A Conversation with Nobel Laureate Randy Schekman

What sparked your interest in research?

The really critical moment came when I was a freshman in college at UCLA. Everyone in the chemistry honors section, taught by the inventor of Carbon 14 dating, Willard Libby, was assigned to a research lab in the chemistry department. I was assigned to work with a phage geneticist, and he had me read Jim Watson’s brand new book, The Molecular Biology of the Gene. It was a revelation for me to see how Watson thought about biology, and an eye-opener to see how one could study cells and cellular mechanisms. The experiment that I did in the lab was trivial. I took calf thymus DNA, hydrolyzed it, separated the bases with paper chromatog- raphy, and quantified the bases using a UV spectrum.

When you started your own lab at Berkeley, you decided to use baker’s yeast to study secretion. Why?

As a graduate student, I worked on E. coli, and I was struck by the ability to do biochemistry with a microorganism. But I wanted to strike off and do something new. I was influenced by the growing use of yeast as a model of eukaryotic biology. Lee Hartwell, and his use of temperature sensitive mutants to dissect the cell division cycle in yeast, was a powerful influence for me.

As a post doc, I worked on human neonatal erythrocytes, a really difficult source of material. I realized I was much more comfortable working with microorganisms. And so I resolved to work on yeast.

I scoured the literature on membrane assembly, particularly on cell division and cytokinesis, and it seemed like vesicles were involved in the growth of the cytokinesis furrow. That was the basis of what I suggested work- ing on when I came to Berkeley.

When Peter Novick joined the lab as a graduate student, we decided to isolate secretory vesicles in cells. Our initial effort using inhibitors to block their fusion didn’t work, fortunately. As an alternative we had to do genetics. I’m not a geneticist. I never pretended to be one. It was risky of course, but it worked out pretty quickly.

Can you tell us about the ups and downs of research?

Of course winning the Prize was wonderful, but there have also been great highs from the results that we obtained over the years. One of the great moments came when Novick cut a thin section through a sec 1 mutant

cell, cells that we knew had accumulated secretory proteins inside. There was a very dramatic moment where he called me down to the microscope room very excitedly. I saw on the screen a cell just chock full of vesicles. That was a eureka moment.

In contrast, months before I got to Berkeley, I worked very hard on an NIH grant applica- tion, and, shortly after I arrived, it was trashed by the reviewers. It was full of rookie mistakes and was overly ambitious. I had no relevant experience with yeast and no preliminary results. I was very successful as a grad student, but I was proposing to do some- thing completely different. Being denied the grant shook my confi- dence. I remember thinking that maybe I should have stuck a little more closely to something I had done in my post doc. And I was also learning how to be a faculty member, lead the lab, and teach. So I did have some moments of uncertainty, but fortunately they didn’t last.

Recently, you became editor of eLife, a new online journal. How is it going?

At eLife, we are winning hearts and minds. We’re getting more and more submissions. We have high standards. We have a unique way of reviewing papers that allows reviewers to consult with each other about their concerns.

We want papers that will have an impact, but I don’t care if we publish papers that don’t generate huge numbers of cita- tions. I think that approach con- tributes to a toxic atmosphere.

I’ll give you an example. Nature recently published papers that claimed adult cells could become embryonic stem cells with just an acid treatment. It seemed too good to be true, and in fact it was too good to be true. Almost immediately no one could reproduce the results. And then they discovered that some of the images in the paper were inverted and copied. Of course Nature doesn’t want this kind of publicity. But here’s the perverse thing, these papers will generate thousands of citations even before they are retracted. So Nature benefits from this kind of nonsense.

At eLife, our editors are scientists who judge the merit of the work, not how sensational it is.

Your research has led to important applications in medicine, such as the manufacture of a significant share of the world’s insulin supply by yeast. Did you ever consider the practical applications of your work?

No. I was always interested in how the cell works, that has always been my passion. I’m concerned about the pressures scientists feel now from the NIH to have some practical benefit for their work and to consider how we would do drug testing, for example. The NIH has set up a National Center for Advancing Translational Sciences. I think this is a waste of public money. I think we should be doing basic science because it’s my conviction that when you discover something fundamental in a curiosity- driven investigator-initiated program, the private sector can exploit that and make better financial decisions than academics. Academic scientists aren’t trained in that way, and we’re not attracted to the academy to do drug discovery. I’m making my plea for curiosity-driven basic science.