had the permease could be fooled into taking up chromate. I guess the valences of chromate and sulfate are similar. Chromate is toxic. Chromic acid’s used in detoxifying 54

glassware. My idea was the following: if you had a mutant that blocked the assembly of the cell surface, then the newly synthesized sulfate permease would not appear at the cell surface, and therefore these cells would not be killed by chromate. Okay? So that was a selection procedure.

03-00:52:24 Hughes: Were you worrying about using chromate?

03-00:52:25 Schekman: Well, I should have been, as will become clear in a moment. Well, you use it in chemical concentrations that are not overtly poisonous.

So the idea was, make mutants, mutagenize the yeast culture, incubate it at a high temperature—a temperature that might be characteristic for a temperature-sensitive lethal mutant but not a temperature at which normal yeast cells would die—starve the cells for sulfate so that they start to induce the production of the sulfate permease, but at the high temperature add chromate to the medium. The hope was with time that the mutants that couldn’t assemble the sulfate permease would not die, whereas wild-type cells would take up the chromate and kill themselves. Okay?

03-00:53:26 Hughes: Okay.

03-00:53:27 Schekman: So we found a colony that survived this exposure, that was temperature- sensitive lethal, and it blocked secretion too—fantastic! And this was actually the first mutant, sec1.

03-00:53:46 Hughes: Now, were you lucky there?

03-00:53:47 Schekman: I’ll tell you why we were lucky, yes. So we could show that this cell accumulates two different secreted enzymes inside the cell. The process of secretion is very rapid in yeast. If you take a normal yeast cell, and you dissolve the cell wall away, and you look inside of the cell, inside of the plasma membrane, at any given moment the intermediates of secretion are sparse. There’s not much because secretion’s just very efficient. But in this case, this mutant, when you incubated the cell at high temperature and then dissolved the cell wall and you looked inside the cell, these two different secreted enzymes were now ten times higher than normal. Then if you shifted the cells back to room temperature you could show that this bolus of secreted enzyme now was discharged at the cell surface. So it really was a bona fide secretion mutant.

So that was great, and we would have carried on with this apparent selection. But I had an undergraduate and I said, “Well, just as an exercise, let’s compare the ability of this mutant to withstand this chromate selection versus 55

wild-type. So take the mutant, grow up the culture, do the shifting conditions at the high temperature and the presence of chromate, and then check the viability of that cell in the chromate medium as a function of time at thirty- seven degrees centigrade, and do the same in parallel with a wild-type cell.” Okay. The expected result was that the mutant unable to take up chromate would survive in the presence of chromate at thirty-seven degrees longer than a wild-type cell would survive at thirty-seven degrees. But in fact, that isn’t what happened. It was exactly the opposite.

03-00:55:37 Hughes: Why?

03-00:55:39 Schekman: The mutant died more rapidly than a wild-type because it turns out that when you block secretion and cell surface growth, the cells choke to death. Basically they die of constipation, and they die whether you’ve got chromate there or not.

03-00:55:54 Hughes: I see.

03-00:55:55 Schekman: So when I saw that I said, well, if an anti-selection procedure works, surely we would be better off just doing a Hartwell-like screen. Let’s just isolate a bunch of temperature-sensitive colonies and screen them for secretion defects. And we did that. We just randomly picked another hundred temperature- sensitive colonies, and we found one more mutant. Then we published it. And although we didn’t actually talk about this chromate business in the paper, I did subsequently reveal that bit of dirty laundry in a retrospective article that I published some years later. [laughter] It was an object lesson.

03-00:56:40 Hughes: But interesting how what you considered almost a throw-away experiment led—

03-00:56:45 Schekman: Yes, just a control. I think we probably would have realized this sooner or later anyway, but it was a funny little story.

Is this where we want to be in the discussion? Are we now at Berkeley?

03-00:56:59 Hughes: Yes, we’re just moving along.

03-00:57:08 Schekman: Okay. Yes, so we had this mutant, and by doing enzyme assays it was really a bona fide secretion mutant. But then George Palade came by for a special honorific couple of lectures, and I hosted him. We’d met before, but he didn’t remember me. I remember vividly, he came to my office, and I told him about this finding, and he was pleased and surprised. He said he wasn’t aware that 56

yeast cells secrete glycoproteins. Why would he be? So I was tickled that I was able to tell George Palade something. [laughter] He gave a couple of inspiring lectures, and it was good to get to know him a little better. There was apparently a dinner meeting with graduate students where Novick told him about his mutant. Although Novick says he doesn’t remember this, I remember him telling me that at that lunch Palade encouraged him to have a look by thin-section microscopy at this mutant.

03-00:58:13 Hughes: Which you hadn’t been using?

03-00:58:13 Schekman: We hadn’t done it yet. We were going to do it, that’s for sure. No question, we would have done it. But it was early days, and we hadn’t gotten around— Anyway, he did it, and that was the eureka moment when Novick called me down to the EM room in the basement of the biochemistry building, and he showed on screen these images of the cell—it was just filled with vesicles.

03-00:58:42 Hughes: Pretty impressive.

03-00:58:45 Schekman: Yes, that was a moment to savor.

03-00:58:52 Hughes: You published that work?

03-00:58:54 Schekman: Yes. So then we published that in April of 1979 in a paper that Dan Koshland communicated to the Proceedings.

03-00:59:03 Hughes: Because you weren’t yet a member of the National Academy of Sciences?

03-00:59:06 03 Schekman: No, of course not.

03-00:59:05 Hughes: Too young.

03-00:59:07 Schekman: I was thirty years old. To that point Dan was kind of skeptical about what I was doing.

03-00:59:20 Hughes: Why?

03-00:59:20 Schekman: Well, I hadn’t published much. Remember, he was the chair of the department, and it came to the point of what we now call mid-career review, and he admonished me, “You’d better publish, you’d better publish.” It was 57

almost three years into my term and I’d published one or two papers. But it wasn’t seen as enough and there weren’t any big breakthroughs. I was trying to study this cell division septum formation in yeast, and it was seemingly obscure. But from that moment, with that paper and the reception that that paper received from referees, Dan became an advocate. I remember he periodically would come to me and say, “What have you learned today?” “More mutants.”

03-01:00:16 Hughes: So he became a Randy fan.

03-01:00:15 Schekman: Yes, he was a real advocate at that point. From that moment on it was clear to me what my direction would be, and I mobilized the group, my nascent group, along those lines. There were some other threads that I’d started before then, but all the new people in the lab joined that project, isolating more mutants, characterizing the glycoprotein forms that were intermediate in this pathway. It was a very, very productive few years.

I remember that first paper, which was in PNAS in April of 1979, was followed just eighteen months later with a really massive paper that Novick wrote, that we published in Cell. This was the first years of this journal Cell in the life sciences. I hadn’t heard of it when we published our first paper in the PNAS, but by the next year everyone in the life sciences had to have their best work published in Cell. This guy [Benjamin] Lewin really captivated the imaginations of the molecular biology field.

03-01:01:27 Hughes: Was it pretty much PNAS before Cell appeared?

03-01:01:33 Schekman: Well, that was the journal of record as far as I was concerned. Certainly, that was the journal that I wanted to publish in when I was a graduate student. We always wanted to have all of our best work in the PNAS, and I felt that way initially as an assistant professor too. But by 1980 PNAS was restricted in length, so you couldn’t have a very long paper, and Cell offered you more space, and there was more of a buzz about Cell.

[Audio File 4]

04-00:00:01 Hughes: Randy, we were talking before the break about the Cell paper, and I’m cribbing from the sheet that you kindly sent me about your significant papers. I notice that it was something about complementation groups, and I don’t know what they are. 58

04-00:00:35 Schekman: Yes, a complementation group is a formal way of describing a gene. A gene is genetically defined by this test that was developed by Seymour Benzer called the cis-trans test.

04-00:00:53 Hughes: Oh yes.

04-00:00:53 Schekman: So if you have mutations in a pathway that affects the production of some product or the ability of the cell to grow, and you have the same mutation in each of the two mating types of a yeast cell, and you mate the cells to make a diploid cell, if the mutations are in the same gene, the diploid cell will still be defective. So that says that those two mutations failed to complement one another. However, the mutations may be in two different genes that feed the pathway, either the production of some molecule or the ability of the cell to grow— Each mutation, let’s say, is temperature-sensitive lethal by itself. If you make a diploid, then the diploid cell should no longer be temperature- sensitive because one will replace the other and therefore they will be said to have complemented one another. And so you establish the genetic complexity of a pathway by this simple cis-trans test complementation groups.

04-00:02:07 Hughes: Was that something new?

04-00:02:09 Schekman: No.

04-00:02:11 Hughes: When did Benzer come up with it?

04-00:02:12 Schekman: He had established this with bacteriophage T4, maybe even in the late fifties.

04-00:02:18 Hughes: Okay.

04-00:02:20 Schekman: It was certainly not new, and it had been applied to yeast, and it was a standard genetic test. This was before one could clone a gene in yeast. So you could easily establish genetic complementation groups, and then you could further refine that analysis by genetic mapping, mapping the mutation by doing recombination analysis. And so people at the time were establishing the genetic map of yeast by doing crosses. The distance between two mutations could roughly be mapped based on the frequency with which the chromosomes harboring these two mutations would recombine with one another, the recombination frequency, which is different than complementation. So one could actually map mutations with respect to each other and get a rough linear sequence of the genes arranged along the yeast chromosomes. 59

Most yeast geneticists would map the mutations, but I resisted this because I felt that knowing the map position with respect to one or another yeast chromosome was not important information to me. I didn’t care where it mapped. See, I wanted to use these mutations to understand the pathway and to understand the mechanism, and the position of a gene on some map was to me irrelevant. Geneticists pooh-poohed my attitude about this. But I knew at the time that it wasn’t going to be too much more down the road [that] people would be able to develop a physical map of the gene. And sure enough, when it became possible to clone genes, then you could actually develop a physical map.

04-00:04:06 Hughes: How are you figuring out exactly where it’s happening? Is it very clear when it’s in the endoplasmic reticulum?

04-00:04:23 Schekman: Oh, okay. So this was this 1980 Cell paper of Novick’s, so he— Let me take a step back. So we had the 1979 paper where he had sec1, and it was already clear even then that you could isolate these mutants in just a random set of temperature-sensitive colonies, but it was going to take a lot of colonies to find more genes. We knew that there had to be more genes. And so we thought all right, well, we still need some kind of a selection procedure or an enrichment procedure. The first one obviously didn’t work because we didn’t, at the time appreciate that these mutant cells were not merely unable to grow at the restrictive temperature, but that as they are held at the restrictive temperature they would die.

04-00:05:15 Hughes: Let me stop you again because you’re talking to a person who isn’t a scientist. You know you haven’t identified all the genes because you know that for the proteins to move along you’ve got to have sequentially lined-up genes that are—

04-00:05:33 Schekman: Palade’s sequence of events in organelles to me demanded lots of different gene products to execute each of these. It was intuitive that it would be a complex pathway, just like the cell division cycle pathway of Hartwell’s was complex, dozens of genes each operating in a different, unique step. After this 1979 paper we had exactly two genes, two different mutations in two genes. There had to be more. So we wanted to have a way of enriching for more mutants. And consistent with the observation that we had already that these cells would die if they were held at the high temperature for too long was that you had to be quick about it. You had to have some selection that could be imposed fairly quickly.

So Novick, observing the sec1 mutant in the microscope, noticed that they became phase refractile as though there was some property of the cell that was refracting light more effectively than a normal cell. Moreover, you could 60

observe, as these cells were incubated at the restrictive temperature, that they stopped dead in their tracks. Unlike Hartwell’s mutants which continued to get bigger even though they arrest with a terminal-unique morphology, in our case the mutants just didn’t get any bigger. The cells just seemed to be dead, but we knew metabolically that they were active and that they were making things and accumulating vesicles, so they had to be making up more proteins. But somehow those wouldn’t allow the cell to enlarge, and so it became obvious to think that maybe the cell was somehow becoming more dense; its buoyant density was increasing.

That was an interesting thought because two years earlier an investigator at Albert Einstein Medical School, Susan [A.] Henry, had observed that when cells are starved for an essential phospholipid, they become dense. She found that these dense cells could be separated from normal cells on a density gradient, an experimental technique that you use typically to separate macromolecules, but which she could use to actually separate cells. So she used a substance that was called Ludox, which is basically a preparation of glass particles which will form a gradient. If you just take this slurry of glass particles in a buffer and you put it in a centrifuge tube and you centrifuge the tube, you form a gradient of particles because they have a different distribution of sizes. Cells would equilibrate at a buoyant density close to the density of the glass particles in that vicinity in a tube. But this was not in 1979-1980 a commercial product. It was a floor polish. Well, it was commercial, but not a scientific product.

So we looked up where one could get this stuff. There was a local commercial supply place in Oakland called the Protex Wax Manufacturing Company. [laughing]. So my first technician, Charles Field, and I went down to inquire about getting a sample of Ludox, and the guy looked at me like, “What do you mean, a sample?” And I said, “Well, a few hundred milliliters would be enough, a pint would be enough,” and he said, “Get out of here.” They sell it in fifty-five gallon drums. And I said, “Well, can you spare a small sample?” So they gave us a big carboy, a five-gallon drum of this stuff. [laughter] We brought it back to the lab, and we mixed it with yeast cells. It was full of toxic stuff that killed yeast cells, so we had to treat this stuff with activated charcoal to absorb the toxins, and then it worked swimmingly well.

And then Novick did another fantastic, memorable experiment where he took his mutant sec1, and he put a genetic marker in the mutant that makes the cells form a colony that turns dark on a Petri plate. It’s a simple mutation that affects the production of an enzyme, acid phosphatase, that is secreted into the cell wall, which doesn’t itself compromise the cell but allows cells to be detected with a histochemical stain. So he took that marked mutant, a small sample or aliquot of those mutant cells grown at room temperature, and he mixed them with a wild-type culture of cells that did produce acid phosphatase. A 99-percent wild type, 1 percent mutant mixture. He mixed the 61

two, and he incubated them for an hour or two at thirty-seven degrees and then took the mixture of cells and applied it to this Ludox gradient.

04-00:10:58 Hughes: Which is in one of those sedimentation columns?

04-00:11:00 Schekman: In a centrifuge tube. He sedimented it for a few minutes, half an hour in a plastic tube. He punctured a hole in the bottom of the tube, and he collected drops, and he plated the cells out. I remember vividly that he spread, I don’t know, ten or so plates out on his desk. You could see, as you marched down the line, the dark colonies were all on the bottom end of the tube, and, overwhelmingly, all the other white colonies were at the top of the tube. So he had effected a physical separation of mutant and wild-type cells on a density gradient. Now, this is not how a geneticist operates. [laughter] This is how a biochemist operates.

04-00:11:43 Hughes: Yes. The dark cells are heavier, right?

04-00:11:44 Schekman: They’re heavier. So that immediately offers the possibility of at least an enrichment, if not a selection, for mutants that can be imposed over a shorter period of time so as not to kill the cells. They would recover from two hours at thirty-seven degrees. So then he took another culture, mutagenized it, grew them up at permissive temperature for a while, and then shifted to a restrictive temperature, ran the gradient, punctured a tube, collected the densest 1 percent of the cells from the tube, spread them out, picked the colonies that were temperature-sensitive lethal in their ability to form a colony, and then systematically screened each one of those for the accumulation of two different secreted enzymes inside the cell. Over the course of a few months he collected several hundred independent isolates, clones, colonies, that conformed to this criterion.

And then—I remember this vividly—another moment in a group meeting where he reported all this complementation stuff. He did the selection in both mating types so that he would be able to make these diploids and do the analysis. So what you do is, you take each clone and you make streaks on a Petri plate, one mating-type streak this way, the other mating-type streak the same way. Then you turn the plate, and you replica plate the two onto a common virgin, fresh plate, but you do it so that each column intersects at a certain point, and at the point of intersection they’ll mate. You do this at room temperature. And then you warm the plate in a thirty-seven degree incubator, and you come back and you see that the lines of temperature-sensitive cells haven’t grown except at the intersections where they complement one another.

04-00:13:49 Hughes: How clever. 62

04-00:13:51 Schekman: Yes. This is the kind of experiment I love to see because it’s elegant and simple. No fancy things: toothpicks, Petri plates. It’s really very elegant. And then you look at the score card, and you can immediately, or virtually immediately, see which mutations complement one another in defining two different genes, which mutations failed to complement each other, which means they’re in the same gene. Then by doing all the pairwise combinations you can take all two hundred mutations, and they fell into twenty-three genes, twenty-three complementation groups.

04-00:14:33 Hughes: That’s a big breakthrough.

04-00:14:35 Schekman: Yes, yes! [laughter] Then you do some genetic things to clean the mutations up. Then you do everything that we did with that first mutant in 1978-79. You repeat it on representative mutations in each of the twenty-three groups. Lots of electron microscopy later, he found that ten genes produce a phenotype indistinguishable from the first mutant, implying that there are at least ten different proteins that are required at that step.

04-00:15:15 Hughes: Amazing. You knew you had to have more genes, but did you have any clue about the complexity of this process?

04-00:15:22 Schekman: No. How would one? Let me finish this and I’ll tell you about that.

04-00:15:32 Hughes: Yes, I’m sorry for interrupting.

04-00:15:34 Schekman: So ten genes gave that, and nine genes caused a completely different phenotype, where instead of seeing vesicles we saw big tubules that were clearly endoplasmic reticulum, implying there were at least nine proteins that were required to move things out of the endoplasmic reticulum. And then a couple of genes showed unusual toroid-shaped structures which turned out to be Golgi membranes, which we found subsequently, conditions that actually allow these structures to build up as real Golgi-like things that you never see in a normal yeast cell, implying that these proteins are required for movement through the Golgi apparatus.

So then you look at the distribution of mutations within all of these genes. Some genes turned up with multiple hits, multiple alleles. Others, a half dozen or so of the genes, we found only one mutation in those genes. And if you just do a simple distribution analysis, you predict that there are going to be many more genes that you didn’t find at all, just because of the odds. But at that point I made a kind of a tactical decision. I said we have twenty-three genes; we don’t know what any of them do. Let’s focus on trying to figure out where 63

they act in the pathway, and then try to figure out actually what they do. That was probably a tactical error. [laughing] But I think it was because I was so keen on trying to turn this into a biochemical project that I didn’t have the insight to look forward over the years and to realize what we should have done was just keep going and just try to isolate as many of the genes as we could, get to a point where we would predict we would be recovering fewer and fewer new genes.

04-00:17:30 Hughes: Why was that a better approach?

04-00:17:34 Schekman: Well, it was not a better approach. It turns out there were many more genes that we could have found, and we should have had them all neatly in our collection.

04-00:17:46 Hughes: But you do eventually.

04-00:17:47 Schekman: We do. Okay. Well, maybe I’m giving you the wrong impression, because what happens next—and this, I would say, adds confusion to the field—is that other people come in, and they do different things, and they isolate more of the mutations. And then they give the gene a different acronym.

04-00:18:07 Hughes: Oh no!

04-00:18:08 Schekman: So if you look at the distribution of these genes, you’ll find several different acronyms based on which lab isolated the mutations. And it would have been neater, as Hartwell did, to have isolated more of them here, and they would all have a sec designation and be part of a consistent nomenclature.

04-00:18:37 Hughes: There’s no ego involved there? [laughing]

04-00:18:37 Schekman: Yes, of course there is, of course there is!

04-00:18:45 Hughes: You want to name them!

04-00:18:46 Schekman: Well, okay. So my technician at the time, who was really the genetics expert in the lab, had trained with this fellow Mortimer, and so he knew yeast genetics. He persuaded me, against my better judgment, that what we really should be doing instead of isolating more mutants was starting to genetically map them. So he spent a couple of years doing a lot of crosses and matings and mapping some of these, and he got some information out of it. But his 64

efforts would have been much better spent repeating what Novick had done. He certainly was capable of doing that, and just getting more of these mutations. There are actually good additional reasons why we would have benefited by having more mutations ourselves. Years later when we had biochemical assays that allowed us to isolate the molecular complexes that were implicated by our genetics, we found complexes that included one subunit defined by a sec gene and another subunit of unknown origin. Then we had to do more work to figure out what that gene was and to show that it would have been a sec gene if we’d actually had the mutation. So it would have helped us if we’d actually done more of this. But not a big deal. I think it was based on my own personal preferences at the time, and the very strong conviction that I wanted to turn this into a biochemical project and just keep doing genetics.

04-00:20:18 Hughes: Well, the fact that you were relying on the technician, whatever his name is—

04-00:20:26 Schekman: Charles Field.

04-00:20:33 Hughes: Does that mean that Novick had gone on to Yale?

04-00:20:36 Schekman: No, no. He was busy doing what I’ll tell you he did next. He had a rich plate of all kinds of stuff. No, I think it was good to not have him continue to isolate more mutants. His talents were better spent doing the next level of analysis of the mutants. So what he did was to apply another standard genetic technique to map the sequence of events in a pathway. So whereas Palade had to develop this autoradiographic procedure to measure where newly synthesized proteins were at different stages in a temporal sequence of events, what we could do with the genetics was to use a genetic formalism to evaluate the sequence of organelles in this pathway. So here’s the logic: you have a pathway, A, B, C, and you have a mutation that blocks step A to B, and another mutation that blocks step B to C. If you introduce both mutations into the same cell, the prediction is that you would accumulate intermediate A, not intermediate B if the sequence is obligately A, B, C. That’s called a genetic epistasis test.

04-00:22:04 Hughes: Epistasis?

04-00:22:06 Schekman: Epistasis test. I knew enough genetics to know that it had been used in describing other pathways. Hartwell used that, for instance. So we had the perfect setup to do that. We had mutants that accumulate ER [endoplasmic reticulum], mutants that accumulate Golgi, mutants that accumulate secretory vesicles. And we made notes. So Novick then made lots of double mutants and then looked again by electron microscopy, and sure enough, exactly as we 65

predicted, the mutant that caused ER to accumulate was epistatic to a mutant that caused Golgi to accumulate, which was epistatic to a mutant that caused secretory vesicles to accumulate. So [it was] a perfect formal genetic proof of the secretory pathway, but with additional rich information, namely lots of genes, and obviously proteins at each stage. Even more importantly—well, importantly at the time—it demonstrated what Palade couldn’t demonstrate, which was that each step was an obligate intermediate in the pathway. So Palade could show that things in a normal pancreatic cell flow through the Golgi apparatus in a temporal sequence, but he couldn’t prove that that was an obligate step. We could, and so that was the subject of the next paper of Novick’s, in 1981 in Cell. So he had other things to do besides going back and isolating more mutants.

04-00:23:35 Hughes: Right. Were people paying attention to this work?

04-00:23:48 Schekman: Yes, I would say so. It was interesting, the reaction was. The yeast community thought this was great; another proof of yeast as a superior organism. So I had nothing but kudos from the yeast community. The mammalian people in the field said, “Yes, this is interesting, but…”

04-00:24:08 Hughes: Because the findings might not apply to the mammalian cell?

04-00:24:12 Schekman: Yes, well, I’ll give you an example. Blobel apparently told his students, when I presented this stuff and he saw it, “Well, these mutations—how does he know that that they affect the pathway, the process, directly?” This was the reaction: you have a mutation, it cripples the cell, how do you know it’s a direct effect? How do you know that the gene product is actually operating on that pathway, as opposed to doing so indirectly by something else?

04-00:24:41 Hughes: Like what?

04-00:24:43 Schekman: Well, it didn’t matter by what.

04-00:24:54 Hughes: But Blobel must have had something in mind.

04-00:24:56 Schekman: Yes, I think he said that he had a colleague at Rockefeller who was studying a mutation that affected flagellar something-or-other, and he spent years on it and couldn’t figure it out. It may have been an indirect effect, not affecting a flagellar structural protein. I don’t know.

The only argument that I could make at the time was that one indirect effect that I thought of was, suppose these mutations are in molecules that are 66

themselves progressing through the pathway, kind of cargo molecules. Suppose you had mutations that cause that protein to unfold, and then it just serves as a blocking agent. It just sort of constipates the pathway at that point. So it’s not actually engaged in the process itself, but it’s merely a passive passenger. But it can act as a log jam, something like that. So I said well, there’s a simple answer that makes that unlikely, and that is, these mutations are genetically recessive. So that means if you have a mutation in this haploid cell, and you mate it to a wild-type cell, if it were a mutant protein that was a dominant inhibitor of the process, the diploid would still be temperature sensitive, and that was not true in any case. They were all genetically recessive. So my genetic argument was that it was unlikely that they were—at least that kind of indirect effect, but rather a direct effect on a protein required for the process. One would expect mutations in such genes/protein to be genetically recessive because the normal copy of the gene in a diploid would provide the protein missing from the mutant gene.

But otherwise, my feeling was well, that’s why I want to do the biochemistry! I had to go in and figure out what these things are, and that would be the only way to address whether the effect was meaningful and direct. So there was that skepticism, and then there was just the general skepticism of the cell biology community: yeast, who’s to say that this has any bearing on mammalian cells, ignoring the evolutionary conservation of all kinds of things. But I think generally speaking it was well received. I got federal funding: I was able to get really good students—people who were interested in this genetic stuff. In fact, I was getting good students who wanted to do the genetics. I was ready to move on to the biochemistry, so I had a lot of trouble persuading otherwise very talented people to do something different, and that was biochemistry.

04-00:27:38 Hughes: Why were they so hipped on the genetic approach?

04-00:27:38 Schekman: Well, because it was working. Do more genetics. The next thing that people wanted to do, because it became available in the early 1980s, was to clone the genes by complementation. It was a bit of a chore to do it back then. Much easier now. But I was stubbornly opposed to doing that.

04-00:27:58 Hughes: It was only circa 1980 that you began to pick that up?

04-00:28:02 Schekman: Yes. In yeast.

04-00:28:03 Hughes: Because it was around before that.

04-00:28:06 Schekman: Yes, Hinnen and Fink had developed a method to clone yeast genes in 1978. 67

04-00:28:06 Hughes: But I guess it was all in E. coli.

04-00:28:07 Schekman: It wasn’t so easy to clone genes before the advent of recombinant DNA technology. [Jonathan] Beckwith had cloned a gene or had isolated a gene—I don’t know if you call it cloning—before the use of restriction enzymes. But you really needed restriction enzymes, and those didn’t come around in any useful way until the mid-1970s. And then there was a recombinant DNA scare at this Asilomar conference, and so there was a moratorium on certain kinds of recombinant DNA research. Gerald Fink, who was then at Cornell University, broke the embargo on doing recombinant experiments in yeast.

04-00:28:52 Hughes: How did he do that?

04-00:28:54 Schekman: Well, he just did it. [laughter] I think the rules were bending at that point, and then he just did it, and it was very dramatic, and he cloned a gene. It was 1978.

04-00:29:06 Hughes: Were you hesitant to adopt recombinant DNA because of the controversy?

04-00:29:10 Schekman: No, no, the controversy didn’t concern me in the least. After all, the research was in baker’s yeast! Give me a break. No, I thought the scientists were being overly cautious. I had a more philosophical—it wasn’t really opposition. It was again, how you marshal your resources. When people in the lab definitely wanted to clone these genes, my reasoning was yes, okay, we’ll clone the gene; we’ll sequence it—it was more trouble back then than it would be now—and the sequence won’t tell us anything because there wasn’t such a big database of genes. And these were going to be new proteins with functions that hadn’t been seen anywhere else.

04-00:30:07 Hughes: Sequencing is even a newer technique than recombinant DNA.

04-00:30:09 Schekman: Well, it was, yes. Look, that was going on at Berkeley. We could have done it. I could have reorganized the lab, and we could have marched through and cloned all these genes and sequenced them, and probably in a few years we would have had all that information. But I felt at the time that we wouldn’t learn what I really wanted to learn, which was how these proteins work.

04-00:30:36 Hughes: You were thinking, who cares about the sequencing, right? 68

04-00:30:41 Schekman: Well, if someone had just told me the sequence that would have been fine. [laughter]

I wanted the people in my lab to marshal their effort to try to develop biochemical reactions that would reflect the requirement for these gene products and then to be able to purify them. If we had that, then cloning the genes would have been useful, because we could have overproduced the protein product, and eventually we could have used the genetic manipulations to tag the gene to help us purify the proteins. So this was probably the unconscious influence of Kornberg on me. Tactically, I shouldn’t have been so single-minded in opposition.

04-00:31:30 Hughes: Well, isn’t there something about young people wanting to latch onto the latest techniques?

04-00:31:37 Schekman: Yes, oh yes.

04-00:31:38 Hughes: There was a lot of hype about DNA sequencing.

04-00:31:42 Schekman: Sure, but we probably should have done more of it. I knew other people would do it, and sure enough other people did it, and former students of mine did it. Eventually we did a fair amount of it ourselves. But that time, sort of mid- 1980s, my push was to try to convince people in the lab to try setting up these biochemical reactions. That was several years of real frustration, a) because people didn’t want to do it, and I had trouble convincing people; and b) because when we finally started doing it, it was tough, and we were groping and I didn’t have much success. I had two postdocs; we published one paper. I’m not sure we got much out of it in terms of a biochemical assay that would be useful.

There were about four years of struggling, maybe ten man-years of effort down the drain without any useful progress. And that was frustrating to me because others, principally Jim Rothman, had done this quite nicely in lysate extracts of mammalian cells, without the advantage of mutants.

04-00:32:58 Hughes: Well, talk about Rothman, because of course I’m wondering where, if at all, your paths intersected. [Rothman and Schekman are co-recipients of the 2013 Nobel Prize in Physiology or Medicine.]

04-00:33:03 Schekman: Okay. So I knew of him from his work in Kennedy’s lab, this fellow that my good friend Bill Wickner had worked with. He had done some really cool experiments measuring the movement of phospholipids across the cytoplasmic 69

membrane in bacteria, as a graduate student with Kennedy. I don’t know if I met him then, but the first time I remember meeting him was I had been here for a year as an assistant professor. Dan Koshland got this unusual letter from Kennedy saying that he had this brilliant student, and people needed to look at him for a faculty position. He was so good that Kennedy just wrote letters around the country. And so we had a job [opening] at the time, and so Rothman came for a visit, and I was his host. He was incredibly impressive, I mean really. I started to talk about my ideas, and he just completed my sentences for me. [laughing]

04-00:34:04 Hughes: Was that discouraging for you?

04-00:34:07 Schekman: Not in itself. I thought wow, this guy is really smart, that’s great. We’re thinking along similar lines.

04-00:34:12 Hughes: Well, I guess it could be exhilarating to learn that somebody thinks the way you do.

04-00:34:17 Schekman: It could be, if his personality had been different. It could have been synergistic because he was thinking about things in very different way. I was going to do at the time this genetic approach.

04-00:34:27 Hughes: Right, and he wasn’t using that at all.

04-00:34:29 Schekman: No way, no way. He was not interested in yeast. He was going to be working on mammalian cells, and he had these ideas for in vitro reactions. And of course that’s what I wanted to do too. But at the time it seemed different enough. But the visit was difficult, I would say, because he was— Well, he’s so arrogant. [laughing] And he was really uncontrolled at the time. He would come back to me after visiting with one of my colleagues, and he would be completely dismissive. He’d say, “Why is that guy wasting his time?” Or, “What an idiot,” and all this kind of thing. [laughing] I think the faculty decided that his personality was not a good fit for the department. And in retrospect, it would have been a disaster for me. It really would have been a disaster. So then of course he was hired by Stanford biochemistry, my old home, and we kept in touch, of course. I would say for the first few years it was quite tense, because we did eventually have similar objectives.

04-00:35:39 Hughes: So there was some competition involved?

04-00:35:41 Schekman: Absolutely, absolutely. That was good, that was good. But it was tense. And so I decided we should have once-a-year joint group meetings for the two lab 70

groups. We did it a couple of times, and it was— It was too much. It was too close, and he’s a very ambitious guy.

04-00:36:04 Hughes: Well, and you’re not un-ambitious.

04-00:36:08 Schekman: I was ambitious too, but in a different way, I would say. He could be very aggressive. I don’t think we ever ended up competing head on very much, so it was okay. It wasn’t bad, but I think it was good that we were not in the same department. That wouldn’t have worked, that wouldn’t have worked. With his personality, he created his own controversies. I think cell biologists were even more dismissive of him than they were of me, because at least I was working with intact cells. The first thing he did was make an extract, and cell biologists thought this is chaos. [laughing] And he has a different style. He is brilliant, there’s no question. He’s so brilliant that he thinks he can figure out nature, and so he starts with a grand idea and then everything he does goes to try to prove his idea was right. And that’s not how I operate.

04-00:37:13 Hughes: Well, say more about that. How do you operate?

04-00:37:19 Schekman: My approach is to develop a technique that will lead to discovering the truth. In this case it was the genetic approach. The purpose of the genetics, for me, was not so much to isolate the mutations, but it was to get back to my graduate experience of having the genes that I knew were involved in an essential process, and then being able to reproduce that requirement in vitro. And that was the key, I would say, to breaking open the DNA replication field in E. coli. Kornberg had a different approach. His approach was you purify an enzyme that conforms to what you predict the replication enzyme will be, and he ended up discovering a very important enzyme. But it turned out not to be the one involved in replication. That was a very powerful message to me, because I used these replication mutants. So that was in my mind what I wanted to do. I wanted to reproduce that kind of approach. And so we had to isolate the mutants first.

That was the plan pretty much right from the start. From the moment we made a decision to do the genetics, my idea of going forward would be we do the genetics, we use the mutants to authenticate the biochemical reactions that I knew we had to have. And then once we could validate the biochemistry as measuring something authentic, physiologically meaningful, we would necessarily be on the right track to discovery. It didn’t matter to me what the molecules were that we would eventually discover; I just wanted to make sure that whatever we did would really demonstrably be involved in the process.

But Rothman’s attitude was very different. It was, here’s how it must work, and these are the kinds of things that must do this, and so we’ll do 71

experiments to try to prove that this idea is right. He got himself into some trouble at several points in his career where he found things that were not true or drew conclusions that turned out not to be true. But on the other hand, he also discovered really important molecules that really are involved, and maybe not in the way that he had predicted but they nonetheless were involved. In fact I would say in the early years, after his cell-free reactions worked, he was actually generating a lot more attention, at least among biochemists, than I was.

04-00:40:10 Hughes: Would you put simple terms on the two approaches, namely, inductive versus deductive approaches?

04-00:40:23 Schekman: Okay, I guess that would apply, sure. We did a little bit of that more inductive approach. His first experiments were based on the observation that a coat protein called clathrin was involved in endocytosis.

04-00:40:49 Hughes: Yes, I want to talk about clathrin.

04-00:40:54 Schekman: He thought, extrapolating from its then imagined role in endocytosis, that clathrin would be a coat that could be used at all stages in making vesicles within the cell for traffic from one station to the next. His first papers as a faculty member at Stanford were an attempt to prove that. The way he attempted to prove it was he would follow a particular viral glycoprotein in a pulse-chase experiment as it was moving through the cell, and at certain time points he would make an extract. Then he would deliberately add to that extract purified clathrin, and then he could show that vesicular intermediates early in the pathway contained this clathrin coat. Of course the way I’m describing it it’s trivial. It was not a fact, because he was doping the extract with clathrin. And so he published his first paper suggesting that clathrin mediated traffic of a viral protein both from the ER and from the Golgi complex to the cell surface. It ain’t so!

04-00:42:14 Hughes: What did you think of that paper? [telephone ringing]

04-00:42:16 Schekman: I didn’t think much of it. Just a sec. [interruption]

04-00:42:22 Hughes: Well, you were saying you didn’t think much of Rothman’s paper.

04-00:42:23 Schekman: I didn’t think much of it, but it was a plausible model that clathrin would be involved. This is where there was some tension in our relationship. [telephone ringing] 72

[Malfunction of recording. Schekman re-created the following two paragraphs when he reviewed the transcripts.]

Hughes: Randy, the audio cut off mistakenly. The notes I took include the following words: meiosis, sporulate, Roger Chin, fluorescent probes, green fluorescent protein. Can you re-create your final statements?

Schekman: Sounds like I may have gotten into a quite long disposition and not sure how those terms fit into a narrative. The words meiosis and sporulation may refer to our work on the yeast clathrin gene where we introduced a deletion into one of the copies of the gene for a heavy chain of clathin in a diploid yeast cell and then subjected the cell to meiotic division to produce four spores, two containing the wild type clathrin heavy chain gene and two containing the deletion gene. We did the deletion in a diploid strain because we, like everyone else, expected that the clathrin gene would be essential for cell viability. Thus a direct deletion of the gene in a haploid cell would produce a dead cell, and nothing to work with. The best way to show this is to do the deletion in a diploid cell where one could see that two of the four products of meiosis were dead. However, much to our surprise, we found that two of the spores were sick but not dead and this led to our controversial suggestion that clathrin is not required for secretion, a direct contradiction of that early finding from the Rothman group. Not sure how much more detail was lost on this topic.

Not sure how the following connects to what I probably was saying about clathirn: Roger Tsien was a former Berkeley colleague who went to UCSD [University of California, San Diego] and won the Nobel Prize in chemistry for the application of the green fluorescent protein (GFP) to real time inspection of events within living cells. I may have mentioned that we can now study the traffic of the viral protein Rothman studied in living cells using a fusion gene where the gene for GFP is attached to the gene for the viral protein. 73

Interview #3: March 07, 2014 [Audio File 5]

05-00:00:00 Hughes: Today is May 7, 2014, and we’re in Dr. Schekman’s office again for the third session. Dr. Schekman, I thought what we would do today, with your approval, is conclude the discussion of science, which of course could take the whole eight hours, but we want to talk about other things.

05-00:00:22 Schekman: Sure, sure.

05-00:00:25 Hughes: That, to my mind, leads to the Lasker Award. Then there’s a skip to the Chancellor’s Advisory Council on Biology, then to the editor-in-chiefship of the PNAS, and then we segue into eLife. If we have time to discuss teaching, that should do it.

05-00:00:55 Schekman: Sure, okay.

05-00:00:57 Hughes: We do have one more session.

05-00:00:58 Schekman: I know.

05-00:00:58 Hughes: All right. We got some traction on your science last time. Does it seem to you a good place to start with the translocation engine?

05-00:01:18 Schekman: Sure. So in the early 1980s, after I’d returned from a sabbatical in Switzerland at the Biozentrum, I had a crop of just unbelievable graduate students who joined the group. I would say when I look back, 1985 was the peak of my career. [laughter] Not that it’s been downhill ever since.

05-00:01:46 Hughes: No, I wouldn’t say so!

05-00:01:47 Schekman: But it really peaked in terms of the independence and brilliance of the students that I had in the lab. The people who stood out were Ray Deshaies, David Baker, two graduate students; Linda Hicke, a graduate student, and Chris Kaiser, a postdoctoral fellow, and Greg Payne, another postdoctoral fellow. Actually, I could go on, but these people have all gone on to have very successful careers themselves.

Deshaies was certainly one of the most creative people I’ve ever known. He continues to be enormously creative. He wanted to work on a part of the 74

pathway that we had not actually succeeded in identifying genes. We had initially found in our collection some gene mutations that seemed to block the initial step in the protein translocation process. But those turned out not to affect that directly, rather indirectly. We had to backtrack in our conclusions about these. But Deshaies then established several genetic approaches that were very specifically probing the translocation reaction.

Notably, he discovered that genes that encode cytoplasmic chaperones, called hsp70s, are required for the posttranslational translocation event in yeast, and this idea just came out of the dark. He came in one day, having read a mini- review that was written by a fellow in Britain about these cytoplasmic chaperone molecules, and he just out of nowhere thought these could be involved in allowing a protein that’s fully synthesized to be held in check before it can be translocated across a membrane. Previously, the dominant view was that proteins have to be transferred across membranes as they’re being made, because if you uncouple that, at least in mammalian cells, they misfold, and they can’t unfold as they’re being transported. It was known in yeast that this process is naturally uncoupled, the translation is uncoupled from translocation, and so it was a mystery—how could these proteins persist and retain their ability to be translocated? And so Ray, just out of nowhere, thought that maybe these cytoplasmic chaperones…

The idea immediately suggested an experimental test, because just at that point there was a woman, Elizabeth Craig in Wisconsin, who had knocked out the genes and had a yeast strain that was conditional for the one remaining copy of this gene. So we got that strain, and over the weekend Ray did the experiment to prove his idea. It was unbelievable, just unbelievable.

05-00:05:04 Hughes: Remarkably fast.

05-00:05:06 Schekman: Yes, yes, unbelievable.

05-00:05:09 Hughes: Some of these chaperones had already been identified? People knew where they were?

05-00:05:15 Schekman: They were known, and they were suggested to play roles in protein folding/misfolding. But no one had made the link to protein translocation until Ray cooked that idea up.

05-00:05:25 Hughes: Why was it necessary to pause —?

05-00:05:36 Schekman: The dominant view at the time, formulated for mammalian cells, which resulted in the Nobel Prize for Günter Blobel, was that proteins pass through a 75

membrane as they’re being made. Part of the reason for thinking that was his observation, which is true in mammals, that if you unlink the two processes, the protein that’s made without access to the membrane folds up in a way that is no longer accessible because it aggregates; the signal peptide which is apolar, hydrophobic, may cause it to aggregate. So the thought was, since in yeast it seemed to be a little different in that it was known that it could be unlinked, the question was how could it be unlinked and not suffer the same fate that had been documented for mammalian cells? That was the mystery, and Ray solved that mystery with his observation. He spent a few more months doing some experiments. Then we found out, quite independently, that Blobel had made a similar observation, though using a biochemical approach not a genetic approach. So we held back, and we submitted and then published the two papers together in Nature, and that was certainly one of my most important papers.3

But on top of that—this was just a weekend experiment for Ray—his major project was to devise a genetic approach to identify the genes that encode the channel in the membrane. He conceived of an absolutely brilliant genetic selection that was very different than what Novick had done, and which worked, again, swimmingly well. It resulted in another one of my most important papers, which we published actually the year before this other one, where we discovered a gene that we called SEC61, which subsequently was found to encode the actual channel-forming subunit of the translocation machine. [Deshaies & Schekman 1987] His selection then led to several other genes that subsequent students and postdocs characterized. He would just throw off ideas like this that just were—not crazy ideas; they were actually productive.

Another postdoc in the lab was working on a project, struggling to find the gene that may encode the enzyme that clips the signal peptide of a secretory protein. As the secretory protein goes into the ER, its N-terminal signal is clipped off, and that’s part of its process. We thought that we could—

05-00:08:28 Hughes: Why is it clipped off?

05-00:08:27 Schekman: Well, because it’s hydrophobic, it’s apolar, and if it weren’t clipped off, it would probably cause the secretory protein to aggregate and not be fully soluble to be secreted.

3 Deshaies, R. J., Koch, B. D., Werner-Washburne, M., Craig, E. A., and Schekman, R. (1988) A subfamily of stress proteins facilitates translocation of secretory and mitochondrial precursor polypeptides. Nature 332, 800-805. 76

05-00:08:46 Hughes: But I thought, in thinking of this process as more or less a chain, moving the protein across the cell to where it’s supposed to end up, through the Golgi apparatus and all that, that you needed a signal to guide it along.

05-00:09:07 Schekman: Yes, you need other kinds of signals, but the initial signal is a hydrophobic N- terminal peptide that guides the nascent chain to the channel and through the ER membrane, and then that signal is no longer needed, and so it gets clipped off because if it persists it gets in the way.

We pursued this work for a couple of years, trying to design selections, and they didn’t work. One morning Deshaies comes in and he says, “I bet we already have a mutant in that gene,” and he explained his logic. Of course it immediately dawned on me that he was right. [laughter] And so the postdoc, this poor other postdoc, went and looked at a particular mutant in our collection that conformed to Deshaies’ predictions. I knew exactly which mutant in the original Novick collection was a likely candidate, and Deshaies was absolutely right!

05-00:10:11 Hughes: So all these mutants that you keep talking about in these papers are naturally occurring mutants?

05-00:10:15 Schekman: Well, they’re created by mutagenesis. All the mutants that we obtained were induced by exposure of yeast cells to chemical mutagens.

05-00:10:32 Hughes: I see. So you’re hoping to block certain functions so that you can then figure out the genetic basis?

05-00:10:35 Schekman: Yes. So the way you do it is you mutagenize a cell, and the mutations go in randomly, and then the challenge is to find the needle in the haystack and pull out the one. We had enrichments for the mutants based on their properties. This one turned up just in the general search for those first two dozen genes that Novick identified. It was a kind of a funny mutant, because it had a mixed phenotype and we didn’t really know what to make of it. But Ray’s logic, about ten years later, was absolutely spot on. Well, it was for the benefit of this postdoc. A couple of weeks later he had the mutant that was right out of our collection, and we knocked our heads together to figure out why that had escaped our attention. Anyway, Ray was like that, just—pshhh—just full of ideas. And he wasn’t the only one.

At the same time, I had another student, equally brilliant, by the name of David Baker. I don’t know if we’ve talked about his work yet. 77

05-00:11:42 Hughes: No, we didn’t, but I read about him and the cell-free system.

05-00:11:45 Schekman: Yes. So my background and my instinct were to do biochemistry. We were busy doing this genetic stuff, and it was fine. But I wanted to get in and establish a biochemical reaction that would allow us to purify and attribute functions to the Sec proteins. We had struggled for years, and my biggest struggle was to convince people in the lab to do experiments of this sort, because the genetics was working, the molecular biology was obvious, but the biochemistry was sort of a gamble. I had a couple of postdocs struggle. We published one paper that I don’t think really taught us anything about this process, and we made certain false assumptions about what to expect.

This guy Baker came in and looked around. He figured no one else was competent. He had another idea that comes out of nowhere about an assay that at least initially seemed a little more complicated than what we had been doing. But he got it to work almost immediately. Linda Hicke, who was in the lab at the time, was working on one of the mutants that affected the process that he had reconstituted in vitro. She showed pretty quickly that, sure enough, when you make a lysate according to his protocol from a mutant cell, she could demonstrate that the reaction was temperature sensitive in vitro, just as it was in vivo.

So that was the link between the two parts of my life. That was exactly the connection that I had dreamt of having, being able to use the genetics for that kind of biochemical dissection. So I knew from that point that would be our gold mine.

05-00:13:55 Hughes: Baker I associate with a cell-free system. When you’re working with a cell- free system, how do you locate yourself topographically?

05-00:14:17 Schekman: You use landmarks. In this case, the landmarks were covalent modifications in a protein that we added to the in vitro reaction. So Baker’s idea was the following, which is different than what we had tried. His idea was to make a lysate of normal wild-type cells, gently lysed so that the internal membranes would remain intact. And then to add a radioactive precursor of a secreted protein that others had already demonstrated could be postranslationally imported into the ER. Remember I told you the proteins in yeast are a little different in that respect than in mammalian cells? Deshaies had shown that this particular precursor that Baker was about to use required the cytoplasmic chaperone to keep it in a somewhat loose configuration which permitted this posttranslational access to the ER membrane. But that had already been done and published, and it was a protocol that we had already used. 78

His key insight was the following: that if the integrity of the membranes were preserved in this lysate, that the protein, having been deposited in the lumen of the ER, might fold and properly engage the machinery necessary for its sorting into a transport vesicle, which would then form and we hoped be able to dock and fuse with the Golgi apparatus. And the way he could show that was once the protein was deposited in the Golgi apparatus, new glycan additions would be made on the core glycan that had been assembled in the ER. The glycans we knew, from work that actually Clint Ballou had done years earlier here at Berkeley, are greatly modified by additional sugar residues, covalent attachment of other sugar residues, that have unique antigenic qualities that could be diagnosed with antibodies that we had in the laboratory. So these antibodies would precipitate what was initially a radioactive protein, but only after they had traversed this essentially first half of the pathway in vitro. So that was a very stringent demand, and it worked. Again, it was one of these things that within weeks. Baker showed that the radioactive secretory tracer acquired glycans characteristic of additions known to occur in ER and in the Golgi membrane.

05-00:16:49 Hughes: Were you surprised?

05-00:16:52 Schekman: Well, I was thrilled and I was amazed! I won’t bore you with our previous frustrated attempts to make this work, but it was based on that same principle that we would look for the addition of these glycan residues in the Golgi; that was an obvious landmark to follow. But Baker’s insight was to start with an in-vitro-translated precursor, whereas before we had started with precursors that we accumulated in vivo in a sec mutant that blocked transport out of the ER, and we tried to reverse that block in vitro. His idea was, just start with a wild-type component and see the normal path. I said, “Okay, it’s asking more to happen than we had asked previously, but it’s worth a shot.” And it worked swimmingly well. So the point is that you could follow that covalent modification. That was perfectly diagnostic of this series of events.

But in order to be sure that it was measuring something physiological, we had the perfect test, which was we had all these mutants that block those steps in the cell. And then we could ask: do these mutants affect the process that we observe in the test tube? And they do. Moreover, since most of these sec proteins are purely soluble cytoplasmic proteins, we could take a soluble protein fraction from a normal cell and mix it with the mutant extract and repair, essentially replace, the missing part and observe the reaction now occurring normally at the high temperature. This was, again, exactly what I did as a graduate student. It was to have what one could call a biochemical complementation assay to allow one to purify, one at a time, each component that had been defined genetically, and that worked well and we progressed.

05-00:19:14 Hughes: It must have been a real high. 79

05-00:19:15 Schekman: It was very high, yes. It was just a wonderful time. I just got these great people, and my job was to stay out of their way. [laughing]

05-00:19:27 Hughes: I was wondering about that, how much you let them run with it.

05-00:19:32 Schekman: Well, you know, you get somebody like Deshaies or Baker or Hicke or this fellow Chris Kaiser—they have their own mind and you only interfere if you try to be too intrusive. I think that was maybe comfortable with my personality too. Kornberg would not have done it that way. He would have been directing their every move.

05-00:19:54 Hughes: Right on top of them and maybe killed the inspiration.

05-00:19:57 Schekman: Well, hard to know. These people have very strong personalities. I think they would have clashed and done it their own way anyway. [laughing]

05-00:20:06 Hughes: How did they deal with each other? Was there an emergent power that emerged from all this brilliance?

05-00:20:14 Schekman: It seems to me they got along really well. They egged each other on. You’d have to ask them how they reflected on it. It was just such a wonderful time.

I don’t know if I’ve told you this, but over the course of the years here I’ve posted award notices, usually in our lunch room, for some big goals. The award was a banquet for the lab at some fancy restaurant in the area. We’ve had, I think, six or seven of them over the years. I think we had two or three during that time. One picture that I show when I give a retrospective lecture is of Ray and Linda Hicke and Ray’s wife, Linda Silveira, who was also a graduate student in my lab, at one of the banquets. I don’t remember what the goal was, but it was one of the grand goals that they were collecting. We had it in Sausalito at some nice restaurant overlooking the bay.

Anyway, Chris Kaiser, using a very different approach, using a more sophisticated genetic analysis than we had done, combined with thin-section electron microscopy, was able to visualize a vesicle intermediate between the ER and the Golgi apparatus, and to demonstrate which genes were required for its formation and those that were required for its docking and fusion with the Golgi apparatus. When these genes were cloned and sequenced, they turned out to correspond to three proteins that Jim Rothman had identified and for which his fame really emerged and was solidified—these proteins that mediate the fusion of vesicles within the Golgi apparatus in his idea called the SNARE hypothesis. This crystallized around the early 1990s. The fact that our 80

genes were formally the same as the genes for the proteins that he had purified, and that they participated in the very events that he had detected in vitro—that was the golden spike that probably drove us together in our ultimate fate, which was good. I think to that point we were more competitive and maybe a little antagonistic, but after that point we knew that our fates were inextricably linked, so we made up and celebrated each other’s discoveries. So that was good.

05-00:23:12 Hughes: He’s characterized of course as a biochemist, and in some of the articles that I read, you as a geneticist. But that’s really not quite true.

05-00:23:21 Schekman: Yes, it’s not that simple; it’s not that simple.

05-00:23:22 Hughes: He’s not using genetic techniques, is he?

05-00:23:28 Schekman: No. Well, if you look at the Nobel citation, their references to me are two, and they’re both for genetic results. [laughing] So for better or worse that’s my fate – to be known as a geneticist.

05-00:23:45 Hughes: Well, you wonder if that isn’t somewhat to distinguish you from Rothman.

05-00:23:54 Schekman: Maybe. And the point of a Nobel, as people need to be reminded, is for a discovery, not for a body of work.

05-00:24:01 Hughes: Yes, I need to be reminded of that.

05-00:24:07 Schekman: So in my case the discovery was of the mutants.

05-00:24:11 Hughes: Why was the Nobel set up that way, I wonder? That was Nobel himself?

05-00:24:16 Schekman: Yes. The stipulation was also for a recent discovery. [laughter] In fact, I think it may even say within the past year, and that’s never happened.

05-00:24:26 Hughes: Look at [Oswald] Avery. [laughing]

05-00:24:29 Schekman: Yes, well there you go. There are many examples of where things are overlooked, and most things are certainly not recognized anywhere near the same year. 81

05-00:24:39 Hughes: Well, I shouldn’t have asked that question, because we’ll discuss the Nobel next time.

05-00:24:43 Schekman: Yes, later.

05-00:24:49 Schekman: I told people twenty years ago, when they were asking what I was doing experimentally and where I was going and the subject of the Nobel came up, I said, “Frankly, after the initial work to isolate and characterize the sec mutants, it doesn’t matter what I do for the rest of my career for that consideration.”

05-00:25:15 Hughes: But there was more to do.

05-00:25:17 Schekman: Well, of course. The point of this is not to win a Nobel Prize, the point is because there’s great stuff to do.

05-00:25:23 Hughes: You’re working out this system.

05-00:25:23 Schekman: Yes, yes, oh yes.

05-00:25:25 Hughes: So where did you go next?

05-00:25:28 Schekman: Well, then we had the opportunity to purify these proteins and to discover their function. And so shortly after Baker’s development, there were at that point many opportunities to have functional assays to purify and characterize things. The reaction that he reconstituted probably recapitulates the action of more than fifty different gene products. So tactically, it was not appropriate to try to tackle all those things at once or even to have different people tackle different things. So what I wanted to do was to focus on a single step in that sequence of events, that we could have a chance of picking up and purifying all the proteins and then putting them together to see how they work.

And so the next graduate student came along, a fellow by the name of Michael Rexach, and a very careful, very stubborn guy, but again really exquisite care. He observed, in the course of the incubation to make these more highly glycan-decorated forms of this secretory protein, that in the lysate the ER membrane, at the initial step where things are deposited, remains intact and sediments very rapidly. So you take the lysate and you put it in a table-top centrifuge and you turn it on and turn it off. All of the ER membranes pellet out of suspension very quickly. But he observed, crucially, that if you monitor this sedimentation as well as monitoring where the newly glycosylated 82

radioactive protein is located in respect to the centrifugal speed, within the first minutes that a species that still had the glycan characteristic of the ER appeared in a very small, slowly sedimenting membrane fraction that was easily separated from the ER membrane using this low-speed spin. So you would do the incubation and take samples and then just spin quickly, take the supernatant fraction and then put that in an ultracentrifuge and spin for a longer time. And you observed, during the course of a thirty-minute incubation, the progressive removal of what’s called the core-glycosylated protein from the ER and its appearance in a slowly sedimenting small vesicle.

Rexach then showed that what turns out to be a vesicle-budding reaction was dependent on the very genes that Chris Kaiser had recently demonstrated to be required for budding of a small vesicle between the ER and Golgi in vivo but not dependent on the genes that Kaiser had shown to be required for the docking and fusion of those vesicles to the Golgi apparatus. So that was a perfect setup for what I wanted to do, which was to be able to focus on a small number of proteins. We had now reduced the complexity of this overall reaction from more than fifty to down to three or four proteins that we knew to be required. And so I said okay, we’re going to focus on those genes and those gene products.

And that’s where Linda Hicke, who had already demonstrated one of the genes that Rexach found to be required for this budding, had already started working on its purification using this biochemical complementation assay. She then discovered that the gene product that she was working on was one subunit of a dimeric protein complex, the other subunit of which we actually hadn’t detected genetically. It wasn’t in our original collection. She could then show, going back, given the protein and then the gene, that it was in fact a bona fide SEC gene, but one that had simply escaped our detection earlier on. So we now had the first dimeric, soluble protein complex of Sec proteins.

A former postdoc, Akihiko Nakano, found a gene that we hadn’t found in our original collection that encodes a small GTP-binding protein. We devised a biochemical means of purifying that in the context of this budding reaction. Then finally, a postdoc and a new graduate student Nancy Pryor and Nina Salama rounded this all out by isolating yet another protein complex based on one SEC gene that we already had and a new one that we hadn’t yet discovered, but which turns out to be real; fulfilled the requirements for that. And then by 1994 we had purified all of the soluble proteins that were required to bud this vesicle.

I have to tell you about a wonderful collaboration that I had for twenty years with an Italian scientist in Geneva by the name of Lelio Orci, quite a remarkable man. The work that this fellow Chris Kaiser did involving genetics and electron microscopy, we published in Cell in 1990. It’s one of the two papers that the Nobel committee cites. Anyway, our skills in electron microscopy were rudimentary compared to the high standards that people had 83

for working on mammalian tissues. This fellow Orci, by the way, had already been for some years collaborating with Jim Rothman, doing important work to use the microscopy to visualize intermediates in the biochemical pathway that Rothman had been studying. I had corresponded with Orci about our work on clathrin, which I think we may have talked about last time.

05-00:31:58 Hughes: Yes, we did.

05-00:32:00 Schekman: Some of the conclusions that we drew about the role of clathrin were consistent with what he had documented in pancreatic beta cells making insulin. So I corresponded with him, probably in the late 1980s, and he never responded.

05-00:32:22 Hughes: You were unknown?

05-00:32:25 Schekman: I was not on his radar. But then when we published this paper with Kaiser, I suddenly in the middle of the day, and it was of course late at night in Geneva, I got a call from him, this distant voice. I hear this thick Italian accent, [imitating Orci’s accent] “Hello Rrrrandy!” I said, “I’m sorry, who is this?” He said, “What’s the matter? You don’t recognize my voice? It’s Lelio Orci, what do you think, I’m some kind of Iraqi terrorist?” [laughter]

05-00:32:58 Hughes: He didn’t!

05-00:32:57 Schekman: Yes. And he’s immediately charming. Then he says, “Oh my God! I saw this paper by Kaiser. Oh! There are certain standards in morphology. I’m going to help you. It’s not for me, it’s for you!” [laughter] So he’s at the same time offending me and then offering his world-class expert assistance, which I embraced immediately. And so we then launched a long-term collaboration that lasted for twenty years. It was wonderful.

05-00:33:36 Hughes: His approach was strictly microscopy?

05-00:33:37 Schekman: It was strictly electron microscopy. He is arguably the best membrane morphologist in the world at this time. After Palade he was the heir apparent.

05-00:33:50 Hughes: Meaning the minute definition of it all?

05-00:33:51 Schekman: Using very skillful techniques, demanding techniques. Let me explain a little: there are people who can cut thin sections of membranes, and you can see 84

membranes. But if you want to see protein molecules on membranes and preserve them in a way that would allow you to label them on a thin section with an antibody conjugated to a gold particle, so you can see the location of the the protein molecules—this skill is a crucial. There’s a technique called immune-electron microscopy where you use an antibody against a protein, and then you label that antibody with some electron-dense particle, such as a colloidal particle of gold that allows you to visualize (because the gold particle scatters electrons in the beam of an electron microscope) where a protein is on a membrane in high resolution. It’s a crucial technique; it still is. But it’s really tricky because the usual techniques that one uses to preserve a specimen for electron microscopy are notoriously damaging, and most proteins are a mere shadow of what they were before, and the antigenicity that would be essential to visualize them is destroyed.

So a senior research associate in the lab where I was a postdoc in John Singer’s lab, a man by the name of [K.T.] Tokuyasu, had developed, even before I got to San Diego, a revolutionary technique of specimen preservation that also preserved a protein’s antigenicity. And that was, he found, a way of very gently fixing cells or tissues and then infusing them with sucrose and then freezing them in liquid nitrogen. And then he had a setup where you could actually cut thin sections while the tissue was still frozen at liquid nitrogen temperature. A very demanding technique! [laughing] One that I never even attempted. Anyway, so you have these frozen sections and then you put them on a grid, which stabilizes it a little bit, and then you can apply antibodies conjugated to a gold particle and they decorate antigens, and then you put them in a microscope and you can see them. It’s a really tough technique that only a few people can really master. Tokuyasu was technically brilliant, but not the kind of guy you could easily collaborate with. He taught me what little I knew about electron microscopy when I was in Singer’s lab, so he was very influential.

05-00:36:26 Hughes: Your lab was using it all along, but I guess without that fine point.

05-00:36:28 Schekman: Not that, no way, no way. I have a graduate student now who has done stuff like that, but it’s a rare talent. It takes more patience to do it than I would have.

But Orci was absolutely the master. His style was, he would focus on individuals with whom he would collaborate. You couldn’t just call him up and ask to collaborate. He selected just a very few collaborators. So at that point he really focused on me, and it was great because it was just at the moment that we had purified these proteins that were involved in budding. So we sent him a sample. I had an EM technician, actually a very good EM technician, Susan Hamamoto, who looked at the samples of vesicles that we were producing in this reconstituted reaction, and she noticed that they had a 85

fuzzy coat on them. We sent the sample to him, and it was unimpeachable. It was really a novel coat protein complex. It was molecularly distinct from the coat that he and Rothman had already described involved in vesicular traffic within the Golgi.

05-00:37:40 Hughes: Now is that COPII?

05-00:37:42 Schekman: COPII, yes. What we did over the many years was study how this coat forms; how it sculpts membranes. We did it with increasingly purified fractions using synthetic membranes. Anyway, he was engaged in virtually all of the most important work that I did over twenty years. Integral.

05-00:38:06 Hughes: Was he critical to actually discovering COPII?

05-00:38:12 Schekman: Yes.

05-00:38:11 Hughes: You wouldn’t with your team—

05-00:38:14 Schekman: Well, I hate to say. Susan Hamamoto, who was my EM technician, had seen the coat first, on the specimens that were produced by the next generation of people in the lab, principally Charles Barlowe, a terrific postdoc in the lab. Susan had seen the coat on these vesicles. But what Orci brought to the effort was the ability to demonstrate that these vesicles were uniformly coated with the subunits of the Sec proteins that we had added to reconstitute the reaction, and he was able to use his immunogold labeling and cryo-immunomicroscopy technique to make that determination, something that we would have been very hard-pressed to do. So he was crucial.

05-00:39:08 Hughes: Are you still working with him?

05-00:39:08 Schekman: Well, he’s retired now. He slowed down. I would have loved to continue with him, but he’s well into his seventies, and his institution slowly phased him out. There’s more of a mandatory retirement [age] in Europe, and it’s a shame. That skill is almost irreplaceable.

He was just out here. His son—small world—was here some years ago on a post-JD law program in our law school. During that time he lived in the International-House he met a young woman who turns out to be the daughter of a woman who taught my children in elementary school. [laughing] Anyway, they just got married, and so Orci was out here, and they had the wedding over near Sausalito. 86

05-00:40:13 Hughes: Nice connections.

05-00:40:17 Schekman: Yes, amazingly small world.

For many years we worked on ever higher resolution imaging and refined analysis of the events in the vesicle-budding cycle. And then about ten or twelve years ago I was asked to attend a [Howard] Hughes [Medical Institute] meeting on Alzheimer’s disease. We’re segueing now into the more recent mammalian stuff. Did you want to go into that?

05-00:40:53 Hughes: Yes, I do—if you’re satisfied with what we’ve said about the preamble.

05-00:41:02 Schekman: Well, there are plenty of stories, but I would say this is a main theme. I was asked to attend a meeting at the Hughes Institute on Alzheimer’s disease. I obviously wasn’t working on it, and I was there sort of as an observer. They thought maybe it would be useful to have somebody who knew about membrane traffic at this meeting. I came away with a feeling of well, first of all, it was far from being mechanistic, but that there were some opportunities to study how the proteins engaged in Alzheimer’s disease may traffic in mammalian cells. And so I decided at that point to begin an effort to explore vesicular traffic in cultured mammalian cells using our biochemical techniques. I had a wonderful Korean postdoc by the name of Jinoh Kim, who is very, very careful, one of the most precise, careful people I’ve had in my lab. He developed, basically, what we had used in yeast, this vesicle-budding reaction. He applied it to lysates of mammalian cells, and we studied the traffic of proteins implicated in Alzheimer’s disease. And that I think began to attract people to my lab who wanted to study aspects of mammalian cell biology, mammalian cell membrane biology.

05-00:42:35 Hughes: Wasn’t that quite a leap to go from the yeast to the mammalian cell?

05-00:42:42 Schekman: Well, it sounds more so than it was. We weren’t using animals; we weren’t using human subjects. We were taking what we had learned in yeast and applied this technique more or less directly to lysates of cultured mammalian cells.

05-00:43:01 Hughes: And did that work?

05-00:43:02 Schekman: It worked nicely, yes. 87

05-00:43:04 Hughes: One would think, from our very prejudiced perspective, that it would be more complicated in the mammalian cell.

05-00:43:10 Schekman: Well, it is in a sense more complicated, but the technique worked the same. In this case what we did was we used a detergent to permeabilize the plasma membrane of cultured cells, mammalian cells. And then we did the same differential centrifugation thing that I told you about. It works just the same, more or less just the same. In some ways there are technical advantages of doing this with mammalian cells over yeast. We didn’t have the genetics that we had with yeast, but the actual technical aspects of it were in some ways better. So once we started doing that, and other people joined the lab and wanted to work on cultured mammalian cells.

05-00:43:53 Hughes: Did that attract a different sort of student? Because the project was obviously applicable to human disease?

05-00:44:01 Schekman: Well, that worked two ways. One is, I thought well, this was a useful direction to go. This was maybe a critical juncture in my own career. There were two directions to go in. One was, we were poised at a place where doing structural analysis of these proteins was the obvious next thing, getting crystals, doing X-ray crystallography. That would have been really a big challenge for me. I’m sure I could have attracted people to the lab to do this kind of thing, who had had experience, but I had no experience or knowledge in that area, and I think I felt inadequate to organize such an effort. Instead, I decided the best thing is for me to give out our reagents and protocols to people who really want to do this, who are in crystallographic laboratories, and just let them do it, and I would just keep in touch with it. And that’s what happened. I think science was served better by that, because other labs are better equipped to do that crystallography than I would have been. So I decided to take a turn and do this leap into mammalian cells, where I still felt comfortable.

05-00:45:17 Hughes: Of course the other thing that’s happening here was not only the leap from yeast to a mammalian cell, but to research that has a more visualizable, practical application. The earlier research was really basic, basic science, was it not?

05-00:45:37 Schekman: Well, it was, except as I like to say now, there was maybe even a more obvious direct application of our yeast work. When the biotech industry decided to exploit yeast as a vehicle for production of useful mammalian proteins, they relied on what we had discovered, namely that yeast has this pathway that’s formally the same. In fact, I consulted with biotech companies to help them do this, and I would say that’s the most dramatic practical application of anything that I have done. But even so, going into mammalian 88

cells, once again my attitude is, more basic science. It may have a disease connection, and as I’ll tell you, it did. But I’m still fundamentally driven by wanting to know how cells work, and I still haven’t patented anything. [laughing] So that work that Jinoh Kim really started the whole new growing effort in my lab, which has morphed into virtually everybody in my lab is working on mammalian cells now.

The first real breakthrough, that we never would have had in yeast, that came from all this, was through another terrific postdoc, Chris Fromme. He was following a little bit what Jinoh did and looking at collagen traffic and not getting anywhere really. And then I had a call from a clinical pediatrician.

05-00:47:08 Hughes: Now, why collagen?

05-00:47:11 Schekman: Okay, we can come back to that later. There’s a story about that, but that’s more recent. The reason we’ve been interested in collagen is, in the ER it forms a rigid, triple-helical rod of around three hundred nanometers in length, which is larger than the size of a COPII vesicle. So we thought there had to be some kind of accommodation made by the coat to encapsulate something as large as a three hundred nanometer rod inside of a vesicle. And that turns out to be true, and we can come to that later if you’re interested. Our approach was always, let’s see if we can get procollagen packaged into vesicles in vitro. Frankly, we weren’t getting anywhere, and it’s obvious years later why we weren’t getting anywhere. But so it was just an initial effort on [Chris’s] part to get into this, because he actually wasn’t trained in this at all.

Then I had a fortuitous call from—when was this—probably around 2003 or so, 2004, from a pediatric geneticist, Simeon Boydjiev at Johns Hopkins, very excited. He said, “We’ve discovered that,” and then he rattled off some human chromosome locus. “We’ve discovered the blah, blah, blah, blah encode something that you’re going to be really interested in.” I said, “Oh really? What is that?” As though I should have known what that locus was, because it had no meaning to me. And he said, “It’s SEC23A.” And moreover, they had identified a point mutation in human SEC23A, which is one of our yeast genes involving this COPII code.

05-00:49:08 Hughes: So he knew your research?

05-00:49:09 Schekman: Oh yes, of course. Well, he didn’t know it, but then when he identified this locus in the mutation it was immediately apparent that he had to do the background work on it. So the story is that he’d been collaborating with a clinician in Riyadh, Saudi Arabia, who was following a Bedouin family. Apparently the Bedouin families are so inbred that they’re fertile territory for finding mutations that otherwise would be blocked by the complex 89

background that the rest of us have. This family emerged with a rare craniofacial disorder where the bones are brittle, and the soft spot on the top of the kid’s head doesn’t close, and they have cataracts. They’re alive, but they’re sick. Apparently there are lots of these strange forms of craniofacial disorder. It’s very fertile territory for human genetics.

I had no idea why they were following this patient group at all, because it was just one family. They had mapped the locus, and it turned out to be SEC23A. The mutation was a missense mutation in a residue, a phenylalanine residue that is found in all SEC23s from yeast to man. And since we already had, through someone else’s efforts, the crystal structure of the yeast protein, we could immediately pinpoint where that mutation was on the surface of the SEC23 molecule. It was on the side of the molecule that’s pointing away from the membrane. It was not pointing towards the membrane, so that mutation didn’t affect anything right at the interface between the coat and the membrane. It was on the other side, which was at the time a kind of a mystery.

So I gave this project to this guy, Chris Fromme, and he immediately launched into it and was able to make the human mutant protein by recombinant expression, and to demonstrate in our cell-free vesicle-budding reaction a pronounced defect associated with what was a very subtle mutation where it just basically wouldn’t bud. But he could show that the protein was nonetheless functional. So that was great. With some more work we learned that this amino acid residue on the surface of SEC23 was a point of contact with the outer layer of the coat. The outer layer of the COPII coat is a cage- forming protein that looks— It actually forms a regular polyhedral structure. The way it assembles on a vesicle that’s about to bud is it interacts with the top surface of SEC23 and then wraps around the membrane and gathers in SEC23 and its partner protein, which in turn have gathered in membrane proteins that are destined for transport. This whole thing then is consumed by the envelopment of the vesicle by this cage. The defect, as we could show biochemically, was that the outer layer of the cage could not adhere to the membranes that were being prepared for budding. And that’s why this defect—

05-00:52:33 Hughes: And that was the single thing that was going wrong?

05-00:52:34 Schekman: A single amino acid substitution in these patients.

05-00:52:45 Hughes: Did that surprise you?

05-00:52:46 Schekman: It’s surprising at many levels, but the most obvious level is how are these kids walking around? We obtained a skin biopsy sample from one of the kids and one of the parents. The parents are heterozygous, and they have no apparent 90

disease, but the kids are homozygous, and they have the disease. So we collaborated again with Orci. If you look at thin sections of the cells from one of the kids, the ER is just hugely bloated up, filled with collagen, which has trouble getting secreted because of this mutation. Yet these skin cells are growing in the laboratory. They’re a little sickly, but they’re growing. But they’re so deficient in secretion it’s worse than the yeast mutants that we isolated twenty-five years earlier.

We can explain why the patients actually survive. And that is— Well, it’s a little more complicated, but the simple explanation is that humans have two copies of SEC23. There’s another copy that’s perfectly normal in these kids, which is expressed in most other tissues in the body. But the few tissues that are pathologic in these kids are, for reasons that can’t be explained yet, almost solely dependent on this copy of the gene that happens to be mutated in these kids. So those tissues are profoundly deficient, whereas others are essentially normal. The mystery is that the skin cells from these kids show such a pronounced defect, and yet there’s no obvious skin malady in these kids.

05-00:54:27 Hughes: A defect in terms of the storage of the collagen?

05-00:54:33 Schekman: Secretion of collagen is greatly diminished.

So that was fantastic, and we published that. It’s the kind of thing that we wouldn’t have found in yeast.

05-00:54:45 Hughes: Randy, does it ever strike you, when you’re doing all this, about the marvelous complexity of the system and of nature in general?

05-00:55:01 Schekman: Sure, sure.

05-00:55:01 Hughes: It boggles my mind that something as complicated as this could evolve and work most of the time.

05-00:55:09 Schekman: Yes, well, I’d say one of the most important lessons from our work is this process, cell protein trafficking, was invented over a billion years ago, and it is complex. It works, it’s complex, and you know when evolution has solved a particular challenging problem it doesn’t try to reinvent the wheel. So these parts have been used ever since. They’ve been changed; they’ve been decorated. 91

05-00:55:43 Hughes: The fact that nature doesn’t reinvent unless it has to explains why you were reasonably confident that what was happening in the yeast cell was going to be true of the mammalian cell?

05-00:55:55 Schekman: Yes, that’s what I say now. But I wonder back then, was I really so confident of what we would find in yeast?

05-00:56:02 Hughes: Well, either you said or I read that many of your colleagues said, when you took up yeast, why in heaven’s name are you speculating that you’re going to learn anything that’s widely applicable?

05-00:56:19 Schekman: Well, there was skepticism for more practical reasons. I had no experience with yeast; I was not trained as a geneticist; I had no preliminary results. [laughter] I think those were more tangible reasons to be skeptical.

But okay, 1976, when I started, one already knew that some parts of the secretory process in yeast were the same as mammalian cells. It was already known that the N-glycan that’s attached in the ER is the same in yeast and in humans. And one knew that glycoproteins were secreted, and one knew that there was an endoplasmic reticulum, and there were vesicles. So at that level you could certainly say that the pathway had to be there. Surprisingly, even after I started, there was some disagreement about whether secreted proteins might pass directly from the cytoplasm across the plasma membrane, just like in E. coli. That was actually still not proven. It seemed far-fetched to me, but there was that level of uncertainty.

05-00:57:42 Hughes: Now, the pathway—or maybe you have to say pathways? I’m looking at it as a continuous system. But are there others?

05-00:57:59 Schekman: Are there other pathways?

05-00:57:58 Hughes: Yes.

05-00:58:00 Schekman: Oh yes. We’re working on one now that’s been known for some years called unconventional secretion. There are some molecules that get secreted that don’t seem to follow the standard secretory pathway. There are some molecules that do progress directly across the plasma membrane, even in yeast. There’s a peptide pheromone that yeast cells secrete that just goes right from the cytosol through the plasma membrane.

05-00:58:23 Hughes: Why? 92

05-00:58:23 Schekman: [laughing] Yes, why. Beats me.

05-00:58:29 Hughes: Maybe the organism needs it really quickly, and it can’t go through this arduous process.

05-00:58:39 Schekman: Well, the standard secretion pathway in yeast is pretty quick. Five minutes. These things that are secreted by an alternate, unconventional pathway are typically peptides or small proteins. This defies any explanation: there are two mating types in yeast, and they each secrete a peptide pheromone that interacts with the other to synchronize cells so that they can mate and form a zygote. One of these peptides is secreted just as I said, right through the plasma membrane. The other one follows the normal secretory pathway even though the peptides in the end are both small peptides. Go figure. I don’t know. This is evolution. This is not physics; this is biology. [laughter]

[Audio File 6]

06-00:00:01 Hughes: This question probably should have come at the beginning of this discussion: Why is this complex system important?

06-00:00:16 Schekman: So, most of the cells in our body manufacture thousands of different proteins. [There are] 23,000 genes in the human genome. Most of the genes encode proteins that work inside the cell and do all the chemistry of life. Most cells also have a specialized process that ends up secreting proteins outside of the cell, and the proteins that are secreted outside of the cell do an awful lot of intervention. They are produced by one cell, and they go to a distant part of the body, and they affect the activity of a distant cell or tissue, like insulin. Insulin is manufactured in the pancreas. It goes into the blood stream. It affects all the tissues that bathe the circulatory system that are responsible for taking up glucose that’s been produced from the diet. There are many other hormones. All of your blood proteins are manufactured inside the cell and have to be shipped outside of the cell. So 10, 15 percent of all proteins made in cells are secreted. Thousands of different proteins have this specialized fate of being secreted outside of the cell. But in order to do that, the cell has had to invent a complex conveyer-belt-like mechanism for shipment that involves progression through a series of intracellular membranes that encapsulate these secretory proteins and eventually can discharge them by the process of membrane fusion where a membrane surrounding a capsule fuses with the plasma membrane of a cell.

And the reason it’s complex is that the cell has decided to use this pathway to create stable intracellular compartments that also derive as branches of this conveyer-belt-like mechanism. For example, the lysosome is an important 93

organelle in the digestion of molecules, both within the cell and [also] molecules that are taken in from outside of the cell. It acquires proteins as a branch from this secretory pathway. Another organelle called the peroxisome has unique catabolic functions, and it acquires some of its content by a branch from the secretory pathway. Lipids flow to different locations, even though they’re all more or less made in the endoplasmic reticulum. So they have to be diverted by various paths to their final destination. And so cells that have a nucleus, beginning with the most primitive eukaryotic microorganisms, created this elaborate mechanism well over a billion years ago. And that complex process was then adopted and adapted to other requirements as evolution progressed. It’s fundamentally different than what happens in bacteria or archaea, so it’s a eukaryotic-specific development of intracellular compartmentation that is much less elaborate in prokaryotes or archaeal organisms.

06-00:03:56 Hughes: And that’s why they’re called simpler organisms. They’re prokaryotes.

06-00:04:01 Schekman: Yes, but yeast is considered a simple organism too, because it’s unicellular. But it’s more complex than a prokaryote.

06-00:04:22 Hughes: Is there anything more that you want to say before we move on from your science?

06-00:04:25 Schekman: One of the questions that I’ve gotten since I’ve returned from Stockholm is, what am I going to do next?

I was happy doing science before I got the call from Stockholm on October 6, and I’m happy continuing to do science now. I’m now, of course, involved in other things, but I’ve been involved in other things [before], as we’ll discuss. I’ll probably be drawn out in other ways in the future, but there’s still nothing more satisfying to me than thinking of a really cool way of testing something and then seeing it work in the laboratory and seeing a well-controlled experiment. I get the same excitement about that that I did when I first started, and I see no reason to stop being excited like that.

06-00:05:19 Hughes: Well, we’re glad that’s true.

Related, because it is a science award and a major one, is the [Albert] Lasker [Award in Basic Medical Research], which you received in 2002 with your colleague Jim Rothman. I know the prestige of the Lasker is probably only slightly below that of the Nobel and is often a step to the Nobel. But is the system of nomination relatively simple? Or maybe I should ask it in a different way: how does it work? 94

06-00:06:06 Schekman: Well, the Lasker Award is organized by a blue-ribbon committee of people, many of whom have won the Lasker, many of whom have won the Nobel. I would say, frankly, it’s the most prestigious committee in the world in terms of the quality of the people, in terms of the achievements of the people on the committee. These are really the best people in biomedical science, not only in the US but in the world. There are people from elsewhere who sit on that committee. And so they have their finger on the pulse of biomedical science. But people are asked to nominate— Here’s a form that I’ve been too busy to fill out for the next year, a nomination packet. So people are identified by the members of the committee and asked to nominate people for the Lasker.

06-00:07:02 Hughes: You can nominate one, or more?

06-00:07:04 Schekman: Typically you nominate one, and then they ask you if there are other people who could share it. There are hundreds of nominations that come into the office in New York. They’re considered by this team, led by one of the great biomedical scientists of his generation, Joe Goldstein at UT [University of Texas] Southwestern, who won the Lasker and the Nobel within one year, at age thirty-five. [laughing] He’s just a stunningly brilliant guy, and he has exquisite judgment. He’s very critical, very critical—scary sometimes.

06-00:07:50 Hughes: Scientifically critical, you mean.

06-00:07:49 Schekman: Yes, oh yes. No, he’s a nice guy. He is very focused, virtually no life outside of science other than his passion for art. He’s a collector and has a wonderful sense of artistic expression. Anyway, he fields these nominations, and then they’re considered by his committee. I don’t know exactly—I’ve never sat on that committee—but they whittle it down to a manageable list, and then they meet in New York in late June. The committee then deliberates over the course of a day, and at the end of the day they make their choice. Then Joe calls the winners, and they’re told not to tell anyone. This is a quaint little tradition at the Lasker. Unlike the Nobel, the Lasker committee has not prepared an elaborate rollout for the award winner, and that doesn’t start until the moment the decision is made to select the person. There are several categories. There’s a basic medical science and there’s a clinical one, and occasionally there’s a public service award, such as Dan Koshland’s.

You’re told not to tell anybody other than maybe your family. And then over the course of the next couple of months they develop publicity materials, and there’s an essay written, and you write an essay. Then there’s a public announcement around September. There are a couple of big events in New York. Mary Lasker, who is really the instigator of all this and a very important person in the history of public support of medical science in the US, very 95

influential, very well connected in Washington, was instrumental in convincing Congress to support cancer research. The Lasker is in honor of her husband who was, I think, a wealthy businessman. She had this favorite restaurant, and so the winners and the members of the committee have a dinner at her favorite restaurant. And then the winners are also interviewed. Usually the winner is asked to pick some colleague to serve as the interviewer. I asked David Sabatini to be my interviewer, so that was very pleasant. He was certainly very familiar with my work. I’ve known him forever. He actually was on the panel that reviewed and trashed my first NIH grant. [laughing] But a wonderful man, really. He was trained in part by Palade, and he has that same sense of style and scholarship as Palade. A really wonderful man. Anyway, it was a great choice to have him do the interview. The major event is a luncheon at the Pierre Hotel, where the winners are accommodated. Have you ever been to the Pierre Hotel?

06-00:11:26 Hughes: No. I don’t move in those circles. [laughing]

06-00:11:28 Schekman: Well, I don’t either. I brought my family—my dad and his wife and my kids. We rented a suite of rooms. This was twelve years ago. It was already, at that point, $1,200 a night. It’s right at the corner of Central Park and Midtown, a very expensive neighborhood. Anyway, so they have a luncheon and all the literati from New York show up. I was amazed at some of the people who were there.

06-00:12:09 Hughes: Non-scientists?

06-00:12:11 Schekman: Oh yes. It’s a major social event.

06-00:12:20 Hughes: Who was there that I would know?

06-00:12:21 Schekman: Well, of course Jim Watson was there. The person who had been the chair of the Lasker before Goldstein is a very famous surgeon named Michael DeBakey. He was there. There was a woman who used to be on What’s My Line, by the name of Kitty Carlisle. Do you remember that name?

06-00:12:44 Hughes: [laughing] No.

06-00:12:46 Schekman: Surely, you watched that program in your youth.

06-00:12:54 Hughes: Oh yes, I watched it. 96

06-00:12:56 Schekman: Kitty Carlisle—she was some socialite. She was at that point already almost ancient at that point. And the mayor of New York. People like that show up to this thing.

06-00:13:14 Hughes: Where were you when you heard?

06-00:13:20 Schekman: Unfortunately, I wasn’t home, so what Goldstein did was he called my office, which was up in the old Stanley Hall. He left a message and then he called my wife. But I was with my best friend Bill Wickner at his home in Vermont, and we were out that evening. I think Nancy got the call, and she didn’t call [me] until the next morning. It was eight o’clock in the morning when she called.

06-00:13:47 Hughes: She didn’t want to wake you up?

06-00:13:52 Schekman: Well, she answered the phone when Goldstein called, but he didn’t tell her what it was about. He said, “Where’s Randy?”

06-00:13:56 Hughes: Oh, I see. It seems to me the Lasker is worth waking up for!

06-00:14:02 Schekman: Yes, so she called very early. It was Saturday morning, and she said, “Joe Goldstein called twice. He wants urgently to speak with you.” So I had a strong suspicion of what it was, and that was confirmed when I got through to him. He was still in New York, and so it was very exciting.

06-00:14:29 Hughes: Is the Lasker awarded for a specific discovery or for a body of work?

06-00:14:40 Schekman: That’s a good question. You know, I don’t know! I should look at the directions here [on a Lasker nomination form].

There was another really major one that I got that was shared with Rothman. I shared a bunch with Rothman. There’s a major Canadian prize called the Gairdner which we won in 1996 for the identification of proteins involved in intracellular traffic and vesicle fusion. Basically they’ve all come down to that.

06-00:15:18 Hughes: Well, that’s what you do, Randy!

06-00:15:23 Schekman: The wording of the Lasker declaration may be a little longer than that, and the Nobel is kind of like that too. You might ask, why didn’t [the Nobel committee] include other people [in the award], for instance this fellow 97

[Thomas C.] Südhof might have been paired with one or two others. I think one could debate who belonged— It’s really complicated how you parse this thing. Südhof shared the Lasker last year with another fellow named Richard Scheller, who was at Stanford and now is the vice president for research at Genentech. The two of them did work that was partly overlapping with Rothman’s. Scheller arguably was the first to really discover what now are called the SNARE proteins and to even to suggest how they might work together. It was really Rothman, though, who demonstrated that more directly, biochemically.

But there was another crucial discovery made after Scheller’s and before Rothman’s of these neurotoxins that are made by the organism that causes botulism. These are toxins that proteolytically clip SNARE proteins. There’s an Italian scientist named Cesare Montecucco who has been overlooked in all these awards, which I think is tragic because his discovery immediately preceded Rothman’s important paper on declaring the SNARE hypothesis. It was Montecucco who demonstrated that the proteins that Scheller had identified actually function in synaptic vesicle fusion at the nerve terminal. And I have argued with people, thus far unsuccessfully, that he should be recognized in some prominent way for that discovery, because it absolutely preceded Rothman and was essential proof that the SNARE proteins function in synaptic vesicle fusion.

06-00:17:48 Hughes: The Lasker is limited to three people?

06-00:17:55 Schekman: It’s limited to three people, though they tend to favor one or two. The Gairdner usually does one or two in several different areas each year. I don’t know if Südhof and Scheller got the Gairdner prize. I don’t remember. Anyway, there was a long period, I gather, of argument in the Lasker committee about how to properly recognize Scheller and Südhof, and finally they settled on them this past year. Now, of course, there will be a lot of argument about whether it was appropriate to have Südhof, as opposed to Scheller, as part of the Nobel. I would say that what Südhof did was more distinctive. What he did was he discovered the calcium regulator of membrane fusion at the synapse, which was unique. And Scheller had not really done that. So I think a case could be made for Südhof, but it’s a tough call. I think a case, frankly, could and should have been made, and was made, for Novick or for Orci. I’m glad I wasn’t part of that committee.

06-00:19:26 Hughes: Well, you will be now.

06-00:19:28 Schekman: The Nobel committee? 98

06-00:19:30 Hughes: Oh no, the Lasker.

06-00:19:34 Schekman: Well no. Rothman is on the Lasker committee, so I’m actually joining the Gairdner committee.

06-00:19:37 Hughes: So it’s not automatic after receiving the Lasker that you become a member of the committee?

06-00:19:42 Schekman: No, no.

06-00:19:42 Hughes: Of course, the committee would get way too large, wouldn’t it?

You’re really talking about the problem of prizes. Ultimately, they can’t be fair, because somebody is usually left out. What we haven’t talked about, and I know it’s true of the Nobel—I’m not sure it’s so true of the Lasker—that the committee also looks at what has just been awarded in recent years. Brilliant research might have been done, but because there’s been a recent Nobel in the field, it’s unlikely to be the subject for the next few years.

06-00:20:27 Schekman: Sure, and sometimes they wait a long time. In 1999 Günter Blobel won the medicine prize by himself, for the discovery of the signal hypothesis, after we had already done our work on sec61 and all of our original work. I thought it was a great prize, and I was delighted that he won it and congratulated him. But other people said that I got dealt out, that Rothman and I should have been part of that. In fact, more than one person said, “Now you’re done. You’re over. That area has been recognized, and that’s it.” [laughing] Okay, well, what am I going to do about that?

06-00:21:19 Hughes: It would seem to me almost automatic that once you have won the Lasker you begin to dream of the Nobel.

06-00:21:29 Schekman: Well, you don’t have to dream. People remind you.

06-00:21:30 Hughes: All the time.

06-00:21:31 Schekman: Constantly. Especially as early October arises. It’s a drumbeat that you can’t avoid. Just before October 7, I was receiving the major prize of the German Biochemical Society [German Society for Biochemistry and Molecular Biology]. I was in Frankfurt, and it was the Friday before the Nobel announcement, and I was giving my lecture at this meeting. The guy who was 99

introducing me said, “Well, so many of the people who’ve won this award go on to win the Nobel. Monday’s coming up; we’ll see what happens.” [laughter] He said, “In fact, this may be the last time that we could have given Schekman this particular prize!” So even if I tried to erase it from my mind— Frankly, this prediction has gone on so long that as time went on, I was slowly sort of okay, never mind about the Nobel. Frankly, I actually thought it was past.

06-00:22:40 Hughes: You’d had enough.

06-00:22:41 Schekman: Well, I was hopeful, but I thought they’ve moved on, and there are so many other things that are more recent that are easily as important. I noticed in recent years that they’re giving more awards in more medically oriented discoveries, almost every other year. And then the previous two years they’d given it for more basic science. So I thought well, there’s little chance that they would give another basic science award. And then in Stockholm, one or two members of the committee let on that Rothman and I had been on their list for so long but that we were being blackballed, for reasons that weren’t explained, by a couple of members of the committee who had only just stepped down. So as soon as they stepped down our nomination was brought back up to the top.

06-00:23:42 Hughes: Do you have any idea of what their problem was?

06-00:23:44 Schekman: No, I have no idea. I have actually no interest in knowing.

06-00:23:51 Hughes: Not in your secret self you don’t want to know?

06-00:23:52 Schekman: Well, it’s sort of immaterial.

06-00:23:56 Hughes: The composition of the Nobel committee is another chancy thing, isn’t it?

06-00:23:59 Schekman: Absolutely, of course. It’s all very subjective.

06-00:24:04 Hughes: Well, it seems we’re into the Nobel despite my planning. So tell the probably by now oft-told story of how you learned that you’d won it.

06-00:24:16 Schekman: Okay. So I was at this meeting in Frankfurt, and I came home Sunday night from the meeting. My wife has Parkinson’s disease, so when I travel I have to have someone with her day and night. So her caregiver was there when I got 100

home, seven-eight o’clock. And we knew the next morning was that morning that I dread every year, the day after which I have called Groundhog Day. Did I tell you this?

06-00:24:59 Hughes: No, you didn’t.

06-00:25:04 Schekman: After the Lasker, and for the next years, Rothman and I would typically speak on the Monday and commiserate. It suddenly dawned on me a few years ago that this was very much like that Bill Murray movie, Groundhog Day, where he wakes up, and he’s doomed to repeat that day every day. I had the same sense that Monday, not every day but every year, it would come up and it was like Groundhog Day. Rothman and his wife had taken to calling that day Passover.

06-00:25:38 Hughes: Oh, that’s funny. [laughter]

06-00:25:41 Schekman: Which I thought is even better. Except, Passover of course was when the Jews put the lamb’s blood on their front door to have the angel of death pass over them, which is something that you wanted, and in this case we didn’t want. I usually do this futile exercise where I go online the day before, and I just see what the buzz is. And the buzz that evening was there was a report from an AP reporter in Stockholm that was on the news. The title was, “Five Discoveries That Have Not Yet Won The Prize.” And of course Rothman and I were on that list. And [Peter] Higgs was on that list, and the three others who didn’t win. Apparently Nancy and her caregiver had already seen that. I said yes, okay, but that and $2.50 will get you a cup of coffee at Starbucks, so it’s meaningless.

That evening is always a bad one for me, and so for years I’ve taken an Ambien that evening, just to knock myself out. Apparently I’m not the only one who does that. [laughing] Fortunately, since I was jet-lagged, I went to bed at nine o’clock and I slept. But unfortunately, I was really dead to the world when the phone rang at 1:20. Nancy heard it, and she blurted out, “This is it!”

06-00:27:35 Hughes: Who else is going to call you at that time?

06-00:27:36 Schekman: Well, usually when someone calls in the middle of the night it’s bad news, right? But fortunately, that didn’t enter my mind, and so I leaped out of bed and stumbled over to the phone. The room was dark, and I picked up the phone. I was so out of it that I don’t have a perfect recollection of my thoughts at the moment. But I was optimistic, let’s say, and then I heard this nice Swedish voice, and at that point I said, “Oh my God!” 101

06-00:28:11 Hughes: Who actually makes the call?

06-00:28:12 Schekman: It’s the secretary in this case of the Karolinska committee. It’s a man that I actually know. His name is Göran Hansson. I knew him because I actually served with him on a committee in Geneva for another prize, and so I actually recognized his voice. The first thing was, “Congratulations,” and the fog was lifting very rapidly. And then he said, “Please be assured this is not a hoax. Remember me? We served on this committee together.” I said, “Yes, I remember you, of course.” He went through the routine, and then he said, “Now, you can’t tell anybody for the next hour-plus.” I said, “Nobody? Can’t I tell my family?” He said, “Yes, but they can’t tell anybody.” So I hugged my wife and got my thoughts together, and then started calling around. So it was 1:20 as I recall, and the press conference was not going to be until 2:30 our time. So I had a little over an hour to collect my thoughts and plan the onslaught. So I first called my dad. [silence] [pause to control emotions] So he, of course— [crying] [pause]. Can we turn this [videotape] off?

06-00:29:57 Hughes: How old is your father?

06-00:29:57 Schekman: He’s eighty-six now. My mom died fourteen years ago. She had a brain tumor. And they both have lived for that moment. [pause]

06-00:30:23 Hughes: Well, you didn’t become a doctor as they originally hoped, but you sort of made up for it. [laughing]

06-00:30:26 Schekman: Yes, they gave up on that dream a long time ago. Interestingly, they didn’t really understand what I wanted to do until I started consulting for Chiron [Corporation, a biotechnology company] and making money as a consultant. Then they said, “Oh, this is what you do!” [laughter] Anyway, my dad’s wife answered the phone, and she shrieked. He was asleep. He wasn’t even aware that this was the day. He said for years he was aware of when that day was, and he said for some reason it had escaped his attention this year, and so he was not prepared to be awakened in the middle of the night. But he was, of course, speechless at that point. Then I called my son Joel. At first he didn’t answer the phone, so I tried my daughter Lauren. My son is in Michigan; my daughter’s in Portland, Oregon. She thought it was the alarm that she’d mis- set, and so she fell out of bed to turn the alarm off but heard my voice, and so answered the phone. She wasn’t shrieking, but she was thrilled.

I tried my son again, and he at that point woke up, and he was surprised, and then apparently they started exchanging messages. Then I called my best friend Bill Wickner, and he gets up really early. I think it was 4:30 in the morning his time, and he was already up and dressed. He was ecstatic. And 102

then I called Bob Sanders here in our press office, because he had given me his home phone and said, “Before the press conference, you have to call me,” which was a good thing. He then mobilized his team. It’s amazing how well organized they are in this respect. He had two of his assistants at my home right at the time of the press conference in Stockholm. It was the middle of the night, and then the TV camera crews started showing up. I called Bob Tjian. He was back East. I left a message on his cell phone but he didn’t answer it. It was eerily quiet before 2:30[pm]. I made my calls—actually I called Rothman and we compared notes.

06-00:33:00 Hughes: You hadn’t called your lab?

06-00:33:03 Schekman: I called my assistant Peggy [Smith at home] I called Bob Lesh, my lab manager. The answering machine picked up my message. I think Bob actually did wake up, and I told him to gather the troops. He was very calm. He wasn’t shrieking. I think they’ve long expected this. I remember once, a few years ago, the week before the Nobel Prizes are announced, when the subject came up at a lab lunch, I said, “Well, this is the Sunday before the Nobel awards.” And one of my graduate students said, “Oh, can we have a sleepover?” [laughter]

So yes, it was eerily quiet for a while, as I shaved and showered and dressed, and then at 2:30—well, then all hell broke loose, and it hasn’t been the same since.

06-00:34:07 Hughes: We notice how you don’t waste a moment, but I’m suspicious that you never wasted a moment even before that.

06-00:34:13 Schekman: Well, even now I waste time. I could be more efficient. But look at my desk. It’s still a mess. Actually I’m slowly getting better, believe it or not.

06-00:34:26 Hughes: What has the Nobel opened a way for you to do that maybe even the Lasker didn’t?

06-00:34:39 Schekman: Well, the Nobel of course is qualitatively different in terms of public perception. Very few people have heard about the Lasker. I was ecstatic with the Lasker, and there’s no better committee than that Lasker committee. The Nobel committee—they’re good people; they’re obviously accomplished people. They spend a lot longer deliberating, over many years. It’s maybe even more thorough. But the Lasker committee, the people are absolutely the best. So their judgment is very acute. 103

06-00:35:19 Hughes: Who does compose the Nobel committee?

06-00:35:24 Schekman: Well, they’re members of the faculty of the Karolinska medical school.

06-00:35:26 Hughes: Exclusively?

06-00:35:30 Schekman: Yes, pretty much. I don’t know that they have representatives outside of Stockholm. They’re very secretive. There’s no electronic communication, no cell phone communication, any materials have to be in writing and have to be left behind in the vault in this inner sanctum. I’ve been in the room, and I swear they probably sweep it for bugs. It’s amazing. So anybody who says they’ve heard rumors about upcoming awards is making it up. So anyway, the Nobel—almost everybody knows about it. As I walk across campus, students recognize me. They want to take selfie pictures with me. And when I traveled in the immediate aftermath of the Nobel [ceremony], even people in hotels where I was staying knew and recognized my name. Waiting in line at the airport, people would congratulate me. That didn’t happen with the Lasker. [laughing] So there’s that immediate change in the public perception. So what is it, other than taking a lot of my time?

I’ll admit to you that I thought long and hard about what to do if this happened. I had actually resolved, years ago, that I would donate my money to create an endowed chair in honor of my mother and sister. I didn’t make that announcement immediately. I made it just a couple of days later, but I had already decided. I did it not just because I felt strongly about having such an endowment, but I did it because I felt if I’m willing to make that kind of financial commitment to this institution that others, who are considerably better positioned to do so, might be motivated to do more than they have done. We desperately need more public support for this institution, and so I thought by that gesture I’d loosen up a few more bucks. And I resolved, even before the Nobel, that I would use whatever influence I had to try to make the case for public higher education, and so I’ve taken advantage of doing that.

06-00:38:13 Hughes: You have another chance to reiterate that point in your talk, that you have yet to write.

06-00:38:20 Schekman: Oh, you mean in my Nobel Lecture?

06-00:38:24 Hughes: In your Nobel Lecture—or can you not stray from science?

06-00:38:25 Schekman: Well, of course I can do that, but that won’t be broadcast as widely. I didn’t say anything, actually, even in my Nobel Prize Lecture about my commitment 104

to public higher education. One thing that struck me immediately was that I was the only laureate in the sciences from a public institution this year, among the U.S. laureates. And that’s unfortunately typical. So I made that point in the weeks after the announcement. I serve on an advisory committee at the University of Michigan, and I was there. I made this remark, and the special assistant to Mary Sue Coleman, the president, said, “You really ought to write an editorial about it and use this occasion to make that case.” And so I did so with her help and Bob Sanders’s help. I tried to shop it around. I sent it to the New York Times. They didn’t even pay any attention. The Washington Post didn’t pay any attention. Even the L.A. Times—no. But we got into the [San Francisco] Chronicle, so it was published in the Chronicle. I was actually disappointed, particularly in the L.A. Times, because I talked about my experience at UCLA and how important that was for me, and the other newspapers weren’t interested.

06-00:40:01 Hughes: Strange. I wonder if that reflects something about this country’s interest in science?

06-00:40:18 Schekman: [sighing] Well, I don’t know that it’s science. I think it’s this country’s interest in public higher education. They didn’t even answer me in the Times or the Washington Post. But the fact is that when you go back East, the strong feelings we have about public higher education in California are just not as prevalent back East. Probably all the editorial board of the New York Times went to Ivy League schools. And the public institutions there are not as strong. So I don’t think it resonated there. There was a reporter, Brian Palmer, who did a piece on me in the Post in the aftermath of the Nobel award. It was a terrific piece, I thought, and he did put in my statements about public higher education. He was one of the best interviews that I had because when I told him about the practical applications of my work, he said, “Did you do any of this in your lab?” And I said no. And he said, “Well, why not?” And I said, “Well, it actually never even occurred to me.” He circled back to that same question over and over again. He was incredulous that it didn’t dawn on me that I could turn this secretion business in yeast into some practical. But at that point it certainly did not occur to me because, as I emphasized to him, I was focused on how a cell works. I told him, frankly, it probably was a mistake, because I could have patented some of these things and profited from them.

06-00:42:09 Hughes: Well, that’s what he was thinking, wasn’t it? It’s not only practical application; it’s putting some—

06-00:42:11 Schekman: Profits.

06-00:42:12 Hughes: —money in your pocket. 105

06-00:42:13 Schekman: When you talk to lay people about why we do science, you look at why there’s public support for the NIH, to the extent that there is. It’s because people expect these discoveries to be for human health. If it weren’t for human health applications, the NIH budget would be miniscule. And so, most people would think that’s obviously what you’re doing. You’re doing [research] because it’s going to help human health.

06-00:42:51 Hughes: It’s written right into the NIH mandate that there will be eventual practical application from the research NIH supports.

06-00:42:57 Schekman: Yes. Anyway, Palmer’s piece was terrific. I think he got it eventually that I wasn’t interested in profiting from my research. He said, “I circled back to this question repeatedly, and I just couldn’t get him to say why he didn’t do the practical work in his own lab.”

06-00:43:11 Hughes: Well, it seems to me he reflects the zeitgeist of the times. Maybe not when you started in science, but certainly after the recombinant DNA revolution and the rise of biotech, what scientist isn’t thinking that commercialization is an option?

06-00:43:31 Schekman: Yes, well I think a lot do. I think a lot do. A lot of my colleagues start companies, they’re entrepreneurial. It just wasn’t ever my thing. Maybe it was to my disadvantage.

06-00:43:44 Hughes: Let’s get back to the chair in cancer research that you endowed with your share of the Nobel Prize money. First of all, is the chair named after your sister and mother?

06-00:44:12 Schekman: Yes. It’s called the Esther and Wendy Schekman Chair in Basic Cancer Biology.

06-00:44:16 Hughes: That’s very nice.

06-00:44:16 Schekman: They both died of cancer, and I wanted to recognize that in some way, but I also wanted to make sure that it’s an award in basic science.

06-00:44:28 Hughes: Is that how you designed it?

06-00:44:28 Schekman: Well, that’s the kind of people we hire here—we’re not hiring clinicians. We do biomedical science. 106

06-00:44:37 Hughes: How will the research funds be awarded?

06-00:44:43 Schekman: Well, it’s a chair. The new [Chancellor Robert J.] Birgeneau plan is—

06-00:44:46 Hughes: Oh, it is a chair. Right, I’m sorry.

06-00:44:47 Schekman: --the proceeds get split up several ways. Some of it goes to the investigator for his or her own research, some of it goes for graduate student support, some of it goes to the department. And we’re nearly there; we got a very large gift from the Li Ka Shing Foundation to supplement this. I invited Mr. Li to come to Stockholm. This was Tij’s [Robert Tjian’s] great idea. Mr. Li doesn’t travel, so he sent two of his associates, one of whom is the director of his charitable foundation. They transmitted a million dollars to the chair, which is terrific. And the campus has helped raise the rest from many donors.

06-00:45:37 Hughes: That’s very strategic of Tij.

06-00:45:39 Schekman: Oh, Tij is brilliant. He’s talented in many ways, but he has a particular talent in cultivating very wealthy people. He’s so good at that it’s uncanny. I think he’s actually a cut above Koshland in that respect. Koshland was wealthy himself and knew these people. But I’m not sure he had Tij’s gift in cultivating these people quite the way Tij does.

06-00:46:01 Hughes: As I’ve heard, because I did a short interview with Tij for the Dan Koshland oral history retrospective, he didn’t know Li Ka-shing before he hopped on a plane [to negotiate a donation for the new biosciences building on campus].

06-00:46:16 Schekman: Well, the credit goes to other people for making that connection for us. Birgeneau I’m sure had something to do with it, and it maybe even started before with [Chancellor] Chang-Lin Tien. This was probably something that has been going on for a long time.

06-00:46:32 Hughes: But it was Mr. Li’s first donation to the University of California, Berkeley, was it not?

06-00:46:40 Schekman: Yes, but he’s been giving lots of money around the world. He’s given away over a billion dollars. So a million for this chair is—pffft—car fare.

06-00:46:51 Hughes: I see how busy you are. Is it a pleasant busy, or is it the price you have to pay for the fame of the Nobel? 107

06-00:47:12 Schekman: I’m not shy and retiring, so it’s okay. [laughter] I don’t mind it. I guess I hadn’t quite anticipated this, but it’s okay. Fortunately, people understand when I’m late with things, so we’ll get past this.

06-00:47:30 Hughes: And you can say no.

06-00:47:31 Schekman: I’m not very good at that. I’ve never been very good at that. When I was a postdoc, my advisor in San Diego, recognizing that weakness— One of the things that he did very well was just say no. At the going-away party, he took me aside and he said, “Randy, when you get to Berkeley I want you to look in the mirror in the morning and practice saying No.” [laughter] I failed miserably.

06-00:47:59 Hughes: Well, I think that’s a good note to end on. 108

Interview #4: March 26, 2014 [Audio File 7]

07-00:00:00 Hughes: It’s March 26, 2014, and we’re in the office of Dr. Schekman for the fourth and last interview in this series. Dr. Schekman, I thought we’d start today with the Chancellor’s Advisory Committee on Biology [CACB]. An obvious question is why did you accept the position of chair, in 2002?

07-00:00:33 Schekman: Well, this committee was started by Dan Koshland over twenty-five years ago when he led the reorganization of the life sciences [at Berkeley].4 That really revolutionized our teaching and research programs here, at least the way they were organized at the department level. He designed the position—first of all, the Chancellor’s Advisory Committee and then the position as chair—to suit his own personal taste, which was to have influence but without having to make administrative decisions. [laughter]

07-00:01:12 Hughes: Sounds like him.

07-00:01:13 Schekman: Yes. Of course Dan Koshland would have had influence no matter what. The former provost or executive vice provost and executive vice chancellor and provost, Paul Gray, once told me that when he wakes up in the morning the first thing he thinks is, what can I do for Dan Koshland today? [laughter]

So Dan organized this committee to have an overarching role in guiding faculty recruitment and interdisciplinary life science programs around campus. Since it wasn’t possible to reorganize all of the departments in which life sciences research is done, he thought there should be some coordination. And he felt that campus leaders should be involved, and not necessarily deans and chairs of departments. So he more or less handpicked a committee, probably reflecting the composition of the committee that he organized, to bring about the programmatic change on the campus. They developed strategies to influence, for example, faculty recruitment. After the reorganization, the principle was that every life science faculty recruitment would be conducted by an interdisciplinary group and not merely the members of the home department. Moreover, that new faculty positions would not necessarily be given back to the department that lost someone through retirement or denial of tenure.

07-00:02:57 Hughes: I’ll bet that caused some trouble.

4 For interviews on the reorganization of biology at Berkeley, see: http://digitalassets.lib.berkeley.edu/roho/ucb/text/reorganization_biology.pdf 109

07-00:03:01 Schekman: Yes, of course there was resistance. There was resistance to that as well as to the reorganization in the first place. But Dan had enormous influence with the then-Chancellor [Ira Michael] Heyman, and Provost [Roderic B.] Park, and subsequently with [Chancellor] Chang-Lin Tien.

[The reorganization] was seen as a benefit—and certainly not to the benefit of him or to his Department of Biochemistry. Indeed, the Department of Biochemistry lost its identity during the reorganization. So it was seen to [be to] the benefit of the campus, and it was intended to revitalize areas that were moribund on campus. I’ll give you two examples. Before the reorganization, there was a really pretty mediocre genetics department in the College of Natural Resources. As a result of the reorganization, genetics became a division of the Department of Molecular and Cell Biology [MCB] and almost immediately acquired new clout in terms of faculty recruitment. [Gerry] Rubin was recruited from the Carnegie Institution [for Science] in Washington to a special chair, an endowed chair that he held while he was on the faculty here. And other people moved into that division who were not in the genetics department before that.

Another example was a really pretty mediocre Department of Anatomy and Physiology that was ostensibly representing cell biology, but it was not doing a very good job, although the last recruit that they had in that department was Roger Tsien! So that was great. But most of the time they weren’t making good decisions. As a result of the reorganization and then subsequently the action of the Chancellor’s Advisory Committee, a new division of cell biology emerged in the Department of MCB. And again, they were able to recruit faculty and new graduate students of a much higher caliber than in the predecessor departments.

07-00:05:17 Hughes: Did you have any direct hand in that before you become chair?

07-00:05:22 Schekman: Early on, no. I was still a junior faculty member. I was probably tenured by the time of the reorganization, but I didn’t have any influence other than my own voice. I was still a little unseasoned to become involved in any administrative direction for the department.

So Dan took on this reorganization and developed strategies of making recommendations on the composition of search committees. The deans initially were resistant to that, because it was and is their prerogative to establish search committees for new faculty. But I think with time they saw it not as an intrusion on their authority but rather simply good advice. And so now the deans—

07-00:06:10 Hughes: Did that mean that the final decision was made by the department? 110

07-00:06:15 Schekman: No, by the dean— Well, by the dean in consultation with the department, on the recommendation of the CACB. And other initiatives that came around were discussed at the CACB—the new building program, which of course Koshland had a role in.

07-00:06:34 Hughes: And research funds? Was there any control over them?

07-00:06:39 Schekman: Not so much, at least not initially. Not that I’m aware of. There may have been fundraising facilitated by that committee, but not so much under Dan’s leadership. More so, I would say, subsequently under Tij’s [Robert Tjian] leadership. Tij was and is a consummate fundraiser. Dan, of course knew all the right people and of course he was wealthy himself. Tij I think has been more assertive in actually going out and bringing people to the campus for fundraising opportunities.

07-00:07:19 Hughes: As this very building [Li Ka Shing Center for Biomedical and Health Sciences] we’re sitting in is evidence.

07-00:07:23 Schekman: And many other things, many other things.

07-00:07:27 Hughes: I understand that the committee—I’m not sure under Dan, but certainly by the time you were chair—was also trying to be very aware of new areas of science and keeping Berkeley up to snuff.

07-00:07:49 Schekman: Yes, yes. That’s a good point. So ideas for hires in areas that were not well represented on campus came from or were vetted by that committee. It was certainly the intention to not allow departments to go stale and instead to be infused by the influences elsewhere on campus.

07-00:08:12 Hughes: Can you give an example of what new areas were incorporated?

07-00:08:17 Schekman: Well, computational biology was not well represented in any particular department, and it’s still spread around. But when you put physical scientists and life scientists together on a committee, as has been the case with the CACB, then things like that emerge and new FTE [Full Time Equivalent] possibilities are suggested. Let’s just historically go through this. So Koshland served as the founding chair of that committee, for probably seven or eight years [1982-93]. And then he recommended Tij to succeed him, and Tij did that. Tij did it for I think nine years [1993-2002] and then he suggested me. That was during the administration of— 111

07-00:09:21 Hughes: It was in 2002.

07-00:09:21 Schekman: [Robert] Berdahl was the chancellor who appointed me as the head. I think there was some concern, although it was never stated to me, that the chairs of the committee were coming from the same department, MCB, and [that the CACB] should have been more broadly representative. But I’m not sure there were other candidates.

07-00:09:52 Hughes: Well, MCB is the largest department, and arguably the most powerful?

07-00:09:56 Schekman: Yes, well that’s the problem, isn’t it? They didn’t want it to have too much influence. But I’m not sure there were other candidates. In fact, when I stepped down, Mike Levine took over as the chair, again from MCB. So if there were candidates from other departments who were viable they might have been considered, but I’m not sure there were.

07-00:10:16 Hughes: Why did you take it?

07-00:10:16 Schekman: Why did I take it? Well, I think it was because of Dan and Tij and what they did, and I saw it as a natural progression of my role on campus. I had been the chair of MCB. I had been the head of the Division of Biochemistry and Molecular Biology for five years, and then I was co-chair of the department for three years, which was all that [Howard] Hughes [Medical Institute] at the time would allow me to do. So I had stepped down from division head and co- chair. Tij had already been chair of CACB for a while, so they were looking to keep me out of mischief, so they asked me to do that, and of course I was willing to do that.

07-00:10:55 Hughes: Hughes limits the amount of time away from practicing science?

07-00:10:58 Schekman: At the time, yes, they did. At the time they had a very specific rule that you couldn’t serve as a chair of a department for more than three years. I think if I had really wanted to continue as chair, they would have made an exception. But I didn’t find the job so appealing, to be honest with you: a lot of dealing with a lot of administrative trauma and putting out fires with few resources.

07-00:11:30 Hughes: I remember Dan saying that it was only when your science was slipping that you would want to be chairman. [laughing] 112

07-00:11:40 Schekman: Yes, well that’s unfortunately traditional, but I hope not true. Tij did manage to avoid doing that. I thought that was very clever of him. But Dan was chair of Biochemistry. Would one argue that his research was slipping? I’m not sure he would have argued that about himself.

We have a system of rotating chairs here at Berkeley, and it’s important that the best people step forward, rather than having hacks do the job. I can tell you, in a lot of places [the chairs] are people who don’t have active research programs. I think the same way about people like that doing administrative jobs, as I think about editors who aren’t active scientists doing that job.

07-00:12:43 Hughes: Well, I read that there’s something like 250 members under the CACB now. Is that pretty accurate? I imagine that most people now think now the reorganization was a pretty good idea. But are those original resentments, particularly to Molecular and Cell Biology and in a way to Dan himself, who was the power behind the throne—or maybe not even behind. [laughter]

07-00:13:20 Schekman: He was the throne.

07-00:13:23 Hughes: Exactly. How are people feeling?

07-00:13:25 Schekman: By the time I became the chair of the committee, I don’t think there was any remaining animosity about the reorganization. I think that subsided pretty quickly as other institutions modeled what we did. I haven’t heard any complaints about that in many years. The more senior people when the reorganization was going on, in particular most of the chairs who lost their positions during the reorganization, they may have resented it. But I remember, representing the younger faculty at the time, that we thought this was precisely what the doctor ordered. And since that group now is the senior citizens, I think it’s probably time for another shake-up.

07-00:14:09 Hughes: Did you have specific goals in mind when you assumed the chairmanship?

07-00:14:14 Schekman: Yes. I wanted to use it as a fundraising vehicle, but I was not successful. I did one thing that I think worked well, and I hope it continues to survive. There was an endowment given by, let’s just say, a wealthy friend of the life sciences at Berkeley, that was used for a few years to give small grants to faculty in the life sciences here on campus. People didn’t apply for it. There was an ad hoc committee that decided who was doing interesting work and might be able to use an infusion of cash. And so it was doled out in $50,000- $60,000 allotments every year to different people, and I thought this was not a terribly wise investment. 113

So when I became the chair of the CACB and Paul Gray was the EVCP [Executive Vice Chancellor & Provost], I urged him to speak to the donor, who was still around at the time, and change the way in which the funds were distributed, to make it funding of interdisciplinary projects that people would apply for. So groups of faculty would get together and propose to purchase a piece of equipment or to start a training grant or to fund a fellow or something like that. These applications would come in, and then a subcommittee of the CACB would evaluate the proposals and just make the awards, and it would be very unbureaucratic. So there was some resistance. Paul Gray was not— I spoke to the donor, and he thought it was perfectly reasonable, and so—

07-00:16:08 Hughes: What was Paul Gray’s reluctance?

07-00:16:13 Schekman: Well, you know, the document on the bequest was written, and the way I was proposing to do it was not entirely consistent with the language of the bequest. It was not a bequest but a gift. Most administrators suffer from inertia, and I didn’t understand. But I wasn’t willing to take no for an answer. So the donor was perfectly happy with this idea, and Paul Gray was persuaded, and so we did it, and that worked. So every year I was CACB chair I organized the solicitation and review of proposals and I think it served the campus well. It’s really difficult now to get money to purchase big pieces of equipment, so if you can show that the campus is putting in seed money you have a stronger case to make for federal support.

07-00:17:06 Hughes: Yes, well that’s one of the ways science is going these days, isn’t it? Each lab doesn’t have its own ultracentrifuge anymore.

07-00:17:15 Schekman: Well, people do have their own ultracentrifuge.

07-00:17:17 Hughes: All right, poor example.

07-00:17:17 Schekman: But these big fancy fluorescence microscopes are beyond the budget for most people, so you have to get together with other people and find some kind of communal support. So that worked.

The other thing that I did during my term was, I led the effort for the stem cell program on campus. It was not really as a result of my being chair of the CACB—it wasn’t done through the CACB. But because I was chair of the CACB, I was asked to lead the effort, given that Prop. 71 [California Stem Cell Research and Cures Initiative] seemed likely to pass. So I organized the campus effort—although my research is not in stem cells—and that was gratifying. Again, I think the fact that the CACB had brought people together made it easier to bring a lot of people together for the stem cell program. 114

People came out of the woodwork to join this effort and helped with writing a training grant, and so that program got going. I stepped down because it was really not my research area, and I felt that others would be better able to handle that.

07-00:18:39 Hughes: You became director of the campus stem cell center in 2005. I don’t remember when you stepped down.

07-00:18:56 Schekman: [After] a few years. I stepped down, and Tij stepped up and helped. A young faculty member in bioengineering, David Schaffer, took over the position of director from me.

07-00:19:23 Hughes: Say something about that controversial proposition.

07-00:19:36 Schekman: Prop. 71.

07-00:19:37 Hughes: Prop. 71. Were you out on your bully pulpit trying to get it passed?

07-00:19:47 Schekman: Well, I did speak to public interest groups. I spoke to my father’s synagogue. I spoke to a community group in Oakland/Piedmont. I went around and spoke on this, and I had my stump speech on that. Obviously, I felt very strongly about the subject, because of the federal restrictions that were imposed by the Bush Administration. At the time it seemed like if California were able to fund this, that that would put us way ahead of the game nationally, so it seemed like an advantage for us to do it. Other campuses, particularly those that have medical schools, I was sure would jump in and take advantage of any funding. So we had to be there to position ourselves to get something. But I think we’ve [at Berkeley] been at a disadvantage for that particular program because we don’t have a medical school, because the stipulation for the funding has really been focused on the practical application of stem cells. Although some has been invested in basic science, much of it has been trying to direct it at practical application, which I think, frankly, is for most purposes premature.

07-00:21:03 Hughes: It’s been such a theme on this campus. Ernest Lawrence tried to get cancer institute funding for the application of the radiation and the radioisotopes produced in the cyclotron and ran up against that same road block of no medical school. He tried to form a liaison with UCSF, but it wasn’t really very productive.

07-00:21:31 Schekman: I see. I wasn’t aware of that. Well, it’s a problem, but I think it’s also, frankly, a strength. I’ve enjoyed being here rather than at a medical school because I 115

don’t ever feel any pressure to do something that has direct medical applications, whereas I think at medical schools, even those that are strong in basic science, there continues to be pressure to work on translational science. I think that’s often misplaced, and so I enjoy being in a place that values basic science.

07-00:22:06 Hughes: And that’s what Berkeley’s best at.

07-00:22:07 Schekman: Yes.

07-00:22:09 Hughes: I looked at the [Berkeley] Stem Cell Center website, and you’re listed along with your Alzheimer’s research, which of course is aimed at eventual application, one hopes.

07-00:22:29 Schekman: Yes, well, when I was the head of the stem cell program I thought I might actually take advantage of embryonic stem cells and do something with Alzheimer’s, create a stem cell line from a patient from a family that has a genetic history of Alzheimer’s. But I thought and I thought and I thought, and I couldn’t justify it in my mind, because I didn’t feel that I was going to learn something fundamental. Maybe it would have some practical application, but I didn’t see how I was going to satisfy my desire to learn something fundamental, and so I never did it.

07-00:23:16 Hughes: There’s the basic scientist again! [laughing]

07-00:23:17 Schekman: It’s just my focus. I don’t mean to diminish what others may do in that respect; it just didn’t appeal to me.

07-00:23:29 Hughes: Going back to the tremendous politics around passing Prop. 71, there was criticism at the time and thereafter, particularly about Klein. I forget what his first name is.

07-00:23:45 Schekman: Yes, Bob [Robert N.] Klein [II].

07-00:23:46 Hughes: Yes. I am putting it bluntly: he more or less promised the California public that if they passed this proposition there would be cures around the corner. How did you feel—

07-00:24:03 Schekman: Well, we were all guilty of hyping, that’s for sure. I’m sure I said things about this that I wouldn’t say now. But even at the time I thought that the best 116

application would not be in tissue replacement therapy, which was being pushed as a major goal, but rather in the ability to create cell lines taken from patients with a genetic disease, and then being able to reproduce the development of the disease with cultured cells in the laboratory, and then to use that as a screening tool for looking for drugs that may intervene. I think that’s still the best practical way that stem cells could be used.

Right now, with the discovery of [Shinya] Yamanaka in 2006, a publication of Yamanaka, where you can take skin cells and turn them into embryonic stem cells, I think that bypasses all of the controversy about using embryos to develop an experimental tool. If embryonic stem cells are ever used for therapy it may have to be from an authentic embryo, rather than from iPS [induced pluripotent stem] cells made in the laboratory by the Yamanaka approach. But for most purposes—

07-00:25:29 Hughes: Why would the Yamanaka method not be useful?

07-00:25:33 Schekman: Well, one of the genes that’s required, of the four that he used to induce this pluripotency, is a tumor-promoting gene. And these stem cells from the mouse, when implanted back into a host, into a mouse, often lead to tumors. So it’s not going to pass muster for any therapy. Now, people have worked a lot on developing alternative strategies to generate iPS cells that may be less dangerous. Most recently there were two papers in Nature that claimed that a simple low pH acid treatment of adult stem cells would turn them into embryonic stem cells. But this looks to be— It’s wrong, and it may be even fraudulent. That’s another story.

07-00:26:34 Hughes: Oh, that’s really recent, isn’t it? My source is the New York Times.

07-00:26:37 Schekman: Yes, it was a month ago.

07-00:26:43 Hughes: Well, of course it’s a huge subject, and we could spend the rest of the time on stem cells. But let’s not, unless there’s anything in conclusion you want to say about it.

07-00:26:56 Schekman: No, but I’m grateful to the people of the state who voted to approve Proposition 71, because it generated funding opportunities for our young colleagues and started new programs of research here. And it allowed us to complete this building [Li Ka Shing Center for Biomedical and Health Sciences] We’re still committed to bringing in people doing interesting things on stem cells. We’ve hired some people, and the field’s now become a part of biology, so that’s good. 117

07-00:27:24 Hughes: The people here are mainly doing very, very basic research?

07-00:27:27 Schekman: Yes, oh yes, oh yes.

07-00:27:31 Hughes: Good. Let’s move on. You were editor-in-chief of PNAS [Proceedings of the National Academy of Sciences] from 2006 to 2011. And again, I ask the basic question—

07-00:27:56 Schekman: Why?

07-00:27:57 Hughes: Why. I know you’d been an editor at at least three other journals.

07-00:28:03 Schekman: Yes, I’d had experience. It was enjoyable for two reasons: one is, I got to meet other scientists in areas that I wouldn’t ordinarily meet because I wouldn’t go to the same meetings with them. And then, when you’re handling papers for broader areas, you’re forced to read the literature a little more [broadly] than you might otherwise. So I found it useful, and, again, it’s my feeling of responsibility. I publish papers; they’re handled by other people; I should do my share. Of course then I end up doing much more than my share.

I was on the editorial board of the PNAS when Nick Cozzarelli was the editor- in-chief. I feel very strongly about the PNAS. I remember first reading the journal when I was in college at UCLA, and I remember it was one of my first contacts with the professional world of scientific research. My first big, important paper when I was here was published in the PNAS. It’s reference number one in the Nobel essay on the subject of the prize. So it’s an important journal, and it’s run by active scientists. It was the journal that I wanted to publish all my best work in when I was a graduate student.

07-00:29:34 Hughes: Run by active scientists, including the editors?

07-00:29:37 Schekman: Yes, everyone is. Everyone, everyone.

07-00:29:39 Hughes: Everybody was active.

07-00:29:41 Schekman: Yes, as opposed to those like Nature—

07-00:29:43 Hughes: Like Science. 118

07-00:29:43 Schekman: Nature and Science and Cell are run by professional editors.

So Nick was doing a great job and really shook things up. He really changed the way in which PNAS was perceived and how people could submit to it. But it still wasn’t quite competing with the very high end to attract papers that went to Cell, Nature or Science. For myself and others, people would not send their best work to the PNAS. So when Nick tragically died, and the journal was floating, and they were looking for his successor, since I’d been on the board, and since I seemed to be a little too interested, they asked me. [laughing] The senior staff asked me. I thought about it a little while, and I thought yes, this is something I could do. I could do this. It would be a big time commitment, but trying to get the journal to be more competitive was something that I thought I could do.

07-00:30:53 Hughes: Your competitors were obvious, right? Nature, Science, and Cell?

07-00:30:55 Schekman: Yes, Nature, Science, and Cell. So that seems to be a recurring theme in my recent life.

07-00:31:04 Hughes: Yes, it does.

07-00:31:05 Schekman: So I felt that there were certain intrinsic advantages of the Proceedings: broadly representative of all the sciences, an editorial board that really represents a sampling of the best scientists in the country. I thought that the major problem with the PNAS and its perception by the outside world was this aspect of members’ privilege, where a member of the National Academy can contribute his or her own work or can sponsor the work of another individual, even if they are inappropriate to serve as a sponsor because they’re not in the same research area. And so I felt people were taking advantage of that, members were taking advantage of that. Everybody was. It was a weakness in the system.

So Nick had taken it on in one way. He took it on by democratizing the submission process. Before Nick, if you were not a member of the academy, you had to find a member of the academy to sponsor your paper. All of my papers had been sponsored up to the point when I was elected [to the academy].

07-00:32:21 Hughes: Now, the weakness is that the sponsor may know nothing about your line of research? 119

07-00:32:25 Schekman: Yes. Often the sponsor would be a senior person in your department who was doing it as a favor. Now, sometimes they were tough. My first PNAS paper that I had communicated when I was a faculty member here was by Clint Ballou, and he was tough, and he really blasted me. He said I didn’t know how to write English. [laughter] Well, he was right! He was right. It was a dose of cold reality, and as a result I took it much more seriously. I actually got a writing coach. So he was right on, and others would not have been so honest.

So anyway, most members of the National Academy have very high standards and wouldn’t wish to embarrass themselves. But I’ve learned, in dealing with the journal, that there are a number who abused the privilege. So what Nick did was he opened an avenue for submission that was unfettered by, not influenced by members. So anybody could just send a paper in and the editorial board would find some member to handle it, not necessarily a colleague. So a lot of people were really resentful of that. It’s astonishing that a lot of the old boys really resented Nick. Apparently there were shouting matches at the National Academy meeting. But he was tough and he could take it. [interruption]

07-00:34:05 Hughes: What was their objection?

07-00:34:12 Schekman: I don’t know what it was. It was somehow a sense that their privileges were being abridged. For example, I think before Cozzarelli a member could contribute or communicate, I don’t know, six papers a year, something like that. In order to create this track for direct submission, without having to go through a member, that quota was reduced to four. And people resented that. It was somehow taking away their power.

07-00:34:46 Hughes: Did it ever devolve to a situation where a scientist, hopefully with a good paper, didn’t have a contact with a member of the NAS and hence couldn’t get on this track?

07-00:35:00 Schekman: Well, yes. I mean in principle, sure. There are lots of scientists at places that don’t have academy members, and then the academy members would be bombarded with requests of this sort. A lot of academy members were perfectly happy later on when I did away with that sponsorship altogether because they didn’t like to be bothered by this.

But anyway, Nick really shook things up by creating this direct track for submission. And I thought we could take it one step further. We could further reduce the quota that members had and impose higher standards for those 120

submissions that were contributed or communicated by a member. So I wrote up my views and they selected me as the editor.

The first thing I did was a poll of the members to find out their attitudes, and I learned that a good number of them were perfectly happy not having to field these requests from people to communicate papers. So I created a different approach initially, where some outside person could directly communicate with a member, and if the member were agreeable, the outside scientist could send the paper in and say, I’ve discussed this with so-and-so and he’s willing to serve as the editor. So that got around a little bit the idea of having a member directly communicate a paper. It put the control in the head office where all the reviews were handled, so one could see what was going on in the process. Previously, when a member communicated a paper on behalf of someone else, they did so completely independently of the journal office. You would just send out the review form, and the member would do everything, and the paper would be tidied up, and then that would be it. The paper would get sent in with the stamp of approval of a member.

07-00:37:10 Hughes: With no further review?

07-00:37:10 Schekman: Right.

07-00:37:11 Hughes: Really!

07-00:37:13 Schekman: Except a perfunctory review by a member of the editorial board. And very few of these papers were challenged. Once a member signed off, said, “I want this published”—

07-00:37:22 Hughes: I can see problems there.

07-00:37:25 Schekman: You bet, you bet. [laughing] Most members are honorable, have high standards, wouldn’t want their young colleagues to submit something that was not right. But some of them just couldn’t be bothered. And a lot of them were members who were long past their prime, or way outside of the relevant research area. So when I went in as editor-in-chief I told the board, I said, “I want these papers challenged, because the journal’s slipping, frankly, and there’s a lot of stuff that’s getting published that couldn’t get published anywhere else.” Even by members, to be quite honest. So of course I—this engendered a great deal of criticism, and most of the five years I spent fielding complaints from members who felt their privileges were being abridged, and some of them were actually quite threatening. [laughing] Some of the worst ones came from Nobel laureates, who had to remind me that they were, after 121

all, Nobel laureates, and who was I to challenge their privileges. And this was a source of amusement for me.

07-00:38:32 Hughes: Did this wear on your soul?

07-00:38:34 Schekman: No, actually no.

07-00:38:36 Hughes: You kind of liked the—

07-00:38:37 Schekman: No, I have to admit I loved it. [laughter]

07-00:38:42 Hughes: I’m not surprised.

07-00:38:43 Schekman: I was channeling Dan Koshland. I was channeling Dan Koshland who had been the editor of the PNAS.

07-00:38:46 Hughes: Yes, I remember.

07-00:38:47 Schekman: I was channeling his spirit, and I think he approved. And we eventually, with the approval of most of the members, did away with this communicating track. So now the only privilege that’s left is that a member can contribute his or her own work, and even then, I challenged some of those. There was just some crap that got sent in.

One case that caused me endless grief was our colleague Peter Duesberg tried to contribute something. He knew that it would come to no good if he had to deal with me, so he quietly put this paper in on his views on aneuploidy in cancer. I didn’t hear about it until one of my board members wrote to the staff and said, “Well, it looks like he hasn’t really addressed the comments of the referees, his own referees.” So it came to my desk and I said oh, here we go again.

So I asked Duesberg’s referee number one, whom I happened to know, I said, “Here’s the paper. Here are your comments that he solicited from you. Tell me, did he actually do what you asked him to do?” And the guy got all upset. He called my voice mail. He said, “I thought this referee process was supposed to be anonymous.” Well, duh, I’m the editor-in-chief. How can it be anonymous to me? And I said, “Just do me a favor. Just take a fresh review form and write down—did Duesberg do what you asked him to do or not.” And of course Duesberg hadn’t. And so I got this scathing comment back from this fellow. So I said, “All right. We’re not going to accept it.” So through the journal, I sent to Duesberg a letter rejecting his paper. And he 122

went ballistic and tried to call me, but I didn’t speak to him. I just refused. So he then went to the president of the National Academy, and the president at that point should have said it’s—

07-00:41:06 Hughes: Who was it at that point?

07-00:41:06 Schekman: His name is Ralph Cicerone. He’s the current president. This was after Bruce Alberts [was president]. The president, I think mistakenly, agreed to consider this matter further, through the elected council of the academy.

07-00:41:19 Hughes: Really.

07-00:41:19 Schekman: Yes. We’ve since developed a procedure to deal with appeals of this sort that didn’t involve the elected officers of the academy. They had no role in this; they shouldn’t have had a role in this. I think he should have just— But anyway, Cicerone agreed to do it, and he appointed a council member to independently review the paper, which meant that this member would solicit two anonymous reviews of the paper, which I had not even done. Of course they came back more highly critical than anything that I said. And so the paper was of course rejected again. And Duesberg then wouldn’t even take that no from the president of the National Academy. He went to— The academy has a series of regional meetings around the country where local members come and talk about issues that they’re interested in. Duesberg makes some presentation, and again I think it was a mistake for Cicerone to even give him a microphone. Bruce Alberts, who was at the meeting, gets up and walks out. [laughing] Fortunately, I wasn’t at the meeting. Duesberg just rants on and on, accusing me of suppressing his career because I embrace the outdated view that HIV causes AIDS, which of course had no relationship to this paper at all. There was a lot of that kind of thing. And there were other nuts too.

But I still feel strongly about the journal. I would have carried on. They asked me to renew my term for another five years. I remember Cicerone calling me from a council meeting with the news that they would reappoint me, and I said I’m happy to continue. I heard from a voice from around the table at the council meeting, someone blurted out, “Yes, it’s not as though anybody else wanted the job.” [laughter] Thanks a lot.

07-00:43:28 Hughes: When you look back, what would you consider to be your favorite contribution to raising the prestige of the PNAS?

07-00:43:44 Schekman: Yes, I think giving the members a new sense of responsibility, and shepherding the literature and making sure that only good work was sent in, 123

and trying to cut out the abuse. And there are unbelievable, unbelievable examples of abuse. Shameful. I saw academy members put their name on a paper that they had nothing to do with, only to be able to contribute it, only to have another publication. There is one academy member, a neuroscientist, who has put [his] name on a paper having to do with DNA repair, completely, completely outside of his area of knowledge. We challenged it; it came to my attention; we challenged it. I had had my eye on this guy before. I sent it to a member of the board who was in that research area, and he said, “I’ve seen this paper. In fact, I still have the PDF.” So he sent me the PDF of this paper. It was formatted for PNAS, but without the name of the academy member on the list of authors, whereas the one that had been submitted included the name of the academy member in the middle of the authors. I had the staff go through both versions of the paper—identical, except for the presence of the academy member’s name.

07-00:45:04 Hughes: Did you confront him?

07-00:45:04

Schekman: Of course I did! I sent it back to him and said, “Explain this.” And the guy just lied. He said, “Oh yes, I’ve been involved, and I thought well, I shouldn’t put my name on the paper, but yes, I decided in the end to put my name on the paper.” Baloney. Just completely, completely dishonest. So of course we rejected the paper. But I know this guy; he’ll just keep plugging away. There are other examples of that. It was just outrageous. Unfortunately, old guys who no longer have a laboratory, they’re just desperately trying to remain relevant.

07-00:45:41 Hughes: Does PNAS have a page limit?

07-00:45:43 Schekman: Yes. Okay, so that’s another thing I did. There was a page limit. Nick had increased it from five to six pages, still a little bit restrictive. So since I wanted to push for moving the journal in the direction of being exclusively online, we created a new feature called PNAS Plus, where if you’re willing to have the paper exclusively online and not in the print version, you can have ten pages.

07-00:46:13 Hughes: I’ll bet that was popular.

07-00:46:13 Schekman: Yes, that was popular, although not everybody has done it, just because people have in their mind the idea that a PNAS paper is going to be a short paper, so they don’t need more than six pages.

07-00:46:25 Hughes: And it doesn’t have to be a more general topic? 124

07-00:46:29 Schekman: No—anything. Initially, what I wanted to do in addition to that was to encourage people to consider having something exclusively online. But I also wanted to broaden the reach of the journal by requiring each author to write a one- to two-page summary statement written for a broad, literate audience. I wrote an example for one of my papers. And some people thought that’s great; I can do that. Any of them could do it. They all teach; they could do it. But actually, a lot of people just couldn’t be bothered. They’d take the abstract from their paper and the last paragraph from their discussion and they’d stitch them together without even attempting a summary. So the staff had to become involved in rewriting these things, and that took a lot of time. They had to hire some professional science writers, because some authors just blow it off. And then I stepped down, and then they changed the policy so that instead of having a one- to two-page they just had a 100-word statement, which I think is inadequate.

07-00:47:37 Hughes: Shall we jump into eLife?

07-00:47:52 Schekman: Sure, sure.

07-00:47:51 Hughes: Tell me how the idea occurred to you.

07-00:47:56 Schekman: So Tij, Bob Tjian, told me that the Wellcome Trust and the Max Planck Society [for the Advancement of Science] were thinking about creating a new journal. The impetus for them was a sense of frustration that the major venues for the work of their most distinguished scholars was languishing because of the difficulty of finding space in these journals that are modeled on a print version, Cell, Nature, and Science. At first I was skeptical. But then Tij got interested in it for [Howard] Hughes [Medical Institute], and it occurred to me that it was an opportunity.

I was perfectly content to continue another five-year term on the PNAS. Cozzarelli had done it for a dozen years, and I saw there was always going to be an opportunity to keep pushing for higher standards. But at that point I think I’d turned— I was sixty-three, and I thought I could do something really different! I’d always done more or less the same thing for a long time, and so I thought at my age I should try something really different, something brand new. So I thought here’s an opportunity to do something with substantial financial support from three of the most powerful organizations, and really carte blanche to do something that could be more effective in challenging the hegemony of these three so-called high-impact journals.

07-00:49:35 Hughes: Which are— 125

07-00:49:37 Schekman: Cell, Nature, and Science, yes. I had grown increasingly frustrated during my years at PNAS with this craziness about impact factor, and the use of impact factor in deciding where one would publish a paper. Impact factor is a crude calculation of the number of citations, divided by the number of papers in the journal, over a two-year period.

07-00:50:06 Hughes: Oh, really? It’s a technical or a quasi-technical calculation?

07-00:50:13 Schekman: I think it’s a phony number. It’s influenced by lots of things, including the small number of papers that generate thousands of citations, many of which are not actually even correct. They just generate a lot of press. This infamous paper in Science, where the claim was made that a bug growing in a salt marsh had replaced all the phosphate in its cell with arsenate. The idea that you could have a DNA based on an arsenate backbone instead of a phosphate— that was big news. NASA had a big press conference. Science made a big splash of publicity for this. But of course it was crap. It was wrong; it was just wrong. Any microbiologist who read the paper critically would know where the error was made and where the data were inadequate.

07-00:51:16 Hughes: Where was it published?

07-00:51:15 Schekman: Science.

07-00:51:16 Hughes: In Science, oh.

07-00:51:19 Schekman: Yeah, Science. As soon as it was published people dismissed it, but it still hasn’t been retracted. No one believes it, and I think probably Science is afraid of being sued by the authors, whatever. I don’t know what the story is. I think it’s cowardly. But I saw that at PNAS—the legal counsel at the National Academy of Sciences was very reluctant to retract a paper against the wishes of the author, for fear of legal action.

07-00:51:50 Hughes: But there were some retractions, I read, even under your tenure.

07-00:51:55 Schekman: Oh, absolutely. Oh yes. But you’ll find that the papers that get retracted are with the consent of the author, where the senior author realizes that some mistake has been made, maybe an honest mistake, or where there has been some data manipulation on the part of a postdoc that the senior author wishes to correct. Almost all of those retractions are voluntary. But there are a few that are involuntary, and those are the messy ones. 126

There was one famous one here on campus, a ridiculous paper that was published in Nature some years ago written by this guy in the College of Natural Resources named [Ignacio] Chapela. He claimed that recombinant DNA was sweeping through the wild populations of maize in Mexico. Well, it may be true, but his experiments didn’t demonstrate that adequately. The technique that he used and the data that he presented were terrible, and yet Nature published it because—Nature, Science, Cell, they’re in the business of selling magazines.

07-00:53:14 Hughes: And that was a hot topic.

07-00:53:16 Schekman: It was going to generate a lot of publicity.

07-00:53:17 Hughes: You really think that whoever was responsible for reviewing the paper saw the deficiencies and yet advised publication?

07-00:53:29 Schekman: No, no, no, I don’t accuse them of being ignorant in that way. But I think they look for things that are going to generate a lot of citations. This impact factor becomes a self-fulfilling goal. They realize that the number is going to be influenced by the number of citations that a paper has. They know that things that are in popular areas or things that seem incredible are going to generate a lot of attention and citations, and therefore they give those papers the edge. They have them evaluated by scientists. But in the case of that Science paper, apparently it was evaluated by geologists and not microbiologists, and they didn’t know the proper experiment. They didn’t know that the salts that one uses to grow a bug have a low level of phosphate in them. In fact, the DNA has phosphate, it doesn’t have arsenate. So why would a geologist know that. Microbial growth medium has trace levels of phosphate that one must take pains to remove.

07-00:54:23 Hughes: So how is eLife going to get around this problem? And others as well, which you didn’t talk about?

07-00:54:30 Schekman: I think part of the problem is the enormous pressure that’s placed on young people to present things that look spectacular. And I think, without necessarily impugning the character of the young scholars, they cut corners. They cherry- pick data. They look with rosy colored glasses at results that others would find meaningless, and they write the paper accordingly. Then in the end it proves not to be true, or to be misrepresented, but it proves appealing to an editor who’s looking for buzz. So a lot of that has to do with these journals being too selective in what they will publish, in a way. That is, they’ll only take a small fraction of the papers that are submitted because they’re looking for the buzz. And so Science publishes only 6 percent of the papers that are submitted, and 127

Nature publishes 8 percent. That means there’s a lot of really good science out there that just doesn’t appeal to them, which they just don’t even look at. And what sneaks through are the things that look really cool. But guess what? Some of it’s suspect. The referees— Even if they’re the most appropriate referees, they can be fooled, and they don’t really see the primary data.

[Audio File 8]

08-00:00:00 Hughes: As you well know, there are three institutional sponsors of eLife, Howard Hughes [Medical Institute], Wellcome Trust, and the Max Planck Institute. Why those institutions, and what does sponsorship actually entail?

08-00:00:27 Schekman: They were the ones who had the feeling that their investigators were having a lot of trouble getting their best work published in these very selective venues. These institutions have also been pushing open access for the publications of their scholars. The high-end journals have resisted that, because they want to hold copyright on the papers, and they’re in the business of selling magazines and not giving them away. The other thing is that these journals are run by professional editors and not by active scientists. So these organizations felt that a better model would be a journal that appealed at the high end but which was run by active scientists and was openly accessible.

Well, there is such a journal. It’s the Public Library of Science, PLOS, which although it didn’t found the open-access movement has certainly done the most to promote it, and with very powerful leaders in the form of Harold Varmus, Pat Brown, and our own Michael Eisen here at Berkeley. One argument would have been why not just contribute to the PLOS organization? But at least initially, though not now, at least initially their ambition was to compete with the journals at the very high end. They thought in order to do that they had to have a professional editorial staff, so they started with that idea. I don’t know if it worked so well for them because professional editors by definition are no longer actively engaged in scholarship and thus lose touch with what is going on in the laboratory. I think PLOS is doing very well, and they’ve been very innovative; the journal PLOS ONE is very innovative. PLOS Biology and PLOS Medicine are still the flagship journals of that series, and they do appeal at the high end. But they just didn’t break into the territory occupied by Cell, Nature, and Science, at least not sufficiently effectively.

And so these organizations, Hughes, Wellcome Trust, Max Planck, felt maybe they could do a better job; maybe they could come up with some magic that would actually break into the top ranks. There is room at the top because of the way the model that these, at least the two commercial and the AAAS running Science the way they operate . So Tij asked me— As I said, I had just re-upped for another five years at PNAS. There was a meeting at Janelia Farm among stakeholders from around the world who were concerned about the life 128

science literature. And there was, as a result of that meeting, some enthusiasm to do this, given the considerable resources that were going to be brought to bear.

08-00:03:35 Hughes: Which were to come from the three institutions?

08-00:03:38 Schekman: Yes, so the three institutions have agreed to pool resources to pay the bills, at least for a five-year period. They created a foundation so that the editorial position of the journal would be completely independent of the funding organizations. And the principle certainly was that, unlike PNAS, there would be no privileges associated with being an investigator at these institutes. We would encourage people who were in these institutes to publish their best work there, but they wouldn’t get any breaks. I wouldn’t have taken the job without that.

So it seemed appealing to me, and I was ready to do something different. I feel very good about the National Academy of Sciences. I’ve just actually been elected to the council of the academy, so I’ll be starting that in a few months. But I just thought this was something else, the opportunity to start something from scratch. Hughes has been very generous with me, and so I felt okay, something I can do.

So I started as editor-in-chief in 2011, and it has been a lot of work; continues to be a lot of work. Challenging the hegemony of these three journals continues to be my biggest problem. We’re going to have an impact factor imposed on us shortly, and it’s not going to be competitive with these journals because, in the case of Science and Nature, they’ve had a hundred-year start in the way the impact factor is calculated. There’s no way that the new journal can compete.

08-00:05:20 Hughes: But eLife, just by the very fact that it is actively publishing, must be taking some business, so to speak, away from the established journals.

08-00:05:29 Schekman: Well, we certainly have business, but whether we’re taking it away from them I wouldn’t care to comment because I know that a lot of the papers we get have already been rejected by Cell, Nature, or Science, or sometimes all of them. I know this informally; no one says it when they send a paper in.

08-00:05:52 Hughes: How can that more than decades-long hierarchy of those top journals—well, Cell is a little bit more recent—be broken? Particularly if the young investigator thinks his or her career is at stake. Publication in one of those journals is the end-all. 129

08-00:06:17 Schekman: I know. Well, I think that’s part of the pathology. I think we, the senior investigators in the life sciences, have created this monster. We’ve transferred our judgment and our authority to people that we wouldn’t otherwise trust to make decisions on our behalf. There are enough people who feel that way that they’re willing to convince their students and postdocs that they want to go with this new journal. So it’s up to me and the editors that I’ve selected for eLife to do a better job. So we’ve done a lot of innovative things that the other journals don’t do.

08-00:06:57 Hughes: Such as?

08-00:06:58 Schekman: Well, one of the major selling points that we have that’s quite different is a consultative approach to the review of a paper. So when a paper comes in, it’s first considered by a senior editor who’s usually a distinguished person who knows the broad area, and they decide if this is a significant contribution, that there’s a real important discovery here. If not, the paper is just rejected. If it’s true, then it’s given over to one of a very large number of members of a board of reviewing editors. There are now about 180 of them, and these are experts in individual areas. We ask that person to serve not merely as an editor but as a referee. And it will become obvious in a moment why. That person then usually selects two other individuals to serve as ad hoc referees. And so they each review the paper independently. That’s just like any other journal. But then, once the reviews are done, they’re posted online at the manuscript website to be seen by each other but not by the author. And then the editor initiates an online consultation session where there’s a back-and-forth over a day or more, where the views of the other referees are considered, and, importantly, everyone knows the others. Their identity is not hidden in the consultation session, so there’s some back-and-forth.

The editor then, having supervised the discussion, is asked to write the decision letter. We ask that that decision letter include the most important comments that need to be conveyed to the author in the event that the paper has been reviewed favorably, and so here’s a prioritized list of things that the author has to do. We hope to make that limited; we don’t want the reviewers to rewrite the paper in their own image. And then the author gets that one decision letter. In other journals you get a series of reviews. In this case, for a favorable decision, you get the one decision letter with a point by point— here’s what you do. The author then is given an opportunity to respond. We hope it’s quick. It goes back to the board member who supervised the process, and we ask that person to make a decision unilaterally, without going back to the referees. Other journals typically go back and forth between the anonymous reviewers and the editor and this can sometimes take more than a year to resolve, and often not favorably. 130

08-00:09:27 Hughes: Which is based on whether the author actually made the changes recommended?

08-00:09:30 Schekman: Yes. And since the editor participated in the discussion, and we hope reviewed the paper him or herself, they should be in a position to evaluate whether the author has responded. Seventy percent of the time that’s done. The decision is made on the spot, almost always favorable at that point, and that cuts down the length of time. Typically in other journals, that can go on for months, back and forth, back and forth.

08-00:10:00 Hughes: I can imagine. Also, if I understand the long-established process right, every reviewer has his or her own ideas about what needs to be changed. There may be no synchronicity between any of the reviews.

08-00:10:15 Schekman: Yes, it’s a problem. But going into this, you know that you’re going to have to actually defend your views in front of your peers. It’s very much like what happens at an NIH review panel where you’re sitting around a table, and you know the other person, and you’ve done your review, and you’re arguing it out. And that’s what we do here at eLife. And so there’s an effort to come to some resolution. Either the paper is not going to pass muster and so we’re just going to reject it, or there’s something there, and here’s what maybe needs to be done, and then actually what really needs to be done and what’s extraneous. So the author gets two lists. One is you’ve got to do these things, and the other is, well, you could do these if you felt like it.

08-00:11:01 Hughes: But we’re not going to reject it if you don’t.

08-00:11:04 Schekman: Yes. The overall length of time it takes from submission to acceptance, for those papers that are accepted, is running around eighty-five days.

08-00:11:18 Hughes: That’s great!

08-00:11:18 Schekman: That includes the time that it takes for the author to respond.

08-00:11:23 Hughes: What might it be at Science, for example?

08-00:11:26 Schekman: If you look at the numbers for Science, Cell, and Nature they are, of course, much higher. Typically double that. Science reports a number that is not double that. It’s only 50 percent more. But unfortunately that number can be gamed in the following way. A paper comes in, it looks interesting, it’s 131

reviewed. Let’s reject it and tell the authors to come back with a revised version. They come back with a revised version; that becomes the effective date of submission. So it’s actually manipulation.

08-00:12:01 Hughes: Oh, I see.

08-00:12:04 Schekman: So I don’t believe the number that Science publishes because I’m sure that it takes longer, in that case, than 120 days. I just don’t believe it. I was tempted to do some oppositional research in the following simple project. I would like a staff member to take all the issues of Science and Nature for a year and send an e-mail to each of the first authors of the papers and ask, “When did you actually first submit this paper?” [laughter] I’m sure we’d get a lot of interesting responses. But others on our eLife leadership team said, “Well, that’s a good project, but we shouldn’t do it. It should be done by an outside group.”

08-00:12:41 Hughes: Well, right. It might look a little self-serving.

08-00:12:45 Schekman: Well, of course that’s precisely what it’s intended to do. So anyway, people who’ve gone through this process, who are otherwise not associated with the journal, generally find it very appealing—not everybody. So we’re winning over confirmed customers as a result, loyal clients, we hope. But it’s slow.

08-00:13:09 Hughes: What about your reviewing editors? Do they like this process?

08-00:13:16 Schekman: Yes, many of them do. It all depends on how committed they are to it. We get some reviewing editors who don’t want to do the extra work. But we pay all of our editors.

08-00:13:29 Hughes: Oh, do you?

08-00:13:30 Schekman: Yes. So that’s an expensive part of our business plan. We spend a lot of money on editors.

08-00:13:40 Hughes: Is that true of the other main journals?

08-00:13:42 Schekman: Well, Cell, Nature, and Science have professional staff. Of course they are paid. And then the editor-in-chief of Science, that’s a paid salary position. But the boards of the other journals, Cell and Science, are not paid positions. And Nature doesn’t have any editorial boards, so it’s all done by their staff in 132

London and New York. But people are people, and some of the board members we have just don’t put in the time.

08-00:14:20 Hughes: Well, they not only have to be committed, but there also has to be a relatively rapid turnaround.

08-00:14:28 Schekman: Yes, and they actually have to do more than a board member typically has to do. They have to participate in this online discussion and hash it out. So I deliberately picked a very large board so that we wouldn’t burden these people with more than one paper a month.

08-00:14:46 Hughes: Did you really pick them all?

08-00:14:49 Schekman: No, I picked the senior editors. There are two deputy editors. The funding organizations felt they wanted to have some hand in the leadership, so I’m ostensibly representing Hughes, and there are investigators from Wellcome Trust and Max Planck who are my deputies. And then there are a bunch of other senior editors that the three of us picked. When we picked the senior editors, we asked each of them to identify ten people in their discipline, based on their experiences with them. I emphasized that we wanted responsible board members who would be called on to quickly respond. Unfortunately, we got good scientists, but not all responsive scientists. So we’ve been removing people from the board and replacing them, and we’ll refine it over time and hope to get people who actually answer their e-mails.

08-00:15:48 Hughes: Is the bulk of the funding that comes from the three institutions going to payment of the editors?

08-00:15:58 Schekman: Well, we may have about ten or so professional staff in Cambridge, UK, and we have significant hosting expenses from the HighWire Press that hosts the journal, and the manuscript server company, eJournal Press, in Maryland that has written the code for our electronic submission system. And there are expenses for publicity and sponsorships. It’s an expensive proposition, even though we’re exclusively online. Print would only be a small fraction of our budget, if we were printing anything.

08-00:16:36 Hughes: One of the problems that you’ve alluded to is the page-limit situation. Please explain why you think that is a drawback to good science.

08-00:16:56 Schekman: If you win the lottery and get a paper published in Nature or Science, typically then what happens is they ask you to reduce it to a postage stamp. And that means you end up pulling the guts out of the paper and putting it in an online 133

supplement that people rarely look at. And I fear not even the referees look at it adequately. So it’s a telescope version of the paper that’s printed. I think this makes it awkward to write a paper. Some people think this improves papers, but I don’t.

08-00:17:38 Hughes: Well, it could also leave out important information.

08-00:17:42 Schekman: Well, it doesn’t get left out, it just gets pushed to—

08-00:17:46 Hughes: The supplement.

08-00:17:48 Schekman: —a supplement, yes. With the advent of electronic publication you have this possibility of unlimited text that’s online. So we felt that we wanted the full story to be published online in a coherent manner, and we actively discourage supplement. We have a way of embedding additional data in primary figures so that you can look at it while you’re reading a paper. We have a really cool electronic way of actually displaying text online that makes it easy to read the text and follow figures on a right-hand column.

08-00:18:35 Hughes: Is there any kind of limit?

08-00:18:37 Schekman: Well, the limit is prudence. We want people to be concise. We don’t want people to be sloppy in the language. But some papers have a dozen figures, not too many. But yes, we don’t want to limit it, and we also encourage people who have really important single experiments to write a short report.

08-00:19:02 Hughes: Are there any other ways that you feel eLife is trying to be or is different?

08-00:19:08 Schekman: We’re starting a new initiative that we hope will build some new customers. One of the feelings that’s developed over the years is that, because it’s so difficult to get something published, people have a whole new story that can take many years to develop, and they can’t publish the next important observation of an existing story. So we’ve created a vehicle: the idea is to be able to build your story at eLife. And so if someone has a founding paper that they publish in eLife, and a postdoc student has an important new observation that bears on the founding paper, we encourage that group to submit a short report. We’re going to call it eLife Advances or eLife Milestones. And so the student or postdoc then has the opportunity to publish—I don’t want to call them installments—but additional citable units based on important developments that had their origin in a founding paper, rather than having to wait five years to have a whole new story published. 134

08-00:20:29 Hughes: That sounds very innovative.

08-00:20:32 Schekman: Yes, I think so. It was suggested by the former director of the Wellcome Trust, Mark Walport.

08-00:20:38 Hughes: Addenda, if that’s what you want to call them?

08-00:20:41 Schekman: No, they won’t be addenda. We’re going to call them either eLife Advances or eLife Milestones. We want to make sure that people aren’t just dumping their next experiment. They have to be significant additions that change the thrust or the accuracy or the believability of the story or maybe even challenge the original story. And we’ve even considered the possibility of having authors of other scientific papers contribute, including a milestone that builds on a paper that’s anchored in eLife. The idea is to build customer loyalty, provide an opportunity for a student to have multiple citable units based on an evolving story, which is the way science is done, but which is not reflected in the literature. And since it’s all online, it’s just another citable unit.

08-00:21:41 Hughes: What about including dissent to any particular conclusion?

08-00:21:45 Schekman: Yes, yes.

08-00:21:46 Hughes: You’d have to monitor that, putting quite a burden on eLife.

08-00:21:53 Schekman: Well, we’re looking for ways to change the toxic atmosphere that now exists around publication and that leads to distortions like these two papers in Nature that you pointed to on this so-called revolutionary technique to make stem cells. This may be fraud. There’s fraud in science. That happens. It has been happening forever. Is it getting worse? I don’t know if it’s getting worse. But I submit that at least part of the problem is the enormous pressure that young scholars feel to publish in these glamour magazines or luxury journals, as I call them. And that pressure is more than some young people can bear.

08-00:22:52 Hughes: Some of these sentiments of yours were expressed in the Guardian article of December 2013. I love some of the language, and “luxury journal” is a great one, and there were others—“journals that pursue trendy fields of science.” You were accused that as a new Nobel laureate, you had the luxury of sticking out your neck. How have you responded to these various criticisms? 135

08-00:23:54 Schekman: Well, first of all, I’ve been amazed at the publicity that was generated by that piece. It was certainly intended to do this, but I had no idea that it would reverberate around the world as it has. So I’m enormously gratified, even with the criticism. [laughter] It doesn’t bother me at all. I’ve been labeled a hypocrite. Well, actually I’ve been arguing against impact factor for years, but who knew? Suddenly, I have a soapbox to stand on, and I intended to take full advantage of it, and so it was no accident that the piece was published on December 10 [the day of the Nobel Prize Award Ceremony]. And it was no accident that I was interviewed on BBC Four that morning, from Stockholm, and argued with an editor at Science.

08-00:24:37 Hughes: You had obviously thought through—

08-00:24:38 Schekman: Well, it wasn’t just me. I had a lot of help! [laughing] I had some great help from the Wellcome Trust, in particular. Oh yes, this was all very, very deliberate. Some of the charges against me, I think I was surprised. Although I have to say I had a lot of responses, personally to me from e-mails from people that I don’t know, and anything that was sent to me personally was very, very supportive.

08-00:25:04 Hughes: Really?

08-00:25:05 Schekman: Oh yes. No one sent me a nasty e-mail, but I read some nasty blogs.

08-00:25:14 Hughes: Well, one criticism that I didn’t really understand was the charge that you had built your career on publishing in these major journals. Well, what else was there?

08-00:25:26 Schekman: Well, there were other journals. And there are people. Michael Eisen, who’s a younger colleague, has taken the position right from the beginning of his career that he wouldn’t publish in these journals. And he’s still done well, but I’m considerably senior to him. Frankly, the problem has gotten worse. But even if I’d had the strong feelings twenty years ago that I have now, if I’d have spoken out, who would have listened?

08-00:26:07 Hughes: True.

08-00:26:08 Schekman: So I have a voice now, and I intend to use it. Call me what you will, but I think the system is broken, and somebody has to stand up, and it’s not going to be enough for me to stand up. If I were just complaining, even using my bully pulpit, then I would be a hypocrite if I weren’t doing something about it. 136

But I’m actually spending a lot more of my time actually trying to do something about it. So I’m not at all concerned.

I’ll tell you another thing. Before that editorial, one of the criticisms that I got as we were ramping up eLife was there were still a lot of people out there who hadn’t heard of us. That isn’t true anymore. This was perfect for publicity for the journal, and that was of course the whole point. And it’s not just the journal actually. The point of the journal is not just— It’s not another business proposition; it’s to change the way that scholars decide where to put their work and how that work is evaluated. When I took on Science magazine, I could only think of the wonderful arguments I would have had with Dan Koshland. [laughing]

08-00:27:37 Hughes: Oh really? He was pretty loyal to Science.

08-00:27:40 Schekman: Yes. Well, and he did a great job.

08-00:27:43 Hughes: Well, he did try to make the review process more scientifically based. I know he dismissed some editors and brought in people that he thought were better scientists.

08-00:28:01 Schekman: Yes, but they were all former scientists. Some of them long ago former scientists, and they were all in a building in downtown Washington [D.C.], completely removed from an academic environment. I met a lot of these people. They’re wonderful, they’re broadly knowledgeable, they’re committed, they’re devoted to it. But they haven’t seen the inside of a laboratory for half a lifetime.

08-00:28:31 Hughes: Is that pretty true of Nature as well?

08-00:28:32 Schekman: Oh yes, absolutely. We all have had the experience in the past of submitting a paper to a journal like that. [The manuscript] goes out for review, and the reviews come back, and there are disparate opinions. And then the editor, who’s sitting in the office in downtown London, has to figure out what to convey to the author. They just package it up and send it to you and say with very little guidance, “Well, it looks like you’ve got some work cut out for you.” Now, when you challenge them this way they deny that. They say they actively take a role in deciding what’s important. And some of them do. But I would say most of them don’t. This online consultation thing that we’re doing at eLife, I argue that any journal could adopt this. It actually doesn’t cost much. But I don’t think that a journal where the decisions are made by a professional editor could do that, because how are they going to go into a conversation on an equal footing with someone who’s actually done the 137

research—and so they wouldn’t do that. They won’t do it anyway, but they wouldn’t do it.

08-00:29:41 Hughes: It’s going to take some revolutionary changes, which of course is what eLife is trying to do.

08-00:29:47 Schekman: Yes, right. So they won’t change unless they have to. And they won’t have to until we start cutting into their clients.

08-00:29:55 Hughes: But look, you’ve only been around for how many—

08-00:29:58 Schekman: A year and a half. Science, Nature, they’ve been around over a hundred years. But here’s the problem: it’s this evil impact factor. This is a number that’s going to be imposed on us, probably in June. It will be a calculation based on two months’ worth of our publications at the end of 2012. A completely phony number. So I just dismiss it. We learned that Thompson Reuters were starting to collect our data. We told them we didn’t want them to; we didn’t want to play their game. They said it’s not up to you; we’re going to do this anyway.

08-00:30:34 Hughes: Well, then you write an editorial.

08-00:30:35 Schekman: Well, of course that’s my first reaction. Go right on the attack. But I’m told by my betters that that’s exactly the wrong thing to do. You don’t want to argue to a weak point; you just look defensive. We get a low number, some phony number. It doesn’t matter. We’ll just look weak, no matter how strongly we make the case. So our attitude is, and it always has been—I don’t care about the number. It’s a phony number; I don’t believe it. We shouldn’t be using it ourselves. No one should be using it. But Nature and Cell advertise that number shamelessly.

08-00:31:19 Hughes: Have you said anything like that in eLife?

08-00:31:24 Schekman: Yes, absolutely. All along, all along. Anybody who looks has seen what our attitude is. In fact, we’ve done more than that. We’ve banded together with a bunch of other editors, people under the auspices of the American Society for Cell Biology, and sponsored a petition called the DORA Initiative, San Francisco Declaration on Research Assessment. We have a number of important principles that we’d like scientists and editors and publishers and universities and review committees to look at and to appreciate what a toxic influence impact factor is and to eschew its use in any evaluation of scholarly output. Bruce Alberts [Editor-in-Chief, Science] signed the document. Science 138

actually is the one of those three that doesn’t use impact factor, because they agree, it’s a phony number. But they still, I think, contribute to the problem.

08-00:32:21 Hughes: One of the fallouts of this is that you have asked your lab or maybe told your lab that they are not to publish—

08-00:32:41 Schekman: Well, we actually never had a discussion. [laughter] When eLife got going, I told people in the lab who had really interesting stuff, I said let’s send it to eLife, and they said okay. We’ve had two papers from Chinese postdocs published in eLife. I don’t know what their private view is, but to me they said they thought it was a great experience. It was fair and it was fast. Chinese postdocs are very worried because they know, going back to China, that one of them has had the experience: no impact factor; our institution will not count this paper. But they also know that I’m going to help them get good jobs, and so that’s of course the charge that’s levied against me: I can say publish in eLife because I can help my guys get jobs, right? Okay, so it’s true. I’m not going to deny that.

08-00:33:36 Hughes: Anything else on eLife? I’m sure there is, but—

08-00:33:43 Schekman: I’m excited; we’re shaking things up. We’re going to be challenged this year because of this stupid impact factor. I say I don’t care about the number, but the worry is postdocs know these things, and they’ll compare journals on the basis of these phony numbers, and they’ll decide where to send their manuscript on the basis of numbers that are insignificant. So my worry is that whatever that number is, we’ll be pegged, and people will say well, I can’t send my paper to you because look at your impact factor. Others say well, of course it’s going to go up with time; you just have to give it time. Well, maybe. But we’re just going to keep the same standards. It’s our admittedly subjective judgment about what constitutes good science. We’re going to continue to foster young scholars and do what we can to encourage them with their work. We’re not going to be as ridiculously selective, because I think that’s part of the problem. We’re going to pick great papers, but we’re going to pick papers that make important but not necessarily revolutionary contributions, because I think that we need to back off on the pressure that people feel.

08-00:35:11 Hughes: Plus the old adage that science is additive, cumulative. Not every stride is a huge breakthrough.

08-00:35:19 Schekman: And frankly, you can’t even predict what’s going to be a huge breakthrough. If you were to look at that PNAS paper that I published in 1979, that Koshland communicated on my behalf, if you were to look over the years at how many 139

times and where it was cited, the impact-factor calculation would have only computed the first two years’ worth of citations to that paper. But I am sure that if you look historically at its citation that that number grew substantially as years went on. And so that number would be— It’s just stupid, and it’s so self-evident.

08-00:35:54 Hughes: Most of the people citing the paper never even read the paper.

08-00:35:55 Schekman: Oh yes, well there’s that. But it’s just stupid that people rely on this impact factor. Yet of course young people feel they have no choice. They feel that this is their burden.

08-00:36:14 Hughes: Well, maybe that’s part of the next topic, namely teaching. Are you trying to instill a different—concept maybe is the word—for what young investigators are trying to do, what their aims are?

08-00:36:38 Schekman: Well, okay, my teaching is to the science. I don’t really talk about publication issues so much, certainly in what I teach.

08-00:36:48 Hughes: But you probably do in your lab.

08-00:36:49 Schekman: Oh, teaching at that level, yes.

08-00:36:51 Hughes: That’s also teaching.

08-00:36:53 Schekman: Yes, of course. Well, how to answer that? [pause] To be honest, I remember thinking that I wanted to have my best papers in Cell, Nature, and Science, too. That was just what it was. But when I was a graduate student, and early on in my career here, I wanted to have my best papers in the PNAS because that was the place to publish back then. I’m sure I’ve been influenced by that almost my entire career. It’s only now, in the last seven years or so, that my attitude about this has changed quite substantially. Maybe it’s because I see the toxic influence that it has on young people. I was the beneficiary of the system back then. I guess I was pretty successful so I could publish where I wanted. I’ve had some papers rejected of course.

But it has just gotten so much worse, I think, as biomedical science has grown. Of course there are many more journal titles now too, but there’s still that triumvirate that has this hegemony. And they’ve of course capitalized by spawning journals themselves, Nature this, Nature that, Cell this, Cell that, and so they’ve capitalized on their name—a good business plan. But they still have the same mentality of artificially restricting the commodity. As we said 140

in that Guardian piece, kind of like the ladies’ fashion or handbag industry creating an artificially limited commodity which just builds on this feeding frenzy that people have.

08-00:38:53 Hughes: Well, talk more directly about the place of teaching in your life. I think of it being a triumvirate: research, administration, teaching. The accusation, particularly at Berkeley, or maybe it’s because I’m here, is that teaching gets the short shrift.

08-00:39:20 Schekman: Well, it’s because when the scholar is evaluated for promotion—although you look at teaching—honestly, it’s not the first thing or the most important thing that you look at. But it is a consideration. And most of us are sufficiently proud in what we do that we want to do a good job at everything we do. When I started I had not had much teaching experience. I was in a medical school basic science department, so I didn’t have much exposure to the undergraduates. So I got here and suddenly I was thrust in front of 150 pre- med students who didn’t necessarily care about the science really, other than what was going to be on the test. And so I had to learn to adjust to that. At first it was difficult. I didn’t enjoy it. But I end up enjoying the performance aspect of it, quite honestly. [laughter]

08-00:40:18 Hughes: I’m not surprised.

08-00:40:19 Schekman: I really do! I got to really enjoy teaching, and I learned the value of it. I wouldn’t have predicted this. But I think it has made me a better public speaker in a way that people lack who don’t have this experience. When you have to explain something to a bunch of people who are intelligent but don’t know the background and don’t even really care who you are, they just want it explained clearly. That’s a challenge. There are so many research seminars that one goes to that are so poorly presented, where the speakers violate the most basic principles of teaching. That lesson was really drawn home to me through my experience particularly in teaching undergraduates here. So I value that, and I’ve enjoyed it. I volunteered some dozen years ago to start teaching a freshman seminar because I wanted to have exposure to the youngest kids here, and that’s been a lot of fun too.

08-00:41:36 Hughes: Teaching freshmen is very different than teaching graduate students.

08-00:41:44 Schekman: Yes, so you have to lower your expectations, although they’re bright kids, and they’ve come with exposure to AP [Advanced Placement] Biology. But still, they’re obviously mixed, and so I’ve had to employ other techniques to keep their attention, not what I do normally in upper division. I have to reach out 141

and engage them more. There has to be more of a discussion. I set up class debates, and they quite enjoy that.

08-00:42:09 Hughes: Are you still teaching freshmen?

08-00:42:12 Schekman: Yes, oh yes. I taught last semester. Last semester when I won [a Nobel Prize], suddenly my mind was elsewhere. [laughter]

08-00:42:19 Hughes: I bet!

08-00:42:23 Schekman: Oh, it was a fun experience. I think I taught the day after the prize was announced, and they came in. It was like nothing had happened.

08-00:42:34 Hughes: Did they know?

08-00:42:34 Schekman: Of course they knew, but they didn’t say anything. Actually, this year I taught the class in a room in Dwinelle that’s designed to get people to interact more, and it has more electronic features. There’s a woman from the service that runs this facility who checked me out when I first used the room and showed me the stuff. She came on that day, and she said wow, how excited she was about my Nobel Prize and talked to the class for a few minutes. Then I went on with my lecture, and I was really kind of excited, more than usual. The students just sat there impassively. I said, “Okay, well, I’ll see you next week.” And then they all gathered around, and they actually all had a couple of cards that they’d made, and they were all signing the cards, and somebody had actually drawn a caricature of me with a picture of the Nobel medal. [laughing]

08-00:43:45 Hughes: Oh, what a kick!

08-00:43:46 Schekman: Yes, that was fun.

I got an e-mail from the instructor of a poetry class that was in that room the hour after, and he said, “My students recognized you. Would you come next week and spend some time after your class, reading poems to my class?” I said, “Okay, well, that sounds fun.” So I picked out a few poems that I quite enjoy, and we had a back-and-forth. There’s one poem that’s particularly moving to me that I can’t even read, so I had them read it. It’s a wonderful poem by Billy Collins. Do you know Billy Collins? He was a poet laureate a few times. He’s very popular, very accessible. 142

08-00:44:34 Hughes: Yes, I know the name, but I have to admit I don’t know his poetry.

08-00:44:42 Schekman: My wife used to read books voraciously, but then as her Parkinson’s advanced, and she really now has dementia, she turned to poetry because it’s easier to read in short bursts. She muckled onto this guy, Billy Collins, so she has all his books, and she brings the books with her wherever she goes, and she reads the poems to people. So of course I picked out a few that I really like, and the one that just gets me is called “The Lanyard.” I can’t—you’ll have to read it. It’s a wonderful poem. It’s about his mother and how she loved him, and she did everything for him, and she gave him life, and what did he give her? He gave her a lanyard. And it just repeats throughout the poem. So, it reminds me—[voice quavering with emotion]

08-00:45:29 Hughes: In your spare time, you should write to him and tell him.

08-00:45:32 Schekman: I should, I should.

08-00:45:36 Hughes: Because one doesn’t think of scientists reading or even thinking about poetry.

08-00:45:43 Schekman: Yes, you’re right. And there are others in his collection that are wonderful. But that one is just— I can’t even read it! So I had one of the kids read it in the class.

08-00:45:53 Hughes: Well, I will definitely look it up.

A subject that I believe is very close to your heart is the public research university.

08-00:46:06 Schekman: Sure, yes.

08-00:46:08 Hughes: Again, you’ve used the prestige of the Nobel to speak on that subject, and I imagine you were speaking about it even before that.

08-00:46:17 Schekman: Oh yes, but who was listening?

08-00:46:20 Hughes: Tell me your thoughts please.

08-00:46:24 Schekman: Well, so I’m a creature of the University of California. 143

08-00:46:26 Hughes: Yes, you are.

08-00:46:29 Schekman: So obviously I feel very strongly about it. In the hours that we’ve recorded, I can’t imagine I haven’t already gone on about this. I went to UCLA. I came from a middle-class background. There was the expectation that I would go to college, but there was never any discussion about which college. My mother wanted me to go to Long Beach State because it was close by and it was maybe cheaper. I could live at home. They didn’t see how they could afford to send me away. But I knew that there was a difference, and I felt strongly I wanted to be in a major university, and there was UCLA and it was great. So I went, and it was virtually free in 1966. I paid $40 a term, and I lived in a student co-op, so that was cheap. I could work a summer job and more or less pay for the school year. And that was true of all of my brothers and sister. My dad never had to pay anything.

And look at what’s happened. The most troublesome thing about my life is to see how the public investment in the future of our children has eroded. The pie is just cut up differently now, much to the disadvantage of public institutions of all sorts, and particularly education, and I would say particularly higher education. California has put more money into prisons over the years than public education. The University of California, when I started, the budget was 80 percent paid by the state. Now it’s closer to 10 percent overall. And so we’ve had to struggle to become more like the privates in learning how to fundraise. But frankly, we’re not as good at it. The university doesn’t pay the same that private universities pay for their fundraisers, and so we can’t pay for the great ones who are treated like football coaches.

So obviously this is an issue about which I feel very strongly. Actually, I’ve been speaking about this for a long time. [Chancellor] Berdahl asked me to write an editorial on that some years ago, which I attempted to get published in the [San Francisco] Chronicle, but which they ignored. I said many of the same things that I eventually said in the piece that they published in December 2013.

I gave the same kind of speech to a group of people at the University of Michigan, where I’m on an advisory board for the Life Sciences Institute there. A woman who works on behalf of the president of the University of Michigan was there, and she said, “God, you’ve got to write an editorial on what you’ve just said.” The point that I made that was the opening argument is: once again, the US has done terrifically well in Nobel prizes in the sciences. Nine of the laureates were from the US, and yet only one of them is from a public institution. Frankly, that’s typical, and what does it say about what people are willing to invest in? And I had the benefit of that. In fact, I was exposed to a Nobel laureate when I was a freshman at UCLA, and it was his class that got me into a research laboratory. So I’d made this point, and 144

this woman said, “You really ought to write an editorial.” So I wrote an editorial. Bob Sanders helped me. We sent it to the New York Times, and pssht, they ignored me. I sent it to the Washington Post; they ignored me. We even sent it to the LA Times, because I spoke a lot about UCLA. They said no.

08-00:50:34 Hughes: Oh, come on!

08-00:50:34 Schekman: I shared this with the president of the National Academy, Ralph Cicerone. He was formerly chancellor of UC Irvine, so he obviously shares my views. And he said, “I know. It’s a hard sell.” He said he’s tried to write editorials on this and they just—people just aren’t interested.

08-00:50:52 Hughes: Why? Why?

08-00:50:53 Schekman: Well, I don’t know why. The New York Times never even answered me. They never even responded. There’s a different tradition here on the West Coast, particularly in California. The University of California is almost unique. Other states have public institutions, but we are uniquely strong among the public institutions. If you look on the East Coast, the public institutions there are not really that competitive. I bet if you look at the editorial staff of the New York Times none of them went to public universities. On the East Coast it’s just a very much different tradition of where the brightest kids want to go. They want to go to the privates. They compete for the Ivies. I think that’s another story about—talk about toxic. The Ivies… [laughing]

08-00:51:53 Hughes: It doesn’t explain the LA Times.

08-00:51:54 Schekman: Well, that’s true. That was really disappointing. But Sanders thinks that they’re just so disorganized there; that they’ve been in such turmoil because of the people who own the LA Times. There’s this guy from Chicago who owns the Times who just slashed their budget. And so their editorial staff was just decimated. So that was how he explained that. I don’t know; I don’t care. If I’d really wanted it in the LA Times, I might have gone to people at UCLA that I know who are more in tune. Sanders may not know the right people there. But anyway, we sent it to the Chronicle, and pssht, the next day they said great, we’ll publish it. Anyway, that’s only a small thing.

I spoke at a [UC Board of] Regents meeting early on. [Janet] Napolitano was just selected as the [UC] president, so she has embraced this and has been parading me around. I went to the [California State] legislature a couple of weeks ago, so she intends to use me and other laureates to try to make the case. But it’s a tough sell. These legislators, they’ll all pay lip service to the University of California even though not many of them went to UC. They say 145

the right things. But our own local congressperson, Nancy Skinner, whom I met when I went up there [Sacramento] a couple of weeks ago, is a big fan of Cal. But when push came to shove, and the recession hit, and the budgets got cut at UC, she didn’t stand up and fight that at all. No. She just knuckled under like the rest of them, and they all cynically used the fact that they couldn’t raise taxes to simply transfer the tax authority to us. We had the ability, in spite of their protest, to raise tuition. But they couldn’t raise taxes, for political reasons. So they just cynically turned their back on us. Although I agree politically with her on most things, I wouldn’t vote for her because of that. I wrote letters to her, online letters, and I got some form letter back, “Oh, we support education.” Baloney.

08-00:54:18 Hughes: Really upsetting.

08-00:54:19 Schekman: Yes. So it’s a hard battle. An editorial by me isn’t going to do much. And unfortunately I don’t think the state budget’s going to go back to where it was. Maybe they’ll be able to slow down the rate of increase of tuition, but I don’t expect the state to step up and restore the budget. And so it’s up to us to raise money philanthropically, which is why I decided to give my prize money—to the University to create an endowed chair to help us recruit the best young scholars in the face of enormous competition from private universities, such as Stanford.

08-00:54:51 Hughes: Well, philanthropically yes. But what about the increasing bond between the university and commercial enterprise? What’s your feeling about that?

08-00:55:08 Schekman: Well, yes—I think you can get some financial support, but it’s really tough. Companies want something for their investment.

Napolitano had me to a dinner at her house with other well-heeled people that she was hoping to encourage to generate funds for science on the UC campuses. The idea was to create a fund that would be devoted to inter- campus research projects. Her staff had designated four areas that she thought would appeal to business types. And they were there. One of them I had met recently—I won’t say whom—is a friend of Cal, but he’s basically given exclusively to our athletic programs here. He gives money to UCSF. He gives money to projects that he thinks will turn into businesses. And that’ll do for some, but would he have invested in my research initially? Of course not, even though my research led, very quickly, to practical applications. But it wasn’t obvious. Of course, this is in their DNA. Businessmen are looking for something that’s going to turn a profit quickly.

This is the problem with the pharmaceutical industry now. They’ve cut back on research and instead they buy startup companies that may have something 146

to offer for their pipeline. They’re not actually in there doing the science necessary to create a new pipeline. I’m always pleased when a company wants to invest in the university, but I’m a little skeptical unless they’re going to give it for scholarship. There may be collaborations that can be formed here. And of course we have many entrepreneurial faculty, certainly in the School of Engineering—very entrepreneurial. But is that going to replace what the state provided? Is that going to make up for the huge cuts that the federal government is slashing from the NIH budget? I don’t think so.

No, it’s organizations like Hughes, where they have a significant endowment, where their mission is to fund basic science. That’s where—or the [Gordon and Betty] Moore Foundation. So I’m hopeful that the very wealthy will see the advantages and will see the successful model of the Hughes Institute and pitch in that way, but for the University of California. But we have to find those people.

08-00:57:59 Hughes: Yes, we do. We’re almost out of time. I want to give you, finally, a chance to say what you want to say, without being prompted by me.

08-00:58:09 Schekman: Haven’t I been saying that?

08-00:58:12 Hughes: Well, you have, but are there no—

08-00:58:12 Schekman: Yes. Well, I’ll conclude as I always do. That how grateful I am for the opportunities that I’ve had, that Pat Brown was there and saw this as his opportunity to create a name for himself as governor of California, and build the state up to the excellence in the UC System that we had, that we still have. My life would have been very different without that. I would have succeeded in something else, but I wouldn’t have— I don’t think I would have had as much fun as I’ve had.

08-00:58:46 Hughes: Nice place to end. Thank you.

[End of Interview]

147

148

149

150 151

152

153

154