Randy Schekman: From dreams to yeast

Randy W. Schekman enters the ornate Thavenius room at the Grand Hotel where our interview is set up. He appears calm and laidback, perhaps a bit worn out after busy schedule of the past days  and the festivities at the City Hall the day before. But he’s in good spirits and enthusiastically answers all of my questions. I start off by congratulating him and asking the mandatory question of how it feels to be rewarded with this years’ Nobel Prize in Medicine, the life-changing news that he received in the middle of an October night. 

“I was so deeply asleep I was just waking up when I answered the phone, and I think I said ‘Oh my god’ a few times. Even if you anticipate this kind of thing, you can’t count on it or prepare for it. It’s been overwhelming and all-consuming,” Schekman says.

He became smitten by science and microbiology early on. Each year from the age of 12 he was involved in science fairs projects and won prizes. He was deeply fascinated by the new worlds revealing themselves to him under the microscope, but he was also drawn to the competitive aspect of the annual science fairs. A few years later the thrilling thought of the Nobel pPrize caught his attention. When he was around 16 years old he saw photos of Nobel pPrize winners in Time magazine. Three very famous bacterial geneticists from the Pasteur institute in Paris, who had done very important work. 

To me, the pleasure was always in doing science, the thrill of discovery and of really being satisfied with something.

“There was this image of them walking down the street in Paris looking very happy. And I thought, this is what I want,” Schekman reminisces. The idea that you could actually achieve science to that level appealed to him he says, but emphasizes that this hasn’t been the actual driving force. “Some people get really obsessive about achieving this particular goal, to win the Nobel Prize, otherwise they won’t be happy. To me, the pleasure was always in doing science, the thrill of discovery and of really being satisfied with something,” Schekman explains.

The Eureka moment

Schekman has been professor of molecular and cell biology at the University of California, Berkeley, since 1976. He won this year’s Nobel Prize in Physiology or Medicine for his role in revealing the machinery that regulates the transport and secretion of proteins in human cells. In the middle of the 1970s he became interested in how proteins move within cells. He decided to use yeast to determine how vesicles containing proteins move inside and outside the cell. “It was already clear that yeast cells make glycoproteins. They are only manufactured by eukaryotic cells. But it wasn’t known what kind of process the yeast cells would use, neither was it known that yeas would use a process similar to human cells.” 

Together with graduate student Peter Novick, Schekman conceived a way of looking for mutants that block secretion. This worked pretty quickly and within a year they had very dramatic results. “One of the great moments of my scientific career was when I looked in the electron-microscope at the yeast cell that was blocked in secretion and the cells were completely full of little vesicles; these little bubbles that people had been talking about. These cells are very efficient normally and they don’t have any little bubbles, but when you block the process it’s just wall to wall with vesicles. I’ll never forget that image and I still have picture of on my bulletin board in my office. It was a classic eureka moment,” Schekman states.

Ultimately, he identified 50 genes involved in vesicle movement and determined the order and role that each of the different gene protein products play, step by step, as they shuttle cargo-laden vesicles in the cell. One of the most important genes he found is the SEC61 gene, which encodes a channel through which secretory proteins under construction pass into the lumen of the endoplasmic reticulum. When this gene is mutant, proteins fail to enter the secretion assembly line. Another significant set of genes he discovered encode different coat proteins that allow vesicle movement from the endoplasmic reticulum and from the Golgi apparatus.

Randy Schekman Copyright © Howard Hughes Medical Institute 2013/Hadar Goren

Importance of basic research

The findings, together with the discoveries of the two other laureates, have not only provided profound and fundamental insight about the precise control system for the transport and delivery of cellular cargo. Disturbances in this system have deleterious effects and contribute to conditions such as neurological diseases, diabetes, and immunological disorders. Schekman’s work has also led to important development in treatments. One-third of the insulin used worldwide by diabetics is produced by yeast, and the entire world’s supply of the hepatitis B vaccine is from yeast. For about twenty years Schekman helped a company to use yeast to manufacture hepatitis virus-like particles. It turned out that hepatitis B infection is a major cause of liver cancer in the world and if there’s a proper immunization then you can block the most liver cancers from forming, he says. 

“Who could possibly have guessed this? I try to make this point whenever I can. The idea that a government agency can direct my work and say what they want you to do because they want a certain outcome. You just can’t do it. Also, people ask you to predict what the next big discovery will be. Any discovery that you can predict isn’t going to be terribly interesting, it’s going to be boring. However, if you discover something fundamental – something really central to a crucial process – there’s a very high probability that there’s a clever entrepreneur who’ll figure out how to use it,” Schekman says.

And have the courage to follow your own convictions.

Alongside his post as professor Randy Schekman is also an investigator at the Howard Hughes Medical Institute. His advice for a young researcher, at the level of an independent investigator beginning his or her career is not to be afraid to gamble a little bit and follow your own convictions.  

“Don’t be risk-averse. I think that’s a major limitation with most independent investigators, even the ones who are productive. And have the courage to follow your own convictions.”

Challenging top journals 

Besides his research he is also involved in eLife: an open-access online journal covering all of the life sciences, which he founded two years ago. For Schekman, the free dissemination of scientific information is a key issue. Schekman recently created some headlines as he declared a boycott of top science journals. He says his lab will no longer send papers to Nature, Cell and Science as he believes they distort the scientific process. 

“They play by their own rules. They’re in the business of selling magazines. I don’t think they’re primarily in the business of fundamental discoveries. They also base their decisions about what to publish on what they can print. And that makes no sense in the 21st century as all the journals have an online presence. Why should science magazines restrict themselves to fifty pages a week?”

The consequence, Schekman thinks, is that a lot of great science gets ignored as it doesn’t make it into the fifty pages of science a week. He also says that many young investigators feel that their career will not happen unless they can publish in any of these three journals. Something he believes introduces a distortion and in some cases leads to manipulation of data to make things look better than they really are. 

The Nobel Prize money, Schekman has announced, will go to create an endowment for the Esther and Wendy Schekman Chair in Basic Cancer Biology at UC Berkeley. Schekman’s mother and sister, for whom the post is named, both died of cancer.